Δευτέρα, 19 Ιουνίου 2017

Clinical background including anticoagulant therapy in patients with atrial fibrillation in a community-based survey: the Saitama AF Registry

Abstract

Atrial fibrillation (AF) is one of the most common cardiac arrhythmias, and carries an increased risk of cardiogenic embolism. Oral anticoagulants (OACs) including warfarin and/or non-vitamin K antagonists can prevent the majority of these events. The Saitama AF Registry was a community-based survey of patients with AF in Saitama City, which represents an urban community in Japan. A total of 75 institutions participated in the registry and attempted to enroll consecutive patients with AF from September 2014 to August 2015. The aim of the present study was to examine the clinical characteristics of patients with AF using data of the Saitama AF Registry. In addition, we investigated the difference in clinical characteristics of the patients between small-sized hospitals and large-sized hospitals. A total of 3591 patients were enrolled; 57.7% of all patients were enrolled from small-sized hospitals, whereas 42.3% were from large-sized hospitals. The patients from small-sized hospitals had higher CHADS2 score than those from large-sized hospitals. Approximately, 80% of all patients were treated with OACs, and the prescription rate was higher in patients with CHADS2 score ≥ 2 from both small-sized hospitals and large-sized hospitals. In conclusion, the present study demonstrated an appropriate use of OACs for high-risk patients with CHADS2 score ≥2 in Saitama City regardless of hospital size.



http://ift.tt/2suCteE

Bio-prospecting Bacterial Diversity of Hot Springs in Northern Himalayan Region of India for Laccases

Abstract

Bacterial diversity of hot springs of northern Himalayan region of India was studied and explored for laccases, the multicopper enzymes applicable in a large number of industries due to their ability to utilize a wide range of substrates. 220 operational taxonomic units (OTUs) out of 5551 sequence reads for bacterial diversity and 3 OTUs out of 19 sequence reads for Laccase like multicopper oxidases (LMCOs) diversity were generated. Bacteroidetes (74.28%) was the most abundant phylum including genus Paludibacter (66.96%), followed by phylum Proteobacteria (24.53%) including genera Chitinilyticum (7.55%) and Cellvibrio (6.14%). In case of laccase diversity, three LMCO sequences showed affiliation with proteobacteria and one with two domain laccase from uncultivable bacteroidetes. LMCO sequences belonged to H and N families.



http://ift.tt/2sl9Ems

Teprotumumab: a new avenue for the management of moderate-to-severe and active Graves’ orbitopathy?



http://ift.tt/2rPKEzT

Computational studies of third-order nonlinear optical properties of pyridine derivative 2-aminopyridinium p-toluenesulphonate crystal

Abstract

We have reported a theoretical investigation on nonlinear optical behaviour, electronic and optical properties and other molecular properties of the organic nonlinear optical crystal 2-aminopyridinium p-toluenesulphonate (APPTS). The computation has been done using density functional theory (DFT) method employing 6-31G(d) basis set and Becke's three-parameter hybrid functional (B3LYP). Calculated values of static hyperpolarizability confirm the good nonlinear behaviour of the molecule. Electronic behaviour and global reactivity descriptor parameters are calculated and analysed using HOMO–LUMO analysis. Energy band gap and simulated UV–visible spectrum show good agreement with experimental results. Other important molecular properties like rotational constant, zero-point vibrational energy, total energy at room temperature and pressure have also been calculated in the ground state.



http://ift.tt/2sJVkEC

A fragment-based approach towards ab-initio treatment of polymeric materials

Abstract

The broad range of applications of \(\pi \) -conjugated polymeric materials in industries such as automobiles, textiles, packaging, medical etc. have led to their extensive studies in both academic and industrial fields. Predicting the structure of these polymers is important for the study of their properties. The present work uses a 'divide and conquer'-type approach for the ab-initio studies of these polymeric systems. The method employs a fragmentation technique with independent fragment optimization for obtaining optimized geometries of the oligomers of various polymeric materials such as polyfuran, polypyrrole, polythiophene and other such \(\pi \) -conjugated polymers. A few test calculations performed in the study provide fair concurrence between the energies and the HOMO–LUMO energy gaps obtained using the fragmentation-based approach with those obtained using the full optimization of the whole oligomer. Also, a significant reduction in time complexity occurs for the present fragment-based approach compared to the parent system optimization. The results are encouraging and prompt for studies of large polymeric materials.



http://ift.tt/2tHHjob

Erratum to: Towards novel Cry toxins with enhanced toxicity/broader: a new chimeric Cry4Ba / Cry1Ac toxin



http://ift.tt/2tHxtCI

The absence of CD56 expression can differentiate papillary thyroid carcinoma from other thyroid lesions

http://orlhealth.blogspot.com/2017/06/the-absence-of-cd56-expression-can.html

The neural cell adhesion molecule CD56 is an antigen important for the differentiation of the follicular epithelium. Recent studies have reported low or absent expression of CD56 in papillary thyroid carcinoma (PTC) and its presence in normal thyroid tissue, benign thyroid lesions, and most follicular non-PTC tumors. Aim: We wish to estimate the value of CD56 in the differentiation of PTC (including follicular variant-PTC [FV-PTC]) from other nontumoral lesions and follicular thyroid neoplasias. Settings and Design: This was a retrospective, case–control study. Subjects and Methods: We analyzed the expression of CD56 in normal thyroid follicular tissue, 15 nonneoplastic thyroid lesions (nodular hyperplasia, Graves' disease, and chronic lymphocytic thyroiditis/Hashimoto), and 38 thyroid follicular cell neoplasms (25 cases of PTC). The immunohistochemical reactions were performed on sections stained with anti-CD56 antibody. Statistical Analysis Used: We used the Chi-square test, values of P< 0.05 being considered statistically significant. Risk analysis was applied on these studied groups, by calculating the odds ratio (OR) value. Results: Our results indicated that CD56 immunoexpression had differentiated PTC from benign nonneoplastic lesions (P = 0.002), as well as from follicular neoplasias (P = 0.046). There were no significant differences regarding CD56 expression between FV-PTC and classical PTC (P = 0.436). The immunoexpression of CD56 has differentiated PTC from other thyroid non-PTC lesions (P < 0.001), with 26.4 OR value. Conclusions: CD56 has been proved to be a useful marker in the diagnosis of PTC, including FV-PTC. Its absence can help differentiate FV-PTC from other thyroid nodules with follicular patterns.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182
6948891480

Erratum to: Training guidelines for endovascular stroke intervention: an international multi-society consensus document



http://ift.tt/2skNr85

Yttrium-90 (Y-90) Resin Microsphere Therapy for Patients with Unresectable Hepatocellular Carcinoma: a Single-Center Experience

Abstract

Background/Aim

Selective intraarterial radionuclide therapy (SIRT) with yttrium-90 (Y-90) resin microspheres presently has successful results in primary or metastatic inoperable liver tumors. This procedure, which is also known as radioembolisation, delivers high doses of radiation selectively to hepatic tumors while minimum healthy liver exposure. The aim of this study was to present our clinical experience of radiomicrosphere therapy for the treatment of patients with unresectable hepatocellular carcinoma (HCC).

Methods

We performed 40 Y-90 microsphere therapies in 28 patients (5 females, 23 males; mean age ± SD 48 ± 8) with HCC during the period from April 2008 through December 2016. Pretreatment Tc-99m microaggregated albumin (MAA) scintigraphy was performed to all patients in order to detect eligibility for SIRT. All patients had pre- and post-biochemical tests (hemogram and serologic tests) and imaging methods (CT or MRI or PET/CT) at regular intervals to detect any possible complication and determine response rates.

Results

The mean shunting to the lungs on MAA scan was 6.5% and the mean ± SD administered dose of Y-90 was 1.55 ± 0.32 GBq in all patients. The estimated doses to the target tumors, normal liver parenchyma and lungs were 105.7 ± 55.3, 25.5 ± 8.2 and 5.8 ± 1.7 Gy, respectively. No significant complication was observed during or early after (first week) the treatment procedure and it was well tolerated by all the patients. Only one patient developed a treatment-related gastroduodenal ulcer 3 weeks after the treatment. In control imaging tests (MRI or FDG PET/CT) performed 2.5 months after the treatment, we observed complete response in 2 (7%) patients, partial response in 10 (36%) patients, stable disease in 5 (18%) patients and progressive disease in 11 (39%) patients.

Conclusion

According to our clinical experience, we can conclude that Y-90 microsphere therapy is a safe and effective treatment option for the patients with unresectable HCC without any serious side effects.



http://ift.tt/2rPHZq9

Surveillance of the Patients with High Risk of Hepatocellular Cancer



http://ift.tt/2skGq74

Validation of a Liver Index and Its Significance for HCC Aggressiveness



http://ift.tt/2rPGb0g

A case of nivolumab-related cholangitis and literature review: how to look for the right tools for a correct diagnosis of this rare immune-related adverse event

Summary

Anti-programmed cell death-1 (PD-1) monoclonal antibodies, such as nivolumab, used for the treatment of several tumors, can trigger effector T-cells against tumor- and self-antigens, leading to the occurrence of different immune-related adverse events. Among them, liver injuries are rare and usually transient. To date, only four cases of immune-related cholangitis in non-small cell lung cancer (NSCLC) patients have been described during nivolumab treatment. Here, we describe laboratory tests, imaging and liver biopsy features that confirm this diagnosis as opposed to other forms of autoimmune liver disease; nevertheless, we also provide evidence of the presence of different clinical-pathological patterns of immune-related cholangitis.



http://ift.tt/2sJPaEa

Phase II study of Amrubicin monotherapy in elderly or poor-risk patients with extensive disease of small cell lung cancer

Summary

Background Previous study indicated that an optional anti-cancer drug for the treatment of small-cell lung cancer (SCLC) is amrubicin. However, no prospective studies have evaluated amrubicin in chemo-naive elderly or poor-risk patients with SCLC. Therefore, this study aimed to evaluate the efficacy of amrubicin as first-line chemotherapy for elderly or poor-risk patients with extensive-disease SCLC (ES-SCLC). Methods Patients with chemotherapy-naive ES-SCLC received multiple cycles of 40 mg/m2 amrubicin for 3 consecutive days every 21 days. The primary endpoint was the overall response rate (ORR), and the secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety. Results Between March 2011 and August 2015, 36 patients were enrolled in this study. Each patient received a median of four treatment cycles (range, 1–6 cycles). ORR was 52.8% [95% confidence interval (CI), 37–69%]. The median PFS and OS periods were 5.0 months (95% CI, 3.4–6.6 months) and 9.4 months (95% CI, 5.2–13.6 months), respectively. Neutropenia was the most common grade 3 or 4 adverse event (69.4%), with febrile neutropenia developing in 13.9% of patients. No treatment-related death occurred. At the time of starting second-line chemotherapy, 19 of 22 patients (86%) had significantly improved or maintained their performance status (PS) relative to their PS at the time of starting amrubicin monotherapy as first-line chemotherapy (P = 0.027). Conclusions The results of the present study suggest that amrubicin could be considered as a viable treatment option for chemotherapy-naive elderly or poor-risk patients with ES-SCLC (Clinical trial registration number: UMIN000011055 http://ift.tt/PmpYKN).



http://ift.tt/2tHIsvY

Decorin gene upregulation mediated by an adeno-associated virus vector increases intratumoral uptake of nab-paclitaxel in neuroblastoma via inhibition of stabilin-1

Summary

The availability of effective medication for the treatment of refractory or recurrent neuroblastoma remains limited. This study sought to investigate the effects of increased decorin (DCN) expression on the intratumoral uptake of nab-paclitaxel as a potential novel approach to NB. Correlation between the clinical characteristics of neuroblastoma and the expression of DCN, secreted protein acidic and rich in cysteine (SPARC) and stabilin-1 was evaluated. The anticancer effect of recombinant adeno-associated virus-DCN (rAAV-DCN) was assessed in vivo and in vitro. And the effect of rAAV-DCN on the intratumoral uptake of paclitaxel was also studied in neuroblastoma-grafted nude mice. Overall, 12.5%, 17.7%, and 71.9% of the tumors stained positive for DCN, SPARC and stabilin-1 respectively and correlated to age, stage and N-MYC status in 96 children and adolescents with neuroblastoma. Transfected neuroblastoma cells stably expressed DCN, with in vivo and in vitro studies demonstrating rAAV-DCN sensitized the anticancer effect of nab-paclitaxel. Systemic rAAV-DCN in neuroblastoma-grafted nude mice inhibited stabilin-1, up-regulated SPARC, and increased the intratumoral uptake of paclitaxel. Macrophage depletion or anti-stabilin-1 monoclonal antibody increased the intratumoral uptake of nab-paclitaxel and its anticancer effects to a degree comparable to that achieved by systemic rAAV-DCN. The systemic administration of rAAV-DCN up-regulates DCN in neuroblastoma and accelerates the intratumoral uptake of nab-paclitaxel by inhibiting stabilin-1 mediated SPARC degradation.



http://ift.tt/2sJHrGn

Urolithins impair cell proliferation, arrest the cell cycle and induce apoptosis in UMUC3 bladder cancer cells

Summary

Ellagitannins have been gaining attention as potential anticancer molecules. However, the low bioavailability of ellagitannins and their extensive metabolization in the gastrointestinal tract into ellagic acid and urolithins suggest that the health benefits of consuming ellagitannins rely on the direct effects of their metabolites. Recently, chemopreventive and chemotherapeutic activities were ascribed to urolithins. Nonetheless, there is still a need to screen and evaluate the selectivity of these molecules and to elucidate their cellular mechanisms of action. Therefore, this work focused on the antiproliferative effects of urolithins A, B and C and ellagic acid on different human tumor cell lines. The evaluation of cell viability and the determination of the half-maximal inhibitory concentrations indicated that the sensitivity to the studied urolithins varied markedly between the different cell lines, with the bladder cancer cells (UMUC3) being the most susceptible. In UMUC3 cells, urolithin A was the most active molecule, promoting cell cycle arrest at the G2/M checkpoint, increasing apoptotic cell death and inhibiting PI3K/Akt and MAPK signaling. Overall, the present study emphasizes the chemopreventive/chemotherapeutic potential of urolithins, highlighting the stronger effects of urolithin A and its potential to target transitional bladder cancer cells.



http://ift.tt/2tHivMZ

“Make OSA great again” Report from the 113th American Thoracic Society International Conference (2017) in Washington DC



http://ift.tt/2tHPeS6

Post-catastrophe Analysis of the Fundão Tailings Dam Failure in the Doce River System, Southeast Brazil: Potentially Toxic Elements in Affected Soils

Abstract

On November 5, 2015, after the collapse of the Fundão tailings dam, a massive amount of iron mine waste was released into the Doce River system in southeast Brazil. The aim of our study was to determine the mass fractions of potentially toxic elements in soil affected by the deposition of material by the waste wave. A preliminary screening was performed with portable X-ray fluorescence spectrometry (PXRF) and principal component analysis (PCA). The EPA 3050B method was further applied to digest the samples for quantitative determination of As, Ba, Cr, Cu, Mn, Ni, Pb, V, and Zn by inductively coupled plasma mass spectrometry. PCA was useful to classify the mine waste samples based on the Fe signal from the PXRF spectra, in spite of the heterogeneous nature of the material discharged into the Doce River system. The anomalous levels of As (up to 164 mg kg−1) and Mn (as high as 2410 mg kg−1) found in some mine waste and affected soil samples are within the background ranges typically observed in the soils of the Iron Quadrangle region. The toxicity characteristic leaching procedure shows no evidence of hazards regarding As, but a high natural background level of Mn was found in the mobile fraction. This preliminary environmental assessment highlights the importance of evaluation of long-term effects on soil directly impacted, as well as on the aquatic biota of the Doce River system and adjacent coastal environment given the large affected area, which includes regions with varying background levels of toxic elements.



http://ift.tt/2surIZN

Book Review



http://ift.tt/2sQyRGk

JHB as a Collaborative Effort



http://ift.tt/2sQn7mZ

A case of nivolumab-related cholangitis and literature review: how to look for the right tools for a correct diagnosis of this rare immune-related adverse event

Summary

Anti-programmed cell death-1 (PD-1) monoclonal antibodies, such as nivolumab, used for the treatment of several tumors, can trigger effector T-cells against tumor- and self-antigens, leading to the occurrence of different immune-related adverse events. Among them, liver injuries are rare and usually transient. To date, only four cases of immune-related cholangitis in non-small cell lung cancer (NSCLC) patients have been described during nivolumab treatment. Here, we describe laboratory tests, imaging and liver biopsy features that confirm this diagnosis as opposed to other forms of autoimmune liver disease; nevertheless, we also provide evidence of the presence of different clinical-pathological patterns of immune-related cholangitis.



http://ift.tt/2sJPaEa

Phase II study of Amrubicin monotherapy in elderly or poor-risk patients with extensive disease of small cell lung cancer

Summary

Background Previous study indicated that an optional anti-cancer drug for the treatment of small-cell lung cancer (SCLC) is amrubicin. However, no prospective studies have evaluated amrubicin in chemo-naive elderly or poor-risk patients with SCLC. Therefore, this study aimed to evaluate the efficacy of amrubicin as first-line chemotherapy for elderly or poor-risk patients with extensive-disease SCLC (ES-SCLC). Methods Patients with chemotherapy-naive ES-SCLC received multiple cycles of 40 mg/m2 amrubicin for 3 consecutive days every 21 days. The primary endpoint was the overall response rate (ORR), and the secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety. Results Between March 2011 and August 2015, 36 patients were enrolled in this study. Each patient received a median of four treatment cycles (range, 1–6 cycles). ORR was 52.8% [95% confidence interval (CI), 37–69%]. The median PFS and OS periods were 5.0 months (95% CI, 3.4–6.6 months) and 9.4 months (95% CI, 5.2–13.6 months), respectively. Neutropenia was the most common grade 3 or 4 adverse event (69.4%), with febrile neutropenia developing in 13.9% of patients. No treatment-related death occurred. At the time of starting second-line chemotherapy, 19 of 22 patients (86%) had significantly improved or maintained their performance status (PS) relative to their PS at the time of starting amrubicin monotherapy as first-line chemotherapy (P = 0.027). Conclusions The results of the present study suggest that amrubicin could be considered as a viable treatment option for chemotherapy-naive elderly or poor-risk patients with ES-SCLC (Clinical trial registration number: UMIN000011055 http://ift.tt/PmpYKN).



http://ift.tt/2tHIsvY

Decorin gene upregulation mediated by an adeno-associated virus vector increases intratumoral uptake of nab-paclitaxel in neuroblastoma via inhibition of stabilin-1

Summary

The availability of effective medication for the treatment of refractory or recurrent neuroblastoma remains limited. This study sought to investigate the effects of increased decorin (DCN) expression on the intratumoral uptake of nab-paclitaxel as a potential novel approach to NB. Correlation between the clinical characteristics of neuroblastoma and the expression of DCN, secreted protein acidic and rich in cysteine (SPARC) and stabilin-1 was evaluated. The anticancer effect of recombinant adeno-associated virus-DCN (rAAV-DCN) was assessed in vivo and in vitro. And the effect of rAAV-DCN on the intratumoral uptake of paclitaxel was also studied in neuroblastoma-grafted nude mice. Overall, 12.5%, 17.7%, and 71.9% of the tumors stained positive for DCN, SPARC and stabilin-1 respectively and correlated to age, stage and N-MYC status in 96 children and adolescents with neuroblastoma. Transfected neuroblastoma cells stably expressed DCN, with in vivo and in vitro studies demonstrating rAAV-DCN sensitized the anticancer effect of nab-paclitaxel. Systemic rAAV-DCN in neuroblastoma-grafted nude mice inhibited stabilin-1, up-regulated SPARC, and increased the intratumoral uptake of paclitaxel. Macrophage depletion or anti-stabilin-1 monoclonal antibody increased the intratumoral uptake of nab-paclitaxel and its anticancer effects to a degree comparable to that achieved by systemic rAAV-DCN. The systemic administration of rAAV-DCN up-regulates DCN in neuroblastoma and accelerates the intratumoral uptake of nab-paclitaxel by inhibiting stabilin-1 mediated SPARC degradation.



http://ift.tt/2sJHrGn

Urolithins impair cell proliferation, arrest the cell cycle and induce apoptosis in UMUC3 bladder cancer cells

Summary

Ellagitannins have been gaining attention as potential anticancer molecules. However, the low bioavailability of ellagitannins and their extensive metabolization in the gastrointestinal tract into ellagic acid and urolithins suggest that the health benefits of consuming ellagitannins rely on the direct effects of their metabolites. Recently, chemopreventive and chemotherapeutic activities were ascribed to urolithins. Nonetheless, there is still a need to screen and evaluate the selectivity of these molecules and to elucidate their cellular mechanisms of action. Therefore, this work focused on the antiproliferative effects of urolithins A, B and C and ellagic acid on different human tumor cell lines. The evaluation of cell viability and the determination of the half-maximal inhibitory concentrations indicated that the sensitivity to the studied urolithins varied markedly between the different cell lines, with the bladder cancer cells (UMUC3) being the most susceptible. In UMUC3 cells, urolithin A was the most active molecule, promoting cell cycle arrest at the G2/M checkpoint, increasing apoptotic cell death and inhibiting PI3K/Akt and MAPK signaling. Overall, the present study emphasizes the chemopreventive/chemotherapeutic potential of urolithins, highlighting the stronger effects of urolithin A and its potential to target transitional bladder cancer cells.



http://ift.tt/2tHivMZ

How accurate are energy intensity projections?

Abstract

Recent projections of energy intensity predict a more rapid decline in intensity than has occurred in the recent past. To assess how well such projections have performed in the past, I assess the accuracy of the business as usual energy intensity projections embedded in the annual World Energy Outlook (WEO) produced by the International Energy Agency since 1994. Changes in energy intensity depend on economic growth, and historical errors in projecting energy intensity can partly be explained by errors in projecting the rate of economic growth. However, recent projections of the elasticity of energy intensity with respect to economic growth probably overstate the likely future reduction in energy intensity even if economic growth is projected accurately. This could be because energy efficiency policies are not implemented as effectively as expected or because the economy-wide rebound effect is larger than modeling assumes.



http://ift.tt/2tmqfog

Motivations for Interest, Disinterest and Uncertainty in Intrauterine Device Use Among Young Women

Abstract

Objective To elucidate salient contraceptive preferences and priorities as they relate to young women's interest or lack thereof in intrauterine device (IUD) use. Methods Qualitative data were drawn from a 2012 survey on contraceptive preferences and IUD interest. Among 413 young (ages 18–29) women, open-ended responses describing reasons for interest, disinterest or uncertainty in future IUD use were examined using a thematic analysis approach. Results Most participants were unsure about (49.2%) or not interested in (30.0%) future IUD use. Themes regarding IUD interest related to specific facets of IUD use (e.g., risks and side effects, ease of use), as well as broader influences on contraceptive decision-making (e.g., social influences, alignment with pregnancy intentions). For interested participants, a sense of empowerment pervaded the responses, with many references to the ease of use and lack of requisite maintenance. Uninterested participants were concerned about the internal nature of the IUD, with many describing "horror stories" and fears that the IUD would cause injury or infertility. Unsure participants provided more detailed and complex responses, carefully weighing the advantages and disadvantages of IUD use. Uncertainty was often driven by an acknowledged need for specific information, rather than overall lack of knowledge. Conclusions for Practice In this analysis, many women had a clear sense of their contraceptive preferences, which frequently did not align with IUDs. While continuing to remove barriers to IUD access is critical, patient-centered counseling approaches offer the opportunity to support women in best matching with a method that aligns with their preferences.



http://ift.tt/2rOXjU1

Book Review



http://ift.tt/2sQyRGk

JHB as a Collaborative Effort



http://ift.tt/2sQn7mZ

Cerebral vasculitis mimicking intracranial metastatic progression of lung cancer during PD-1 blockade

Abstract

Background

Stimulation of the immune system by targeting the PD-1/PD-L1 pathway can result in activation of anti-tumor immunity. Besides its clinical benefit immune checkpoint therapy leads to significant immune-related adverse events (irAEs). Some rare irAEs are not well described yet but are critical in patient management.

Case presentation

Here, we describe a case of autoimmune cerebral vasculitis/encephalitis after PD-1 inhibitor treatment for metastatic adenocarcinoma of the lung. Upon PD-1 blockade, the patient developed cerebral lesions, while having disease stabilization of extracranial metastases. Imaging suggested that the patient had new progressing brain metastases. Despite stereotactic irradiation the lesions progressed further. The largest lesion became symptomatic and had to be surgically resected. On examination, cerebral vasculitis was detected but not evidence of metastatic lung cancer. Analysis of the patient's serum revealed the presence of antinuclear antibodies that were already present before starting PD-1 blockade. In addition, we also found anti-vascular endothelial antibodies in the serum.

Conclusion

This finding suggests that the patient had preformed autoantibodies and the checkpoint inhibitor induced a clinically relevant autoimmune disease. Taken together, encephalitic lesions in patients under PD-1/PD-L1 blockade can mimic metastatic brain lesions and this rare irAE has to be considered as a differential diagnosis in patients treated with immunotherapy.



http://ift.tt/2stR8GC

New Cancer Immunotherapy Agents in Development: a report from an associated program of the 31 st Annual Meeting of the Society for Immunotherapy of Cancer, 2016

Abstract

This report is a summary of 'New Cancer Immunotherapy Agents in Development' program, which took place in association with the 31st Annual Meeting of the Society for Immunotherapy of Cancer (SITC), on November 9, 2016 in National Harbor, Maryland. Presenters gave brief overviews of emerging clinical and pre-clinical immune-based agents and combinations, before participating in an extended panel discussion with multidisciplinary leaders, including members of the FDA, leading academic institutions and industrial drug developers, to consider topics relevant to the future of cancer immunotherapy.



http://ift.tt/2rKieMI

Safe and effective administration of T-VEC in a patient with heart transplantation and recurrent locally advanced melanoma

Abstract

Background

Immunotherapy plays a key role in the treatment of metastatic melanoma. Patients with autoimmune conditions and/or on immunosuppressive therapy due to orthotropic transplants, however, are systematically excluded from clinical trials. Talimogene laherparepvec (T-VEC) is the first oncolytic virus to be approved by the FDA for cancer therapy. To our knowledge, this is the first report of T-VEC being administered in the setting of an organ transplant recipient.

Case presentation

Here we present the case of a patient with recurrent locally advanced cutaneous melanoma receiving salvage T-VEC therapy in the setting of orthotropic heart transplantation. After 5 cycles of therapy, no evidence of graft rejection has been observed to date, and the patient achieved a complete remission, and is currently off therapy.

Conclusion

This case advocates for further investigation on the safety and efficacy of immunotherapeutic approaches, such as T-VEC, in solid organ transplant recipients.



http://ift.tt/2su0qT1

Intratumorally injected pro-inflammatory allogeneic dendritic cells as immune enhancers: a first-in-human study in unfavourable risk patients with metastatic renal cell carcinoma

Abstract

Background

Accumulating pre-clinical data indicate that the efficient induction of antigen-specific cytotoxic CD8+ T cells characterizing viral infections is caused by cross-priming where initially infected DCs produce an unique set of inflammatory factors that recruit and activate non-infected bystander DCs. Our DC-based immunotherapy concept is guided by such bystander view and accordingly, we have developed a cellular adjuvant consisting of pre-activated allogeneic DCs producing high levels of DC-recruiting and DC-activating factors. This concept doesn't require MHC-compatibility between injected cells and the patient and therefore introduces the possibility of using pre-produced and freeze-stored DCs from healthy blood donors as an off- the-shelf immune enhancer. The use of MHC-incompatible allogeneic DCs will further induce a local rejection process at the injection site that is expected to further enhance recruitment and maturation of endogenous bystander DCs.

Methods

Twelve intermediate and poor risk patients with newly diagnosed metastatic renal cell carcinoma (mRCC) where included in a phase I/II study. Pro-inflammatory allogeneic DCs were produced from a leukapheresis product collected from one healthy blood donor and subsequently deep-frozen. A dose of 5–20 × 106 DCs (INTUVAX) was injected into the renal tumor twice with 2 weeks interval before planned nephrectomy and subsequent standard of care.

Results

No INTUVAX-related severe adverse events were observed. A massive infiltration of CD8+ T cells was found in 5 out of 12 removed kidney tumors. No objective tumor response was observed and 6 out of 11 evaluable patients have subsequently received additional treatment with standard tyrosine kinase inhibitors (TKI). Three of these 6 patients experienced an objective tumor response including one sunitinib-treated patient who responded with a complete and durable regression of 4 brain metastases. Median overall survival (mOS) is still not reached (currently 42.5 months) but has already passed historical mOS in patients with unfavourable risk mRCC on standard TKI therapy.

Conclusions

Our findings indicate that intratumoral administration of proinflammatory allogeneic DCs induces an anti-tumor immune response that may prolong survival in unfavourable risk mRCC-patients given subsequent standard of care. A randomized, multi-center, phase II mRCC trial (MERECA) with INTUVAX in conjuction with sunitinib has been initiated.

Trial registration

Clinicaltrials.gov identifier: NCT01525017.



http://ift.tt/2rKOY8J

Adoptive cell therapy using PD-1 + myeloma-reactive T cells eliminates established myeloma in mice

Abstract

Background

Adoptive cellular therapy (ACT) with cancer antigen-reactive T cells following lymphodepletive pre-conditioning has emerged as a potentially curative therapy for patients with advanced cancers. However, identification and enrichment of appropriate T cell subsets for cancer eradication remains a major challenge for hematologic cancers.

Methods

PD-1+ and PD-1 T cell subsets from myeloma-bearing mice were sorted and analyzed for myeloma reactivity in vitro. In addition, the T cells were activated and expanded in culture and given to syngeneic myeloma-bearing mice as ACT.

Results

Myeloma-reactive T cells were enriched in the PD-1+ cell subset. Similar results were also observed in a mouse AML model. PD-1+ T cells from myeloma-bearing mice were found to be functional, they could be activated and expanded ex vivo, and they maintained their anti-myeloma reactivity after expansion. Adoptive transfer of ex vivo-expanded PD-1+ T cells together with a PD-L1 blocking antibody eliminated established myeloma in Rag-deficient mice. Both CD8 and CD4 T cell subsets were important for eradicating myeloma. Adoptively transferred PD-1+ T cells persisted in recipient mice and were able to mount an adaptive memory immune response.

Conclusions

These results demonstrate that PD-1 is a biomarker for functional myeloma-specific T cells, and that activated and expanded PD-1+ T cells can be effective as ACT for myeloma. Furthermore, this strategy could be useful for treating other hematologic cancers.



http://ift.tt/2rKif3e

Nivolumab as salvage treatment in a patient with HIV-related relapsed/refractory Hodgkin lymphoma and liver failure with encephalopathy

Abstract

Background

We report the first case to our knowledge of a patient with relapsed/refractory classical hodgkin lymphoma and liver failure with encephalopathy along with human immunodeficiency virus/acquired immunodeficiency syndrome infection, successfully treated with nivolumab without major side effects and encouraging prolonged disease control.

Case presentation

In December 2015, at the time of the patient's progression from his Hodgkin lymphoma after fourth line treatment, he developed persistent fevers, abdominal distension, jaundice and worsening of his liver function tests. Magnetic resonance imaging of abdomen/pelvis demonstrated hepatomegaly with innumerable new liver lesions, splenomegaly with multiple splenic nodules and several new mediastinal, intraperitoneal and retroperitoneal lymphadenopathy. In accordance with the patient's wishes before admission, and after agreement with the family, nivolumab (3 mg/kg every 2 weeks) was given. Of note, antiretroviral therapy was on hold due to liver function tests, his viral load was undectable and cluster of differentiation 4 counts were 103/uL at the time of nivolumab administration. One week after the first dose of nivolumab both his hepatic encephalopathy and constitutional symptoms started to improve, and after 2 doses, (January 2016) his LFTs were almost back to normal. After 5 months of nivolumab treatment (10 doses), restaging (computerized tomography scans of neck, chest, abdomen, pelvis) done on May 2016 showed resolution of hepatosplenomegaly with two residual small hepatic lesions, heterogeneous spleen with no splenic lesions, and stable non-enlarged retroperitoneal lymph nodes without intraabdominal lymphadenopathy; consistent with partial response.

Conclusions

We report a case of a patient with human immunodeficiency virus/acquired immunodeficiency syndrome -related relapsed/refractory classical Hodgkin lymphoma and acute liver failure with encephalopathy successfully treated with nivolumab after failing all standard therapeutic options. Unlike classic cytotoxic chemotherapy, which relies on preserved organ function to ameliorate potential severe side effects (i.e. myelosuppression), elimination of monoclonal antibodies is fairly independent of baseline renal and hepatic function since they are usually metabolized by circulating phagocytes and/or by their target antigen-expressing cell.



http://ift.tt/2su1t5E

GITR ligand fusion protein agonist enhances the tumor antigen–specific CD8 T-cell response and leads to long-lasting memory

Abstract

Background

The expansion of antigen-specific CD8 T cells is important in generating an effective and long-lasting immune response to tumors and viruses. Glucocorticoid-induced tumor necrosis factor receptor family-related receptor (GITR) is a co-stimulatory receptor that binds the GITR ligand (GITRL). Agonism of GITR can produce important signals that drive expansion of effector T cell populations.

Methods

We explored two separate murine tumor models, CT26 and TC-1, for responsiveness to GITR Ligand Fusion Protein(GITRL-FP) monotherapy. In TC-1, GITRL-FP was also combined with concurrent administration of an E7-SLP vaccine. We evaluated tumor growth inhibition by tumor volume measurements as well as changes in CD8 T cell populations and function including cytokine production using flow cytometry. Additionally, we interrogated how these therapies resulted in tumor antigen-specific responses using MHC-I dextramer staining and antigen-specific restimulations.

Results

In this study, we demonstrate that a GITR ligand fusion protein (GITRL-FP) is an effective modulator of antigen-specific CD8 T cells. In a CT26 mouse tumor model, GITRL-FP promoted expansion of antigen-specific T cells, depletion of regulatory T cells (Tregs), and generation of long-lasting CD8 T cell memory. This memory expansion was dependent on the dose of GITRL-FP and resulted in complete tumor clearance and protection from tumor rechallenge. In contrast, in TC-1 tumor–bearing mice, GITRL-FP monotherapy could not prime an antigen-specific CD8 T cell response and was unable to deplete Tregs. However, when combined with a vaccine targeting E7, treatment with GITRL-FP resulted in an augmentation of the vaccine-induced antigen-specific CD8 T cells, the depletion of Tregs, and a potent antitumor immune response. In both model systems, GITR levels on antigen-specific CD8 T cells were higher than on all other CD8 T cells, and GITRL-FP interacted directly with primed antigen-specific CD8 T cells.

Conclusions

When taken together, our results demonstrate that the delivery of GITRL-FP as a therapeutic can promote anti-tumor responses in the presence of tumor-specific CD8 T cells. These findings support further study into combination partners for GITRL-FP that may augment CD8 T-cell priming as well as provide hypotheses that can be tested in human clinical trials exploring GITR agonists including GITRL-FP.



http://ift.tt/2rKc6E9

Zika virus infection in Vietnam: current epidemic, strain origin, spreading risk, and perspective

Abstract

Zika virus infection and its associated microcephaly have being receiving global concern. This infection has spread widely since the first outbreak was recorded in Africa in 1952. Now, it has been reported in over 70 countries on five continents including Africa, North and South America, Asia, and Europe. Vietnam is one of the most recent countries which had cases of Zika virus infection at the end of 2016. This country has also reported the first case of a microcephaly-born baby which was probably linked to Zika virus infection. However, information on the Zika virus epidemic in Vietnam is still limited. This brief report intends to update the current Zika virus epidemic, and to discuss challenges and perspectives in controlling this infection in Vietnam.



http://ift.tt/2rxaSYT

Development of a peptide ELISA to discriminate vaccine-induced immunity from natural infection of hepatitis A virus in a phase IV study

Abstract

Hepatitis A virus (HAV) is a highly infectious agent that causes acute liver disease. The infection can trigger the production of antibodies against the structural and non-structural proteins of HAV. Nonetheless, vaccination with an HAV vaccine leads to the production of a primary antibody against the structural proteins. Because the non-structural proteins are only produced during active virus replication, there is no or very little antibody production against the non-structural proteins. However, the current commercial immunoassay cannot distinguish between antibodies produced during natural infection and those from vaccination against HAV. In our study, six immune-dominant epitopes from the non-structural proteins were designed, synthesized, linked together and cloned into pGEX-5X-1 plasmid. The recombinant protein was expressed in E. coli and purified by Ni2+-coated magnetic agarose beads. Then the purified recombinant protein was used as an ELISA antigen to detect antibodies for HAV non-structural proteins in serum samples. Seventy-seven attenuated and 89 inactivated vaccinated samples collected from our previous phase IV study of HAV vaccines were detected by peptide ELISA developed in this study. The mean OD450 value for the vaccination samples and acute infection samples were 0.529 (0.486 for the attenuated group and 0.567 for the inactivated group) and 1.187, respectively. According to the receiver operating characteristic (ROC) curve, the sensitivity and specificity of the peptide ELISA were 93.80% and 91.00%, respectively. This peptide ELISA was confirmed to discriminate vaccine-induced immunity from natural infection of HAV in a phase IV study with high sensitivity and specificity.



http://ift.tt/2sQbz38

Willingness to Communicate Orally: The Case of Iranian EFL Learners

Abstract

This study sets out to develop a questionnaire on willingness to communicate (WTC) orally specific to English as a Foreign Language setting. It also aims to investigate the effect of three independent variables of interlocutor, age and gender on the same construct of WTC orally. Exploratory factor analysis resulted in three dimensions to WTC, namely WTC with teacher, with classmate, and stranger. Also Cronbach's alpha of .86 indicated a high internal consistency. Mixed between–within subjects analysis of variance was used to assess the impact of interlocutors, age and gender on participants' WTC across the three WTC subscale scores. The results showed no interaction effect between any of pairs of variables but the main effect of interlocutor on WTC orally. The results are discussed in the context of language teaching and some pedagogical implications are suggested.



http://ift.tt/2sjTJET

Short- and long-term outcomes from percutaneous endoscopic gastrostomy with jejunal extension

Abstract

Background

There is a paucity of data regarding the safety and efficacy of percutaneous endoscopic gastrostomy with jejunal extension (PEG-J). We evaluated adverse events related to PEG-J and determined the clinical impact of PEG-J in those with chronic pancreatitis (CP).

Methods

This cohort study included all patients who underwent PEG-J placement in a tertiary-care academic medical center between 2010 and 2012. Main outcome measurements were (1) short- and long-term complications related to PEG-J and (2) changes in weight and hospitalizations during the 12-month period before and after PEG-J in the CP subgroup.

Results

Of 102 patients undergoing PEG-J placement, the overall technical success rate was 97 %. During a median follow-up period of 22 months (1–46 months, n = 90), at least one tube malfunction occurred in 52/90 (58 %; 177 episodes) after a median of 53 days (3–350 days), requiring a median of two tube replacements. Short-term (<30 days) tube malfunction occurred in 28/90 (31 %) and delayed in 24/90 (27 %); these included dislodgement (29 %), clogging (26 %) and kinking (14 %). In the CP subgroup (n = 58), mean body weight (kg) (70 vs. 71, p = 0.06) and body mass index (kg/m2, 26 vs. 27, p = 0.05) increased post-PEG-J. Mean number of hospitalizations (5 vs. 2, p < 0.0001) and inpatient days per 12 months (22 vs. 12, p = 0.005) decreased.

Conclusions

While we observed no major complications related to PEG-J, half of patients had at least one episode of tube malfunction. In the CP subgroup, jejunal feeding via PEG-J significantly reduced the number of hospitalizations and inpatients days, while improving nutritional parameters.



http://ift.tt/2stNCfC

Robotic-assisted colorectal surgery in obese patients: a case-matched series

Abstract

Background

Reports demonstrate laparoscopic colorectal surgery in obese patients is associated with higher conversion to laparotomy and complication rates. While several advantages of robotic-assisted surgery have been reported, outcomes in obese patients have not been adequately studied. Therefore, this study compares outcomes of robotic-assisted surgery in non-obese and obese patients.

Methods

A retrospective review of 331 consecutive robotic procedures performed at a single institution between 2009 and 2015 was performed. Patients were divided into non-obese (BMI <30 kg/m2) and obese (BMI ≥30 kg/m2) groups, and were clinically matched by gender, age, and procedure performed. Intraoperative and postoperative complications, operative time, estimated blood loss, and length of stay were examined.

Results

Following matching, each group included 108 patients comprised of 50 men and 58 women. Mean BMI was 24.6 ± 3.15 and 36.2 ± 5.67 kg/m2 (p < 0.0001), and the mean age was 59.2 ± 11.28 years for non-obese patients and 57.1 ± 12.44 for obese patients (p = 0.18). Surgeries included low anterior resection, right colectomy, left colectomy, sigmoid colectomy, excision of rectal endometriosis, total proctocolectomy, APR, subtotal colectomy, ileocecectomy, proctectomy, rectopexy, transanal excision of rectal mass, and colostomy site hernia repair. The mean operative time was 272.69 ± 115.43 and 282.42 ± 120.51 min (p = 0.55), estimated blood loss 195.23 ± 230.37 and 289.19 ± 509.27 mL (p = 0.08), conversion to laparotomy 6.48 and 9.26 % (p = 0.45), and length of stay 5.38 ± 4.94 and 4.56 ± 4.04 days (p = 0.18) for the non-obese and obese groups, respectively. Twenty of the non-obese patients had postoperative complications as compared to 27 of the obese patients (p = 0.30). However, the prevalence of wound complications was higher in obese patients (1.9 vs 9.3 %; p = 0.03).

Conclusion

There is no difference in conversion to laparotomy and overall complication rates in non-obese and obese patients undergoing robotic-assisted colorectal surgery. However, obesity is associated with a higher prevalence of wound complications. Robotic-assisted surgery may minimize conversion to laparotomy and complications typically seen in obese patients due to improved visualization, instrumentation, and ergonomics.



http://ift.tt/2rK8iTq

Novel effective and repeatedly available ring-thread counter traction for safer colorectal endoscopic submucosal dissection

Abstract

Background

Although several methods to create an effective counter traction for safer endoscopic submucosal dissection (ESD) have been reported, these methods do not overcome problems regarding delivery and ease of use. This randomized prospective study assessed the usefulness of ring-shaped thread counter traction, which not only allowed the safer colorectal ESD but also the easiest and lower cost counter traction without any special devices.

Methods

Forty-five patients diagnosed with colorectal lateral spreading tumors over 20 mm were allocated to the conventional ESD group (CE) (n = 22) and the ring-shaped thread counter traction ESD group (RE) (n = 21). The ring-shaped thread was hooked and lifted up to the contralateral mucosa with a hemoclip. The primary outcome was the dissected area per minute during ESD (cm2/min) (UMIN000020160).

Results

There were significant differences in the dissection time (min), with 130.0 (56.0–240.0) versus 80 (35.0–130.0) min for the CE and RE groups, respectively (P = 0.001). For the dissected areas per minute (cm2/min), there was a significant difference, with 0.125 (0.1–0.18) versus 0.235 (0.16–0.36) min (P = 0.003) for the CE and RE groups, respectively. There were 1 cases of perforation during ESD in the CE compared to 0 for the RE, and this was no significantly different (P = 0.31). The procedure time of producing and setting the ring-shaped thread counter traction was approximately 1.80 (0.80–3.30) min only.

Conclusions

The ring-shaped thread counter traction is simple, effective, lower cost and does not require special devices to obtain repeated counter traction.



http://ift.tt/2stRdu4

Robust augmented reality registration method for localization of solid organs’ tumors using CT-derived virtual biomechanical model and fluorescent fiducials

Abstract

Background

Augmented reality (AR) is the fusion of computer-generated and real-time images. AR can be used in surgery as a navigation tool, by creating a patient-specific virtual model through 3D software manipulation of DICOM imaging (e.g., CT scan). The virtual model can be superimposed to real-time images enabling transparency visualization of internal anatomy and accurate localization of tumors. However, the 3D model is rigid and does not take into account inner structures' deformations. We present a concept of automated AR registration, while the organs undergo deformation during surgical manipulation, based on finite element modeling (FEM) coupled with optical imaging of fluorescent surface fiducials.

Methods

Two 10 × 1 mm wires (pseudo-tumors) and six 10 × 0.9 mm fluorescent fiducials were placed in ex vivo porcine kidneys (n = 10). Biomechanical FEM-based models were generated from CT scan. Kidneys were deformed and the shape changes were identified by tracking the fiducials, using a near-infrared optical system. The changes were registered automatically with the virtual model, which was deformed accordingly. Accuracy of prediction of pseudo-tumors' location was evaluated with a CT scan in the deformed status (ground truth). In vivo: fluorescent fiducials were inserted under ultrasound guidance in the kidney of one pig, followed by a CT scan. The FEM-based virtual model was superimposed on laparoscopic images by automatic registration of the fiducials.

Results

Biomechanical models were successfully generated and accurately superimposed on optical images. The mean measured distance between the estimated tumor by biomechanical propagation and the scanned tumor (ground truth) was 0.84 ± 0.42 mm. All fiducials were successfully placed in in vivo kidney and well visualized in near-infrared mode enabling accurate automatic registration of the virtual model on the laparoscopic images.

Conclusions

Our preliminary experiments showed the potential of a biomechanical model with fluorescent fiducials to propagate the deformation of solid organs' surface to their inner structures including tumors with good accuracy and automatized robust tracking.



http://ift.tt/2rK8gLi

Intraoperative localization of the parathyroid glands with indocyanine green and Firefly(R) technology during BABA robotic thyroidectomy

Abstract

Background

It is unclear whether near-infrared (NIR) light-induced indocyanine green (ICG) fluorescence can effectively identify, and thus permit the preservation of, parathyroid glands in bilateral axillo-breast approach (BABA) robotic thyroidectomy. This case–control study with a prospectively recruited consecutive series and a retrospectively selected control group assessed the usefulness of ICG with Firefly(R) technology to identify the parathyroid glands intraoperatively during BABA robotic thyroidectomy.

Methods

All consecutive patients (N = 22) who were scheduled to undergo BABA robotic thyroidectomy for papillary thyroid carcinoma in December 2013–August 2015 and met the study eligibility criteria were recruited prospectively. ICG fluorescence was used with the Firefly system (NIR illuminator: 805 nm; filter: 825 nm) integrated in the da Vinci Si robot system to identify the lower parathyroid glands. Parathyroid hormone levels were recorded on postoperative days 0, 1, 2, and 14. Propensity score matching was used to identify an age-, gender-, tumor size-, and operation type-matched group of control patients who underwent BABA robotic thyroidectomy without the Firefly system. The two groups were compared in terms of parathyroid-related outcomes.

Results

ICG fluorescence-mediated identification of the parathyroid and thyroid glands required on average (range) 203 ± 89 (125–331) and 207 ± 112 (130–356) s, respectively. The mean (range) fluorescence duration in these glands was 20.8 ± 6.0 (16.6–35.8) and 20.1 ± 7.3 (15.5–33.8) min, respectively. The ICG group had a significantly lower rate of incidental parathyroidectomy than the control group (0 vs. 15.9%, P = 0.048).

Conclusions

ICG with NIR light may feasibly and safely identify the parathyroid glands in BABA robotic thyroidectomy.



http://ift.tt/2su99VD

Do Adult Somatic Cells Undergo Reprogramming or Endogenous Pluripotent Stem Cells get Activated to Account for Plasticity, Regeneration and Cancer Initiation?



http://ift.tt/2tlEpG4

Studies on vertical transmission of Trichinella spiralis in experimentally infected guinea pigs ( Cavia porcellus )

Abstract

An experimental study to enhance knowledge on the capability of Trichenella spiralis to pass from guinea pigs to progeny at different periods of pregnancy or lactation was performed. For this purpose, 18 female adult guinea pigs were inoculated with 100 or 1000 T. spiralis muscle larvae (ML) during early, late gestation and during lactation period. The presence of T. spiralis (ML) in mothers and newborns was studied through enzymatic digestion from muscle samples. ML were observed in 9 of 42 newborn guinea pigs and levels of infection were significantly higher when infections of mothers were done during late gestation (p = 0.0046) with the high infective dose (p = 0.0043). T. spiralis ML were not recovered from any of the newborns from mothers infected in the lactation period. Ten out of 18 infected mothers presented larvae 1 in their mammary glands. Muscle samples from the tongue and the masseter showed the highest larval burdens. These observations confirm previous reports on that ML of T. spiralis are capable to pass through placental tissues to reach and encyst in striated muscle groups of newborn guinea pigs. This study may also reinforce the importance of preventive programs to control trichinellosis in those endemic areas where pregnant women would have high risk of infection.



http://ift.tt/2rJUtnX

Surgical Checklists: Prevention Is Better Than Cure



http://ift.tt/2rxojYy

Hemorrhoid Treatment Needs a Relook: More Room for Conservative Management Even in Advanced Grades of Hemorrhoids



http://ift.tt/2sQ83Ww

A novel workflow combining plaque imaging, plaque and plasma proteomics identifies biomarkers of human coronary atherosclerotic plaque disruption

Abstract

Background

Atherosclerotic plaque rupture is the culprit event which underpins most acute vascular syndromes such as acute myocardial infarction. Novel biomarkers of plaque rupture could improve biological understanding and clinical management of patients presenting with possible acute vascular syndromes but such biomarker(s) remain elusive. Investigation of biomarkers in the context of de novo plaque rupture in humans is confounded by the inability to attribute the plaque rupture as the source of biomarker release, as plaque ruptures are typically associated with prompt down-stream events of myocardial necrosis and systemic inflammation.

Methods

We developed a novel approach to identify potential biomarkers of plaque rupture by integrating plaque imaging, using optical coherence tomography, with both plaque and plasma proteomic analysis in a human model of angioplasty-induced plaque disruption.

Results

We compared two pairs of coronary plaque debris, captured by a FilterWire Device, and their corresponding control samples and found matrix metalloproteinase 9 (MMP9) to be significantly enriched in plaque. Plaque contents, as defined by optical coherence tomography, affect the systemic changes of MMP9. Disruption of lipid-rich plaque led to prompt elevation of plasma MMP9, whereas disruption of non-lipid-rich plaque resulted in delayed elevation of plasma MMP9. Systemic MMP9 elevation is independent of the associated myocardial necrosis and systemic inflammation (measured by Troponin I and C-reactive protein, respectively). This information guided the selection of a subset of subjects of for further label free proteomics analysis by liquid chromatography tandem mass spectrometry (LC–MS/MS). We discovered five novel, plaque-enriched proteins (lipopolysaccharide binding protein, Annexin A5, eukaryotic translocation initiation factor, syntaxin 11, cytochrome B5 reductase 3) to be significantly elevated in systemic circulation at 5 min after plaque disruption.

Conclusion

This novel approach for biomarker discovery in human coronary artery plaque disruption can identify new biomarkers related to human coronary artery plaque composition and disruption.



http://ift.tt/2rORuWm

Early postoperative imaging after non-bariatric gastric resection: a primer for radiologists

Abstract

Surgical resection represents the mainstay treatment and only potentially curative option for gastric carcinoma, and is increasingly performed laparoscopically. Furthermore, other tumours and selected cases of non-malignant disorders of the stomach may require partial or total gastrectomy. Often performed in elderly patients, gastric resection remains a challenging procedure, with significant morbidity (14–43% complication rate) and non-negligible postoperative mortality (approximately 3%). This paper provides an overview of contemporary surgical techniques for non-bariatric gastric resection, reviews and illustrates the expected postoperative imaging appearances, common and unusual complications after partial and total gastrectomy. Albeit cumbersome or unfeasible in severely ill or uncooperative patients, contrast fluoroscopy remains useful to rapidly check for anastomotic patency and integrity. Currently, emphasis is placed on multidetector CT, which comprehensively visualizes the surgically altered anatomy and consistently detects complications such as anastomotic leaks and fistulas, duodenal stump leakage, afferent loop syndrome, haemorrhages, pancreatic fistulas and porto-mesenteric venous thrombosis. Our aim is to help radiologists become familiar with early postoperative imaging, in order to understand the surgically altered anatomy and to differentiate between expected imaging appearances and abnormal changes heralding iatrogenic complications, thus providing a consistent basis for correct choice between conservative, interventional or surgical treatment.

Teaching points

Radical gastrectomy is associated with frequent postoperative morbidity and non-negligible mortality.

In cooperative patients fluoroscopy allows checking for anastomotic patency and leaks.

Multidetector CT with / without oral contrast comprehensively visualizes the operated abdomen.

Awareness of surgically altered anatomy and expected postoperative appearances is warranted.

Main complications include anastomotic and duodenal leaks, haemorrhages and pancreatic fistulas.



http://ift.tt/2rwElCd

Methods of probing the interactions between small molecules and disordered proteins

Abstract

It is generally recognized that a large fraction of the human proteome is made up of proteins that remain disordered in their native states. Despite the fact that such proteins play key biological roles and are involved in many major human diseases, they still represent challenging targets for drug discovery. A major bottleneck for the identification of compounds capable of interacting with these proteins and modulating their disease-promoting behaviour is the development of effective techniques to probe such interactions. The difficulties in carrying out binding measurements have resulted in a poor understanding of the mechanisms underlying these interactions. In order to facilitate further methodological advances, here we review the most commonly used techniques to probe three types of interactions involving small molecules: (1) those that disrupt functional interactions between disordered proteins; (2) those that inhibit the aberrant aggregation of disordered proteins, and (3) those that lead to binding disordered proteins in their monomeric states. In discussing these techniques, we also point out directions for future developments.



http://ift.tt/2rx3Umu

How Schwann cells facilitate cancer progression in nerves

Abstract

Recent studies have demonstrated a critical role for nerves in enabling tumor progression. The association of nerves with cancer cells is well established for a variety of malignant tumors, including pancreatic, prostate and the head and neck cancers. This association is often correlated with poor prognosis. A strong partnership between cancer cells and nerve cells leads to both cancer progression and expansion of the nerve network. This relationship is supported by molecular pathways related to nerve growth and repair. Peripheral nerves form complex tumor microenvironments, which are made of several cell types including Schwann cells. Recent studies have revealed that Schwann cells enable cancer progression by adopting a de-differentiated phenotype, similar to the Schwann cell response to nerve trauma. A detailed understanding of the molecular and cellular mechanisms involved in the regulation of cancer progression by the nerves is essential to design strategies to inhibit tumor progression.



http://ift.tt/2sPHhNY

Regulation of neural circuit formation by protocadherins

Abstract

The protocadherins (Pcdhs), which make up the most diverse group within the cadherin superfamily, were first discovered in the early 1990s. Data implicating the Pcdhs, including ~60 proteins encoded by the tandem Pcdha, Pcdhb, and Pcdhg gene clusters and another ~10 non-clustered Pcdhs, in the regulation of neural development have continually accumulated, with a significant expansion of the field over the past decade. Here, we review the many roles played by clustered and non-clustered Pcdhs in multiple steps important for the formation and function of neural circuits, including dendrite arborization, axon outgrowth and targeting, synaptogenesis, and synapse elimination. We further discuss studies implicating mutation or epigenetic dysregulation of Pcdh genes in a variety of human neurodevelopmental and neurological disorders. With recent structural modeling of Pcdh proteins, the prospects for uncovering molecular mechanisms of Pcdh extracellular and intracellular interactions, and their role in normal and disrupted neural circuit formation, are bright.



http://ift.tt/2rx2Pv4

Risk analysis and outcomes of bronchopulmonary sequestrations

Abstract

Background

Researched and discussed the risks and outcomes of bronchopulmonary sequestrations, especially the intralobar type.

Methods

A retrospective review of our experiences with bronchopulmonary sequestrations from January 2012 to April 2015 is reported. The present study researched and discusses the risks and outcomes of bronchopulmonary sequestrations, especially the intralobar type, compared with other types of bronchopulmonary sequestrations in symptoms, surgery, pathology, and excretion.

Results

A total of 126 bronchopulmonary sequestrations were diagnosed. All fetal chest cases (18–30 weeks) of solid or high-echo masses were diagnosed antenatally and then confirmed by ultrasound. Enhanced computed tomography was used to confirm the diagnosis. Eighty-three boys and 43 girls were included. The mean age at surgery was 4.2 ± 0.5 months. There were 103 cases of left, 22 cases of right, and 1 case of bilateral sequestration. There were 62 extralobar cases, 51 intralobar cases, 13 cases within the diaphragm, and a rare bilateral case. A preoperative history of recurrent respiratory tract infection was present in 39 cases, including 10 extralobar and 29 intralobar cases. Operations were completed successfully, and diagnoses were confirmed pathologically. Thirty-seven cases were associated with congenital bronchopulmonary malformation changes, of which 4 were extralobar, 31 were intralobar, and 2 were within the diaphragm.

Conclusions

The intralobar type was relatively uncommon among bronchopulmonary sequestrations. However, due to communication with normal lung tissue, infection is common in the intralobar type. Computed tomography examinations are very important immediately after birth. It is necessary to resect the mass in early childhood.



http://ift.tt/2tkP18b

Co-delivery of doxorubicin and AS1411 aptamer by poly(ethylene glycol)-poly( β -amino esters) polymeric micelles for targeted cancer therapy

Abstract

Recently, targeted drug delivery systems (TDDS) have offered a great potential and benefits towards the anti-tumor drug delivery. In this work, we designed the TDDS using a biocompatible poly(ethylene glycol)-poly(β-amino esters) amphiphilic block copolymer (PEG-PAEs) synthesized by Michael addition polymerization for combinatorial therapy. Further, the chemotherapeutic agents' doxorubicin (DOX) and AS1411 DNA aptamer (Apt) are encapsulated in the PEG-PAEs NPs (PDANs) for co-delivery therapeutics. PDANs have shown the monodisperse spherical shape, smooth surface with a net positive charge (average diameter—183.1 ± 27.2 nm, zeta potential—31.2 ± 6.3 mV), and good colloidal stability (critical micelle concentration of PEG-PAEs is about 6.3 μg/mL). The pH-sensitive PAEs endowed PDANs both pH-triggered drug release characteristics and enhanced endo/lysosomal escape ability, thus improving the localization and cytotoxicity of DOX. AS1411 Apt conjugated PDANs precisely targeted nucleolin and their uptake correlates to a significant activity enhancement only in tumor cells (MCF-7) but not in normal cells (MCF-10A). Thus, PDANs can be a very promising targeted drug delivery platform for effective breast cancer therapy.

Graphical abstract

Scheme 1 Schematic illustration of the preparation and cellular uptake of targeted co-delivery system


http://ift.tt/2rwV8VC

Magnetic M x O y @N-C as heterogeneous catalysts for the catalytic oxidation of aniline solution with sulfate radicals

Abstract

Metal nanoparticles have been combined with magnet metal–organic frameworks (MOFs) to afford new materials that demonstrate an efficient catalytic degradation, high stability, and excellent reusability in areas of catalysis because of their exceptionally high surface areas and structural diversity. Magnetic Mx Oy @N-C (M = Fe, Co, Mn) nanocrystals were formed on nitrogen-doped carbon surface by using 8-hydroxyquinoline as a C/N precursor. The Co@N-C, MnO@N-C, and Fe/Fe2O3@N-C catalysts were characterized by X-ray diffraction (XRD), Raman, scanning electron microscopy (SEM), high-resolution transmission electron microscopy (HRTEM), N2 adsorption/desorption, and X-ray photoelectron spectroscopy (XPS). The catalytic performances of catalysts were thoroughly investigated in the oxidation of aniline solution based on sulfate radicals (SO4−.) toward Fenton-like reaction. Magnetic Mx Oy @N-C exhibits an unexpectedly high catalytic activity in the degradation of aniline in water. A high magnetic Mx Oy @N-C catalytic activity was observed after the evaluation by aniline degradation in water. Aniline degradation was found to follow the first-order kinetics, and as a result, various metals significantly affected the structures and performances of the catalysts, and their catalytic activity followed the order of Co > Mn > Fe. The nanoparticles displayed good magnetic separation under the magnetic field.

Graphical Abstract



http://ift.tt/2rwIiqs

Seven esophageal perforation cases after aortic replacement/stenting for thoracic aortic dissection or aneurysm

Abstract

Background

Esophageal perforation after aortic replacement/stenting for aortic dissection or aneurysm is a rare but severe complication. However, its cause, standard treatment, and prognosis are unclear. We analyzed the treatment and outcome retrospectively from seven cases experienced at our hospital.

Case presentation

The median age of the patients was 70 years (range, 41–86), and six of the seven cases were male. As the first treatment, aortic replacement techniques were performed in five, and thoracic endovascular aortic repair (TEVAR) procedure was performed in two. We evaluated the treatment of the perforation, the cause of death, and the median survival time after reparative surgery (esophagectomy).

Initial treatment of the perforation was esophagectomy without reconstruction in six and esophagogastric bypass (later, esophagectomy was performed) in one. Three of seven cases could be discharged from hospital or moved to another hospital, but two of these three cases died of major bleeding on postoperative days 320 and 645. The other four esophagectomy cases died in hospital because of sepsis on postoperative days 14, 30, and 41 and major bleeding on postoperative day 54. The one surviving case was a 65-year-old man who underwent reconstruction, and was still alive without signs of infection at 424 days postoperatively.

Conclusion

The prognosis of esophageal perforation cases after aortic replacement/stenting for thoracic aortic dissection or aneurysm is poor, though there were some cases with relatively long survival. Therefore, the indication for invasive esophagectomy should be decided carefully. Control of infection including regional infection is essential for successful treatment.



http://ift.tt/2rwjG0X

Successful radical resection of pancreatic head carcinoma in a patient with replaced right hepatic artery originating from posterior inferior pancreaticoduodenal artery: a case report

Abstract

Anatomical variations of hepatic arteries may be problematic in pancreaticoduodenectomy (PD). We experienced pancreatic head cancer in a patient with rare variation of hepatic artery and performed PD successfully with the resection of this artery. A 75-year-old woman showed pancreatic head tumor on CT. Preoperative CT detected rare variation of hepatic artery; posterior segmental branch of right hepatic artery (RHA-PB) originating from posterior inferior pancreaticoduodenal artery. The image also demonstrated that there was a junction between RHA-PB and anterior branch of right hepatic artery (RHA-AB). We performed PD for suspected pancreatic head cancer. We divided RHA-PB for complete resection of cancer because we preoperatively knew that there was the junction between RHA-PB and RHA-AB. She was discharged uneventfully, and there was no evidence of local recurrence throughout the whole course. Careful preoperative assessment of hepatic blood supply is the key to perform successful PD even in this troublesome situation.



http://ift.tt/2rw5dC7

Evaluation of the association between sleep apnea and polyunsaturated fatty acids profiles in patients after percutaneous coronary intervention

Abstract

The long-term outcome is poor in patients with sleep apnea and cardiovascular disease. Polyunsaturated fatty acid (PUFA) is also known as an independent predictor for adverse clinical events. However, the profile of PUFA in sleep apnea patients with coronary artery disease (CAD) is still unclear. This study aimed to clarify the association between sleep apnea and PUFA profiles in patients with CAD. Two hundred seventy-four consecutive patients undergoing percutaneous coronary intervention (PCI) were screened for sleep apnea using nocturnal oximetry. Oxygen desaturation index down to 4% (4%ODI) ≥5 was used as an indicator of sleep apnea. Baseline characteristics, including PUFA profiles, were compared between patients with and without sleep apnea. Among 243 enrolled patients, 134 (55%) had sleep apnea. The sleep apnea group included a significantly higher rate of patients with obesity, insulin-requiring diabetes, peripheral artery disease (PAD), and a higher C-reactive protein level than the non-sleep apnea group. The sleep apnea group had a significantly lower eicosapentaenoic acid (EPA) to arachidonic acid (AA) ratio than the non-sleep apnea group (0.33 vs. 0.44, respectively, p = 0.024). Additionally, EPA value and EPA/AA ratio were significantly correlated with 4%ODI (r = −0.15, p = 0.028; r = −0.16, p = 0.019, respectively). Results of logistic regression analysis indicated that the comorbidities of obesity, PAD, heart failure and EPA/AA ratio had a significant association with sleep apnea. Our results suggested that patients with sleep apnea who underwent PCI had a lower EPA/AA ratio than those without sleep apnea, and EPA value and EPA/AA ratio were significantly correlated with 4%ODI.



http://ift.tt/2tFRlGc

Interval robotic cytoreduction following neoadjuvant chemotherapy in advanced ovarian cancer

Abstract

The objective of this study is to review our experience with robotic interval cytoreduction following neoadjuvant chemotherapy for advanced ovarian cancer. We retrospectively reviewed patients with advanced ovarian cancer treated with neoadjuvant chemotherapy (NAC) and interval robotic cytoreduction (IRC) between 2011 and 2016 at the University of Rochester Medical Center. Demographic information, chemotherapy treatment, operative results, and follow-up were extracted from medical records. Twenty-nine patients underwent IRC after a mean of 3.9 cycles of NAC. The mean operative time was 165 min with a mean EBL of 107 cc. The mean length of stay was 2.0 days. One case (3.3%) was converted to an open procedure because of extensive tumor not amenable to robotic cytoreduction. Overall, 19 (66%) patients underwent an R0 cytoreduction, 8 (28%) an optimal (<1 cm) cytoreduction, and 2 (7%) a suboptimal cytoreduction. The median overall survival was 39.7 months and median progression-free survival was 21.2 months. Interval robotic cytoreduction following NAC is feasible and may be preferable to open interval cytoreductive surgery, in specific patients, to minimize morbidity and length of hospital stay.



http://ift.tt/2sIki76

Early Detection and Assessment of Liver Fibrosis by using Ultrasound RF Time Series

Abstract

Early characterization and grading of liver fibrosis are important because this condition can progress into cirrhosis, which is irreversible unless discovered timely and effectively treated. In this study, we aim to extract new features regarding the dynamics of the time series of ultrasound (US) radio frequency (RF) data and examine their effectiveness for noninvasive, cost-effective, and rapid grading of early liver fibrosis. We propose the combination of spectral and fractal features with the time-domain features of US RF time series, which were averaged over a region of interest. Experiments on early liver fibrosis staging were conducted using two classifiers, namely, support vector machines (SVM) and random forests. Experimental results showed that the proposed method achieved the highest classification accuracy of 96.67% and an average classification accuracy of 77.33% for differentiating the stages of liver fibrosis by using random forest. Hence, RF time series can be used for in vivo tissue characterization of liver fibrosis. This study describes a promising tool for non-invasive early detection and grading of liver fibrosis.



http://ift.tt/2sHTJiD

Introduction of Maximum Stress Parameter for the Evaluation of Stress Shielding Around Orthopedic Screws in the Presence of Bone Remodeling Process

Abstract

The current study introduces a novel parameter called maximum stress parameter (MSP) which supersedes the conventional parameter known as stress transfer parameter (STP). It also incorporates the bone remodeling algorithm into the finite element analysis. The results from MSP can be approved by those of STP; however, MSP is preferable due to its benefits, which is discussed in this study. The current study simulates a 48 months healing process and investigates the effect of screw parameters using a two-dimensional finite element model in the presence of bone remodeling process. Lower MSP values demonstrate a more homogeneous stress distribution between the screw and bone, which results in less stress shielding. However, the reciprocal of MSP, shown as RMSP is defined in order to enable the comparison between MSP and STP. The results of current study demonstrate that increasing the number of threads and outer diameter, and decreasing pitch and Young's modulus of screw improve the performance of screw and reduce the possibility of screw loosening. The results also show that MSP is a promising parameter, which can supersede STP in future studies, and increase the reliability of results.



http://ift.tt/2tFGlss

Abstracts from the ASENT 19th Annual Meeting



http://ift.tt/2sLpxnx

Applicability of upflow anaerobic sludge blanket and dynamic membrane-coupled process for the treatment of municipal wastewater

Abstract

This study investigated the applicability of dynamic membrane filter (DMF) technology in an upflow anaerobic sludge blanket (UASB) and DMF-coupled process for the treatment of municipal wastewater. The overall treatment performance and effects of hydraulic retention time (HRT), operating flux, and mesh pore size on the UASB + DMF were assessed. The UASB + DMF-coupled process demonstrated removal efficiencies of over 64 and 86% for TCOD and TSS, respectively. The effects of filtration flux and support mesh pore size were investigated and it was found that while there was little impact on the treatment performance, a 67% increase in operating flux resulted in a 25% increase in fouling rate. Similarly, with smaller mesh pore size (Mesh 500 with pore size of 28 μm) the fouling rate increased by fourfold as compared to Mesh 300 (pore size of 46 μm). In consideration of the operation duration and contaminant removal, the DMF with Mesh 300 support layer and operating at 100 L/m2-h was the most efficient configuration for treating the effluent of the UASB operated with a HRT of 6 h. Microbial analyses of the foulant layer revealed changes in relative abundance as compared to the bulk sludge, particularly with the hydrogenotrophic methanogens completely outcompeting the acetoclastic methanogens. Overall, the coupled process improved the system robustness and reduced variability of the treated effluent.



http://ift.tt/2sKZsor

Effects of gas condition on acetic acid fermentation by Clostridium thermocellum and Moorella thermoacetica ( C. thermoaceticum )

Abstract

Fermentation with acetogens can be affected by cultivation gas phase, but to date, there is not enough evidence on that matter for Clostridium thermocellum and Moorella thermoacetica. In this work, the effects of sparged CO2 as well as sparged and non-sparged N2 on these microorganisms were studied using glucose and cellobiose as substrates. It was revealed that sparged CO2 and non-sparged N2 supported growth and acetic acid production by C. thermocellum and M. thermoacetica, while sparged N2 inhibited both of the microorganisms. Notably, part of the sparged CO2 was fermented by the co-culture system and contributed to an overestimation of the products from the actual substrate as well as an erring material balance. The best condition for the co-culture was concluded to be N2 without sparging. These results demonstrate the importance of cultivation conditions for efficient fermentation by anaerobic clostridia species.



http://ift.tt/2tlcs1o

Hospital readmission within 10 years post stroke: frequency, type and timing

Abstract

Background

The aim of this study was to examine the hospital readmissions in a 10 year follow-up of a stroke cohort previously studied for acute and subacute complications and to focus on their frequency, their causes and their timing.

Methods

The hospital records of 243 patients, 50% of a cohort of 489 patients acutely and consecutively admitted to our stroke unit in 2002/3, were subjected to review 10 years after the incidental stroke and all acute admissions were examined. The main admitting diagnoses were attributed to one of 18 predefined categories of illness. Additionally, the occurrence of death was registered.

Results

After 10 years 68.9% of patients had died and 72.4% had been readmitted to the hospital with a mean number of readmissions of 3.4 (+15.1 SD). 20% of the readmissions were due to a vascular cause, 17.3% were caused by infection, 9.3% by falls with (6.1%) and without fracture, 5.7% by a hemorrhagic event. The readmission rate was highest in the first 6 months post stroke with a rate of 116.2 admissions/100 live patient-years. Falls with fractures occurred maximally 3–5 years post stroke.

Conclusions

Hospital readmissions over the 10 years following stroke are caused by vascular events, infections, falls and hemorrhagic events, where the first 6 months are a period of particular vulnerability. The magnitude and the spectrum of these long-term complications suggest the need for a more comprehensive approach to post stroke prophylaxis.



http://ift.tt/2sOY5oi

Derivatization of Dextran for Multiply Charged Ion Formation and Electrospray Ionization Time-of-Flight Mass Spectrometric Analysis

Abstract

We present the use of a simple, one-pot derivatization to allow the polysaccharide dextran to carry multiple positive charges, shifting its molecular weight distribution to a lower m/z range. We performed this derivatization because molecular weight measurements of polysaccharides by mass spectrometry are challenging because of their lack of readily ionizable groups. The absence of ionizable groups limits proton abstraction and suppresses proton adduction during the ionization process, producing mass spectra with predominantly singly charged metal adduct ions, thereby limiting the detection of large polysaccharides. To address this challenge, we derivatized dextran T1 (approximately 1 kDa) by attaching ethylenediamine, giving dextran readily ionizable, terminal amine functional groups. The attached ethylenediamine groups facilitated proton adduction during the ionization process in positive ion mode. Using the low molecular weight dextran T1, we tracked the number of ethylenediamine attachments by measuring the mass shift from underivatized to derivatized dextran T1. Using electrospray ionization time-of-flight mass spectrometry, we observed derivatized dextran chains ranging from two to nine glucose residues with between one and four attachments/charges. Our success in shifting derivatized dextran T1 toward the low m/z range suggests potential for this derivatization as a viable route for analysis of high molecular weight polysaccharides using electrospray ionization time-of-flight mass spectrometry.

Graphical Abstract



http://ift.tt/2tFAGCN

Fast Determination of Ingredients in Solid Pharmaceuticals by Microwave-Enhanced In-Source Decay of Microwave Plasma Torch Mass Spectrometry

Abstract

Rapid qualitative and quantitative analysis of solid samples (e.g., pharmaceutical preparations) by using a small and low-resolution mass spectrometer without MS/MS function is still a challenge in ambient pressure ionization mass spectrometric analysis. Herein, a practically efficient method termed microwave-enhanced in-source decay (MEISD) using microwave plasma torch desorption ionization coupled with time-of-flight mass spectrometry (MPTDI-TOF MS) was developed for fast analysis of pharmaceutical tablets using a miniature TOF mass spectrometer without tandem mass function. The intensity of ISD fragmentation was evaluated under different microwave power values. Several factors, including desorption distance and time that might affect the signal intensity and fragmentation, were systematically investigated. It was observed that both the protonated molecular ions and major fragment ions from the active ingredients in tablets could be found in the full-scan mass spectra in positive ion mode, which were comparable to those obtained by a commercial LTQ-XL ion trap mass spectrometer. The structures of the ingredients could be elucidated in detail using the MEISD method, which promotes our understanding of the desorption/ionization processes in microwave plasma torch (MPT). Quantitative analysis of 10 tablets was achieved by full-scan MPTDI-TOF MS with low limit of detection (LOD, 0.763 mg/g), acceptable relative standard deviation (RSD < 7.33%, n =10), and 10 s for each tablet, showing promising applications in high throughput screening of counterfeit drugs.

Graphical Abstract



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Long-term clinical benefit from salvage EGFR tyrosine kinase inhibitors in advanced non-small-cell lung cancer patients with EGFR wild-type tumors

Abstract

Background

Erlotinib has been approved for the management of NSCLC patients after failure of the first or subsequent line of chemotherapy. Although the efficacy of erlotinib is clearly associated with the presence of EGFR mutations, there is a subset of patients with EGFR wild-type (EGFRwt) tumors who impressively respond.

Patients and methods

Patients with EGFRwt NSCLC who received salvage (≥2nd line) treatment with erlotinib for a prolonged period (>6 months), were sought from the database of the Hellenic Oncology Research Group. We retrospectively analyzed the clinical, pathological and molecular characteristics of the patients with available tumor material.

Results

Forty-four patients that received erlotinib for >6 months (median 10.1 months) were enrolled in the study. The majority of them were male, never-smokers with adenocarcinoma histology and a good performance status. KRAS and PIK3CA mutations were detected in 21% (9/42 tested) and 13% (4/30 tested) of the patients, respectively. The ALK-EML4 translocation was found in 10% (2/20 tested); there was no patient with HER2 or BRAF mutated tumor. Twelve (54.5%) tumor specimens were considered positive for EGFR-overexpression. Eleven patients experienced a partial response (objective response rate 25%; 95% CI 12–38%) and the remaining 33 had stable disease. The median progression-free survival and overall survival were 10.1 (95% CI 8.6–11.6 months) and 24.1 (95% CI 11.2–37 months), respectively.

Conclusions

Treatment with erlotinib significantly improves the clinical outcome in a subset of NSCLC patients with EGFRwt tumors. Further molecular analysis of such tumor specimens could provide a more comprehensive characterization of this particular group of patients. Nevertheless, the presence of other mutations should not prevent the treating physician from using erlotinib at later lines of salvage therapy for NSCLC patients.



http://ift.tt/2tkuOiS

Cancer chemoprevention through dietary flavonoids: what’s limiting?

Abstract

Flavonoids are polyphenols that are found in numerous edible plant species. Data obtained from preclinical and clinical studies suggest that specific flavonoids are chemo-preventive and cytotoxic against various cancers via a multitude of mechanisms. However, the clinical use of flavonoids is limited due to challenges associated with their effective use, including (1) the isolation and purification of flavonoids from their natural resources; (2) demonstration of the effects of flavonoids in reducing the risk of certain cancer, in tandem with the cost and time needed for epidemiological studies, and (3) numerous pharmacokinetic challenges (e.g., bioavailability, drug–drug interactions, and metabolic instability). Currently, numerous approaches are being used to surmount some of these challenges, thereby increasing the likelihood of flavonoids being used as chemo-preventive drugs in the clinic. In this review, we summarize the most important challenges and efforts that are being made to surmount these challenges.



http://ift.tt/2tFeAQD

News from the field



http://ift.tt/2sPj7n4

Agrobacterium tumefaciens -mediated transformation of oleaginous yeast Lipomyces species

Abstract

Interest in using renewable sources of carbon, especially lignocellulosic biomass, for the production of hydrocarbon fuels and chemicals has fueled interest in exploring various organisms capable of producing hydrocarbon biofuels and chemicals or their precursors. The oleaginous (oil-producing) yeast Lipomyces starkeyi is the subject of active research regarding the production of triacylglycerides as hydrocarbon fuel precursors using a variety of carbohydrate and nutrient sources. The genome of L. starkeyi has been published, which opens the door to production strain improvements through the development and use of the tools of synthetic biology for this oleaginous species. The first step in establishment of synthetic biology tools for an organism is the development of effective and reliable transformation methods with suitable selectable marker genes and demonstration of the utility of the genetic elements needed for expression of introduced genes or deletion of endogenous genes. Chemical-based methods of transformation have been published but suffer from low efficiency. To address these problems, Agrobacterium-mediated transformation was investigated as an alternative method for L. starkeyi and other Lipomyces species. In this study, Agrobacterium-mediated transformation was demonstrated to be effective in the transformation of both L. starkeyi and other Lipomyces species. The deletion of the peroxisomal biogenesis factor 10 gene was also demonstrated in L. starkeyi. In addition to the bacterial antibiotic selection marker gene hygromycin B phosphotransferase, the bacterial β-glucuronidase reporter gene under the control of L. starkeyi translation elongation factor 1α promoter was also stably expressed in six different Lipomyces species. The results from this study demonstrate that Agrobacterium-mediated transformation is a reliable and effective genetic tool for homologous recombination and expression of heterologous genes in L. starkeyi and other Lipomyces species.



http://ift.tt/2sKTVy6

Morphology and the gradient of a symmetric potential predict gait transitions of dogs

Abstract

Gaits and gait transitions play a central role in the movement of animals. Symmetry is thought to govern the structure of the nervous system, and constrain the limb motions of quadrupeds. We quantify the symmetry of dog gaits with respect to combinations of bilateral, fore–aft, and spatio-temporal symmetry groups. We tested the ability of symmetries to model motion capture data of dogs walking, trotting and transitioning between those gaits. Fully symmetric models performed comparably to asymmetric with only a \(22\%\) increase in the residual sum of squares and only one-quarter of the parameters. This required adding a spatio-temporal shift representing a lag between fore and hind limbs. Without this shift, the symmetric model residual sum of squares was \(1700\%\) larger. This shift is related to (linear regression, \(n=5\) , \(p=0.0328\) ) dog morphology. That this symmetry is respected throughout the gaits and transitions indicates that it generalizes outside a single gait. We propose that relative phasing of limb motions can be described by an interaction potential with a symmetric structure. This approach can be extended to the study of interaction of neurodynamic and kinematic variables, providing a system-level model that couples neuronal central pattern generator networks and mechanical models.



http://ift.tt/2rNo3UH

Structural characterization of Mg substituted on A/B sites in $$\hbox {NiFe}_2\hbox {O}_4$$ NiFe 2 O 4 nanoparticles using autocombustion method

Abstract

In the present paper, we are reporting the synthesis of pure nickel and magnesium ferrite [ \(\hbox {NiFe}_2\hbox {O}_4\) , \(\hbox {MgFe}_2\hbox {O}_4\) ] and magnesium-substituted nickel ferrite \((\hbox {Ni}_{1-x}\hbox {Mg}_{x/y}\hbox {Fe}_{2-y}\hbox {O}_4; x=y=0.60)\) on A/B sites with particles size in nanometer range using autocombustion technique. In this study, it has been observed that with increase in sintering temperature, the estimated bulk density of the materials increases. The XRD patterns of the samples show the formation of single-phase materials and the lattice parameters are estimated from XRD patterns. From Raman spectra, the Raman shift of pure \(\hbox {NiFe}_2\hbox {O}_4\) and \(\hbox {MgFe}_2\hbox {O}_4\) are comparable with the experimental values reported in literature. The Raman spectra give five Raman active modes \((A_ + E_{g} + 3F_{2g})\) which are expected in the spinel structure.



http://ift.tt/2sHDtOD

Magnetic interactions and electronic structure of $$\hbox {Pt}_{2}\hbox {Mn}_{1-x}\hbox {Y}_{x} \hbox {Ga (Y = Cr and Fe)}$$ Pt 2 Mn 1 - x Y x

Abstract

First-principles density functional theory-based calculations have been carried out to predict the effects of Mn replacement by Fe and Cr on electronic as well as magnetic properties of \(\hbox {Pt}_{2}\hbox {MnGa}\) and \(\hbox {Ni}_{2}\hbox {MnGa}\) . All the materials studied here are predicted to have conventional Heusler alloy structure in their ground state and they are found to be electronically stable on the basis of their respective formation energy. The replacement of Mn by Fe leads to a ferromagnetic ground state whereas in case of Mn replacement by Cr an intrasublattice antiferromagnetic configuration has been observed to have lower energy. We study the magnetic exchange interaction between the atoms for the materials with ferromagnetic and antiferromagnetic configurations to show the effects of Fe and Cr substitution at Mn site on the magnetic interactions of these systems. Detailed analysis of electronic structure in terms of density of states has been carried out to study the effect of substitution.



http://ift.tt/2tF6980

Analgesia nociception index (ani) monitoring in patients with thoracic paravertebral block: a randomized controlled study

Abstract

The goal of the study was to evaluate the effectiveness of analgesia nociception index (ANI) monitoring during intraoperative period for patients with thoracic paravertebral block (TPVB) undergoing breast surgery under general anesthesia. This prospective randomized trial was performed after receiving ethics committee approval in 44 patients who were scheduled to undergo breast surgery under general anesthesia. TPVB was performed in the preoperative period using 20 mL of bupivacaine 0.25% at T4 level. Anesthesia maintenance was provided with sevoflurane in O2: air mixture and remifentanil infusion. Intraoperative concentration of sevoflurane was adjusted according to BIS monitoring keeping the values between 40–60. In a randomized manner patients were divided into two groups. In Group control (n:22) intraoperative remifentanil infusion rate was regulated according to hemodynamic parameters, in Group ANI (n:22) remifentanil infusion rate was titrated to keep ANI monitoring values between 50–70. Total remifentanil consumption was recorded as micrograms. Demographic data, anesthesia and surgery time, intraoperative hemodynamic parameters, post-anesthesia recovery time and requirement of additional analgesic in the recovery drug were recorded. There were no significant difference in demographic data, intraoperative hemodynamic parameters, post-anesthesia recovery time and requirement of additional analgesic drug. There was a statistically significant difference between groups in total remifentanil consumption (Group ANI: 629.6 ± 422.4 mcg, Group control: 965.2 ± 543.6 mcg) (p = 0.027). In patients under general anesthesia ANI monitorisation can help optimisation of opioid consumption and provide data about nociception/antinociception intraoperatively but further experimental and clinical trials in a large scale are needed.



http://ift.tt/2sHBwSn

In vivo evaluation of the bone integration of coated poly(vinyl-alcohol) hydrogel fiber implants

Abstract

Recently, it has been shown that constructs of poly(vinyl alcohol) (PVA) hydrogel fibers reproduce closely the tensile behavior of ligaments. However, the biological response to these systems has not been explored yet. Here, we report the first in vivo evaluation of these implants and focus on the integration in bone, using a rabbit model of bone tunnel healing. Implants consisted in bundles of PVA hydrogel fibers embedded in a PVA hydrogel matrix. Half of the samples were coated with a composite coating of hydroxyapatite (HA) particles embedded in PVA hydrogel. The biological integration was evaluated at 6 weeks using histology and micro-CT imaging. For all implants, a good biological tolerance and growth of new bone tissue are reported. All the implants were surrounded by a fibrous layer comparable to what was previously observed for poly(ethylene terephthalate) (PET) fibers currently used in humans for ligament reconstruction. An image analysis method is proposed to quantify the thickness of this fibrous capsule. Implants coated with HA were not significantly osteoconductive, which can be attributed to the slow dissolution of the selected hydroxyapatite. Overall, these results confirm the relevance of PVA hydrogel fibers for ligament reconstruction and adjustments are proposed to enhance its osseointegration.

Graphical abstract



http://ift.tt/2sioDNU

One-dimensional Bi 2 Mo x W 1-x O 6 sosoloids: controllable synthesis by electrospinning process and enhanced photocatalytic performance

Abstract

One-dimensional Bi2MoxW1-xO6 (x = 0, 0.2, 0.5, 0.67, and 1) photocatalysts have been successfully synthesized for the first time by a straightforward electrospinning technique with a calcination process. The as-formed Bi2MoxW1-xO6 nanofibers are composed of inter-linked nanosheets of 30–50 nm in size and characterized by thermogravimetric and differential scanning calorimetric, Fourier transform infrared, Raman spectra, X-ray powder diffraction, scanning electron microscope, Brunauer-Emmett-Teller, transmission electron microscope, UV-Vis spectroscopy, photoluminescence, HPLC, and EIS. The photodegradation behaviors towards organic dyes, including rhodamine B (RhB) and methylene blue (MB) are investigated, and the results illustrate that Bi2Mo0.25W0.75O6 nanofibers exhibit the highest photocatalytic performance under visible light irradiation than Bi2MoxW1-xO6 (x = 0, 0.2, 0.5, 0.67, and 1) samples. The possible mechanisms of the enhanced photocatalytic properties are discussed in detail.



http://ift.tt/2sOULJV

Influence of titanium dioxide nanoparticles on cadmium and lead bioaccumulations and toxicities to Daphnia magna

Abstract

Titanium dioxide nanoparticles (TiO2 NPs) have attracted considerable concerns due to the increasing production and widespread applications, while their influences on other co-existing pollutants in real environment are not well studied. In this paper, the colloidal stability of TiO2 NPs in the exposure medium was first evaluated, and then, the medium was modified so that TiO2 NP suspension remained stable over the exposure period. Finally, using the optimized exposure medium, the effects of cadmium (Cd) and lead (Pb) on Daphnia magna both in the absence and presence of TiO2 NPs were investigated. Results showed that 2 mg L−1 of TiO2 NPs was well dispersed in 1:20 diluted Elendt M7 medium without EDTA, and no immobility was observed. The presence of the nanoparticles increased the bioaccumulation and toxicity of Cd to the daphnias. On the contrary, while Pb bioaccumulation was enhanced by three to four times, toxicity of Pb was reduced in the presence of TiO2 NPs. The decreased toxicity of Pb was more likely attributed to the decreased bioavailability of free Pb ion due to adsorption and speciation change of Pb in the presence of TiO2 NPs. Additionally, surface-attached TiO2 NPs combined with adsorbed heavy metals caused adverse effects on daphnia swimming and molting behavior, which is supposed to lead to chronic toxicity.



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Natan Zundel Majerowick, M.D.



http://ift.tt/2tERrhi

Predicting massive transfusion in placenta previa



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Erratum to: Robot-assisted laparoscopic pyeloplasty in the pediatric population: a review of technique, outcomes, complications, and special considerations in infants



http://ift.tt/2sOEzsb

Expression and Characterization of Glucose Oxidase from Aspergillus niger in Yarrowia lipolytica

Abstract

Glucose oxidase (GOX) is currently used in clinical, pharmaceutical, food and chemical industries. The aim of this study was expression and characterization of Aspergillus niger glucose oxidase gene in the yeast Yarrowia lipolytica. For the first time, the GOX gene of A. niger was successfully expressed in Y. lipolytica using a mono-integrative vector containing strong hybrid promoter and secretion signal. The highest total glucose oxidase activity was 370 U/L after 7 days of cultivation. An innovative method was used to cell wall disruption in current study, and it could be recommended to use for efficiently cell wall disruption of Y. lipolytica. Optimum pH and temperature for recombinant GOX activity were 5.5 and 37 °C, respectively. A single band with a molecular weight of 80 kDa similar to the native and pure form of A. niger GOX was observed for the recombinant GOX in SDS-PAGE analysis. Y. lipolytica is a suitable and efficient eukaryotic expression system to production of recombinant GOX in compered with other yeast expression systems and could be used to production of pure form of GOX for industrial applications.



http://ift.tt/2sK7VrZ

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