Chitosan-modified PLGA nanoparticles tagged with 5TR1 aptamer for in vivo tumor-targeted drug delivery

Publication date: 1 August 2017
Source:Cancer Letters, Volume 400
Author(s): Sahar Taghavi, Mohammad Ramezani, Mona Alibolandi, Khalil Abnous, Seyed Mohammad Taghdisi
In this study, we reported epirubicin (Epi) encapsulated nanoparticles (NPs) formulated with biocompatible and biodegradable poly (lactic-co-glycolic acid) (PLGA) modified with chitosan (CS) through a physical adsorption method. Using chitosan, the solubility and surface charge of PLGA was modified to make efficient drug carriers for cancer cells. To improve the anti-tumor efficacy, we developed targeted therapy of tumor cells using a 5TR1 DNA aptamer (Apt) against the MUC1 receptor. To prove the MUC1 receptor-mediated uptake of Epi-PLGA-CS-Apt NPs in the cells, competition experiments were carried out.In vitro experiments, cytotoxicity assay and fluorescence uptake assay demonstrated that fabricated NPs with or without aptamers showed significantly high therapeutic efficiency in MCF7 cells (breast cancer cell) compared with free Epi, while in BALB/c mice bearing C26 cells (murine colon carcinoma cell), targeted NP groups exhibited significant tumor growth inhibition and higher inclination to tumor compared with non-targeted NPs. Hence, our in vivo results revealed that non-targeted NPs may diffuse away from the tumor site and release Epi in the extracellular space and decrease concentration of the drug in the targeted tissue. This study indicated Epi-PLGA-CS-Apt has great potential as a promising nanoplatform for in vivo cancer therapy and could be of great value in medical use.

Graphical abstract

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Development of a scoring system to predict massive postpartum transfusion in placenta previa totalis

Abstract

Purpose

It is important to predict massive postpartum hemorrhage in patients with placenta previa totalis (PPT) and a method that accurately predicts this event is needed. The present study developed a scoring system that predicts massive transfusion in patients with PPT.

Methods

This single-center retrospective cohort study comprised 238 patients with PPT who underwent caesarean section between January 2004 and December 2010. Massive transfusion was defined as the transfusion of ≥8 units of packed red blood cells within 24 h after delivery. Multivariate regression analysis was used to estimate the risks of massive transfusion. A probability score model was then constructed and tested for performance. Subsequently, the model was validated in other patients with PPT (n = 117).

Results

Thirty-one patients (13.0%) underwent massive transfusion. Ultrasound suspicion of placental adhesion, previous caesarean section, gestational age <37 weeks, sponge-like appearance of the cervix, and anterior placenta were all independent predictors of massive transfusion. The performance for the score model revealed good calibration (Hosmer–Lemeshow chi-squared 1.64; P = 0.44), and its discrimination (the area under the receiver operating characteristic for this model was 0.84) was better than when suspicion of placental adhesion was used alone (0.67; P < 0.001). In the validation set, the performance was 0.88.

Conclusion

The scoring system developed using the five independent risk factors had better performance to predict massive transfusion in patients with PPT than when suspicion of placental adhesion was used alone. However, further large-scale studies are warranted to clarify the usefulness and accuracy of this model.

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Sedative effects of oral pregabalin premedication on intravenous sedation using propofol target-controlled infusion

Abstract

Purpose

The sedative effects of pregabalin during perioperative period have not been sufficiently characterized. The aim of this study was to verify the sedative effects of premedication with pregabalin on intravenous sedation (IVS) using propofol and also to assess the influences of this agent on circulation, respiration, and postanesthetic complications.

Methods

Ten healthy young volunteers underwent 1 h of IVS using propofol, three times per subject, on separate days (first time, no pregabalin; second time, pregabalin 100 mg; third time, pregabalin 200 mg). The target blood concentration (C _T) of propofol was increased in a stepwise fashion based on the bispectral index (BIS) value. Ramsay's sedation score (RSS) was determined at each propofol C _T. Propofol C _T was analyzed at each sedation level. Circulation and respiration during IVS and complications were also verified.

Results

Propofol C _T was reduced at BIS values of 60 and 70 in both premedicated groups (100 mg: p = 0.043 and 0.041; 200 mg: p = 0.004 and 0.016, respectively) and at a BIS value of 80 in the pregabalin 200 mg group (p < 0.001). Propofol C _T was decreased at RSS 4–6 in the pregabalin 100 mg group (RSS 4: p = 0.047; RSS 5: p = 0.007; RSS 6: p = 0.014), and at RSS 3–6 in the pregabalin 200 mg group (RSS 3–5: p < 0.001; RSS 6: p = 0.002).

Conclusion

We conclude that oral premedication with pregabalin reduces the amount of propofol required to obtain an acceptable and adequate sedation level.

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MEP monitoring during aortic surgery: what we truly know

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The Greek Version of the Ohkuma Questionnaire for Dysphagia Screening

http://otorhinolaryngology-crete.blogspot.gr/2017/05/the-greek-version-of-ohkuma.html

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

6948891480

alsfakia@gmail.com

Cross-cultural translation of the Western Ontario Cuff Index in Chinese and its validation in patients with rotator cuff disorders

Abstract

Background

The Western Ontario Rotator Cuff Index (WORC) is a scale designed to evaluate the impact of rotator cuff (RC) disorders on patients' general quality of life. Our study aims to adapt the WORC for Chinese patients and to assess its reliability, validity, and responsiveness in Chinese patients with RC disorders.

Methods

First, we developed the Chinese version of the WORC (C-WORC) in a five-step procedure of translation and cross-cultural adaptation. Next, the recruiting patients finished all three rounds of scales of the C-WORC, the Medical Outcomes Study Short-Form 36 (SF-36), and the Oxford Shoulder score (OSS). Then we calculated Cronbach's alpha, the intra-class correlation coefficient (ICC), Pearson's or Spearman's correlation coefficient (r or r _s), the effect size (ES), and the standardized response mean (SRM) to evaluate the reliability, validity and responsiveness of the C-WORC, respectively.

Results

Overall, 124 patients with RC disorders successfully completed the first two rounds of the scales, and 108 patients completed the last round of the scales. Good or excellent internal consistency (Cronbach's alpha = 0.872–0.954) was found in the overall scale and subscales of C-WORC, as well as good or excellent test-retest reliability (ICC = 0.828–0.961). Moderate or good correlations (r/r _s  = 0.472–0.787) were obtained between the physical subscales of the C-WORC and the OSS and the physical subscales of SF-36; the results were also obtained for the emotions subscale of the C-WORC and the mental subscales of SF-36 (r/r _s  = 0.520–0.713), which, adequately illustrated that good validity was included in the C-WORC. In addition, good responsiveness was also observed in the overall scale and subscales of the C-WORC (ES = 1.57–2.27, SRM = 1.52–2.28).

Conclusions

The C-WORC scale is reliable, valid and responsible for the evaluation of Chinese-speaking patients with RC disorders and would be an effective instrument.

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Predictors of seeking financial compensation following motor vehicle trauma: inception cohort with moderate to severe musculoskeletal injuries

Abstract

Background

Compensation related factors have been repeatedly associated with poor recovery following orthopaedic trauma. There is limited research into the factors associated with seeking financial compensation. Further understanding of these factors could facilitate injury recovery by purposeful compensation scheme design. The aim of this study was to investigate the predictors of seeking financial compensation, namely making a claim and seeking legal representation, following motor vehicle related orthopaedic trauma. The study was conducted in New South Wales (NSW), Australia, in motor vehicle crash and workers' compensation schemes.

Methods

Participants were patients admitted with upper or lower extremity factures following a motor vehicle crash to two trauma hospitals. Data were collected at baseline within two weeks of injury. Participants were followed up at six months. Analysis involved: descriptive statistics for baseline characteristics; comparison of compensable and non-compensable participants with Analysis of Variance (ANOVA) and chi-squared tests; and logistic regression for predictor models.

Results

The cohort consisted of 452 participants with a mean age 40 years; 75% male; 74% working pre-injury; 30% in excellent pre-injury health; 56% sustained serious injuries with an Injury Severity Score (ISS) 9-15; 61% had a low-middle range household income; and 35% self-reported at fault in the crash. There was no significant difference in pre-injury/baseline health between compensable and non-compensable participants. Follow up data was available for 301 (67%) participants.

The significant predictor of claiming compensation in the adjusted analysis was higher body mass index (BMI) (overweight Odds Ratio [OR] 3.05, 95% Confidence Interval [CI] 1.63-5.68; obese OR 1.63, 95% CI 0.83-3.20). Participants less likely to claim were: involved in a motorcycle crash (OR 0.47, 95% CI 0.28-0.82); socioeconomically less disadvantaged (OR 0.37, 95% CI 0.17-0.82) or least disadvantaged (OR 0.39, 95% CI 0.17-0.90); at risk for short term harm (injury) due to alcohol consumption (OR 0.56, 95% CI 0.32-0.97); and with fair-poor pre-injury health (OR 0.30, 95% CI 0.09-0.94). The predictors for seeking legal representation were speaking a language other than English at home (OR 2.80, 95% CI 1.2-6.52) and lower household income (OR 3.63, 95% CI 1.22-10.72). Participants less likely to seek legal representation were least socioeconomically disadvantaged (OR 0.15, 95% CI 0.04-0.50).

Conclusions

Seeking financial compensation was associated with a higher pre-injury BMI rather than injury-related factors. Seeking legal representation was solely related to socio-economic factors.

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Gluten-free diet is not recommended for people without celiac disease

Gluten is not associated with a risk of coronary heart disease in people without celiac disease—and restricting gluten may result in a low intake of whole grains, which are associated with...

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Is levothyroxine requirement the same for tablet and soft gel formulations?

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The relationship of 19 functional polymorphisms in iodothyronine deiodinase and psychological well-being in hypothyroid patients

Abstract

Purpose

Levothyroxine supplementation is insufficient for the management of one tenth of patients with hypothyroidism. Iodothyronine deiodinases have been suggested to play a role in residual hypothyroid symptoms of these patients by controlling local thyroid hormone homeostasis. Previous research has suggested a relationship between commonly inherited variations in type 2 iodothyronine deiodinase and impaired well-being. We evaluated the prevalence of iodothyronine deiodinase genotypes and their association with psychological well-being in the Korean hypothyroid population.

Methods

A prospective observational study. We enrolled 196 hypothyroid subjects (136 chronic autoimmune thyroiditis and 60 thyroid cancer) and assessed baseline well-being using six validated questionnaires. Genotyping was conducted for 19 single nucleotide polymorphisms in type 1, 2, and 3 iodothyronine deiodinase using Sequenom MassARRAY matrix-assisted laser desorption/ionization time-of-flight mass spectrometry in all patients.

Results

Frequencies of iodothyronine deiodinase genotypes and well-being scores were not different in hypothyroid subjects according to their disease types. Minor genotypes of a few iodothyronine deiodinase 1 variants (rs11206244, rs2294512, and rs4926616) were associated with reduced psychological well-being. However, iodothyronine deiodinase 2 and 3 variants had no effect on baseline well-being.

Conclusion

Minor variations in iodothyronine deiodinase 1 were associated with decreased well-being in the Korean hypothyroid population, whereas iodothyronine deiodinase 2 and 3 were not. Due to controversial results among different ethnicities, further studies to clarify the effects of iodothyronine deiodinase polymorphisms on psychological well-being are warranted in hypothyroid individuals.

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Infiltrative right atrial angiosarcoma

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BJPsych Advances

BJPsych Advances, published by Royal College of Psychiatrists, last updated on 2017-05-02, available at http://apt.rcpsych.org

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Trunk rotation,Cervical induced horizontal nystagmus,“neck torsion test” (NTT),There is a “cervicotonic provocation nystagmus” in response to objective reaction to cervical straining with a static trunk excursion.

http://otorhinolaryngology-crete.blogspot.gr/2017/05/cervico-vestibular-muscle-afferents.html

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

6948891480

alsfakia@gmail.com

Prolonged endotracheal intubation is the main indication of tracheostomy, performed after two weeks of intubation. Although there were no major early complications, laryngotracheal stenosis is still a challenging sequel for tracheostomy that needs to be investigated to be prevented.

http://otorhinolaryngology-crete.blogspot.com/2017/05/prolonged-endotracheal-intubation-is.html

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

6948891480

alsfakia@gmail.com

Virtual reality-based assessment of basic laparoscopic skills using the Leap Motion controller

Abstract

Background

The majority of the current surgical simulators employ specialized sensory equipment for instrument tracking. The Leap Motion controller is a new device able to track linear objects with sub-millimeter accuracy. The aim of this study was to investigate the potential of a virtual reality (VR) simulator for assessment of basic laparoscopic skills, based on the low-cost Leap Motion controller.

Methods

A simple interface was constructed to simulate the insertion point of the instruments into the abdominal cavity. The controller provided information about the position and orientation of the instruments. Custom tools were constructed to simulate the laparoscopic setup. Three basic VR tasks were developed: camera navigation (CN), instrument navigation (IN), and bimanual operation (BO). The experiments were carried out in two simulation centers: MPLSC (Athens, Greece) and CRESENT (Riyadh, Kingdom of Saudi Arabia). Two groups of surgeons (28 experts and 21 novices) participated in the study by performing the VR tasks. Skills assessment metrics included time, pathlength, and two task-specific errors. The face validity of the training scenarios was also investigated via a questionnaire completed by the participants.

Results

Expert surgeons significantly outperformed novices in all assessment metrics for IN and BO (p < 0.05). For CN, a significant difference was found in one error metric (p < 0.05). The greatest difference between the performances of the two groups occurred for BO. Qualitative analysis of the instrument trajectory revealed that experts performed more delicate movements compared to novices. Subjects' ratings on the feedback questionnaire highlighted the training value of the system.

Conclusions

This study provides evidence regarding the potential use of the Leap Motion controller for assessment of basic laparoscopic skills. The proposed system allowed the evaluation of dexterity of the hand movements. Future work will involve comparison studies with validated simulators and development of advanced training scenarios on current Leap Motion controller.

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Synthesis and Evaluation of the Novel Prostamide, 15-Deoxy, {Delta}12,14-Prostamide J2, as a Selective Antitumor Therapeutic

15-deoxy, ^12,14-prostaglandin J₂-ethanolamide, also known as 15-deoxy, ^12,14-prostamide J₂ (15d-PMJ₂) is a novel product of the metabolism of arachidonoyl ethanolamide (AEA) by COX-2. 15d-PMJ₂ preferentially induced cell death and apoptosis in tumorigenic A431 keratinocytes and B16F10 melanoma cells compared with nontumorigenic HaCaT keratinocytes and Melan-A melanocytes. Activation of the ER stress execution proteins, PERK and CHOP10, was evaluated to determine whether this process was involved in 15d-PMJ₂ cell death. 15d-PMJ₂ increased the phosphorylation of PERK and expression of CHOP10 in tumorigenic but not nontumorigenic cells. The known ER stress inhibitors, salubrinal and 4-phenylbutaric acid, significantly inhibited 15d-PMJ₂–mediated apoptosis, suggesting ER stress as a primary apoptotic mediator. Furthermore, the reactive double bond present within the cyclopentenone structure of 15d-PMJ₂ was identified as a required moiety for the induction of ER stress apoptosis. The effect of 15d-PMJ₂ on B16F10 melanoma growth was also evaluated by dosing C57BL/6 mice with 0.5 mg/kg 15d-PMJ₂. Tumors of animals treated with 15d-PMJ₂ exhibited significantly reduced growth and mean weights compared with vehicle and untreated animals. TUNEL and IHC analysis of tumor tissues showed significant cell death and ER stress in tumors of 15d-PMJ₂–treated compared with control group animals. Taken together, these findings suggest that the novel prostamide, 15d-PMJ₂, possesses potent antitumor activity in vitro and in vivo. Mol Cancer Ther; 16(5); 838–49. ©2017 AACR.

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Hey Factors at the Crossroad of Tumorigenesis and Clinical Therapeutic Modulation of Hey for Anticancer Treatment

Hairy and Enhancer-of-split related with YRPW motif (Hey) transcription factors are important regulators of stem cell embryogenesis. Clinical relevance shows that they are also highly expressed in malignant carcinoma. Recent studies have highlighted functions for the Hey factors in tumor metastasis, the maintenance of cancer cell self-renewal, as well as proliferation and the promotion of tumor angiogenesis. Pathways that regulate Hey gene expression, such as Notch and TGFβ signaling, are frequently aberrant in numerous cancers. In addition, Hey factors control downstream targets via recruitment of histone deacetylases (HDAC). Targeting these signaling pathways or HDACs may reverse tumor progression and provide clinical benefit for cancer patients. Thus, some small molecular inhibitors or monoclonal antibodies of each of these signaling pathways have been studied in clinical trials. This review focuses on the involvement of Hey proteins in malignant carcinoma progression and provides valuable therapeutic information for anticancer treatment. Mol Cancer Ther; 16(5); 775–86. ©2017 AACR.

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Dual Targeting of Epithelial Ovarian Cancer Via Folate Receptor {alpha} and the Proton-Coupled Folate Transporter with 6-Substituted Pyrrolo[2,3-d]pyrimidine Antifolates

Folate uptake in epithelial ovarian cancer (EOC) involves the reduced folate carrier (RFC) and the proton-coupled folate transporter (PCFT), both facilitative transporters and folate receptor (FR) α. Although in primary EOC specimens, FRα is widely expressed and increases with tumor stage, PCFT was expressed independent of tumor stage (by real-time RT-PCR and IHC). EOC cell line models, including cisplatin sensitive (IGROV1 and A2780) and resistant (SKOV3 and TOV112D) cells, expressed a 17-fold range of FRα and similar amounts (within ~2-fold) of PCFT. Novel 6-substituted pyrrolo[2,3-d]pyrimidine thienoyl antifolates AGF94 and AGF154 exhibited potent antiproliferative activities toward all of the EOC cell lines, reflecting selective cellular uptake by FRα and/or PCFT over RFC. When IGROV1 cells were pretreated with AGF94 at pH 6.8, clonogenicity was potently inhibited, confirming cell killing. FRα was knocked down in IGROV1 cells with lentiviral shRNAs. Two FRα knockdown clones (KD-4 and KD-10) showed markedly reduced binding and uptake of [³H]folic acid and [³H]AGF154 by FRα, but maintained high levels of [³H]AGF154 uptake by PCFT compared to nontargeted control cells. In proliferation assays, KD-4 and KD-10 cells preserved in vitro inhibition by AGF94 and AGF154, compared to a nontargeted control, attributable to residual FRα- and substantial PCFT-mediated uptake. KD-10 tumor xenografts in severe-compromised immune-deficient mice were likewise sensitive to AGF94. Collectively, our results demonstrate the substantial therapeutic potential of novel 6-substituted pyrrolo[2,3-d]pyrimidine antifolates with dual targeting of PCFT and FRα toward EOCs that express a range of FRα, along with PCFT, as well as cisplatin resistance. Mol Cancer Ther; 16(5); 819–30. ©2017 AACR.

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Nodal Signaling as a Developmental Therapeutics Target in Oncology

The tumor microenvironment is a vital feature of oncogenesis and tumor progression. There are several parallels between cancer cells and early developmental stem cells, including their plasticity and signaling mechanisms. In early fetal development, Nodal is expressed for endodermal and mesodermal differentiation. This expression has been shown reemerge in the setting of epithelial cancers, such as breast and melanoma. High Nodal expression correlates to an aggressive tumor grade in these malignancies. Nodal signal begins with its interaction with its coreceptor, Cripto-1, leading to activation of Smad2/Smad3 and ultimately downstream transcription and translation. Lefty is the natural inhibitor of Nodal and controls Nodal signaling during fetal development. However, cancer cells lack the presence of Lefty, thus leading to uncontrolled tumor growth. Given this understanding, inhibition of the Nodal pathway offers a new novel therapeutic target in oncology. Mol Cancer Ther; 16(5); 787–92. ©2017 AACR.

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Characterization of the Anti-PD-1 Antibody REGN2810 and Its Antitumor Activity in Human PD-1 Knock-In Mice

The Programmed Death-1 (PD-1) receptor delivers inhibitory checkpoint signals to activated T cells upon binding to its ligands PD-L1 and PD-L2 expressed on antigen-presenting cells and cancer cells, resulting in suppression of T-cell effector function and tumor immune evasion. Clinical antibodies blocking the interaction between PD-1 and PD-L1 restore the cytotoxic function of tumor antigen-specific T cells, yielding durable objective responses in multiple cancers. This report describes the preclinical characterization of REGN2810, a fully human hinge-stabilized IgG4(S228P) high-affinity anti–PD-1 antibody that potently blocks PD-1 interactions with PD-L1 and PD-L2. REGN2810 was characterized in a series of binding, blocking, and functional cell-based assays, and preclinical in vivo studies in mice and monkeys. In cell-based assays, REGN2810 reverses PD-1–dependent attenuation of T-cell receptor signaling in engineered T cells and enhances responses of human primary T cells. To test the in vivo activity of REGN2810, which does not cross-react with murine PD-1, knock-in mice were generated to express a hybrid protein containing the extracellular domain of human PD-1, and transmembrane and intracellular domains of mouse PD-1. In these mice, REGN2810 binds the humanized PD-1 receptor and inhibits growth of MC38 murine tumors. As REGN2810 binds to cynomolgus monkey PD-1 with high affinity, pharmacokinetic and toxicologic assessment of REGN2810 was performed in cynomolgus monkeys. High doses of REGN2810 were well tolerated, without adverse immune-related effects. These preclinical studies validate REGN2810 as a potent and promising candidate for cancer immunotherapy. Mol Cancer Ther; 16(5); 861–70. ©2017 AACR.

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Acquired Resistance to the Hsp90 Inhibitor, Ganetespib, in KRAS-Mutant NSCLC Is Mediated via Reactivation of the ERK-p90RSK-mTOR Signaling Network

Approximately 25% of non–small cell lung cancer (NSCLC) patients have KRAS mutations, and no effective therapeutic strategy exists for these patients. The use of Hsp90 inhibitors in KRAS-mutant NSCLC appeared to be a promising approach, as these inhibitors target many KRAS downstream effectors; however, limited clinical efficacy has been observed due to resistance. Here, we examined the mechanism(s) of acquired resistance to the Hsp90 inhibitor, ganetespib, and identified novel and rationally devised Hsp90 inhibitor combinations, which may prevent and overcome resistance to Hsp90 inhibitors. We derived KRAS-mutant NSCLC ganetespib-resistant cell lines to identify the resistance mechanism(s) and identified hyperactivation of RAF/MEK/ERK/RSK and PI3K/AKT/mTOR pathways as key resistance mechanisms. Furthermore, we found that ganetespib-resistant cells are "addicted" to these pathways, as ganetespib resistance leads to synthetic lethality to a dual PI3K/mTOR, a PI3K, or an ERK inhibitor. Interestingly, the levels and activity of a key activator of the mTOR pathway and an ERK downstream target, p90 ribosomal S6 kinase (RSK), were also increased in the ganetespib-resistant cells. Genetic or pharmacologic inhibition of p90RSK in ganetespib-resistant cells restored sensitivity to ganetespib, whereas p90RSK overexpression induced ganetespib resistance in naïve cells, validating p90RSK as a mediator of resistance and a novel therapeutic target. Our studies offer a way forward for Hsp90 inhibitors through the rational design of Hsp90 inhibitor combinations that may prevent and/or overcome resistance to Hsp90 inhibitors, providing an effective therapeutic strategy for KRAS-mutant NSCLC. Mol Cancer Ther; 16(5); 793–804. ©2017 AACR.

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Fluorinated N,N'-Diarylureas As Novel Therapeutic Agents Against Cancer Stem Cells

Colorectal cancer is the second-leading cause of cancer-related mortality in the United States. More than 50% of patients with colorectal cancer will develop local recurrence or distant organ metastasis. Cancer stem cells play a major role in the survival and metastasis of cancer cells. In this study, we examined the effects of novel AMP-activated protein kinase (AMPK) activating compounds on colorectal cancer metastatic and stem cell lines as potential candidates for chemotherapy. We found that activation of AMPK by all fluorinated N,N-diarylureas (FND) compounds at micromolar levels significantly inhibited the cell-cycle progression and subsequent cellular proliferation. In addition, we demonstrated that select FNDs significantly increased apoptosis in colorectal cancer metastatic and cancer stem cells. Therefore, FNDs hold considerable promise in the treatment of metastatic colorectal cancer, through elimination of both regular cancer cells and cancer stem cells. Mol Cancer Ther; 16(5); 831–7. ©2017 AACR.

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Characterization of a Dual Rac/Cdc42 Inhibitor MBQ-167 in Metastatic Cancer

The Rho GTPases Rac (Ras-related C3 botulinum toxin substrate) and Cdc42 (cell division control protein 42 homolog) regulate cell functions governing cancer malignancy, including cell polarity, migration, and cell-cycle progression. Accordingly, our recently developed Rac inhibitor EHop-016 (IC₅₀, 1,100 nmol/L) inhibits cancer cell migration and viability and reduces tumor growth, metastasis, and angiogenesis in vivo. Herein, we describe MBQ-167, which inhibits Rac and Cdc42 with IC₅₀ values of 103 and 78 nmol/L, respectively, in metastatic breast cancer cells. Consequently, MBQ-167 significantly decreases Rac and Cdc42 downstream effector p21-activated kinase (PAK) signaling and the activity of STAT3, without affecting Rho, MAPK, or Akt activities. MBQ-167 also inhibits breast cancer cell migration, viability, and mammosphere formation. Moreover, MBQ-167 affects cancer cells that have undergone epithelial-to-mesenchymal transition by a loss of cell polarity and inhibition of cell surface actin-based extensions to ultimately result in detachment from the substratum. Prolonged incubation (120 hours) in MBQ-167 decreases metastatic cancer cell viability with a GI₅₀ of approximately 130 nmol/L, without affecting noncancer mammary epithelial cells. The loss in cancer cell viability is due to MBQ-167–mediated G₂–M cell-cycle arrest and subsequent apoptosis, especially of the detached cells. In vivo, MBQ-167 inhibits mammary tumor growth and metastasis in immunocompromised mice by approximately 90%. In conclusion, MBQ-167 is 10x more potent than other currently available Rac/Cdc42 inhibitors and has the potential to be developed as an anticancer drug, as well as a dual inhibitory probe for the study of Rac and Cdc42. Mol Cancer Ther; 16(5); 805–18. ©2017 AACR.

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Selective Killing of SMARCA2- and SMARCA4-deficient Small Cell Carcinoma of the Ovary, Hypercalcemic Type Cells by Inhibition of EZH2: In Vitro and In Vivo Preclinical Models

The SWI/SNF complex is a major regulator of gene expression and is increasingly thought to play an important role in human cancer, as evidenced by the high frequency of subunit mutations across virtually all cancer types. We previously reported that in preclinical models, malignant rhabdoid tumors, which are deficient in the SWI/SNF core component INI1 (SMARCB1), are selectively killed by inhibitors of the H3K27 histone methyltransferase EZH2. Given the demonstrated antagonistic activities of the SWI/SNF complex and the EZH2-containing PRC2 complex, we investigated whether additional cancers with SWI/SNF mutations are sensitive to selective EZH2 inhibition. It has been recently reported that ovarian cancers with dual loss of the redundant SWI/SNF components SMARCA4 and SMARCA2 are characteristic of a rare rhabdoid-like subtype known as small-cell carcinoma of the ovary hypercalcemic type (SCCOHT). Here, we provide evidence that a subset of commonly used ovarian carcinoma cell lines were misdiagnosed and instead were derived from a SCCOHT tumor. We also demonstrate that tazemetostat, a potent and selective EZH2 inhibitor currently in phase II clinical trials, induces potent antiproliferative and antitumor effects in SCCOHT cell lines and xenografts deficient in both SMARCA2 and SMARCA4. These results exemplify an additional class of rhabdoid-like tumors that are dependent on EZH2 activity for survival. Mol Cancer Ther; 16(5); 850–60. ©2017 AACR.

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Modulating Therapeutic Activity and Toxicity of Pyrrolobenzodiazepine Antibody-Drug Conjugates with Self-Immolative Disulfide Linkers

A novel disulfide linker was designed to enable a direct connection between cytotoxic pyrrolobenzodiazepine (PBD) drugs and the cysteine on a targeting antibody for use in antibody–drug conjugates (ADCs). ADCs composed of a cysteine-engineered antibody were armed with a PBD using a self-immolative disulfide linker. Both the chemical linker and the antibody site were optimized for this new bioconjugation strategy to provide a highly stable and efficacious ADC. This novel disulfide ADC was compared with a conjugate containing the same PBD drug, but attached to the antibody via a peptide linker. Both ADCs had similar efficacy in mice bearing human tumor xenografts. Safety studies in rats revealed that the disulfide-linked ADC had a higher MTD than the peptide-linked ADC. Overall, these data suggest that the novel self-immolative disulfide linker represents a valuable way to construct ADCs with equivalent efficacy and improved safety. Mol Cancer Ther; 16(5); 871–8. ©2017 AACR.

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Preclinical Antitumor Efficacy of BAY 1129980--a Novel Auristatin-Based Anti-C4.4A (LYPD3) Antibody-Drug Conjugate for the Treatment of Non-Small Cell Lung Cancer

C4.4A (LYPD3) has been identified as a cancer- and metastasis-associated internalizing cell surface protein that is expressed in non–small cell lung cancer (NSCLC), with particularly high prevalence in the squamous cell carcinoma (SCC) subtype. With the exception of skin keratinocytes and esophageal endothelial cells, C4.4A expression is scarce in normal tissues, presenting an opportunity to selectively treat cancers with a C4.4A-directed antibody–drug conjugate (ADC). We have generated BAY 1129980 (C4.4A-ADC), an ADC consisting of a fully human C4.4A-targeting mAb conjugated to a novel, highly potent derivative of the microtubule-disrupting cytotoxic drug auristatin via a noncleavable alkyl hydrazide linker. In vitro, C4.4A-ADC demonstrated potent antiproliferative efficacy in cell lines endogenously expressing C4.4A and inhibited proliferation of C4.4A-transfected A549 lung cancer cells showing selectivity compared with a nontargeted control ADC. In vivo, C4.4A-ADC was efficacious in human NSCLC cell line (NCI-H292 and NCI-H322) and patient-derived xenograft (PDX) models (Lu7064, Lu7126, Lu7433, and Lu7466). C4.4A expression level correlated with in vivo efficacy, the most responsive being the models with C4.4A expression in over 50% of the cells. In the NCI-H292 NSCLC model, C4.4A-ADC demonstrated equal or superior efficacy compared to cisplatin, paclitaxel, and vinorelbine. Furthermore, an additive antitumor efficacy in combination with cisplatin was observed. Finally, a repeated dosing with C4.4A-ADC was well tolerated without changing the sensitivity to the treatment. Taken together, C4.4A-ADC is a promising therapeutic candidate for the treatment of NSCLC and other cancers expressing C4.4A. A phase I study (NCT02134197) with the C4.4A-ADC BAY 1129980 is currently ongoing. Mol Cancer Ther; 16(5); 893–904. ©2017 AACR.

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Inhibition of Isoprenylcysteine Carboxylmethyltransferase Induces Cell-Cycle Arrest and Apoptosis through p21 and p21-Regulated BNIP3 Induction in Pancreatic Cancer

Pancreatic cancer remains one of the most difficult to treat human cancers despite recent advances in targeted therapy. Inhibition of isoprenylcysteine carboxylmethyltransferase (ICMT), an enzyme that posttranslationally modifies a group of proteins including several small GTPases, suppresses proliferation of some human cancer cells. However, the efficacy of ICMT inhibition on human pancreatic cancer has not been evaluated. In this study, we have evaluated a panel of human pancreatic cancer cell lines and identified those that are sensitive to ICMT inhibition. In these cells, ICMT suppression inhibited proliferation and induced apoptosis. This responsiveness to ICMT inhibition was confirmed in in vivo xenograft tumor mouse models using both a small-molecule inhibitor and shRNA-targeting ICMT. Mechanistically, we found that, in sensitive pancreatic cancer cells, ICMT inhibition induced mitochondrial respiratory deficiency and cellular energy depletion, leading to significant upregulation of p21. Furthermore, we characterized the role of p21 as a regulator and coordinator of cell signaling that responds to cell energy depletion. Apoptosis, but not autophagy, that is induced via p21-activated BNIP3 expression accounts for the efficacy of ICMT inhibition in sensitive pancreatic cancer cells in both in vitro and in vivo models. In contrast, cells resistant to ICMT inhibition demonstrated no mitochondria dysfunction or p21 signaling changes under ICMT suppression. These findings not only identify pancreatic cancers as potential therapeutic targets for ICMT suppression but also provide an avenue for identifying those subtypes that would be most responsive to agents targeting this critical enzyme. Mol Cancer Ther; 16(5); 914–23. ©2017 AACR.

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Highly Potent, Anthracycline-based Antibody-Drug Conjugates Generated by Enzymatic, Site-specific Conjugation

Antibody–drug conjugates (ADC) are highly potent and specific antitumor drugs, combining the specific targeting of mAbs with the potency of small-molecule toxic payloads. ADCs generated by conventional chemical conjugation yield heterogeneous mixtures with variable pharmacokinetics, stability, safety, and efficacy profiles. To address these issues, numerous site-specific conjugation technologies are currently being developed allowing the manufacturing of homogeneous ADCs with predetermined drug-to-antibody ratios. Here, we used sortase-mediated antibody conjugation (SMAC) technology to generate homogeneous ADCs based on a derivative of the highly potent anthracycline toxin PNU-159682 and a noncleavable peptide linker, using the anti-HER2 antibody trastuzumab (part of Kadcyla) and the anti-CD30 antibody cAC10 (part of Adcetris). Characterization of the resulting ADCs in vitro and in vivo showed that they were highly stable and exhibited potencies exceeding those of ADCs based on conventional tubulin-targeting payloads, such as Kadcyla and Adcetris. The data presented here suggest that such novel and highly potent ADC formats may help to increase the number of targets available to ADC approaches, by reducing the threshold levels of target expression required. Mol Cancer Ther; 16(5); 879–92. ©2017 AACR.

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Lipid Nanoparticle-Mediated Delivery of Anti-miR-17 Family Oligonucleotide Suppresses Hepatocellular Carcinoma Growth

Hepatocellular carcinoma (HCC) is one of the most common human malignancies with poor prognosis and urgent unmet medical need. Aberrant expression of multiple members of the miR-17 family are frequently observed in HCC, and their overexpression promotes tumorigenic properties of HCC cells. However, whether pharmacologic inhibition of the miR-17 family inhibits HCC growth remains unknown. In this study, we validated that the miR-17 family was upregulated in a subset of HCC tumors and cell lines and its inhibition by a tough decoy inhibitor suppressed the growth of Hep3B and HepG2 cells, which overexpress the miR-17 family. Furthermore, inhibition of the miR-17 family led to a global derepression of direct targets of the family in all three HCC cell lines tested. Pathway analysis of the deregulated genes indicated that the genes associated with TGFβ signaling pathway were highly enriched in Hep3B and HepG2 cells. A miR-17 family target gene signature was established and used to identify RL01-17(5), a lipid nanoparticle encapsulating a potent anti-miR-17 family oligonucleotide. To address whether pharmacologic modulation of the miR-17 family can inhibit HCC growth, RL01-17(5) was systemically administrated to orthotopic Hep3B xenografts. Suppression of Hep3B tumor growth in vivo was observed and tumor growth inhibition correlated with induction of miR-17 family target genes. Together, this study provides proof-of-concept for targeting the miR-17 family in HCC therapy. Mol Cancer Ther; 16(5); 905–13. ©2017 AACR.

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Role of STAT3 and FOXO1 in the Divergent Therapeutic Responses of Non-metastatic and Metastatic Bladder Cancer Cells to miR-145

Although miR-145 is the most frequently downregulated miRNA in bladder cancer, its exact stage association and downstream effector have not been defined. Here, we found that miR-145 was upregulated in human patients with bladder cancer with lymph node metastasis and in metastatic T24T cell line. Forced expression of miR-145 promoted anchorage-independent growth of T24T cells accompanied by the downregulation of forkhead box class O1 (FOXO1). In contrast, in non-metastatic T24 cells, miR-145 overexpression inhibited cell growth with upregulation of FOXO1, and the knockdown of FOXO1 abolished the miR-145–mediated inhibition of cell growth. Mechanistic studies revealed that miR-145 directly bound to and attenuated 3'-untranslated region (UTR) activity of foxo1 mRNA in both T24 and T24T cells. Interestingly, miR-145 suppressed STAT3 phosphorylation at Tyr705 and increased foxo1 promoter transcriptional activity in T24 cells, but not in T24T cells, suggesting a role of STAT3 in the divergent responses to miR-145. Supporting this was our finding that STAT3 knockdown mimicked miR-145–mediated upregulation of FOXO1 in T24T cells and inhibition of anchorage-independent growth. Consistently, ectopic expression of miR-145 promoted tumor formation of xenograft T24T cells, whereas such promoting effect became inhibitory due to specific knockdown of STAT3. Together, our findings demonstrate the stage-specific association and function of miR-145 in bladder cancers and provide novel insights into the therapeutic targeting of miR-145. Mol Cancer Ther; 16(5); 924–35. ©2017 AACR.

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Calcium-Dependent Enhancement by Extracellular Acidity of the Cytotoxicity of Mitochondrial Inhibitors against Melanoma

Extracellular acidity is a hallmark of cancers and is independent of hypoxia. Because acidity potentiates malignant phenotypes, therapeutic strategies that enhance the targeting of oncogenic mechanisms in an acidic microenvironment should be effective. We report here that drugs which abrogate mitochondrial respiration show enhanced cytotoxicity against melanoma cells in a normoxic but acidic extracellular pH, independent from P53 mutations, BRAF (V600E) mutations, and/or resistance against BRAF inhibitors. Conversely, the cytotoxicity against melanoma cells of mitochondrial inhibitors is impaired by a neutral or alkaline extracellular pH, and in vivo systemic alkalinization with NaHCO₃ enhanced subcutaneous tumor growth and lung metastasis of B16F10 cells in mice treated with the mitochondrial inhibitor phenformin. Intracellular calcium (Ca²⁺) was significantly increased in melanoma cells treated with mitochondrial inhibitors at an acidic extracellular pH and an intracellular Ca²⁺ chelator, BAPTA/AM, inhibited cytoplasmic Ca²⁺ as well as melanoma cell death. Surprisingly, ROS scavengers synergized with increased apoptosis in cells treated with mitochondrial inhibitors, suggesting that ROS contributes to cell survival in this context. Notably, the cytotoxic enhancement of mitochondrial inhibitors by acidity was distinct from PGC1alpha-driven mitochondrial addiction, from therapy-induced senescence, and from slow, JARID1B-high–associated cell cycling, all of which have been shown to promote vulnerability to mitochondrial inhibition. These data indicate that extracellular pH profoundly modulates the cytotoxicity of mitochondrial inhibitors against cancer cells. Mol Cancer Ther; 16(5); 936–47. ©2017 AACR.

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Cell-Free DNA from Ascites and Pleural Effusions: Molecular Insights into Genomic Aberrations and Disease Biology

Collection of cell-free DNA (cfDNA) from the blood of individuals with cancer has permitted noninvasive tumor genome analysis. Detection and characterization of cfDNA in ascites and pleural effusions have not yet been reported. Herein, we analyzed cfDNA in the ascites and pleural effusions from six individuals with metastatic cancer. In all cases, cfDNA copy number variations (CNV) were discovered within the effusate. One individual had a relevant alteration with a high copy amplification in EGFR in a never smoker with lung cancer, who showed only MDM2 and CDK4 amplification in a prior tissue biopsy. Another subject with metastatic breast cancer had cytology-positive ascites and an activating PIK3CA mutation identified in the tissue, blood, and ascites collectively. This individual had tumor regression after the administration of the mTOR inhibitor everolimus and had evidence of chromotripsis from chromosomal rearrangements noted in the cell-free ascitic fluid. These results indicate that cfDNA from ascites and pleural effusions may provide additional information not detected with tumor and plasma cell-free DNA molecular characterization, and a context for important insights into tumor biology and clonal dynamic change within primary tumor and metastatic deposits. Mol Cancer Ther; 16(5); 948–55. ©2017 AACR.

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Safe and Effective Sarcoma Therapy through Bispecific Targeting of EGFR and uPAR

Sarcomas differ from carcinomas in their mesenchymal origin. Therapeutic advancements have come slowly, so alternative drugs and models are urgently needed. These studies report a new drug for sarcomas that simultaneously targets both tumor and tumor neovasculature. eBAT is a bispecific angiotoxin consisting of truncated, deimmunized Pseudomonas exotoxin fused to EGF and the amino terminal fragment of urokinase. Here, we study the drug in an in vivo "ontarget" companion dog trial as eBAT effectively kills canine hemangiosarcoma and human sarcoma cells in vitro. We reasoned the model has value due to the common occurrence of spontaneous sarcomas in dogs and a limited lifespan allowing for rapid accrual and data collection. Splenectomized dogs with minimal residual disease were given one cycle of eBAT followed by adjuvant doxorubicin in an adaptive dose-finding, phase I–II study of 23 dogs with spontaneous, stage I–II, splenic hemangiosarcoma. eBAT improved 6-month survival from <40% in a comparison population to approximately 70% in dogs treated at a biologically active dose (50 μg/kg). Six dogs were long-term survivors, living >450 days. eBAT abated expected toxicity associated with EGFR targeting, a finding supported by mouse studies. Urokinase plasminogen activator receptor and EGFR are targets for human sarcomas, so thorough evaluation is crucial for validation of the dog model. Thus, we validated these markers for human sarcoma targeting in the study of 212 human and 97 canine sarcoma samples. Our results support further translation of eBAT for human patients with sarcomas and perhaps other EGFR-expressing malignancies. Mol Cancer Ther; 16(5); 956–65. ©2017 AACR.

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HSP70 Inhibition Synergistically Enhances the Effects of Magnetic Fluid Hyperthermia in Ovarian Cancer

Hyperthermia has been investigated as a potential treatment for cancer. However, specificity in hyperthermia application remains a significant challenge. Magnetic fluid hyperthermia (MFH) may be an alternative to surpass such a challenge, but implications of MFH at the cellular level are not well understood. Therefore, the present work focused on the examination of gene expression after MFH treatment and using such information to identify target genes that when inhibited could produce an enhanced therapeutic outcome after MFH. Genomic analyzes were performed using ovarian cancer cells exposed to MFH for 30 minutes at 43°C, which revealed that heat shock protein (HSP) genes, including HSPA6, were upregulated. HSPA6 encodes the Hsp70, and its expression was confirmed by PCR in HeyA8 and A2780cp20 ovarian cancer cells. Two strategies were investigated to inhibit Hsp70-related genes, siRNA and Hsp70 protein function inhibition by 2-phenylethyenesulfonamide (PES). Both strategies resulted in decreased cell viability following exposure to MFH. Combination index was calculated for PES treatment reporting a synergistic effect. In vivo efficacy experiments with HSPA6 siRNA and MFH were performed using the A2780cp20 and HeyA8 ovarian cancer mouse models. A significantly reduction in tumor growth rate was observed with combination therapy. PES and MFH efficacy were also evaluated in the HeyA8 intraperitoneal tumor model, and resulted in robust antitumor effects. This work demonstrated that HSP70 inhibition combination with MFH generate a synergistic effect and could be a promising target to enhance MFH therapeutic outcomes in ovarian cancer. Mol Cancer Ther; 16(5); 966–76. ©2017 AACR.

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Retraction: Proteasome Inhibition Blocks NF-{kappa}B and ERK1/2 Pathways, Restores Antigen Expression, and Sensitizes Resistant Human Melanoma to TCR-Engineered CTLs

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The angle of mandible was found to be the most accurate landmark for identifying the cervical level, which corresponded to C2 and C2–C3 disc space. The hyoid bone, thyroid cartilage, and cricoid cartilage were not reliable to predict the cervical levels : The lateral flexion and extension radiographs of cervical spine in standing position : Anterior Cervical Surgical Landmarks (the hyoid bone, thyroid cartilage, and cricoid cartilage).The main corresponding cervical levels for the mandibular angle were C2 on both of the flexion and extension films, for the hyoid bone were the C3–C4 interspace on flexion film and C3 on extension film, for the thyroid cartilage C5 on both of flexion and extension films, and for the cricoid cartilage C6 on flexion film and C5–C6 interspace on extension film, respectively.

http://otorhinolaryngology-crete.blogspot.com/2017/05/the-angle-of-mandible-was-found-to-be.html

Radiographic Evaluation of the Reliability of Neck Anatomic Structures as Anterior Cervical Surgical Landmarks

στο World Neurosurgery

Μετάφραση άρθρου

Publication date: July 2017

Source:World Neurosurgery, Volume 103

Author(s): Jia-Ming Liu, Liu-Xue Du, Xu Xiong, Xuan-Yin Chen, Yang Zhou, Xin-Hua Long, Shan-Hu Huang, Zhi-Li Liu

BackgroundAccurate location of the skin incision is helpful to decrease the technical difficulty and save the operative time in anterior cervical spine surgery. Spine surgeons usually use the traditional neck anatomic structures (the hyoid bone, thyroid cartilage, and cricoid cartilage) as landmarks during the surgery. However, the reliability of these landmarks has not been validated in actual practice.ObjectiveTo find out which landmark is the most accurate for identifying the cervical levels in anterior cervical spine surgery.MethodsThe lateral flexion and extension radiographs of cervical spine in standing position from 30 consecutive patients from January 2015 to February 2015 were obtained. The cervical vertebral bodies from C2 to C7 were divided equally into 2 segments. The cervical segments corresponding to each of the surface landmarks were recorded on the flexion and extension radiographs, respectively, and the displacement of corresponding cervical segments from the flexion to extension radiographs for each landmark was calculated.ResultsBased on the measurements, the main corresponding cervical levels for the mandibular angle were C2 on both of the flexion and extension films, for the hyoid bone were the C3–C4 interspace on flexion film and C3 on extension film, for the thyroid cartilage C5 on both of flexion and extension films, and for the cricoid cartilage C6 on flexion film and C5–C6 interspace on extension film, respectively. The ratios of displacement within 2 segments from flexion to extension were 83.3% (25/30) for mandibular angle, 56.7% (17/30) for hyoid bone, 66.7% (20/30) for thyroid cartilage, and 56.7% (17/30) for cricoid cartilage, respectively. The mean displacement from flexion to extension films were significantly less than 2 cervical segments for the mandibular angle but greater than 2 segments for the other landmarks. Significant differences were found between mandibular angle and the other 3 landmarks for the displacement from flexion to extension.ConclusionsThe angle of mandible was found to be the most accurate landmark for identifying the cervical level, which corresponded to C2 and C2–C3 disc space. The hyoid bone, thyroid cartilage, and cricoid cartilage were not reliable to predict the cervical levels.

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

6948891480

alsfakia@gmail.com

Histopathological Comparisons of Staphylococcus aureus and Pseudomonas aeruginosa Experimental Infected Porcine Burn Wounds

Abstract

Chronic skin wounds are a significant human health concern and are often complicated by infection with Pseudomonas aeruginosa and Staphylococcus aureus, particularly methicillin resistant S. aureus (MRSA). Translating the knowledge gained from extensive study of virulence mechanisms and pathogenesis of these bacterial species to new treatment modalities has been lacking in part due to a paucity of animal models able to recapitulate human disease. Our groups recently described a novel porcine chronic burn wound model for the study of bacterial infection; however, the histopathology of infection has yet to be described. The objective of this study is to define the histopathology of this model using important human chronic wound bacterial isolates. Porcine full-thickness burn wounds topically inoculated with P. aeruginosa strain PAO1, MRSA S. aureus strain USA300 or both bacteria were used to define and quantify histopathologic lesions. The development of a systemic, well-defined rubric for analysis allowed for evaluation of differences between infection groups. These differences, which included epithelial migration and proliferation, stromal necrosis, fluid accumulation and intensity and character of the innate and adaptive inflammatory cell responses, were identified temporally between infection groups. Mono-species infected wounds developed a hyper-proliferative wound edge. Co-infected wounds at day 35 had the largest wound sizes, increased amounts of neutrophilic inflammation, immaturity of the wound bed, and retention of necrotic tissue. Infection, regardless of species, inhibited wound contracture at all time points evaluated. Most importantly, this model recapitulated key features of chronic human wounds. Thus, this model will allow researchers to study novel treatment modalities in a biologically relevant animal model while monitoring both host and bacterial responses. This article is protected by copyright. All rights reserved.

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Characterization of Mycobacterium marinum Infections in Zebrafish Wounds and Sinus Tracts

Abstract

The impaired healing of Mycobacterium tuberculosis-infected wounds is a clinical challenge, and the mechanisms involved are still not clear. The zebrafish model of Mycobacterium marinum infection has provided surprising insights into the pathogenesis of tuberculosis in humans. Similarly, the major principles and phases of cutaneous wound healing are conserved among adult mammals and adult zebrafish. Here, we injected Mycobacterium marinum into the dorsal muscles of adult zebrafish and observed the development of chronic wound pathology. Deep sequencing showed that gene expression related to muscles was down-regulated, whereas expressions of the IL-1β, TNF-α, dram1 genes and the transcript of mir1-2 gene were up-regulated in infected wounds of zebrafish compared to control zebrafish. Muscles are immune-responsive tissues. Thus, muscles may play a role in the anti-Mycobacterium tuberculosis immunologic process, which leads to apoptosis of the infected muscle cell and formation of the subcutaneous sinus tract. This article is protected by copyright. All rights reserved.

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Periosteal turndown flap for posterior occipitocervical fusion: a technique review

Abstract

Purpose

Recently, several authors have proposed techniques for improving the fusion rate in pediatric posterior occipitocervical fusion including a variety of implants and the use of bone morphogenetic protein. A technique by Koop et al. using a periosteal flap for occipitocervical arthrodesis was described in 1984.

Methods

A straight incision is made about the posterior neck to expose the occipitocervical region from the inion superiorly to the lowest cervical vertebrae to be fused inferiorly. The occiput is exposed superficial to the periosteum, which is then reflected and elevated from the occiput. The attachment is preserved at the caudal base of the flap and reflected over the intended area of fusion. When possible, fixation is then performed with cables, wires, screws, hooks, or plates.

Case example

A 6-year-old male with an occiput to C2 distraction injury underwent posterior spinal fusion from occiput to C3 using sublaminar wires, periosteal turndown flap, and autologous iliac crest bone graft.

Conclusion

In small children with traumatic upper cervical spine instability, the periosteal turndown technique may be used as a safe adjunct for occipitocervical fusions.

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Erratum to: Real-time adult authentication scheme for digital contents using X.509 certificate in ubiquitous Web environment

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Bitter Melon Enhances Natural Killer Mediated Toxicity against Head and Neck Cancer Cells

Natural Killer (NK) cells are one of the major components of innate immunity, with the ability to mediate antitumor activity. Understanding the role of NK cell mediated tumor killing in controling of solid tumor growth is still in the developmental stage. We have shown recently that bitter melon extract (BME) modulates the regulatory T cell (Treg) population in head and neck squamous cell carcinoma (HNSCC). However, the role of BME in NK cell modulation against HNSCC remains unknown. In this study, we investigated whether BME can enhance the NK cell killing activity against HNSCC cells. Our results indicated that treatment of human NK cell line (NK3.3) with BME enhances ability to kill HNSCC cells. BME increases granzyme B accumulation and translocation/accumulation of CD107a/LAMP1 in NK3.3 cells exposed to BME. Further, an increase in cell surface expression of CD16 and NKp30 in BME treated NK3.3 cells was observed when co-cultured with HNSCC cells. Collectively, our results demonstrated for the first time that BME augments NK cell mediated HNSCC killing activity, implicating an immunomodulatory role of BME.

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Interacting convection modes in a saturated porous medium of nearly square planform: a special case

Abstract

A multitude of convection modes may occur within a confined rectangular box of saturated porous medium when the associated dimensionless Rayleigh number R is above some critical value. For particular sizes of box, however, it is possible for multiple modes (typically three) to share a common critical Rayleigh number. For box shapes close to these geometries, modes can interact and compete nonlinearly near the onset of convection. The generic examples of this phenomenon can be conveniently classified as belonging to one of two distinctive classes distinguished by whether or not fixed points are possible with all three modes having a non-zero amplitude. It transpires that this classification is not quite exhaustive for there is one particular case which falls outside this pattern. This last case, which is described by a system of evolution equations that is structurally different from that applying in the generic situation, is explored in this paper. Some rich dynamical behaviours are uncovered and, in particular, it is shown that at sufficiently large R stable states arise in which all three modes persist. This contrasts to the typical generic behaviour where a single mode is preferred. The bifurcation sequence that develops as the Rayleigh number grows is mapped out from primary through to tertiary stages. In addition, it is found that a cusp bifurcation is present and that the details of the ordering of the various bifurcations are shown to be sensitive to the precise geometry of the box.

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An HNF4{alpha}-microRNA-194/192 Signaling Axis Maintains Hepatic Cell Function [Metabolism]

HNF4α controls the expression of liver-specific protein-coding genes. However, some microRNAs (miRNAs) are also modulated by HNF4α, and it is not known whether they are direct targets of HNF4α, and whether they influence the hepatic function. In this study, we found that HNF4α regulates miRNAs, indicated by marked down-regulation of miR-194 and miR-192 (miR-194/192) in liver-specific Hnf4a-null (Hnf4aΔH) mice. Transactivation of the shared miR-194/192 promoter was dependent on HNF4α expression, indicating that miR194/192 is a target gene of HNF4α. Screening of potential mRNAs targeted by miR-194/192 revealed that expression of genes involved in glucose metabolism [glycogenin 1 (Gyg1)], cell adhesion and migration [activated leukocyte cell adhesion molecule (Alcam)], tumorigenesis and tumor progression [Rap2b and epiregulin (Ereg)], protein SUMOylation (Sumo2), epigenetic regulation [Setd5 and Cullin 4B (Cln4b)], and the epithelial-mesenchymal transition [moesin (Msn)] was up-regulated in Hnf4aΔH mice. Moreover, we also found that miR-194/192 binds the 3′-UTR of these mRNAs. siRNA knockdown of HNF4α suppressed miR-194/192 expression in human hepatocellular carcinoma (HCC) cells and resulted in up-regulation of their mRNA targets. Inhibition and overexpression experiments with miR-194/192 revealed that Gyg1, Setd5, Sumo2, Cln4b, and Rap2b are miR-194 targets, while Ereg, Alcam, and Msn are miR-192 targets. These findings reveal a novel HNF4α network controlled by miR-194/192 that may play a critical role in maintaining the hepatocyte-differentiated state by inhibiting expression of genes involved in dedifferentiation and tumorigenesis. These insights may contribute to the development of diagnostic markers for early HCC detection, and targeting of the miR-194/192 pathway could be useful for managing HCC.

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Cystinosin, the small GTPase Rab11, and the Rab7 effector RILP regulate intracellular trafficking of the chaperone-mediated autophagy receptor LAMP2A [Molecular Bases of Disease]

The lysosomal storage disease cystinosis, caused by cystinosin-deficiency, is characterized by cell malfunction, tissue failure and progressive renal injury despite cystine-depletion therapies. Cystinosis is associated with defects in chaperone-mediated autophagy (CMA), but the molecular mechanisms are incompletely understood. Here, we show CMA substrate accumulation in cystinotic kidney proximal tubule cells. We also found mislocalization of the CMA lysosomal receptor LAMP2A, and impaired substrate translocation into the lysosome caused by defective CMA in cystinosis. The impaired LAMP2A trafficking and localization were rescued either by the expression of wild-type cystinosin or by the disease-associated point mutant CTNS-K280R which has no cystine transporter activity. Defective LAMP2A trafficking in cystinosis was found to associate with decreased expression of the small GTPase Rab11 and the Rab7 effector RILP. Defective Rab11 trafficking in cystinosis was rescued by treatment with small-molecule CMA activators. RILP expression was restored by upregulation of the transcription factor EB (TFEB), which was downregulated in cystinosis. Although LAMP2A expression is independent of TFEB, TFEB upregulation corrected lysosome distribution and lysosomal LAMP2A localization in Ctns-/- cells but not Rab11 defects. The upregulation of Rab11, Rab7, or RILP, but not its truncated form RILP-C33, rescued LAMP2A-defective trafficking in cystinosis, while dominant-negative Rab11 or Rab7 impaired LAMP2A trafficking. Treatment of cystinotic cells with a CMA activator increased LAMP2A localization at the lysosome and increased cell survival. Altogether, we show that LAMP2A trafficking is regulated by cystinosin, Rab11, and RILP and that CMA upregulation is a potential clinically relevant mechanism to increase cell survival in cystinosis.

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TRIM24 Promotes While TRIM32 Inhibits Cardiomyocyte Hypertrophy via Regulation of Dysbindin Protein Levels [Signal Transduction]

We have previously shown that Dysbindin is a potent inducer of cardiomyocyte hypertrophy via activation of Rho-dependent SRF signaling. We now performed a Yeast-two hybrid screen using Dysbindin as bait against a cardiac cDNA library to identify the cardiac Dysbindin interactome. Amongst several putative binding proteins, we identified Tripartite motif-containing protein 24 (TRIM24) and confirmed this interaction by co-immunoprecipitation and co-immunostaining. Another TRIM family protein, TRIM32 has earlier been reported as an E3 ubiquitin ligase for Dysbindin in skeletal muscle. Consistently, we found that TRIM32 degraded Dysbindin in neonatal rat ventricular cardiomyocytes (NRVCMs) as well. Surprisingly however, TRIM24 did not promote Dysbindin decay but rather protected Dysbindin against degradation by TRIM32. Correspondingly, TRIM32 attenuated the activation of SRF-signaling and hypertrophy due to Dysbindin, whereas, TRIM24 promoted these effects in NRVCMs. The present study also implies that TRIM32 is a key regulator of cell viability and apoptosis in cardiomyocytes via simultaneous activation of p53 and Caspase-3/-7, and inhibition of XIAP (X-linked inhibitor of apoptosis). In conclusion, we here provide a novel mechanism of post-translational regulation of Dysbindin and hypertrophy via TRIM24 and TRIM32, and importance of TRIM32 in cardiomyocyte apoptosis in vitro.

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Myostatin Inhibits Osteoblastic Differentiation by Suppressing Osteocyte-derived Exosomal microRNA-218: A Novel Mechanism in Muscle-Bone Communication. [Molecular Bases of Disease]

Muscle and bone are closely associated in both anatomy and function, but the mechanisms that coordinate their synergistic action remain poorly defined. Myostatin, a myokine secreted by muscles, has been shown to inhibit muscle growth, and the disruption of the myostatin gene has been reported to cause muscle hypertrophy and increase bone mass. Extracellular vesicle-exosomes that carry microRNA (miRNA), mRNA, and proteins are known to perform an important role in cell-cell communication. We hypothesized that myostatin may play a crucial role in muscle-bone interactions and may promote direct effects on osteocytes and on osteocyte-derived exosomal miRNAs, thereby indirectly influencing the function of other bone cells. We report herein that myostatin promotes expression of several bone regulators such as sclerostin (SOST), DKK1, and RANKL in cultured osteocytic (Ocy454) cells, concomitant with the suppression of miR-218 in both parent Ocy454 cells and derived exosomes. Exosomes produced by Ocy454 cells that had been pretreated with myostatin could be taken up by osteoblastic MC3T3 cells, resulting in a marked reduction of Runx2, a key regulator of osteoblastic differentiation, and in decreased osteoblastic differentiation, via the down-regulation of the Wnt signaling pathway. Importantly, the inhibitory effect of myostatin-modified osteocytic exosomes on osteoblast differentiation is completely reversed by expression of exogenous miR-218, through a mechanism involving miR-218-mediated inhibition of SOST. Together, our findings indicate that myostatin directly influences osteocyte function and thereby inhibits osteoblastic differentiation, at least in part, through the suppression of osteocyte-derived exosomal miR-218, suggesting a novel mechanism in muscle-bone communication.

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Sirtuin E is a fungal global transcriptional regulator that determines the transition from the primary growth to the stationary phase [Metabolism]

In response to limited nutrients, fungal cells exit the primary growth phase, enter the stationary phase, and cease proliferation. Although fundamental to microbial physiology in many environments, the regulation of this transition is poorly understood, but likely involves many transcriptional regulators. These may include the sirtuins, which deacetylate acetyllysine residues of histones, and epigenetically regulate global transcription. Therefore, we investigated the role of a nuclear sirtuin, sirtuin E (SirE), from the ascomycete fungus, Aspergillus nidulans. An A. nidulans strain with a disrupted sirE gene (SirEΔ) accumulated more acetylated histone H3 during the stationary growth phase when sirE was expressed at increased levels in the wild type. SirEΔ exhibited decreased mycelial autolysis, conidiophore development, sterigmatocystin biosynthesis, and production of extracellular hydrolases. Moreover, the transcription of the genes involved in these processes was also decreased, indicating that SirE is a histone deacetylase that up-regulates these activity in the stationary growth phase. Transcriptome analyses indicated that SirE repressed primary carbon and nitrogen metabolism and cell-wall synthesis. Chromatin immunoprecipitation demonstrated that SirE deacetylates acetylated K9 residues in histone H3 at the gene promoters of α-1,3-glucan synthase (agsB), glycolytic phosphofructokinase (pfkA), and glyceraldehyde 3-phosphate (gpdA), indicating that SirE represses the expression of these primary metabolic genes. In summary, these results indicate that SirE facilitates the metabolic transition from the primary growth phase to stationary phase. Because the observed gene expression profiles in stationary phase matched those resulting from carbon starvation, SirE appears to control this metabolic transition via a mechanism associated with the starvation response.

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Genetic Metabolic Complementation establishes a requirement for GDP-Fucose in Leishmania [Microbiology]

To survive in its sand fly vector, the trypanosomatid protozoan parasite Leishmania first attaches to the midgut to avoid excretion, but eventually it must detach for transmission by the next bite. In Leishmania major strain Friedlin, this is controlled by modifications of the stage-specific adhesin lipophosphoglycan (LPG). During differentiation to infective metacyclics, D-arabinopyranose (D-Arap) caps the LPG side-chain galactose residues, blocking interaction with the midgut lectin PpGalec, thereby leading to parasite detachment and transmission. Previously we characterized two closely related L. major genes (FKP40 and AFKP80) encoding bifunctional proteins with kinase / pyrophosphorylase activities required for salvage and conversion of L-Fucose and/or D-Arap into the nucleotide-sugar substrates required by glycosyltransferases. While only AFKP80 yielded GDP-D-Arap from exogenous D-Arap, both proteins were able to salvage L-Fucose to GDP-Fucose. We now show that Δafkp80- null mutants ablated D-Arap modifications of LPG as predicted, while Δfkp40- null mutants resembled wild-type (WT). Fucoconjugates had not been reported previously in L. major, but unexpectedly we were unable to generate fkp40-/afkp80- double mutants, unless one of the A/FKPs was expressed ectopically. To test whether GDP-Fucose itself was essential for Leishmania viability, we employed "genetic metabolite complementation. First, the trypanosome de novo pathway enzymes GDP-mannose dehydratase (GMD) and GDP-fucose synthetase (GMER) were expressed ectopically; from these cells, the Δfkp40-/Δafkp80- double mutant was now readily obtained. As expected, the Δfkp40-/Δafkp80-/+TbGMD-GMER line lacked the capacity to generate GDP-Arap, while synthesizing abundant GDP-Fucose. These results establish a requirement for GDP-Fucose for Leishmania major viability, and predict the existence of an essential fucoconjugate(s).

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Eicosapentaenoic Acid Downregulates Expression of the Selenoprotein P Gene by Inhibiting SREBP-1c Independently of the AMPK Pathway in H4IIEC3 Hepatocytes [Cell Biology]

Selenoprotein P (encoded by SELENOP in humans, Selenop in rat), a liver-derived secretory protein, induces resistance to insulin and vascular endothelial growth factor (VEGF) in type 2 diabetes. Suppression of selenoprotein P may provide a novel therapeutic approach to treating type 2 diabetes; however, few drugs inhibiting SELENOP expression in hepatocytes have been identified. The present findings demonstrate that eicosapentaenoic acid (EPA) suppresses SELENOP expression by inactivating sterol regulatory element-binding protein-1c (SREBP-1c, encoded by Srebf1 in rat) in H4IIEC3 hepatocytes. Treatment with EPA caused concentration- and time-dependent reduction in SELENOP promoter activity. EPA activated AMP-activated protein kinase (AMPK); however, inhibitory effect of EPA on SELENOP promoter activity was not canceled with an AMPK inhibitor compound C and dominant-negative AMPK transfection. Deletion mutant promoter assays and computational analysis of transcription factor-binding sites conserved among the species resulted in identification of a sterol regulatory element (SRE) -like site in the SELENOP promoter. A chromatin immunoprecipitation (ChIP) assay revealed that EPA decreases binding of SREBP-1c to the SELENOP promoter. Knockdown of Srebf1 resulted in a significant downregulation of Selenop expression. Conversely, SREBP-1c overexpression inhibited the suppressive effect of EPA. These data provide a novel mechanism of action for EPA involving improvement of systemic insulin sensitivity through the regulation of selenoprotein P production independently of the AMPK pathway and suggest an additional approach to developing anti-diabetic drugs.

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Pareto Optimization of a Half Car Passive Suspension Model Using a Novel Multiobjective Heat Transfer Search Algorithm

Most of the modern multiobjective optimization algorithms are based on the search technique of genetic algorithms; however the search techniques of other recently developed metaheuristics are emerging topics among researchers. This paper proposes a novel multiobjective optimization algorithm named multiobjective heat transfer search (MOHTS) algorithm, which is based on the search technique of heat transfer search (HTS) algorithm. MOHTS employs the elitist nondominated sorting and crowding distance approach of an elitist based nondominated sorting genetic algorithm-II (NSGA-II) for obtaining different nondomination levels and to preserve the diversity among the optimal set of solutions, respectively. The capability in yielding a Pareto front as close as possible to the true Pareto front of MOHTS has been tested on the multiobjective optimization problem of the vehicle suspension design, which has a set of five second-order linear ordinary differential equations. Half car passive ride model with two different sets of five objectives is employed for optimizing the suspension parameters using MOHTS and NSGA-II. The optimization studies demonstrate that MOHTS achieves the better nondominated Pareto front with the widespread (diveresed) set of optimal solutions as compared to NSGA-II, and further the comparison of the extreme points of the obtained Pareto front reveals the dominance of MOHTS over NSGA-II, multiobjective uniform diversity genetic algorithm (MUGA), and combined PSO-GA based MOEA.

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Asymptomatic Brain Edema after Hemodialysis Initiation in a Patient with Severe Uremia

A 66-year-old man with severe renal insufficiency presented with mild confusion associated with uremia. Cranial magnetic resonance imaging (MRI) showed no remarkable changes. The patient was placed on short-duration hemodialysis (2 hours) with smaller surface area and low blood flow (100 mL/min) to avoid dialysis disequilibrium syndrome (DDS). His consciousness gradually improved and he did not develop apparent DDS symptoms. However, T2-weighted FLAIR MRI showed increased signal intensities bilaterally in the cortical and subcortical areas of the occipital lobe on day 15. In other words, cranial MRI showed cerebral edema, indicating asymptomatic DDS. On day 29, cranial MRI showed a return to findings on admission. In this case, because the patient did not have apparent DDS symptoms despite MRI changes, we diagnosed asymptomatic cerebral edema. The patient was discharged on regular intermittent HD without any neurological deficits. No further neurological disturbances were noted during 1-year follow-up. MRI findings in ESKD patients without DDS symptoms help to clarify the diagnosis of cerebral edema. In this case, the patient did not have apparent DDS symptoms and was therefore diagnosed with asymptomatic cerebral edema.

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Experimental Research on Longitudinal Steel Bar Bond Properties in Modified Recycled Aggregate Concrete Beam-Column Interior Joint under Cyclic Loading

Three recycled aggregate concrete (RAC) beam-column interior-joint specimens (including two modified recycled aggregate concrete interior joints with replacement of fly ash ratio of 15%) were tested under cyclic loading in order to study the bond behavior of the longitudinal steel bar at RAC joint. The tests obtained load-strain hysteresis curves of longitudinal bars. The relative bond strength of longitudinal bar in characteristic stages was calculated. The test results indicated that the longitudinal steel bar in RAC joint is able to supply a stable bond stress both in the full crack stage and in the ultimate stage, meaning that the requirements of stress transferring and displacement coordinating between RAC and reinforcements can be satisfied. The larger the diameter of steel bar, the more serious the bond strength degradation. The RAC with fly ash can improve the interface compactness and bond strength of recycled aggregate in full crack stage. When beam-column interface of concrete compression zone reaches ultimate strain, the compressive stress of the longitudinal reinforcement cannot be exerted. The bond stress of the steel bar cannot realize the pull and compressive stress conversion in the length of the core area of the joint owing to the stress hysteresis of the compression rebars.

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Frozen Jacobian Multistep Iterative Method for Solving Nonlinear IVPs and BVPs

In this paper, we present and illustrate a frozen Jacobian multistep iterative method to solve systems of nonlinear equations associated with initial value problems (IVPs) and boundary value problems (BVPs). We have used Jacobi-Gauss-Lobatto collocation (J-GL-C) methods to discretize the IVPs and BVPs. Frozen Jacobian multistep iterative methods are computationally very efficient. They require only one inversion of the Jacobian in the form of LU-factorization. The LU factors can then be used repeatedly in the multistep part to solve other linear systems. The convergence order of the proposed iterative method is , where is the number of steps. The validity, accuracy, and efficiency of our proposed frozen Jacobian multistep iterative method is illustrated by solving fifteen IVPs and BVPs. It has been observed that, in all the test problems, with one exception in this paper, a single application of the proposed method is enough to obtain highly accurate numerical solutions. In addition, we present a comprehensive comparison of J-GL-C methods on a collection of test problems.

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Serum Sclerostin Levels in Patients with Ankylosing Spondylitis and Rheumatoid Arthritis: A Systematic Review and Meta-Analysis

Objective. Current studies of serum sclerostin levels in AS and RA patients are inconsistent. This meta-analysis was performed to identify the association of serum sclerostin level with AS and RA patients. Methods. Embase, PubMed, MEDLINE, and Cochrane Library databases (up to 25 January 2017) were used to collect all relevant published articles. Studies were pooled and standard mean difference (SMD) with 95% confidence interval (CI) was calculated. All data analyses were performed using RevMan 5.3. Results. Totally eight studies of AS including 420 AS patients and 317 healthy controls (HC) and three studies of RA including 145 RA patients and 127 HC were finally included in this meta-analysis. The results revealed that the serum sclerostin levels in both AS patients (; 95% ; ) and RA patients (; 95% ; ) were not significantly different from those in HC. Conclusion. The difference of serum sclerostin levels in AS and RA patients was not significantly different from HC, indicating that the sclerostin may not associate with the development of AS and RA.

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The Research of Disease Spots Extraction Based on Evolutionary Algorithm

According to the characteristics of maize disease spot performance in the image, this paper designs two-histogram segmentation method based on evolutionary algorithm, which combined with the analysis of image of maize diseases and insect pests, with full consideration of color and texture characteristic of the lesion of pests and diseases, the chroma and gray image, composed of two tuples to build a two-dimensional histogram, solves the problem of one-dimensional histograms that cannot be clearly divided into target and background bimodal distribution and improved the traditional two-dimensional histogram application in pest damage lesion extraction. The chromosome coding suitable for the characteristics of lesion image is designed based on second segmentation of the genetic algorithm Otsu. Determining initial population with analysis results of lesion image, parallel selection, optimal preservation strategy, and adaptive mutation operator are used to improve the search efficiency. Finally, by setting the fluctuation threshold, we continue to search for the best threshold in the range of fluctuations for implementation of global search and local search.

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Charting Availability of Processed and Unprocessed Foods in School Neighbourhood Nutrition Environments in an Urban Australian Setting

School Neighbourhood Nutrition Environments (SNNEs) can facilitate or impede healthy eating. This study describes the SNNEs surrounding 6 Good Start Program (GSP) schools in 5 suburbs in Logan, Queensland. Relative density of healthy and unhealthy food outlets was calculated for SNNEs surrounding GSP (6) and non-GSP (10) schools within the 5 suburbs. Relative accessibility of minimally processed and highly processed food and drink in SNNEs of the 6 GSP schools was determined using shelf measurements of snack foods. Unhealthy outlets greatly outnumber healthy outlets (mean relative density 15.6%, median 19.1%). The majority of outlets stock predominantly highly processed food and drink. Study areas are dominated by unhealthy food outlets and highly processed food.

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Fast Recall for Complex-Valued Hopfield Neural Networks with Projection Rules

Many models of neural networks have been extended to complex-valued neural networks. A complex-valued Hopfield neural network (CHNN) is a complex-valued version of a Hopfield neural network. Complex-valued neurons can represent multistates, and CHNNs are available for the storage of multilevel data, such as gray-scale images. The CHNNs are often trapped into the local minima, and their noise tolerance is low. Lee improved the noise tolerance of the CHNNs by detecting and exiting the local minima. In the present work, we propose a new recall algorithm that eliminates the local minima. We show that our proposed recall algorithm not only accelerated the recall but also improved the noise tolerance through computer simulations.

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Capsular Polysaccharide is a Main Component of Mycoplasma ovipneumoniae in the Pathogen-Induced Toll-Like Receptor-Mediated Inflammatory Responses in Sheep Airway Epithelial Cells

Mycoplasma ovipneumoniae (M. ovipneumoniae) is characterized as an etiological agent of primary atypical pneumonia that specifically infects sheep and goat. In an attempt to better understand the pathogen-host interaction between the invading M. ovipneumoniae and airway epithelial cells, we investigated the host inflammatory responses against capsular polysaccharide (designated as CPS) of M. ovipneumoniae using sheep bronchial epithelial cells cultured in an air-liquid interface (ALI) model. Results showed that CPS derived from M. ovipneumoniae could activate toll-like receptor- (TLR-) mediated inflammatory responses, along with an elevated expression of nuclear factor kappa B (NF-κB), activator protein-1 (AP-1), and interferon regulatory factor 3 (IRF3) as well as various inflammatory-associated mediators, representatively including proinflammatory cytokines, such as IL1β, TNFα, and IL8, and anti-inflammatory cytokines such as IL10 and TGFβ of TLR signaling cascade. Mechanistically, the CPS-induced inflammation was TLR initiated and was mediated by activations of both MyD88-dependent and MyD88-independent signaling pathways. Of importance, a blockage of CPS with specific antibody led a significant reduction of M. ovipneumoniae-induced inflammatory responses in sheep bronchial epithelial cells. These results suggested that CPS is a key virulent component of M. ovipneumoniae, which may play a crucial role in the inflammatory response induced by M. ovipneumoniae infections.

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The impact of the “Yogic Lifestyle” on cancer prognosis and survival: Can we target cancer stem cells with yoga?

Kavita Beri

International Journal of Yoga 2017 10(2):95-98

Cancer has recently been known to originate from stem cell-like cells, called cancer stem cells (CSCs). Their unique properties of self-duplication, multiplication, as well as migration give the CSC resistance over conventional cancer therapies. Newer therapies are in developmental stage to target these stem cell-like populations and become the vanguard of future treatments. Several complementary and alternative treatments have been used in cancer management as an adjunct to conventional therapy to improve the overall quality of life and reduce recurrence. Yoga stands as the third most popular of all complementary and alternative medicine treatments currently used in cancer patients today. Preliminary results show that yoga modulates neural, hormonal, and immune functions at a cellular level. The scope of this commentary is to discuss the current evidence-based medicine on yoga and its effect on CSCs.

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Comment on models in medicine

Thyyar Madabushi Ravindranath

International Journal of Yoga 2017 10(2):110-110



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Anatomical correlation of core muscle activation in different yogic postures

Mrithunjay Rathore, Soumitra Trivedi, Jessy Abraham, Manisha B Sinha

International Journal of Yoga 2017 10(2):59-66

Faulty postures due to sedentary lifestyle cause weakening of core muscles which contributes to increased incidence of musculoskeletal disorders (MSDs). Although a few research studies have quantified the core muscle activity in various yogic exercises used in rehabilitation programs, evidence correlating it to functional anatomy is scarce. Such information is important for exercise prescription when formulating treatment plans for MSDs. Therefore, the objective of this review article is to examine the literature and analyze the muscle activity produced across various yoga postures to determine which type of yoga posture elicits the highest activation for the core muscle in individuals. Literature search was performed using the following electronic databases: Cochrane Library, NCBI, PubMed, Google Scholar, EMBASE, and web of science. The search terms contained: Core muscle activation and yogic posture OR yoga and rehabilitation OR intervention AND Electromyography. Activation of specific core muscle involved asanas which depended on trunk and pelvic movements. Description of specific yogic exercise as they relate to core muscles activation is described. This information should help in planning yogic exercises that challenge the muscle groups without causing loads that may be detrimental to recovery and pain-free movement. Knowledge of activation of muscles in various yogic postures can assist health-care practitioners to make appropriate decisions for the designing of safe and effective evidence-based yoga intervention for MSDs.

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Yoga practice improves the body mass index and blood pressure: A randomized controlled trial

Ashutosh Chauhan, Deepak Kumar Semwal, Satyendra Prasad Mishra, Ruchi Badoni Semwal

International Journal of Yoga 2017 10(2):103-106

Background: Yoga, an ancient Indian system of exercise and therapy is an art of good living or an integrated system for the benefit of the body, mind, and inner spirit. Regular practice of yoga can help to increase blood flow to the brain, reduce stress, have a calming effect on the nervous system, and greatly help in reducing hypertension. Aim: Aim of the present study is to evaluate the effect of 1-month yoga practice on body mass index (BMI), and blood pressure (BP). Materials and Methods: The present study was conducted to determine the effect of yoga practice on 64 participants (age 53.6 ± 13.1 years) (experimental group) whereas the results were compared with 26 healthy volunteers (control group). We examined the effects of yoga on physiological parameters in a 1-month pilot study. Most of the participants were learner and practiced yoga for 1 h daily in the morning for 1 month. BMI and BP (systolic and diastolic) were studied before and after 1 month of yoga practice. Results: Yoga practice causes decreased BMI (26.4 ± 2.5–25.22 ± 2.4), systolic BP (136.9 ± 22.18 mmHg to 133 ± 21.38 mmHg), and diastolic BP (84.7 ± 6.5 mmHg to 82.34 ± 7.6 mmHg). On the other hand, no significant changes were observed in BMI and BP of control group. Conclusion: This study concludes that yoga practice has potential to control BMI and BP without taking any medication.

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13-series resolvins mediate the leukocyte-platelet actions of atorvastatin and pravastatin in inflammatory arthritis [Research]

Rheumatoid arthritis is an inflammatory condition characterized by overzealous inflammation that leads to joint damage and is associated with an increased incidence of cardiovascular disease. Statins are frontline therapeutics for patients with cardiovascular disease and exert beneficial actions in rheumatoid arthritis. The mechanism that mediates the beneficial actions of statins in rheumatoid arthritis remains of interest. In the present study, we found that the administration of 2 clinically relevant statins—atorvastatin (0.2 mg/kg) or pravastatin (0.2 mg/kg)—to mice during inflammatory arthritis up-regulated systemic and tissue amounts of a novel family of proresolving mediators, termed 13-series resolvins (RvTs), and significantly reduced joint disease. Of note, administration of simvastatin (0.2 mg/kg) did not significantly up-regulate RvTs or reduce joint inflammation. We also found that atorvastatin and pravastatin each reduced systemic leukocyte activation, including platelet-monocyte aggregates (~25–60%). These statins decreased neutrophil trafficking to the joint as well as joint monocyte and macrophage numbers. Atorvastatin and pravastatin produced significant reductions (~30–50%) in expression of CD11b and major histocompatibility complex class II on both monocytes and monocyte-derived macrophages in joints. Administration of an inhibitor to cyclooxygenase-2, the initiating enzyme in the RvT pathway, reversed the protective actions of these statins on both joint and systemic inflammation. Together, these findings provide evidence for the role of RvTs in mediating the protective actions of atorvastatin and pravastatin in reducing local and vascular inflammation, and suggest that RvTs may be useful in measuring the anti-inflammatory actions of statins.—Walker, M. E., Souza, P. R., Colas, R. A., Dalli, J. 13-series resolvins mediate the leukocyte-platelet actions of atorvastatin and pravastatin in inflammatory arthritis.

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Epithelial Src homology region 2 domain-containing phosphatase-1 restrains intestinal growth, secretory cell differentiation, and tumorigenesis [Research]

Shp-1 (Src homology region 2 domain-containing protein tyrosine phosphatase-1) is a phosphatase that is highly expressed in hematopoietic and epithelial cells. Whereas its function is largely characterized in hematopoietic cells, its role in epithelial cells, such as intestinal epithelial cells (IECs), is not well known. Here, we generated mice with an IEC-specific deletion of Shp-1 (Src homology region 2 domain–containing phosphatase-1; Shp-1^IEC-KO). We showed that the loss of epithelial Shp-1 leads to an intestinalomegaly that is associated with an increase in epithelial cell proliferation and size. Histologic analysis demonstrates significant perturbation of the crypt-villus architecture with an apparent increase in the number of goblet and Paneth cells and increased expression of their respective markers {Muc2 (mucin 2), αDef, and Sox9 [SRY (sex determining region Y)-box 9]}. Expansion of intermediate cells—common progenitors of goblet and Paneth cell lineages—is also observed in Shp-1^IEC-KO mice. Although sustained activation of Wnt/β-catenin and PI3K/Akt/mammalian target of rapamycin signaling is observed, Shp-1^IEC-KO mice fail to develop any intestinal tumors after 15 mo; however, the loss of Shp-1 in IECs markedly enhances tumor load Apc^Min/+ mice. These findings show a novel role for Shp-1 in the regulation of IEC growth and secretory lineage allocation, possibly via modulation of PI3K/Akt-dependent signaling pathways. Finally, Shp-1 does not function as a classic tumor suppressor gene in the intestinal epithelium.—Leblanc, C., Langlois, M.-J., Coulombe, G., Vaillancourt-Lavigueur, V., Jones, C., Carrier, J. C., Boudreau, F., Rivard, N. Epithelial Src homology region 2 domain–containing phosphatase-1 restrains intestinal growth, secretory cell differentiation, and tumorigenesis.

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Potentiation of receptor responses induced by prolonged binding of G{alpha}13 and leukemia-associated RhoGEF [Research]

Diverse cellular functions are controlled by RhoA-GTPases, which are activated by trimeric G proteins via RhoGEFs, among others. In this study, we focused on the signaling from GPCRs to RhoA via Gα₁₃ and leukemia-associated RhoGEF (LARG). The activation of Gα₁₃ was elucidated in living cells with high temporal and spatial resolution by means of FRET. The inactivation after agonist withdrawal occurred in the same range (t_1/2 = 25.3 ± 2.2 s; mean ± sem; n = 22) as described for other Gα proteins. The interaction of Gα₁₃ and LARG and the thereby-induced LARG translocation to the plasma membrane were at least 1 order of magnitude more stable after agonist withdrawal, exceeding Gα₁₃ deactivation in the absence of LARG several fold. Consequently, we observed an almost 100-fold higher agonist sensitivity of the Gα₁₃ LARG interaction compared to the Gα₁₃ activation in the absence of LARG.—Bodmann, E.-L., Krett, A.-L., Bünemann, M. Potentiation of receptor responses induced by prolonged binding of Gα₁₃ and leukemia-associated RhoGEF.

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Strenuous exercise triggers a life-threatening response in mice susceptible to malignant hyperthermia [Research]

In humans, hyperthermic episodes can be triggered by halogenated anesthetics [malignant hyperthermia (MH) susceptibility] and by high temperature [environmental heat stroke (HS)]. Correlation between MH susceptibility and HS is supported by extensive work in mouse models that carry a mutation in ryanodine receptor type-1 (RYR1^Y522S/WT) and knockout of calsequestrin-1 (CASQ1-null), 2 proteins that control Ca²⁺ release in skeletal muscle. As overheating episodes in humans have also been described during exertion, here we subjected RYR1^Y522S/WT and CASQ1-null mice to an exertional-stress protocol (incremental running on a treadmill at 34°C and 40% humidity). The mortality rate was 80 and 78.6% in RYR1^Y522S/WT and CASQ1-null mice, respectively vs. 0% in wild-type mice. Lethal crises were characterized by hyperthermia and rhabdomyolysis, classic features of MH episodes. Of importance, pretreatment with azumolene, an analog of the drug used in humans to treat MH crises, reduced mortality to 0 and 12.5% in RYR1^Y522S/WT and CASQ1-null mice, respectively, thanks to a striking reduction of hyperthermia and rhabdomyolysis. At the molecular level, azumolene strongly prevented Ca²⁺-dependent activation of calpains and NF-B by lowering myoplasmic Ca²⁺ concentration and nitro-oxidative stress, parameters that were elevated in RYR1^Y522S/WT and CASQ1-null mice. These results suggest that common molecular mechanisms underlie MH crises and exertional HS in mice.—Michelucci, A., Paolini, C., Boncompagni, S., Canato, M., Reggiani, C., Protasi, F. Strenuous exercise triggers a life-threatening response in mice susceptible to malignant hyperthermia.

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