Πέμπτη, 18 Μαΐου 2017

Burkitt lymphoma as a lead point for jejunojejunal intussusception in a human immunodeficiency virus patient

Abstract

Intussusception is commonly seen in children but is rare in adults and represents only 5% of all intussusceptions causing 1% of intestinal obstructions. More than 50% of these intussusceptions in adults are due to intestinal neoplasms, including malignant lymphoma, e.g., Burkitt lymphoma. These lymphomas are more common in human immunodeficiency virus (HIV)-positive patients than in the general population. We present a case of a young male who was diagnosed with HIV when he developed intestinal obstruction and intussusception secondary to Burkitt lymphoma. He was managed with surgical resection followed by chemotherapy and antiretroviral treatment. HIV patients presenting with acute abdomen pose a diagnostic challenge to clinicians due to a wide range of differential diagnoses including inflammatory, infectious and neoplastic conditions. In a young HIV patient presenting with acute abdomen, intussusception caused by Burkitt lymphoma should be considered in the differential.



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A case of diminished pericardial effusion after treatment of a giant hepatic cyst

Abstract

A 75-year-old woman was discovered to have a pericardial effusion when she was admitted to our hospital because of a giant hepatic cyst. We could not detect the cause of the effusion and diagnosed idiopathic pericardial effusion. The patient underwent transcutaneous drainage of the hepatic cyst and an injection of antibiotics. There was no communication between the pericardial effusion and the hepatic cyst. Although the hepatic cyst was reduced in size, the pericardial effusion showed no remarkable change immediately after treatment; however, 5 months later, the pericardial effusion was found to be diminished. The pericardial effusion might have been caused by the physical pressure of the giant hepatic cyst and disturbance in the balance between the production and reabsorption of the pericardial fluid. When we experience a huge hepatic cyst, we should take into account its influence against the surrounding organs, including the intrapleural space.



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New data about semicircular canal morphology and locomotion in modern hominoids

Abstract

The labyrinth has two functional parts: the cochlea for audition and the vestibular system for equilibrioception. In the latter, the semicircular ducts and the otolithic organs are sensitive to rotational and linear accelerations of the head, respectively. The labyrinthine morphology influences perception accuracy, hence the adaptation to a specific locomotor pattern. The aim of this study is to determine the relationship between locomotion and semicircular canal morphology using geometric morphometrics, and to explain these links with existing functional models. The influence of factors other than functional constraints on labyrinthine morphology is discussed. The left bony labyrinth of 65 specimens was extracted virtually. Five extant hominoid species with various locomotion modes were sampled. A set of 13 landmarks was placed on the semicircular canals. After a Procrustes fit, their coordinates were analyzed using a principal component analysis. It was found that labyrinthine morphology is significantly distinct between species. More specifically, the differences involve a posterolateral projection of the lateral semicircular canal and the rotation of this canal relative to the vertical canals. This rotation occurs in the sagittal plane, which is consistent with previous studies based on traditional morphometrics. Among extant hominoids, the shape of the canals potentially discriminates species based on posture. This result could be used to reconstruct the locomotor pattern of fossil hominoids.



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Additional effects of dietary advanced glycation end products

The excellent review by Smith et al1 makes a convincing case for the contribution of dietary advanced glycation end products (AGEs) to the development of food allergy. There is also additional evidence that AGEs may be involved in asthma. Induced sputum levels of the AGE pentosidine are higher in patients with asthma than in those without asthma, and increase with age at a markedly faster rate in patients with asthma than in controls, such that they are higher in young patients with asthma than in old people without asthma.

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Polyfunctionality of bona fide resident lung CD69+ natural killer cells

We read with great interest the recent article from Marquardt et al1 dedicated to the detailed characterization of human lung natural killer (NK) cells. On the basis of the expression of CD69, they nicely distinguished bona fide resident CD69+ from circulating CD69− CD56dim NK cells in a large cohort of patients undergoing pulmonary lobectomy. They have shown that NK cells in the lung are highly differentiated and predominantly circulating ones, which contrasts with lung CD3+ T cells.

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Reply

We thank Hervier et al1 for providing comments on our article2 characterizing natural killer (NK) cells in the human lung. Based on analysis of CD69 expression, our results suggest that most CD56bright NK cells are tissue-resident, whereas most CD56dim NK cells in the lung circulate.2 Our results also indicate that the total lung NK cell population is largely hypofunctional. Hervier et al1 regret the fact that we studied NK cell functionality only as a whole, that is, regardless of the cells' status as tissue-resident (CD69-expressing) or circulating.

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Reply

We thank Dr Miller for his letter1 in response to our recent Rostrum article in the Journal.2 We agree that there is a strong body of literature linking advanced glycation end products (AGEs) in the diet and diseases such as atherosclerosis, renal failure, cataracts, and forms of dementia such as Parkinson disease and Alzheimer disease.3-5 The focus of our article was to point out that increase in dietary AGEs and sugars (particularly fructose), which leads to the formation of AGEs, appears to have epidemiological associations with the rise of severe food allergy and there are laboratory correlates showing that the activation of the receptor for advanced glycation end products (RAGE) has pivotal roles in allergic inflammation.

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The potential role of infectious agents and pelvic inflammatory disease in ovarian carcinogenesis

The etiological cause of ovarian cancer is poorly understood. It has been theorized that bacterial or viral infection as well as pelvic inflammatory disease could play a role in ovarian carcinogenesis.

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Differences in age-specific HPV prevalence between self-collected and health personnel collected specimen in a cross-sectional study in Ghana

HPV infections are ubiquitous and particularly common among sexually active young women. However, there are regional and national variations in age-specific HPV prevalence, which have implications for cervical...

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Using Participatory Action Research to Develop a Working Model That Enhances Psychiatric Nurses’ Professionalism: The Architecture of Stability

Abstract

Ward rules in psychiatric care aim to promote safety for both patients and staff. Simultaneously, ward rules are associated with increased patient violence, leading to neither a safe work environment nor a safe caring environment. Although ward rules are routinely used, few studies have explicitly accounted for their impact. To describe the process of a team development project considering ward rule issues, and to develop a working model to empower staff in their daily in-patient psychiatric nursing practices. The design of this study is explorative and descriptive. Participatory action research methodology was applied to understand ward rules. Data consists of audio-recorded group discussions, observations and field notes, together creating a data set of 556 text pages. More than 100 specific ward rules were identified. In this process, the word rules was relinquished in favor of adopting the term principles, since rules are inconsistent with a caring ideology. A linguistic transition led to the development of a framework embracing the (1) Principle of Safety, (2) Principle of Structure and (3) Principle of Interplay. The principles were linked to normative guidelines and applied ethical theories: deontology, consequentialism and ethics of care. The work model reminded staff about the principles, empowered their professional decision-making, decreased collegial conflicts because of increased acceptance for individual decisions, and, in general, improved well-being at work. Furthermore, the work model also empowered staff to find support for their decisions based on principles that are grounded in the ethics of totality.



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Erectile dysfunction medicines show no link to melanoma in new analysis

Use of the erectile dysfunction drug Viagra does not cause the development of melanoma, a deadly form of skin cancer. This is the main finding of new research led by investigators at NYU Langone Medical Center and its Perlmutter Cancer Center and...

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Scarlet Fever



A 20-year-old man presented to his primary care physician with a 3-day history of swollen tonsils, sore throat, fevers, chills, and rash. The nonpruritic rash had started on his abdomen, spread to his chest and back, and then appeared on his arms, legs, and face. He had no known allergies or exposures to new medications and had no history of similar rash. Examination revealed exudative tonsillitis (Panel A), strawberry tongue, and cervical adenopathy with tenderness. Skin examination revealed diffuse blanching erythema with punctate papules that caused the skin on his chest, abdomen, back, arms, and legs to have a sandpaper-like quality (Panel B shows the left side of his abdomen). His neck and right flank had linear petechial patches. A rapid test for streptococcal pharyngitis was positive. The finding of acute streptococcal pharyngitis along with the diffuse rash led to a diagnosis of scarlet fever. The rash of scarlet fever is a delayed-type hypersensitivity to an exotoxin and therefore occurs in persons who have had a previous exposure to Streptococcus pyogenes. The rash classically manifests with linear petechial confluences that are known as Pastia's lines, which were seen in this patient. The patient was treated with antibiotic agents and had complete resolution of his symptoms within 3 days.

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

Chemotherapy for Malignant Pleural Mesothelioma: Past, Present and Future

Abstract

Purpose of Review

This paper aims to propose an update on therapeutic medical options for malignant pleural mesothelioma (MPM).

Recent Findings

For 13 years, the standard of care in MPM patients has been cisplatin/pemetrexed chemotherapy. Recently, the Cis/Pem/bevacizumab triplet emerged as a new option for MPM patients eligible for bevacizumab, and not as a candidate for multimodality therapy trials, as validated by the last NCCN and French guidelines. Immunotherapy is also emerging as a promising option on its own or in combination with first-line Cis/Pem, or even as a valuable alternative to chemotherapy, radical surgery, and multimodality strategies.

Summary

Targeted therapies and immunotherapy are new promising treatments in MPM as single agents or in combination with chemotherapy. However, the key challenge remains to find reliable predictive biomarkers for these innovative, exciting, and expensive treatments to select the best patients for each strategy. After years of nihilism and negative trials, numerous therapeutic strategies can now be offered to mesothelioma patients and the future looks brighter.



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Allergic respiratory disease (ARD), setting forth the basics: proposals of an expert consensus report

The variability of symptoms observed in patients with respiratory allergy often hampers classification based on the criteria proposed in guidelines on rhinitis and asthma.

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Chemo-enzymatic synthesis of a glycosylated peptide containing a complex N -glycan based on unprotected oligosaccharides by using DMT-MM and Endo-M

Abstract

For chemo-enzymatic synthesis of a glycosylated peptide, 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM) was used for the synthesis of a N-acetylglucosaminyl peptide and a pseudoglycopeptide by solid-phase peptide synthesis without the requirement of protecting groups on the carbohydrate. We also performed transglycosylation of an N-glycan to the N-acetylglucosaminyl peptide using endo-β-N-acetylglucosaminidase from Mucor hiemalis (Endo-M) to synthesize a glycopeptide containing a complex N-glycan.



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Therapie der akuten lymphatischen Leukämie des Erwachsenen

Zusammenfassung

Hintergrund

Die akute lymphatische Leukämie (ALL) ist die häufigste maligne Erkrankung im Kindesalter und hat an den akuten Leukämien des Erwachsenenalters einen Anteil von etwa 20 %.

Ergebnisse

In den vergangenen Jahrzehnten wurden bezüglich der Charakterisierung der ALL und der Optimierung ihrer Therapie wesentliche Fortschritte erzielt. Es wurden biologische Subgruppen und Risikogruppen mit unterschiedlichem klinischem Verlauf identifiziert. Auf der Zuordnung zu diesen Untergruppen basieren aktuelle, individualisierte risikoadaptierte Therapieprotokolle. Etwa 90% der erwachsenen ALL-Patienten erreichen nun eine komplette Remission, und die Heilungschancen erhöhten sich in den vergangenen 30 Jahren von unter 10 % auf über 50 %.

Schlussfolgerungen

Wesentlich für die Verbesserung der Therapieergebnisse waren eine Optimierung der Chemotherapie und Supportivbehandlung, die Integration der Stammzelltransplantation in die Erstlinienbehandlung, individualisierte Therapiemodifikationen unter Berücksichtigung der minimalen Resterkrankung und zielgerichtete Therapien wie der Einsatz von Tyrosinkinaseinhibitoren bei der Ph/BCR-ABL-positiven ALL (Ph: Philadelphia-Chromosom, BCR: „breakpoint cluster region", ABL: „Abelson murine leukemia viral oncogene homolog 1").



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Acoustic Perturbation Measures Improve with Increasing Vocal Intensity in Individuals With and Without Voice Disorders

In vocally healthy children and adults, speaking voice loudness differences can significantly confound acoustic perturbation measurements. This study examines the effects of voice sound pressure level (SPL) on jitter, shimmer, and harmonics-to-noise ratio (HNR) in adults with voice disorders and a control group with normal vocal status.

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Inspiratory Phonation in Baby Voice

This study aimed to evaluate the developmental occurrence of inspiratory phonations (IPs) in the spontaneous cries of healthy infants across the first 10 weeks of life.

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Keeping the Voice Fit in the Group Fitness Industry: A Qualitative Study to Determine What Instructors Want in a Voice Education Program

This study aimed to provide a descriptive summary of (1) group fitness instructors' (GFIs') experiences of occupational voice use and education, and (2) the content and mode of delivery desired by GFIs in an education and training program.

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Resonance Tube Phonation in Water—the Effect of Tube Diameter and Water Depth on Back Pressure and Bubble Characteristics at Different Airflows

Resonance tube phonation with tube end in water is a voice therapy method in which the patient phonates through a glass tube, keeping the free end of the tube submerged in water, creating bubbles. The purpose of this experimental study was to determine flow-pressure relationship, flow thresholds between bubble types, and bubble frequency as a function of flow and back volume.

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Changes in clinical laboratory parameters and pharmacodynamic markers in response to blinatumomab treatment of patients with relapsed/refractory ALL

Abstract

Background

Blinatumomab has shown a remission rate of 69% in an exploratory single-arm, phase II dose-escalation study in adult patients with relapsed/refractory B-precursor acute lymphoblastic leukemia (ALL). We evaluated changes in laboratory parameters and immunopharmacodynamic markers in patients who received blinatumomab in the exploratory phase II study.

Methods

Data from 36 adults with relapsed/refractory ALL receiving blinatumomab as 4-week continuous IV infusions in various dose cohorts were analyzed for changes in liver enzymes, first-dose parameters, peripheral blood cell subpopulations, and cytokine/granzyme B release. Associations with clinical response were evaluated.

Results

Liver enzymes and inflammatory parameters transiently increased primarily during the first treatment week without clinical symptoms and reversed to baseline levels thereafter. B and T cells showed expected depletion and redistribution kinetics, respectively. Similarly, thrombocytes and T cells displayed an initial decline in cell counts, whereas neutrophils peaked during the first days after infusion start. T-cell redistribution coincided with upregulation of LFA-1 and CD69. Patients who responded to blinatumomab had more pronounced T-cell expansion, which was associated with proliferation of CD4+ and CD8+ T cells and memory subsets. Release of cytokines and granzyme B primarily occurred during the first week of cycle 1, except for IL-10, which was released in subsequent cycles. Blinatumomab step-dosing was associated with lower cytokine release and lower body temperature.

Conclusions

In this study of relapsed/refractory ALL, blinatumomab-induced changes in laboratory parameters were transient and reversible. The evaluated PD markers demonstrated blinatumomab activity, and the analysis of cytokines supported the rationale for stepwise dosing.

(ClinicalTrials.gov Identifier NCT01209286.)



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Lysyl oxidase overexpression accelerates cardiac remodeling and aggravates angiotensin II-induced hypertrophy [Research]

Lysyl oxidase (LOX) controls matrix remodeling, a key process that underlies cardiovascular diseases and heart failure; however, a lack of suitable animal models has limited our knowledge with regard to the contribution of LOX to cardiac dysfunction. Here, we assessed the impact of LOX overexpression on ventricular function and cardiac hypertrophy in a transgenic mouse model with a strong cardiac expression of human LOX (TgLOX). TgLOX mice exhibited high expression of the transgene in cardiomyocytes and cardiofibroblasts, which are associated with enhanced LOX activity and H2O2 production and with cardiofibroblast reprogramming. LOX overexpression promoted an age-associated concentric remodeling of the left ventricle and impaired diastolic function. Furthermore, LOX transgenesis aggravated angiotensin II (Ang II)–induced cardiac hypertrophy and dysfunction, which triggered a greater fibrotic response that was characterized by stronger collagen deposition and cross-linking and high expression of fibrotic markers. In addition, LOX transgenesis increased the Ang II–induced myocardial inflammatory infiltrate, exacerbated expression of proinflammatory markers, and decreased that of cardioprotective factors. Mechanistically, LOX overexpression enhanced oxidative stress and potentiated the Ang II–mediated cardiac activation of p38 MAPK while reducing AMPK activation. Our findings suggest that LOX induces an age-dependent disturbance of diastolic function and aggravates Ang II–induced hypertrophy, which provides novel insights into the role of LOX in cardiac performance.—Galán, M., Varona, S., Guadall, A., Orriols, M., Navas, M., Aguiló, S., de Diego, A., Navarro, M. A., García-Dorado, D., Rodríguez-Sinovas, A., Martínez-González, J., Rodriguez, C. Lysyl oxidase overexpression accelerates cardiac remodeling and aggravates angiotensin II–induced hypertrophy.



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Human salivary peptide histatin-1 stimulates epithelial and endothelial cell adhesion and barrier function [Research]

Histatins are multifunctional histidine-rich peptides secreted by the salivary glands and exclusively present in the saliva of higher primates, where they play a fundamental role in the protection of the oral cavity. Our previously published results demonstrated that histatin-1 (Hst1) promotes cell–substrate adhesion in various cell types and hinted that it could also be involved in cell–cell adhesion, a process of fundamental importance to epithelial and endothelial barriers. Here we explore the effects of Hst1 on cellular barrier function. We show that Hst1 improved endothelial barrier integrity, decreased its permeability for large molecules, and prevented translocation of bacteria across epithelial cell layers. These effects are mediated by the adherens junction protein E-cadherin (E-cad) and by the tight junction protein zonula occludens 1, as Hst1 increases the levels of zonula occludens 1 and of active E-cad. Hst1 may also promote epithelial differentiation as Hst1 induced transcription of the epithelial cell differentiation marker apolipoprotein A-IV (a downstream E-cad target). In addition, Hst1 counteracted the effects of epithelial–mesenchymal transition inducers on the outgrowth of oral cancer cell spheroids, suggesting that Hst1 affects processes that are implicated in cancer progression.—Van Dijk, I. A., Ferrando, M. L., van der Wijk, A.-E., Hoebe, R. A., Nazmi, K., de Jonge, W. J., Krawczyk, P. M., Bolscher, J. G. M., Veerman, E. C. I., Stap, J. Human salivary peptide histatin-1 stimulates epithelial and endothelial cell adhesion and barrier function.



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Sphingomyelin synthase 2 deficiency inhibits the induction of murine colitis-associated colon cancer [Research]

Sphingomyelin synthase 2 (SMS2) is the synthetic enzyme of sphingomyelin (SM), which regulates membrane fluidity and microdomain structure. SMS2 plays a role in LPS-induced lung injury and inflammation; however, its role in inflammation-mediated tumorigenesis is unclear. We investigated the effect of SMS2 deficiency on dextran sodium sulfate (DSS)–induced murine colitis and found inhibition of DSS-induced inflammation in SMS2-deficient (SMS2–/–) mice. DSS treatment induced a significant increase in ceramide levels, with a decrease of SM levels in SMS2–/– colon tissue, and demonstrated attenuation of the elevation of both inflammation-related gene expression and proinflammatory cytokines and chemokines, leukocyte infiltration, and MAPK and signal transducer and activator of transcription 3 activation. After undergoing transplantation of wild-type bone marrow, SMS2–/– mice also exhibited inhibition of DSS-induced inflammation in the colon, which suggested that SMS2 deficiency in bone marrow–derived immune cells was not involved in the inhibition of colitis. Finally, in an azoxymethane/DSS-induced cancer model, SMS2 deficiency significantly decreased tumor incidence in the colon. Our results demonstrate that SMS2 deficiency inhibits DSS-induced colitis and subsequent colitis-associated colon cancer via inhibition of colon epithelial cell–mediated inflammation; therefore, inhibition of SMS2 may be a potential therapeutic target for human colitis and colorectal cancer.—Ohnishi, T., Hashizume, C., Taniguchi, M., Furumoto, H., Han, J., Gao, R., Kinami, S., Kosaka, T., Okazaki, T. Sphingomyelin synthase 2 deficiency inhibits the induction of murine colitis-associated colon cancer.



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Small GTPase Rab1B is associated with ATG9A vesicles and regulates autophagosome formation [Research]

ATG9 is a membrane protein that is essential for autophagy and is considered to be directly involved in the early steps of autophagosome formation. Yeast Atg9 is mainly localized to small vesicles (Atg9 vesicles), whereas mammalian ATG9A is reportedly localized to the trans-Golgi network, the endosomal compartment, and other unidentified membrane structures. To dissect the ATG9A-containing membranes, we examined the subcellular localization of ATG9A and performed immunoisolation of those membranes. ATG9A-green fluorescent protein in human culture cells was observed as numerous puncta that move rapidly throughout the cytoplasm. We isolated these cytoplasmic membranes and found that they were small vesicles that resemble the yeast Atg9 vesicle. One of the proteins obtained via proteomic analyses of the mammalian ATG9A vesicle was Rab1, a small GTPase that is essential in endoplasmic reticulum-to-Golgi vesicle trafficking. Knockdown studies of Rab1B showed a suppression of autophagy. In these Rab1B-depleted cells, ATG9A accumulated in intermediate membrane structures at autophagosome formation sites. These results indicate that Rab1B is involved in regulating the proper development of autophagosomes.—Kakuta, S., Yamaguchi, J., Suzuki, C., Sasaki, M., Kazuno, S., Uchiyama, Y. Small GTPase Rab1B is associated with ATG9A vesicles and regulates autophagosome formation.



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Know thy enemy: The markets frustrate OPEC’s efforts to push up oil prices

20170520_FNC727.png

Print section Print Rubric:  OPEC is fighting not just shale producers but the futures market—and losing Print Headline:  Know thy enemy Print Fly Title:  OPEC policy UK Only Article:  standard article Issue:  Why Israel needs a Palestinian state Fly Title:  Know thy enemy Main image:  20170520_FNP001_0.jpg BORROWING three words from Mario Draghi, the central banker who helped save the euro zone, Khalid al-Falih, Saudi Arabia’s energy minister, and his Russian counterpart, Alexander Novak, on May 15th promised to do “whatever it takes” to curb the glut in the global oil markets. Ahead of a May 25th meeting of OPEC, the oil producers’ cartel, they promised to extend cuts agreed last year by nine months, to March 2018, pushing oil prices up sharply, to around $50 a barrel. But to make the rally last, a more apt three-word phrase might be: “know thy enemy”. In two ...

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Breast cancer and exposure to tobacco smoke during potential windows of susceptibility

Abstract

Purpose

An association between smoking and breast cancer is unresolved, although a higher risk from exposure during windows of susceptibility has been proposed. The objective of this prospective study was to evaluate the association between tobacco smoke and breast cancer with a focus on timing of exposure, especially during early life.

Methods

Sister study participants (n = 50,884) aged 35–74 were enrolled from 2003 to 2009. Women in the United States and Puerto Rico were eligible if they were breast cancer-free but had a sister with breast cancer. Participants completed questionnaires on smoking and environmental tobacco smoke (ETS) exposure. Cox regression was used to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (95% CIs) for breast cancer risk.

Results

During follow-up (mean = 6.4 years), 1,843 invasive breast cancers were diagnosed. Neither active smoking nor adult ETS was associated with breast cancer risk. However, never smoking women exposed to ETS throughout their childhood had a 17% higher risk of breast cancer (95% CI 1.00–1.36) relative to those with no exposure. In utero ETS exposure was also associated with breast cancer (HR = 1.16, 95% CI 1.01–1.32) and the HR was most elevated for women born in earlier birth cohorts (<1940, HR = 1.44, 95% CI 1.02–2.02; 1940–1949, HR = 1.28, 95% CI 1.01–1.62).

Conclusion

In utero ETS and ETS exposure during childhood and adolescence were associated with increased risk of breast cancer and associations varied by birth cohort.



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Body Size of Male Youth Soccer Players: 1978–2015

Abstract

Background

Studies of the body size and proportions of athletes have a long history. Comparisons of athletes within specific sports across time, though not extensive, indicate both positive and negative trends.

Objective

To evaluate secular variation in heights and weights of male youth soccer players reported in studies between 1978 and 2015.

Methods

Reported mean ages, heights, and weights of male soccer players 9–18 years of age were extracted from the literature and grouped into two intervals: 1978–99 and 2000–15. A third-order polynomial was fitted to the mean heights and weights across the age range for each interval, while the Preece–Baines model 1 was fitted to the grand means of mean heights and mean weights within each chronological year to estimate ages at peak height velocity and peak weight velocity for each time interval.

Results

Third-order polynomials applied to all data points and estimates based on the Preece–Baines model applied to grand means for each age group provided similar fits. Both indicated secular changes in body size between the two intervals. Secular increases in height and weight between 1978–99 and 2000–15 were especially apparent between 13 and 16 years of age, but estimated ages at peak height velocity (13.01 and 12.91 years) and peak weight velocity (13.86 and 13.77 years) did not differ between the time intervals.

Conclusion

Although the body size of youth soccer players increased between 1978–99 and 2000–15, estimated ages at peak height velocity and peak weight velocity did not change. The increase in height and weight likely reflected improved health and nutritional conditions, in addition to the selectivity of soccer reflected in systematic selection and retention of players advanced in maturity status, and exclusion of late maturing players beginning at about 12–13 years of age. Enhanced training programs aimed at the development of strength and power are probably an additional factor contributing to secular increases in body weight.



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Cyclin D1 restrains oncogene-induced autophagy by regulating the AMPK-LKB1 signaling axis

Autophagy activated after DNA damage or other stresses mitigates cellular damage by removing damaged proteins, lipids and organelles. Activation of the master metabolic kinase AMPK enhances autophagy. Here we report that cyclin D1 restrains autophagy by modulating the activation of AMPK. In cell models of human breast cancer or in a cyclinD1-deficient model, we observed a cyclin D1-mediated reduction in AMPK activation. Mechanistic investigations showed that Cyclin D1 inhibited mitochondrial function, promoted glycolysis and reduced activation of AMPK (pT172), possibly through a mechanism that involves cyclin D1-Cdk4/Cdk6 phosphorylation of LKB1. Our findings suggest how AMPK activation by cyclin D1 may couple cell proliferation to energy homeostasis.

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MET exon 14 mutation encodes an actionable therapeutic target in lung adenocarcinoma

Targeting somatically activated oncogenes has revolutionized the treatment of non-small cell lung cancer (NSCLC). Mutations in the gene mesenchymal-epithelial transition (MET) near the exon 14 splice sites are recurrent in lung adenocarcinoma and cause exon skipping (METΔ14). Here we analyzed 4,422 samples from 12 different malignancies to estimate the rate of said exon skipping. METΔ14 mutation and transcript were most common in lung adenocarcinoma. Endogenously expressed levels of METΔ14 transformed human epithelial lung cells in a Hepatocyte growth factor (HGF)-dependent manner. Additionally, overexpression of the orthologous mouse allele induced lung adenocarcinoma in a novel, immunocompetent mouse model. Met inhibition showed clinical benefit in this model. Additionally, we observed a clinical response to crizotinib in a patient with METΔ14-driven NSCLC, only to observe new missense mutations in the MET activation loop, critical for binding to crizotinib, upon clinical progression. These findings support genomically selected clinical trials directed towards METΔ14 in a fraction of NSCLC patients, confirm second-site mutations for further therapeutic targeting prior to and beyond acquired resistance, and provide an in vivo system for the study of METΔ14 in an immunocompetent host.

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Mismatch Repair Proteins Initiate Epigenetic Alterations During Inflammation-Driven Tumorigenesis

Aberrant silencing of genes by DNA methylation contributes to cancer, yet how this process is initiated remains unclear. Using a murine model of inflammation-induced tumorigenesis, we tested the hypothesis that inflammation promotes recruitment of epigenetic proteins to chromatin, initiating methylation and gene silencing in tumors. Compared to normal epithelium and non-inflammation-induced tumors, inflammation-induced tumors gained DNA methylation at CpG islands, some of which are associated with putative tumor suppressor genes. Hypermethylated genes exhibited enrichment of repressive chromatin marks and reduced expression prior to tumorigenesis, at a time point coinciding with peak levels of inflammation-associated DNA damage. Loss of MutS homolog 2 (MSH2), a mismatch repair (MMR) protein, abrogated early inflammation-induced epigenetic alterations and DNA hypermethylation alterations observed in inflammation-induced tumors. These results indicate that early epigenetic alterations initiated by inflammation and MMR proteins lead to gene silencing during tumorigenesis, revealing a novel mechanism of epigenetic alterations in inflammation-driven cancer. Understanding such mechanisms will inform development of pharmacotherapies to reduce carcinogenesis.

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Targeting FBW7 as a strategy to overcome resistance to targeted therapy in non-small cell lung cancer

Inhibition of epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) signaling is highly effective in a subgroup of non-small cell lung cancer (NSCLC) patients with distinct clinicopathological features. However, resistance to EGFR and ALK inhibitors inevitably occurs, and the molecular mechanism underlying resistance is not fully understood. In this study, we report a PI3K/Akt- and MEK/Erk-independent resistance mechanism by which loss of the E3 ubiquitin ligase F-box and WD repeat domain containing 7 (FBW7α) leads to targeted therapy resistance via stabilization of anti-apoptotic protein MCL-1. Using a panel of in vitro and in vivo studies, we showed that the regulatory machinery responsible for MCL-1 protein degradation was a step-wise event involving phosphorylation and nucleus translocation. Erk cooperated with GSKβ to phosphorylate MCL-1 Ser159 residue, which enabled MCL-1 to translocate into the nucleus and bind FBW7. Defects in this sequence impaired MCL-1 degradation and cell apoptosis, recapitulating phenotypes observed in FBW7 deficiency. Downregulation of FBW7 was found in EGFR inhibitor-resistant human NSCLC specimens and correlated with increased MCL-1 protein expression. Reactivation of FBW7 sensitized resistant cells to targeted therapy and facilitated MCL-1 degradation. Overall, our study provides proof-of-principle insight into a PI3K/Akt- and MEK/Erk-independent resistant model and suggests that targeting FBW7 can overcome resistance to targeted therapy.

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Inhibition of mitochondrial matrix chaperones and anti-apoptotic Bcl-2 family proteins empower antitumor therapeutic responses

Rational therapeutic approaches based on synthetic lethality may improve cancer management. Based on a high-throughput drug screen, we provide preclinical proof of concept that targeting the mitochondrial Hsp90 chaperone network (mtHsp90) and inhibition of Bcl-2, Bcl-xL and Mcl-1 is sufficient to elicit synthetic lethality in tumors recalcitrant to therapy. Our analyses focused on BH3 mimetics that are broad acting (ABT263 and Obatoclax) or selective (ABT199, WEHI-539 and A1210477), along with the established mitochondrial matrix chaperone inhibitor Gamitrinib-TPP. Drug combinations were tested in various therapy-resistant tumors in vitro and in vivo in murine model systems of melanoma, triple-negative breast cancer and patient-derived orthotopic xenografts of human glioblastoma (PDX). We found that combining BH3-mimetics and Gamitrinib-TPP blunted cellular proliferation in a synergistic manner by massive activation of intrinsic apoptosis. In like manner, suppressing either Bcl-2, Bcl-xL or Mcl-1 recapitulated the effects of BH3-mimetics and enhanced the effects of Gamitrinib-TPP. Mechanistic investigations revealed that Gamitrinib-TPP activated a PERK-dependent integrated stress response which activated the pro-apoptotic BH3 protein Noxa and its downstream targets Usp9X and Mcl-1. Notably, in the PDX glioblastoma and BRAFi-resistant melanoma models, this drug combination safely and significantly extended host survival. Our results show how combining mitochondrial chaperone and Bcl-2 family inhibitors can synergize to safely degrade the growth of tumors recalcitrant to other treatments.

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Expansion of tumor-infiltrating CD8+ T cells expressing PD-1 improves the efficacy of adoptive T cell therapy

Recent studies have found that tumor-infiltrating lymphocytes (TIL) expressing PD-1 can recognize autologous tumor cells, suggesting that cells derived from PD-1+ TIL can be used in adoptive T cell therapy (ACT). However, no study thus far has evaluated the antitumor activity of PD-1-selected TIL in vivo. In two mouse models of solid tumors, we show that PD-1 allows identification and isolation of tumor-specific TIL without previous knowledge of their antigen specificities. Importantly, despite the high proportion of tumor-reactive T cells present in bulk CD8 TIL before expansion, only T cell products derived from sorted PD-1+, but not from PD-1- or bulk CD8 TIL, specifically recognized tumor cells. The fold-expansion of PD-1+ CD8 TIL was 10 times lower than that of PD-1- cells, suggesting that outgrowth of PD-1- cells was the limiting factor in the tumor specificity of cells derived from bulk CD8 TIL. The highly differentiated state of PD-1+ cells was likely the main cause hampering ex vivo expansion of this subset. Moreover, PD-1 precisely identified marrow-infiltrating, myeloma-specific T cells in a mouse model of multiple myeloma. In vivo, only cells expanded from PD-1+ CD8 TIL contained tumor progression, and their efficacy was enhanced by PDL-1 blockade. Overall, our data provide a rationale for the use of PD-1-selected TIL in ACT.

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Ivermectin lipid-based nanocarriers as novel formulations against head lice

Abstract

The use of pyrethroids to control the human head louse, Pediculus humanus capitis De Geer (Anoplura: Pediculidae), has suffered considerable loss of efficacy due to the evolution of resistance. Thus, the development of efficiently insecticide delivery systems is imperative for the control of head lice. We studied the insecticidal activity of ivermectin-loaded lipid nanocapsules (IVM-LNC) against permethrin-resistant head lice from Argentina. The LNC, prepared by a phase inversion procedure, were characterized in terms of size, surface potential, and physical stability. These nanoparticles were nearly spherical with mean diameters of 55 nm and narrow size distribution (PI ≤ 0.2). The KT50 mortality values of head lice after exposure to two IVM-LNC formulations (0.11 and 0.28%) were significantly smaller (5 and 3 h, respectively) compared to those exposed only to LNC control group (8 h). This investigation showed the effectiveness in the encapsulation of ivermectin (IVM) into stable LNC dispersion with a potential clinical activity against head lice.



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Occurrence of Ornithonyssus sylviarum in pet birds from the district of Setúbal, Portugal

Abstract

Ornithonyssus sylviarum is a blood-feeding ectoparasite of birds and the most serious pest in poultry farms in North America. Although the mites are typically adapted to temperate climates, information on this mite in Europe is sparse, and Dermanyssus gallinae is considered to be the only mite impacting the poultry industry. The present study reports the occurrence of O. sylviarum in pet birds in Portugal. Mites were collected directly from birds and with traps placed in cages and nests at 20 different sampling places belonging to 6 municipalities in the district of Setúbal. In a total of 217 birds, O. sylviarum was identified in 47 out of 147 (32.0%) canaries (Serinus canaria), 14 out of 21 (14.3%) estrildid finches, 1 out of 24 (4.2%) budgerigars (Melopsittacus undulatus) and 1 out of 15 (6.7%) lovebirds (Agapornis spp.). Mites of the genus Dermanyssus were identified in 8 canaries (5.4%), 8 estrildid finches (38.1%) and 1 lovebird (6.7%). No mites were found in 6 cockatiels (Nymphicus hollandicus), 2 African grey parrots (Psittacus erithacus), 1 Bourke's parrot (Neophema bourkii) and 1 rose-ringed parakeet (Psittacula krameri). Considering the zoonotic potential and the risk of dissemination to poultry, the present findings underline the need for further monitoring of O. sylviarum in the wild and domestic avifauna in Portugal.



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Structural analysis of the dual function thioesterase SAV606 unravels the mechanism of Michael addition of glycine to an {alpha},{beta}-unsaturated thioester [Protein Structure and Folding]

Thioesterases catalyze hydrolysis of acyl thioesters to release carboxylic acid or macrocyclization to produce the corresponding macrocycle in the biosynthesis of fatty acids, polyketides, or nonribosomal peptides. Recently, we reported that the thioesterase CmiS1 from Streptomyces sp. MJ635-86F5 catalyzes the Michael addition of glycine to an α,β-unsaturated fatty acyl thioester followed by thioester hydrolysis in the biosynthesis of the macrolactam antibiotic cremimycin. However, the molecular mechanisms of CmiS1-catalyzed reactions are unclear. Here, we report on the functional and structural characterization of the CmiS1 homolog SAV606 from Streptomyces avermitilis MA-4680. In vitro analysis indicated that SAV606 catalyzes the Michael addition of glycine to crotonic acid thioester and subsequent hydrolysis yielding (R)-N-carboxymethyl-3-aminobutyric acid. We also determined the crystal structures of SAV606 both in ligand-free form at 2.4 Å resolution and in complex with (R)-N-carboxymethyl-3-aminobutyric acid at 2.0 Å resolution. We found that SAV606 adopts an α/β hotdog fold and has an active site at the dimeric interface. Examining the complexed structure, we noted that the substrate-binding loop comprising Tyr53-Asn61 recognizes the glycine moiety of (R)-N-carboxymethyl-3-aminobutyric acid. Moreover, we found that SAV606 does not contain an acidic residue at the active site, which is distinct from canonical hotdog thioesterases. Site-directed mutagenesis experiments revealed that His59 plays a crucial role in both the Michael addition and hydrolysis via a water molecule. These results allow us to propose the reaction mechanism of the SAV606-catalyzed Michael addition and thioester hydrolysis and provide new insight into the multiple functions of a thioesterase family enzyme.

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Structure-function analysis of human sucrase-isomaltase identifies key residues required for catalytic activity [Enzymology]

Sucrase-isomaltase (SI) is an intestinal membrane-associated α-glucosidase that breaks down di- and oligosaccharides to absorbable monosaccharides. SI has two homologous functional subunits (sucrase and isomaltase) that both belong to the glycoside hydrolase family 31 (GH31) and differ in substrate specificity. All GH31 enzymes share a consensus sequence harboring an aspartic acid residue as a catalytic nucleophile. Moreover, crystallographic structural analysis of isomaltase predicts that another aspartic acid residue functions as a proton donor in hydrolysis. Here, we mutagenized the predicted proton donor residues and the nucleophilic catalyst residues in each SI subunit. We expressed these SI variants in COS-1 cells and analyzed their structural, transport, and functional characteristics. All of the mutants revealed expression levels and maturation rates comparable to those of the wild type species and the corresponding non-mutated subunits were functionally active. Thereby we determined rate and substrate specificity for each single subunit without influence from the other subunit. This approach provides a model for functional analysis of the single subunits within a multi-domain protein, achieved without the necessity to express the individual subunits separately. Of note, we also found that glucose product inhibition regulates the activities of both SI subunits. We experimentally confirmed the catalytic function of the predicted proton donor residues, and sequence analysis suggested that these residues are located in a consensus region in many GH31 family members. In summary, these findings reveal the kinetic features specific for each human SI subunit and demonstrate that the activities of these subunits are regulated via product inhibition.

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Coagulation factor VIIa-mediated protease-activated receptor 2 activation leads to {beta}-catenin accumulation via the AKT/GSK3{beta} pathway and contributes to breast cancer progression [Cell Biology]

Cell migration and invasion are very characteristic features of cancer cells that promote metastasis, which is one of the most vulnerable causes of mortality among cancer patients. Emerging evidence has shown that coagulation factors can directly mediate cancer associated complications either by enhancing thrombus formation or by initiating various signaling events leading to metastatic cancer progression. It is well-established that apart from its distinct role in blood coagulation, coagulation factor FVIIa enhances aggressive behaviors of breast cancer cells, but the underlying signaling mechanisms still remain elusive. To this end we investigated FVIIa's role in the migration and invasiveness of the breast cancer cell line MDA-MB-231. Consistent with previous observations, we observed that FVIIa increased the migratory and invasive potential of these cells. We also provide molecular evidence that protease-activated receptor 2 (PAR2) activation, followed by PI3K-AKT activation and GSK3-β inactivation is involved in these processes and that β-catenin a well known tumor regulatory protein, contribute to this signaling pathway. The pivotal role of β-catenin was further indicated by the upregulation of its downstream targets Cyclin D1, c-Myc, COX-2, MMP-7, MMP-14 and Claudin-1. β-catenin knock-down almost completely attenuated the FVIIa-induced enhancement of breast cancer migration and invasion. These findings provide a new perspective to counteract the invasive behavior of breast cancer, indicating that blocking PI3K-AKT pathway-dependent β-catenin accumulation may represent a potential therapeutic approach to control breast cancer.

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Altered learning, memory and social behavior in type 1 taste receptor subunit 3 knockout mice is associated with neuronal dysfunction [Metabolism]

The type 1 taste receptor member 3 (T1R3) is a G protein-coupled receptor (GPCR) involved in sweet taste perception. Besides the tongue, the T1R3 receptor is highly expressed in brain areas implicated in cognition, including the hippocampus and cortex. As cognitive decline is often preceded by significant metabolic or endocrinological dysfunctions, regulated by the sweet taste perception system, we hypothesized that a disruption of the sweet taste perception in the brain could have a key role in the development of cognitive dysfunction. To assess the importance of the sweet taste receptors in the brain, we conducted transcriptomic and proteomic analyses of cortical and hippocampal tissues isolated from T1R3 knockout (T1R3KO) mice. The effect of an impaired sweet taste perception system on cognition functions were examined by analyzing synaptic integrity and performing animal behavior on T1R3KO mice. While T1R3 knockout (T1R3KO) mice did not present a metabolically-disrupted phenotype, bioinformatic interpretation of the high-dimensionality data indicated a strong neurodegenerative signature associated with significant alterations in pathways involved in neuritogenesis, dendritic growth and synaptogenesis. Furthermore, a significantly reduced dendritic spine density was observed in T1R3KO mice together with alterations in learning and memory functions as well as sociability deficits. Taken together our data suggest that the sweet taste receptor system plays an important neurotrophic role in extra-lingual central nervous tissue which underpins synaptic function, memory acquisition and social behavior.

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NleB/SseK effectors from Citrobacter rodentium, Escherichia coli, and Salmonella enterica display distinct differences in host substrate specificity [Signal Transduction]

Many Gram-negative bacterial pathogens use a syringe-like apparatus called a type III secretion system to inject virulence factors into host cells. Some of these effectors are enzymes that modify host proteins to subvert their normal functions. NleB is a glycosyltransferase that modifies host proteins with N-acetyl-D-glucosamine to inhibit antibacterial and inflammatory host responses. NleB is conserved among the attaching/effacing pathogens enterohemorrhagic E. coli (EHEC), enteropathogenic E. coli (EPEC), and Citrobacter rodentium. Moreover, Salmonella enterica strains encode up to three NleB orthologs named SseK1, SseK2, and SseK3. However, there are conflicting reports regarding the activities and host protein targets among the NleB/SseK orthologs. Therefore, here we performed in vitro glycosylation assays and cell culture experiments to compare the activities and substrate specificities of these effectors. SseK1, SseK3, EHEC NleB1, EPEC NleB1, and C. rodentium NleB blocked TNF-mediated NF-κB pathway activation, whereas SseK2 and NleB2 did not. C. rodentium NleB, EHEC NleB1, and SseK1 glycosylated host glyceraldehyde 3-phosphate dehydrogenase (GAPDH). C. rodentium NleB, EHEC NleB1, EPEC NleB1, and SseK2 glycosylated the Fas-associated death domain protein (FADD). SseK3 and NleB2 were not active against either substrate. We also found that EHEC NleB1 glycosylated two GAPDH arginine residues, R197 and R200 and that these two residues were essential for GAPDH-mediated activation of tumor necrosis factor (TNF) Receptor-Associated Factor 2 (TRAF2) ubiquitination. These results provide evidence that members of this highly conserved family of bacterial virulence effectors target different host protein substrates and exhibit distinct cellular modes of action to suppress host responses.

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Role of Sod Gene in Response to Static Magnetic Fields in Pseudomonas aeruginosa

Abstract

The protective role of superoxide dismutase (SOD) against non-ionizing radiation such as static electromagnetic field (200 mT) has been studied in wild-type and mutant strain of Pseudomonas aeruginosa lacking cytosolic Mn-SOD (sodM), Fe-SOD (sodB), or both SODs (sodMB). Our results showed that inactivation of sodM and/or sodB genes increases the sensitivity of P. aeruginosa toward stress induced by the static magnetic field (200 mT). Furthermore, our results showed an enhancement of SOD, catalase, and peroxidases after exposure to the magnetic field. However, wild-type cells maintained significantly higher activities of antioxidant enzymes than mutant strains. The malondialdehyde produced by the oxidative degradation of unsaturated lipids and fatty acids showed significant increase in mutant strains compared to the wild-type. The overall results showed that the SOD has a protective role against a stress induced by static electromagnetic field in P. aeruginosa.



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Enhanced tumor therapy via drug co-delivery and in situ vascular-promoting strategy

Publication date: 28 July 2017
Source:Journal of Controlled Release, Volume 258
Author(s): Mingxing Yin, Songwei Tan, Yuling Bao, Zhiping Zhang
Conventional tumor starving therapy by reducing its vessel density may be effective at early treatment but potentially contributes to tumor hypoxia, drug resistance and metastasis. A new strategy through enhancing tumor angiogenesis in combination with effective chemotherapeutic drugs, has shown successful tumor growth and spread inhibition. To achieve in situ release of angiogenic and antitumor drugs in tumor, we designed a precise ratiometric polymeric hybrid micelle system for co-delivering nitric oxide and paclitaxel. The hybrid micelles could accumulate in tumor via the long blood circulation and enhanced permeability and retention (EPR) effect, promote the drug accumulation and penetration in tumor by in situ increased vascular permeability, blood perfusion and vessel density, achieve the synergistic antitumor effect of nitric oxide and paclitaxel through modified tumor microenvironment, overcome multidrug resistance and inhibit metastasis. This study presents a combinational therapy against tumor progression and spread, which shows great potential in cancer therapy of the future.

Graphical abstract

image


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Statin use, candidate mevalonate pathway biomarkers, and colon cancer survival in a population-based cohort study

Statin use, candidate mevalonate pathway biomarkers, and colon cancer survival in a population-based cohort study

British Journal of Cancer advance online publication, May 18 2017. doi:10.1038/bjc.2017.139

Authors: Ronan T Gray, Maurice B Loughrey, Peter Bankhead, Chris R Cardwell, Stephen McQuaid, Roisin F O'Neill, Kenneth Arthur, Victoria Bingham, Claire McGready, Anna T Gavin, Jacqueline A James, Peter W Hamilton, Manuel Salto-Tellez, Liam J Murray & Helen G Coleman



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Efficacy of anti-PD-1 therapy in patients with melanoma brain metastases

Efficacy of anti-PD-1 therapy in patients with melanoma brain metastases

British Journal of Cancer advance online publication, May 18 2017. doi:10.1038/bjc.2017.142

Authors: Sagun Parakh, John J Park, Shehara Mendis, Rajat Rai, Wen Xu, Serigne Lo, Martin Drummond, Catherine Rowe, Annie Wong, Grant McArthur, Andrew Haydon, Miles C Andrews, Jonathan Cebon, Alex Guminski, Richard F Kefford, Georgina V Long, Alexander M Menzies, Oliver Klein & Matteo S Carlino



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Hallmarks of response to immune checkpoint blockade

Hallmarks of response to immune checkpoint blockade

British Journal of Cancer advance online publication, May 18 2017. doi:10.1038/bjc.2017.136

Authors: Alexandria P Cogdill, Miles C Andrews & Jennifer A Wargo



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Stroma-regulated HMGA2 is an independent prognostic marker in PDAC and AAC

Stroma-regulated HMGA2 is an independent prognostic marker in PDAC and AAC

British Journal of Cancer advance online publication, May 18 2017. doi:10.1038/bjc.2017.140

Authors: Carina Strell, Karin Jessica Norberg, Artur Mezheyeuski, Jonas Schnittert, Praneeth R Kuninty, Carlos Fernández Moro, Janna Paulsson, Nicolai Aagaard Schultz, Dan Calatayud, Johannes Matthias Löhr, Oliver Frings, Caroline Sophie Verbeke, Rainer Lothar Heuchel, Jai Prakash, Julia Sidenius Johansen & Arne Östman



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Frozen shoulder and risk of cancer: a population-based cohort study

Frozen shoulder and risk of cancer: a population-based cohort study

British Journal of Cancer advance online publication, May 18 2017. doi:10.1038/bjc.2017.146

Authors: Alma B Pedersen, Erzsébet Horváth-Puhó, Vera Ehrenstein, Mikael Rørth & Henrik T Sørensen



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GP participation in increasing uptake in a national bowel cancer screening programme: the PEARL project

GP participation in increasing uptake in a national bowel cancer screening programme: the PEARL project

British Journal of Cancer advance online publication, May 18 2017. doi:10.1038/bjc.2017.129

Authors: Sally C Benton, Piers Butler, Katy Allen, Michelle Chesters, Sally Rickard, Sally Stanley, Richard Roope, Daniel Vulkan & Stephen W Duffy



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Sequencing of DICER1 in sarcomas identifies biallelic somatic DICER1 mutations in an adult-onset embryonal rhabdomyosarcoma

Sequencing of DICER1 in sarcomas identifies biallelic somatic DICER1 mutations in an adult-onset embryonal rhabdomyosarcoma

British Journal of Cancer advance online publication, May 18 2017. doi:10.1038/bjc.2017.147

Authors: Leanne de Kock, Barbara Rivera, Timothée Revil, Paul Thorner, Catherine Goudie, Dorothée Bouron-Dal Soglio, Catherine S Choong, John R Priest, Paul J van Diest, Jantima Tanboon, Anja Wagner, Jiannis Ragoussis, Peter FM Choong & William D Foulkes



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Targeted sequencing-based analyses of candidate gene variants in ulcerative colitis-associated colorectal neoplasia

Targeted sequencing-based analyses of candidate gene variants in ulcerative colitis-associated colorectal neoplasia

British Journal of Cancer advance online publication, May 18 2017. doi:10.1038/bjc.2017.148

Authors: Sanjiban Chakrabarty, Vinay Koshy Varghese, Pranoy Sahu, Pradyumna Jayaram, Bhadravathi M Shivakumar, Cannanore Ganesh Pai & Kapaettu Satyamoorthy



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Transoral endoscopic thyroidectomy: our initial experience using a new endoscopic technique

Abstract

Background

A transoral approach has been experimentally introduced to the field of thyroid surgery and several groups in Asia have recently used the technique to treat patients. We performed transoral endoscopic thyroidectomies on patients with thyroid cancer or a benign tumor.

Methods

We reviewed the medical records of patients who underwent transoral endoscopic thyroid surgery between July 2016 and January 2017. A midline incision was made in the vestibule, and a 10 mm cannula was placed; then, the working space was widened by insufflating CO2 at a pressure of 5–6 mmHg. Two lateral incisions were made in the vestibule near the first molars, and 5-mm-diameter cannulas were inserted. A 10-mm 30° telescope was inserted through the midline cannula and instruments were positioned through the lateral cannulas. Thyroid surgery was endoscopically performed using conventional endoscopic instruments.

Results

We performed 18 thyroid surgeries (15 thyroid lobectomies, one completion thyroidectomy, and two total thyroidectomies) in 17 patients. The postoperative pathology was papillary thyroid cancer in 11 cases (61.1%), a follicular carcinoma in two cases (one patient) (11.1%) and benign in five cases (27.8%). The average tumor diameter was 1.75 cm (range 0.5–7.5 cm). No patient reported sensory changes around the lower lip. No patient developed permanent recurrent laryngeal nerve palsy or hypocalcemia. No patient developed a wound infection or a fistula between the oral incision and anterior neck.

Conclusions

The transoral endoscopic approach provides a short, direct route to the thyroid gland and seems to be safe and feasible. It is important to further develop and refine the surgical techniques. The approach is optimal, and will become widely used for thyroid surgery in the near future.



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Comparison of the multichannel intraluminal impedance pH and conventional pH for measuring esophageal acid exposure: a propensity score-matched analysis

Abstract

Background

The modalities for evaluating acid reflux in medical care for gastroesophageal reflux disease (GERD) include conventional pH (C-pH), wireless pH (Bravo®) and multichannel intraluminal impedance pH (MII-pH), which have been reported to vary with respect to the duration of acid reflux. In this study, we examined the difference between the acid reflux in C-pH and MII-pH among patients with GERD.

Methods

Prior to initial laparoscopic fundoplication carried out on 297 cases from December 1994 to April 2016, an upper gastrointestinal endoscopy and C-pH or MII-pH were conducted. A propensity score-matched analysis was carried out about five factors including age, sex, BMI, the extent of reflux esophagitis (Los Angeles classification), and the presence of hiatal hernia (HH), ultimately leading to the creation of a C-pH group (81 cases) and MII-pH group (81 cases) as the subjects.

Results

Concerning pH < 4 holding time (18.9 vs. 7.3%, p < 0.001), DeMeester score (58.5 vs. 24.4, p < 0.001), and the number of times reflux continued for longer than 5 min (8.8 vs. 4.1 times/day, p = 0.002), the C-pH group had significantly higher values for each, while the positive rate of acid reflux (Positive pH) was significantly higher in the C-pH group (p < 0.001), at 80% in the C-pH group and 42% in the MII-pH group. In terms of the correlation between the extent of reflux esophagitis and pH < 4 holding time, a moderate level of positive correlation was seen in both the C-pH group and MII-pH group (r of each = 0.427, r = 0.408); moreover, regardless of the presence of HH, the holding time was significantly higher in the C-pH group than the MII-pH group (p of each <0.001, p = 0.040).

Conclusion

While the values of each parameter regarding acid reflux are calculated as lower in MII-pH than in C-pH, there is no difference in the evaluation of the pathology between the two modalities.



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Systematic review and meta-analysis of laparoscopic mesh versus suture repair of hiatus hernia: objective and subjective outcomes

Abstract

Background

Hiatus hernia (HH) contributes to the pathophysiology of gastroesophageal reflux disease (GERD). Mesh-augmentation of surgical repair might be associated with a reduced risk of recurrence and GERD. However, recurrence rates, mesh-associated complications and quality of life (QOL) after mesh versus suture repair are debated. The aim of this meta-analysis was to determine HH recurrence following mesh-augmentation versus suture repair. Secondary aims were to compare complications, mortality, QOL and GERD symptoms following different repair techniques.

Methods

A systematic literature search of the PubMed, Medline, Embase, Cochrane Library, and Springer database was performed to identify relevant studies comparing mesh-augmentation versus suture repair of the esophageal hiatus. Data pertinent to the benefit versus risk outcomes for these techniques were extracted and compared by meta-analysis. The odd ratio (OR) and mean differences (MD) with 95% confidence intervals were calculated.

Results

Eleven studies (4 randomized, 9 non-randomized) comparing mesh (n = 719) versus suture (n = 755) repair were identified. Mesh-augmentation was associated with a reduced overall recurrence rate compared to suture repair [2.6 vs. 9.4%, OR 0.23 (95% CI 0.14–0.39), P < 0.00001]. There was no significant difference in the incidence of complications (P = 0.400) between groups. Improvement in QOL measured by SF-36 was greater following biological mesh-augmentation compared to suture repair (MD = 13.68, 95% CI 2.51–24.85, P = 0.020), as well as GERD-HRQL. No differences were seen for the GIQLI scores with permanent mesh (P = 0.530). Dysphagia improvements were better following suture repair (MD = 1.47, 95% CI 0.20–2.74, P = 0.020).

Conclusions

Mesh repair of HH conferred some advantages and disadvantages at short-term follow-up. Compared to a suture repair alone, mesh-augmentation might be associated with less short-term recurrences, and biological mesh was associated with improved short-term QOL. However, these advantages were offset by more dysphagia. Long-term outcomes are still needed to determine the place of mesh repair of HH.



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Can laparoscopic surgery prevent incisional hernia in patients with Crohn’s disease: a comparison study of 750 patients undergoing open and laparoscopic bowel resection

Abstract

Background

Incisional hernia (IH) is a frequent occurrence following open surgery for Crohn's disease (CD). This study compares the IH rates of patients with CD undergoing open versus laparoscopic bowel resection.

Methods

Seven hundred and fifty patients with CD operated by the authors at the Mount Sinai Medical Center, New York, USA, were reviewed from a prospectively maintained surgical database. Five hundred patients with Crohn's disease undergoing open surgery were compared to 250 patients undergoing laparoscopic bowel resection.

Results

The mean duration of follow-up in the study population was 6.8 years. Patients undergoing open surgery had a significantly higher age at onset of disease, age at surgery, longer duration of disease, lower serum albumin, history of multiple previous resections, were more likely to be on steroids, needed more blood transfusions, and had an increased necessity for an ileostomy during resection. Nevertheless, the incidence of IH at 36 months was nearly identical in both groups (10.8 vs. 8.4% for open vs laparoscopic). 16% of the patients in the laparoscopic group (range: 7–20%) required conversion to open surgery. Patients undergoing laparoscopic resection that required conversion to open surgery had the highest IH rate at 18%. There was a significant correlation between IH and the length of the midline vertical extraction incision. Patients undergoing laparoscopic resection with intracorporeal anastomosis and small transverse or trocar site extraction incisions had no IH.

Conclusions

A marked decrease or complete elimination of IH in patients with CD undergoing bowel resection may be possible using advanced laparoscopic techniques that require intra-abdominal anastomosis and use of the smallest transverse extraction incisions.



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Long-term durability of preserved aortic root after repair of acute type A aortic dissection

Abstract

Background

Optimal management of aortic root in type A aortic dissection (AAD) is controversial. To determine the most appropriate strategy, we studied the late outcomes after conservative repair of aortic root.

Methods

234 AAD patients (mean age 68 ± 12 years) underwent surgical repair using supracommissural replacement (SCR) for aortic root reconstruction from 1989 to 2014. Ascending aortic replacement or hemi-arch replacement was performed in 180 patients (non-arch group), whereas total arch replacement (TAR) was performed in 54 patients. In both groups, proper and firm reapproximation of proximal edge was performed exactly at the sinotubular junction (STJ). The long-term durability of preserved aortic root (mean follow-up 89 months) was evaluated.

Results

Hospital mortality occurred in 25 of 234 patients (10.6%). Aorta-related deaths occurred in five patients (four in non-arch; one in TAR), with over 90% 10-year actuarial survival rate in each group. Among 19 aorta-related events, there were only four proximal events (three in non-arch; one in TAR). The 10-year freedom rate from proximal aorta-related events exceeded 90%, with no significant difference in both groups. Freedom rate from moderate aortic regurgitation at 10 years was statistically similar between non-arch (86.3%) and TAR (85.7%) groups.

Conclusions

The long-term durability of SCR with proximal aortic reapproximation exactly at the STJ was acceptable with low rates of proximal aortic events. This technique can be the standard technique for aortic root reconstruction in AAD patients, except those with aortic root pathology.



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Advances in the Development of Janus Kinase Inhibitors in Inflammatory Bowel Disease: Future Prospects

Abstract

Inflammatory bowel disease (IBD) is caused by a dysregulation of the immune system, inducing the production of proinflammatory cytokines and adhesion molecules. A better understanding of the mucosal immune response in IBD has led to the development of new drugs directed at inflammatory cytokines and leukocyte-trafficking molecules. Beyond tumor necrosis factor antagonists and anti-integrin molecules, which act by blocking the interaction between gut-specific lymphocytes and their receptor on vascular endothelium, the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway represents a new target in IBD. JAK inhibitors are small molecules able to selectively target the activity of specific JAKs that play a role in signal transmission via interleukins. This review presents an overview of the role of the JAK/STAT signaling pathway and updated information for JAK molecules, which are promising drugs in IBD. Currently developed to treat ulcerative colitis and Crohn's disease, tofacitinib (in a phase III study) and filgotinib (in a phase II study), respectively, are the JAK inhibitors in the most advanced stage of development for IBD. However, the utility of, and adverse events associated with, these new drugs remain to be determined and clarified (in particular, the risk of herpes zoster infections), depending on the efficacy and tolerance determined from definitive studies. The availability of these drugs could enhance the therapeutic approach to IBD in the coming years, and reinforce the concept of personalized medicine for IBD patients.



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Methanol extract of Dicranopteris linearis L. leaves impedes acetaminophen-induced liver intoxication partly by enhancing the endogenous antioxidant system

The present study investigated the potential of methanolic extract of Dicranopteris linearis (MEDL) leaves to attenuate liver intoxication induced by acetaminophen (APAP) in rats.

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Practitioners’ perspectives on evaluating treatment outcomes in traditional Chinese medicine

There are no generally accepted standards for evaluation of treatment outcomes in traditional Chinese medicine (TCM). Pattern differentiation and individual treatments are recognized as the most distinguishing...

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Comparing Oncoplastic Breast Conserving Surgery with Mastectomy and Immediate Breast Reconstruction: Case-Matched Patient Reported Outcomes

Oncoplastic breast conserving surgery (OBCS) allows women who may otherwise have mastectomy and immediate reconstruction (MxIR) the choice to conserve their breast yet avoid deformity. We compared the outcome of these options.

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Analysis of Risk Factors Associated with Unplanned Re-Operations following Pediatric Plastic Surgery

Unplanned re-operation (UR) is an outcome measure with multiple advantages that can be used as a standardized tool to assess an institution’s quality and safety of medical care. The goal of our study was to identify parameters associated with an increased likelihood of UR following plastic surgery in patients less than eighteen years of age using a large validated national multi-center database.

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DIEP flap for breast reconstruction: Is abdominal fat thickness associated with postoperative complications?

Some surgeons consider a high body mass index (BMI) or important abdominal fat excess as contraindications for breast reconstruction with free DIEP flap. The aim of this study was to identify factors associated with postoperative complications using this type of flap, with an emphasis on BMI and abdominal subcutaneous fat thickness.

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Sensory Outcomes Following Brachial Plexus Birth Palsy: A Systematic Review

Brachial plexus birth palsy (BPBP) affects close to 1.5 in 1,000 live births and can lead to significant functional impairment and reduced quality-of-life. To date, studies have focused on grading motor function and strength to assess patient outcomes, with less attention paid to sensory recovery. The authors aimed to systematically review the current literature on sensory outcomes following BPBP.

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Characterizing infections in prosthetic breast reconstruction: A validity assessment of national health databases

Current guidelines in the United States only require reporting 30-day postoperative outcomes to standardized databases, including the National Surgical Quality Improvement Program (NSQIP). Thus, many breast implant related complications go unreported in standard databases. We sought to characterize late periprosthetic infections following implant-based breast reconstruction.

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Breast-conserving therapy for breast cancer: Cosmetic results and options for delayed reconstruction

Optimizing of the cosmetic outcome after breast conservative therapy (BCT) is important. We aim to determine the cosmetic outcome following BCT, factors influencing this cosmesis, and identify the most favourable options for delayed breast reconstruction.

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Lesion location associated with balance recovery and gait velocity change after rehabilitation in stroke patients

Abstract

Purpose

Impaired gait function after stroke contributes strongly to overall patient disability. However, the response to rehabilitation varies between individuals. The aims of this study were to identify predictors of gait velocity change and to elucidate lesion location associated with change of balance and gait function.

Methods

We reviewed 102 stroke patients. The patients were divided into two groups according to gait ability post-rehabilitation, and we analyzed differences in their characteristics, such as demographic information, lesion factors, and initial balance function. Multivariate regression analyses were performed to examine the predictors of rehabilitation response. Lesion location and volume were measured on brain magnetic resonance images. We generated statistical maps of the lesions related to functional gains in gait and balance using voxel-based lesion symptom mapping (VLSM).

Results

The group of patients who regained independent ambulation function showed a smaller lesion size, a shorter duration from stroke onset, and higher initial balance function. In the regression model, gait velocity changes were predicted with the initial Berg balance scale (BBS) and duration post-onset. Absolute BBS changes were also correlated with the duration post-onset and initial BBS, and relative BBS changes were predicted by the baseline BBS. Using VLSM, lesion locations associated with gait velocity changes and balance adjusting for other factors were the insula, internal capsule, and adjacent white matter.

Conclusion

Initial balance function as well as the interval between stroke onset and the initiation of therapy might influence balance recovery and gait velocity changes. Damage to the insula and internal capsule also affected gait velocity change after rehabilitation.



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Raman Spectroscopy of Lattice-Matched Graphene on Strongly Interacting Metal Surfaces

TOC Graphic

ACS Nano
DOI: 10.1021/acsnano.7b02686
ancac3?d=yIl2AUoC8zA


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Tuning the Shell Number of Multishelled Metal Oxide Hollow Fibers for Optimized Lithium-Ion Storage

TOC Graphic

ACS Nano
DOI: 10.1021/acsnano.7b02275
ancac3?d=yIl2AUoC8zA


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Aktuelle Therapieoptionen beim rupturierten abdominellen Aortenaneurysma

Zusammenfassung

Die endovaskuläre Behandlung von rupturierten Bauchaortenaneurysmen (rEVAR) hatte in Beobachtungsstudien großer Zentren mit entsprechender Erfahrung vielversprechende Überlebensraten gezeigt, die denen der offenen Operation überlegen waren. Die hierzu durchgeführten randomisiert-kontrollierten Studien zeigten vergleichbare Ergebnisse, die jedoch den breiteren Einsatz der rEVAR assoziiert nahelegen. Für den Einsatz der rEVAR und für die bestmögliche Versorgung von rupturierten Bauchaortenaneurysmen sowohl mit rEVAR, aber auch offener Operation ist ein standardisiertes Behandlungsprotokoll mit der entsprechenden Schulung aller beteiligter Berufsgruppen sowie eine adäquate räumliche, technische und materialtechnische Ausstattung im Gefäßzentrum notwendig.



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Combined immune checkpoint blockade (anti-PD-1/anti-CTLA-4): evaluation and management of adverse drug reactions



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Characterization of a bi-functional cellulase produced by a gut bacterial resident of Rosaceae branch borer beetle, Osphranteria coerulescens (Coleoptera: Cerambycidae)

S01418130.gif

Publication date: October 2017
Source:International Journal of Biological Macromolecules, Volume 103
Author(s): Atousa Hatefi, Ali Makhdoumi, Ahmad Asoodeh, Omid Mirshamsi
A cellulolytic bacterium was obtained from the digestive tract of Osphranteria coerulescens. The breakdown of woody and cellulosic substances by this insect may be relative in part to its symbiont bacteria. Under optimal cultural conditions the novel isolate produced 5.35U/ml cellulase after 72h. The enzyme was purified to 36 fold with a 0.59% yield and showed a specific activity of 9.0U/mg. It presented its maximum activity at 60°C and pH 5, while it was stable in a wide range of temperature from 20 to 60°C and pH from 5 to 10. The purified enzyme had a molecular weight of 42.50kDa based on SDS-PAGE and zymogram analyses. It demonstrated high ions and solvent stability and its activity was stimulated by Mn2+, Na+, DMSO and chloroform. The enzyme could hydrolyze CMC, avicel, cellulose and sawdust. TLC analysis represented the cellobiose as the hydrolytic product of CMC. With regard to endo/exo glucanase activity and wide pH, temperature and solvent stability, it has potential for industrial application.



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Effect of chemical denaturants on the conformational stability of GyrB subunit of DNA gyrase from Salmonella enterica serovar Typhi

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Publication date: October 2017
Source:International Journal of Biological Macromolecules, Volume 103
Author(s): Deepali Gupta, Ekta Sachdeva, Md. Anzarul Haque, Safikur Rahman, Rohit Bansal, Abdul. S. Ethayathulla, Md. Imtaiyaz Hassan, Punit Kaur
DNA gyrase, a type II topoisomerase maintains the topology of DNA by introducing negative supercoils using energy generated by ATP hydrolysis. It is composed of two subunits, GyrA and GyrB (GyrA2GyrB2 hetero-tetramer). GyrB comprises two domains, a 43kDa amino N-terminus (GBNTD) and 47kDa carboxyl C- terminus (GBCTD). Till now no study has been reported in terms of stability of Gyrase B and its domains using chemical denaturants related to its function. To understand the role of each domain in GyrB subunit, we estimated the thermodynamic stability of GBF and its individual domains using urea and GdmCl. Changes in secondary and tertiary structures were monitored using circular dichroism and fluorescence spectroscopy. The Cm values for GBNTD, GBCTD and GBF proteins were found to be 2.25, 1.65 and 1.82M during GdmCl-induced denaturation and 2.95, 2.25 and 2.67M for urea-induced denaturation. It is observed that GBNTD is more stable than GBCTD and it contributes to overall stability of GyrB. The lower Cm and ΔG values reflect the flexibility of GBCTD to form the catalytic site along with GANTD for cleavage or religation reaction. Both GdmCl- and urea-induced denaturation of GyrB domains were reversible over the entire range of concentration.



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Inhibitory effect of alliin from Allium sativum on the glycation of superoxide dismutase

S01418130.gif

Publication date: October 2017
Source:International Journal of Biological Macromolecules, Volume 103
Author(s): Shehwaz Anwar, Hina Younus
Inhibition of glycation is an important approach for alleviating diabetic complications. Alliin, the most abundant sulphur compound in garlic has been demonstrated to possess antidiabetic activity. However, there is no scientific evidence supporting its antiglycating activity. The objective of this study was to determine the inhibitory effect of alliin on glucose and methyglyoxal (MG)-induced glycation of an important antioxidant enzyme, superoxide dismutase (SOD). Glycation of SOD resulted in a decrease in enzyme activity, fragmentation/cross-linking, reduced cross-reactivity with anti-SOD antibodies, both tertiary and secondary structural changes, and formation of AGEs and fibrils. Alliin offered protection against glucose or MG induced glycation of SOD. The antiglycating potential of alliin appears to be comparable with that of quercetin which is reported to be a potent natural inhibitor of glycation. Alliin has a good antiglycating effect and hence is expected to have therapeutic potential in the prevention of glycation-mediated diabetic complications.



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Optimization of polysaccharides extraction from Dictyophora indusiata and determination of its antioxidant activity

Publication date: October 2017
Source:International Journal of Biological Macromolecules, Volume 103
Author(s): Xiaoyan Liu, Yixuan Chen, Linxiu Wu, XiaoQi Wu, Yifan Huang, Bin Liu
Response surface methodology (RSM) was used to optimize the extraction conditions of polysaccharides from the fruiting body of Dictyophora indusiata (DIP). Effect of extraction time, extraction temperature and solid to liquid ratio on the yield of DIP was investigated. The optimum extraction conditions for DIP were as follows: extraction time, 2.1h, solid to liquid ratio, 1:37, and extraction temperature, 92°C. Under these conditions, the experimental extraction yield of DIP was 15.95±0.144%, which was matched closely to the predicted value. During the antioxidant experiments in vitro, DIP exhibited a strong reducing capacity and strong scavenging activity on DPPH, superoxide, and hydroxyl radicals. The EC50 of DIP on DPPH, hydroxyl and superoxide radicals was 0.89mg/L, 0.51mg/mL and 0.68mg/mL, respectively. This suggests that polysaccharides from D. indusiata have the potential to be the resources of natural antioxidants.



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Respiratory support after extubation: noninvasive ventilation or high-flow nasal cannula, as appropriate



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External validation of SAPS 3 and MPM0-III scores in 48,816 patients from 72 Brazilian ICUs

The performance of severity-of-illness scores varies in different scenarios and must be validated prior of being used in a specific settings and geographic regions. Moreover, models’ calibration may deteriorat...

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Despite £$€ concerns, upfront MRI before guided biopsy improved detection, QOL + cost effective for… https://t.co/5zFMGrvVoD

Despite £$€ concerns, upfront MRI before guided biopsy improved detection, QOL + cost effective for… https://t.co/5zFMGrvVoD

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DNA recovery from latent fingermarks treated with an infrared fluorescent fingerprint powder

Fingermarks have been used for over 100 years as a means of identifying individuals involved in crime, by virtue of the patterns deposited at crime scenes or on items of evidential value [1]. In 1997, van Oorschot et al. [2] demonstrated that fingermark residues also provide enough DNA for the generation of DNA profiles. Technological and scientific advances have improved the ability to obtain at least partial DNA profiles from evidence handled by an individual, primarily through the increased sensitivity in DNA typing procedures.

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Cockroach Allergy and Urban Asthma



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Combined immune checkpoint blockade (anti-PD-1/anti-CTLA-4): evaluation and management of adverse drug reactions



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Two mitogenomes in Gruiformes ( Amaurornis akool / A. phoenicurus ) and the phylogenetic placement of Rallidae

Abstract

Rallidae, with 34 genera including 142 species, is the largest family in the Gruiformes, the phylogenetic placement of this family was still in debate. The complete mitochondrial genomes (mitogenomes), with many advantageous characters, have become popular markers in phylogenetic analyses. We sequenced the mitogenomes of brown crake (Amaurornis akool) and white-breasted waterhen (Amaurornis phoenicurus), analyzed the genomic characters of mitogenomes in Rallidae, and explored the phylogenetic relationships between Rallidae and other four families in Gruiformes based on mitogenome sequences of 32 species with Bayesian method. The mitogenome of A. akool/A. phoenicurus was 16,950/17,213 bp in length, and contained 37 genes typical to avian mitogenomes and one control region, respectively. The genomic characters of mitogenomes in Rallidae were similar. The phylogenetic results indicated that, among five families, Rallidae had closest relationship with Heliornithidae, which formed a sister taxa to Gruidae, while Rhynochetidae located in the basal lineage. Within Rallidae, Rallina was ancestral clade. Gallirallus & Rallus and Aramides were closely related, Gallicrex & Amaurornis and Fulica & Gallinula had close relationships, and these two taxa formed a sister clade to Porphyrio & Coturnicops. Our phylogenetic analyses provided solid evidence for the phylogenetic placement of Rallidae and the evolutionary relationships among different genus within this family. In addition, the mitogenome data presented here provide useful information for further molecular systematic investigations on Gruiformes as well as conservation biology research of these species.



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Erratum to: Glucagon-Like Peptide-1 Receptor Agonists (GLP-1RAs) in the Brain–Adipocyte Axis



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Ocrelizumab: First Global Approval

Abstract

Ocrelizumab (Ocrevus™) is a humanised anti-CD20 monoclonal antibody that has been developed by Genentech, Inc. (a subsidiary of Roche) for the treatment of multiple sclerosis (MS). The drug is designed to deplete B cells, which play an important role in the pathogenesis of MS. In March 2017, ocrelizumab was approved in the USA for the treatment of patients with relapsing or primary progressive forms of MS; currently, it is awaiting approval in the EU for the same indications. This article summarizes the milestones in the development of ocrelizumab leading to its first global approval for the treatment of MS.



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Salvia plebeia Extract Inhibits Xanthine Oxidase Activity In Vitro and Reduces Serum Uric Acid in an Animal Model of Hyperuricemia

10-1055-s-0043-111012_pmb0290-1.jpg

Planta Med
DOI: 10.1055/s-0043-111012

Hyperuricemia is a clinical condition characterized by an elevated level of serum uric acid and is a key risk factor for the development of gout and metabolic disorders. The existing urate-lowering therapies are often impractical for certain patient populations, providing a rationale to explore new agents with improved safety and efficacy. Here, we discovered that Salvia plebeia extract inhibited the enzyme activity of xanthine oxidase, which is a key enzyme generating uric acid in the liver. In an animal model of hyperuricemia, S. plebeia extract reduced serum urate to the levels observed in control animals. The urate-lowering effect of S. plebeia extract in vivo was supported by the identification of compounds that inhibit xanthine oxidase enzyme activity in vitro. Nepetin, scutellarein, and luteolin contributed significantly to S. plebeia bioactivity in vitro. These compounds showed the highest potency against xanthine oxidase with IC50 values of 2.35, 1.74, and 1.90 µM, respectively, and were present at moderate quantities. These observations serve as a basis for further elaboration of the S. plebeia extracts for the development of new therapeutics for hyperuricemia and related diseases.
[...]

Georg Thieme Verlag KG Stuttgart · New York

Article in Thieme eJournals:
Table of contents  |  Abstract  |  Full text



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Alternating Acetaminophen and Ibuprofen versus Monotherapies in Improvements of Distress and Reducing Refractory Fever in Febrile Children: A Randomized Controlled Trial

Abstract

Background

No evidence can be found in the medical literature about the efficacy of alternating acetaminophen and ibuprofen treatment in children with refractory fever.

Objective

Our objective was to assess the effect of alternating acetaminophen and ibuprofen therapy on distress and refractory fever compared with acetaminophen or ibuprofen as monotherapy in febrile children.

Methods

A total of 474 febrile children with axillary temperature ≥38.5 °C and fever history ≤3 days in a tertiary hospital were randomly assigned to receive either (1) alternating acetaminophen and ibuprofen (acetaminophen 10 mg/kg per dose with shortest interval of 4 h and ibuprofen 10 mg/kg per dose with shortest interval of 6 h and the shortest interval between acetaminophen and ibuprofen ≥2 h; n = 158), (2) acetaminophen monotherapy (10 mg/kg per dose with shortest interval of 4 h; n = 158), or (3) ibuprofen monotherapy (10 mg/kg per dose with shortest interval of 6 h; n = 158). The mean Non-Communicating Children's Pain Checklist (NCCPC) score was measured every 4 h, and axillary temperatures were measured every 2 h.

Results

In total, 471 children were included in an intention-to-treat analysis. No significant clinical or statistical difference was found in mean NCCPC score or temperature during the 24-h treatment period in all febrile children across the three groups. Although the proportion of children with refractory fever for 4 h and 6 h was significantly lower in the alternating group than in the monotherapy groups (4 h: 11.54% vs. 26.58% vs. 21.66%, respectively [p = 0.003]; 6 h: 3.85% vs. 10.13% vs. 17.83%, respectively [p < 0.001]), the mean NCCPC score of children with refractory fever for 4 or 6 h was not lower than those in either of the monotherapy groups. The number of patients who developed persistent high body temperature was consistent across all study groups.

Conclusions

Alternating acetaminophen and ibuprofen can reduce the proportion of children with refractory fever, but if one cycle of alternating therapy cannot reduce febrile distress as defined by NCCPC score, two or more cycles of alternating therapy may have minimal to no clinical efficacy in some cases.

The trial was registered with the Chinese Clinical Trial Registry as ChiCTR-TRC-13003440 and the WHO Registry Network as U1111-1146-6714.



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Association of post-treatment hypoalbuminemia and survival in Chinese patients with metastatic renal cell carcinoma

Abstract

Background

Hypoalbuminemia adversely affects the clinical outcomes of various cancers. The purpose of this study was to estimate the prognostic value of hypoalbuminemia 3–5 weeks after treatment in patients with metastatic renal cell carcinoma (mRCC) who received sorafenib or sunitinib as first-line treatment.

Methods

In this single-center, retrospective study, we assessed the progression-free survival (PFS) and overall survival (OS) of 184 mRCC patients who received first-line sorafenib or sunitinib treatment. PFS and OS were compared between patients with post-treatment hypoalbuminemia (post-treatment albumin level <36.4 g/L) and those with normal post-treatment albumin level (albumin level ≥36.4 g/L). The Memorial Sloan Kettering Cancer Center (MSKCC) risk model stratified mRCC patients into three risk categories. Prognostic values of all patient characteristics including MSKCC risk category were determined by using univariate and multivariate Cox regression models. Prognostic value was further determined using the Harrell concordance index and receiver operating characteristic curve analysis.

Results

The median PFS and OS of the 184 patients were 11 months (95% confidence interval [CI] 9–12 months) and 23 months (95% CI 19–33 months), respectively. Patients with post-treatment hypoalbuminemia had significantly shorter median PFS (6 months [95% CI 5–7 months]) and OS (11 months [95% CI 9–15 months]) than patients who had normal post-treatment albumin levels (PFS: 12 months [95% CI 11–16 months], P < 0.001; OS: 31 months [95% CI 24–42 months], P < 0.001), respectively. Multivariate analysis showed that post-treatment hypoalbuminemia was an independent predictor of PFS (hazard ratio [HR], 2.113; 95% CI 1.390–3.212; P < 0.001) and OS (HR, 2.388; 95% CI 1.591–3.585; P < 0.001). Post-treatment hypoalbuminemia could also be combined with the MSKCC risk category for better prediction about OS. The model that included post-treatment hypoalbuminemia and MSKCC risk category improved the predictive accuracy for PFS and OS (c-index: 0.68 and 0.73, respectively) compared with the basic MSKCC risk model (c-index: 0.67 and 0.70, respectively). The prognostic values for PFS and OS of the integrated MSKCC risk model involving post-treatment hypoalbuminemia were significantly more accurate than the basic MSKCC risk model using likelihood ratio analysis (both P < 0.001).

Conclusions

Post-treatment hypoalbuminemia can be considered an independent prognostic factor for patients with mRCC who undergo first-line treatment with tyrosine kinase inhibitors. Additionally, integrating post-treatment serum albumin level into the basic MSKCC risk model can improve the accuracy of this model in predicting patient overall survival and progression-free survival.



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[Editorial] Policy lacking to prevent adverse health for poor UK children

In the UK, 4 million children, about one in four, live in poverty, 100 000 more than in the previous year. A report launched on April 11, Poverty and Child Health—commissioned by charities, the Royal College of Paediatrics and Child Health, and the Child Poverty Action Group—illustrates paediatricians' concern about the negative impact of child poverty on their health. The report is based on an online survey of over 250 paediatricians across the UK. Two-thirds of the respondents said that poverty and low income contribute very much to the ill health of children they work with, pointing to food insecurity and living in what is described as cold, damp, overcrowded housing, as major contributing factors to health deterioration.

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[Editorial] Thyroid cancer screening

Whether screening for a disease is beneficial or not is widely debated. Last week, the US Preventive Services Task Force (USPSTF) recommended against screening for thyroid cancer in adults who show no signs or symptoms of the disease, concurring with its 1996 recommendation.

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[Perspectives] Julie Moore: NHS leader who walks the wards

When asked what makes a good manager in the UK's National Health Service (NHS), it's not the obvious core skills—leadership, willingness to delegate, critical thinking—that Dame Julie Moore chooses to emphasise. Moore, Chief Executive of University Hospitals Birmingham (USB) NHS Foundation Trust, is eager to talk of values: in essence, the determination to make things better for patients. Indeed the words “values” and “patient care” form a kind of leitmotif to her discourse; she returns to them time and time again.

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[Perspectives] John Elliotson, Thomas Wakley, and the mesmerism feud

From the first edition of The Lancet in 1823, the journal's founder and editor Thomas Wakley vowed to expose and denounce quackery. In his first leading article—an innovation borrowed from the radical journalist William Cobbett—Wakley pledged that he would seek to end “mystery and concealment” in medicine in order to “detect and expose the impositions of ignorant practitioners”. This, however, was rather easier said than done in the dimly lit world of early 19th-century science.

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