Optimal Body Mass Index Range for Patients With Colorectal Cancer—Reply

In Reply We read with interest the Letter by Kim and colleagues suggesting that researchers should be careful in drawing general conclusions about associations between body mass index (BMI) and cancer outcomes given that obesity definitions using BMI may differ in whites vs Asians and Pacific Islanders. Specifically, we agree that analyses should be examined separately by race. In our cohort, we noted nonsignificant associations for linear and nonlinear effects (P > .40) in API participants. Given the smaller numbers of patients in specific race groups, however, it was not possible to draw firm conclusions, but results do support the need to consider race-specific associations in larger studies. We also believe that analyses that examine body composition, rather than just BMI, will help to clarify how obesity influences outcomes in future work. Work will furthermore need to consider how body composition influences mortality in different race groups including whites, blacks, Asians and Pacific Islanders, and Hispanics.

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Optimal Body Mass Index Range for Patients With Colorectal Cancer

To the Editor We are intrigued by the article by Kroenke et al showing evidence that a body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) range defined by the World Health Organization (WHO) as "high-overweight" (BMI, 28 to (p1137)

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DNA Mismatch Repair and Mutations in Stage III Colon Cancer

This secondary analysis of 2 randomized clinical trials examines the association of DNA mismatch repair status and somatic gene mutations in the primary tumor of patients with stage III colon cancer treated with adjuvant chemotherapy.

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A Rapidly Expanding Scalp Mass

A woman in her 80s presented with a 2-week history of an enlarging left parietal scalp mass that continued to enlarge. She subsequently developed progressive generalized weakness, slowed speech, and focal right-handed weakness. What is your diagnosis?

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Molecular Markers in Colorectal Cancer

The knowledge of molecular abnormalities underlying colorectal tumorigenesis and the progression of dysplastic precursors to invasive and ultimately metastatic lesions has advanced by comprehensive sequencing studies. From genome-scale analyses we know that a handful of 24 genes are commonly affected by somatic mutations in colorectal cancer (CRC), whereas recurrent copy-number alterations and chromosomal translocations are much rarer in this disease. Although some of these molecular abnormalities result in genes acting as drivers of cancer progression, translation for therapeutic purposes is still very limited and encompasses only exclusion of RAS-mutated cancers from epidermal growth factor receptor–targeted treatment with monoclonal antibodies as the standard of care and targeted approaches for tumors with B-Raf proto-oncogene (BRAF) mutations and those amplified with v-erb-b2 leukemia viral oncogene homolog 2 (ERBB2 [formerly known as HER2]). However, CRC is probably the first cancer historically discovered to have subclasses with features so distinct that they could be considered as separate diseases. Approximately 15% of CRCs manifest a hypermutation phenotype, with a median number of 700 somatic mutations, and 75% of these tumors display a high frequency of the microsatellite instability (MSI-H) phenotype owing to mutation or inactivation of key proteins functioning in DNA mismatch repair (deficient MMR [dMMR]). These dMMR tumors can develop from an inherited germline mutation in an MMR gene (MutL protein homolog 1 [MLH1], MutS protein homolog 2 [MSH2], MutS protein homolog 2 [MSH6], and PMS homolog 2 [PMS2]), that is, Lynch syndrome, or more commonly owing to epigenetic inactivation of the MLH1 gene and the CpG island methylator phenotype. More important, the latter sporadic dMMR tumors carry somatic mutations in the BRAF oncogene in approximately half of cases. The remaining fraction of 25% CRCs with a hypermutation phenotype does not manifest the MSI-H phenotype and usually harbor somatic mutations in the gene encoding DNA repair polymerase ε or somatic mutations in the MMR pathways.

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KRAS Variant as a Predictive Biomarker of Cetuximab Response

In their interesting report, Weidhaas et al posit that a germline mutation in the 3′ untranslated region of the KRAS variant is a predictive marker of improved response to cetuximab for patients with locally advanced head and neck squamous cell carcinoma (HNSCC). While the results presented therein are intriguing, we would advise caution regarding their interpretation. The study by Weidhaas et al has several strengths; first, being focused on a well-characterized germline polymorphism that has been previously described as a predictive biomarker in a similar context for colon cancer. The evaluation of a single marker increases statistical power by limiting the number of comparisons performed; however, while only 1 variant was analyzed, multiple hypotheses were evaluated, thereby increasing the potential for inflated type I error.

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Health-related Quality of Life and Psychological Wellbeing in Adults with Differences of Sex Development (DSD)

Abstract

Objective

Rare congenital conditions with incongruence of chromosomal, gonadal, and phenotypic sex have been classified as Differences/ Disorders of Sex Development (DSD). Included in DSD are conditions with diverse genetic aetiology, varying levels of prenatal androgen effects, phenotypes, and subsequently, different medical treatments. Quality of life (QoL) and psychological wellbeing are indicators of successful psychosocial adaptation to the conditions. We sought to investigate the HRQOL and psychological wellbeing in this population.

Design

This multicentre clinical evaluation study was part of a German network related to DSD funded by the German Ministry of Science and Education (BMBF 2003 to 2007).

Methods

To assess health-related quality of life (HRQoL), we used the Short Form Health Survey (SF-36) and for psychological wellbeing, the Brief Symptom Inventory (BSI). Participants were classified into five groups: females with CAH, females with XY DSD conditions where there is a partial androgen effect (partial androgen insensitivity, mixed/ partial gonadal dysgenesis, disorders of androgen biosynthesis), females with XY DSD without androgen effect (complete androgen insensitivity, complete gonadal dysgenesis), males with XY DSD, and individuals with DSD conditions and other gender.

Results

Participants included 110 adults with DSD (age range 17-62). We found a trend of lowered mental HRQoL and significant higher physical HRQoL for participants as compared to the norm. The high physical HRQoL especially applied to females with androgen effect and XY karyotype. Participants reported significant higher psychological distress compared to the norm. Forty-seven participants (42.7%) reported distress in a clinically relevant range on the BSI.

Conclusions

Although we did not find significant impairments in overall HRQoL, participants reported significant impaired psychological wellbeing. Specialised interdisciplinary care should focus in particular on psychological issues to ensure good overall health and wellbeing.

This article is protected by copyright. All rights reserved.

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Comparison of functional assays used in the clinical development of a placental malaria vaccine

Publication date: Available online 21 December 2016
Source:Vaccine
Author(s): Caroline Pehrson, Kristine K. Heno, Yvonne Adams, Mafalda Resende, Line Mathiesen, Max Soegaard, Willem A. de Jongh, Thor G. Theander, Ali Salanti, Morten A. Nielsen
BackgroundMalaria in pregnancy is associated with significant morbidity in pregnant women and their offspring. Plasmodium falciparum infected erythrocytes (IE) express VAR2CSA that mediates binding to chondroitin sulphate A (CSA) in the placenta. Two VAR2CSA-based vaccines for placental malaria are in clinical development. The purpose of this study was to evaluate the robustness and comparability of binding inhibition assays used in the clinical development of placental malaria vaccines.MethodsThe ability of sera from animals immunised with different VAR2CSA constructs to inhibit IE binding to CSA was investigated in three in vitro assays using 96-well plates, petri dishes, capillary flow and an ex vivo placental perfusion assay.ResultsThe inter-assay variation was not uniform between assays and ranged from above ten-fold in the flow assay to two-fold in the perfusion assay. The intra-assay variation was highest in the petri dish assay. A positive correlation between IE binding avidity and the level of binding after antibody inhibition in the petri dish assay indicate that high avidity IE binding is more difficult to inhibit. The highest binding inhibition sensitivity was found in the 96-well and petri dish assays compared to the flow and perfusion assays where binding inhibition required higher antibody titers.ConclusionsThe inhibitory capacity of antibodies is not easily translated between assays and the high sensitivity of the 96-well and petri dish assays stresses the need for comparing serial dilutions of serum. Furthermore, IE binding avidity must be in the same range when comparing data from different days. There was an overall concordance in the capacity of antibody-mediated inhibition, when comparing the in vitro assays with the perfusion assay, which more closely represents in vivo conditions. Importantly the ID1-ID2a protein in a liposomal formulation, currently in a phase I trial, effectively induced antibodies that inhibited IE adhesion in placental tissue.



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A novel “in-feed” delivery platform applied for oral DNA vaccination against IPNV enables high protection in Atlantic salmon (Salmon salar)

Publication date: Available online 21 December 2016
Source:Vaccine
Author(s): Miguel Reyes, Cesar Ramírez, Ivan Ñancucheo, Ricardo Villegas, Guillermo Schaffeld, Luis Kiman, Javier Gonzalez, Patricio Oyarzun
BackgroundDNA vaccination has emerged as a promising tool against infectious diseases of farmed fish. Oral delivery allows stress-free administration that is ideal for mass immunization and of paramount importance for infectious pancreatic necrosis (IPN) and other viral disease that affect young salmonids and cause economic losses in aquaculture worldwide.MethodsWe describe the development and in vivo assessment of an "in-feed" formulation strategy for oral immunization with liposomal DNA vaccines, by delivering a vaccine construct coding for an immunogenic region of the VP2 capsid protein. A challenge against IPNV was carried out to determine the vaccine efficacy, by comparing the mortality of pre-smolt Atlantic salmons immunized and non-immunized with the oral vaccine. The antibody response (ELISA) and hematological parameters after immunization were examined, as well as the vaccine effect on the growth and internal structures of fry salmons (histological analysis). The vaccine distribution in the experimental tank after oral administration was investigated by HPLC and PCR amplification.ResultsThe oral vaccine induced detectable levels of VP2-specific antibodies and conferred significant protection following IPNV challenge, with relative percent survivals (RPS) of 58.2%, for single dose (1mgpDNA/kgfish⋅d), and 66% for double dose (2mgpDNA/kgfish⋅d). We further provide evidence in favour of the vaccine safety to fish and demonstrated absence of pDNA in the tank water, but presence of vaccine residues in faeces and unconsumed feed sediments (solid wastes).ConclusionThe delivery platform for liposomal DNA vaccination via feed was successfully proved against IPNV in Atlantic salmon, showing the oral vaccine to be immunogenic and safe for fish, and providing significant protection after oral administration. The "in-feed" technology for oral DNA vaccination holds potential to be applied against IPNV and other pathogens that currently threaten the aquaculture worldwide.



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B cell and antibody responses in mice induced by a putative cell surface peptidase of Pneumocystis murina protect against experimental infection

Publication date: Available online 21 December 2016
Source:Vaccine
Author(s): Sanbao Ruan, Yang Cai, Alistair J. Ramsay, David A. Welsh, Karen Norris, Judd E. Shellito
RationalePneumocystis pneumonia is a major cause of morbidity and mortality in HIV-infected subjects, cancer patients undergoing chemotherapy and solid organ transplant recipients. No vaccine is currently available. By chemical labeling coupled with proteomic approach, we have identified a putative surface protein (SPD1, Broad Institute gene accession number PNEG_01848) derived from single suspended P. murina cysts. SPD1 was expressed in an insect cell line and tested for vaccine development.MethodsMice were immunized with SPD1 plus adjuvant MF-59 by subcutaneous injection. Three weeks after the last immunization, CD4+ cells were depleted with anti-CD4 antibody GK1.5. The mice were then challenged with 2×10⁵Pneumocystis organisms. Mice were sacrificed at 4 and 6weeks after PC challenge. Spleen/lung cells and serum were harvested. B cells and memory B cells were assessed via flow cytometry. Specific Pneumocystis IgG antibody was measured by ELISA before and after challenge. Infection burden was measured as real-time PCR for P. murina rRNA.ResultsNormal mice infected with Pneumocystis mounted a serum IgG antibody response to SPD1. Serum from rhesus macaques exposed to Pneumocystis showed a similar serum IgG response to purified SPD1. SPD1 immunization increased B cell and memory B cell absolute cell counts in CD4-depleted Balb/c mice post Pneumocystis challenge in spleen and lung. Immunization with SPD1 significantly increased specific Pneumocystis IgG antibody production before and after challenge. Mice immunized with SPD1 showed significantly decreased P. murina copy number compared with mice that did not receive SPD1 at 6weeks after challenge.ConclusionImmunization with SPD1 provides protective efficacy against P. murina infection. SPD1 protection against Pneumocystis challenge is associated with enhanced memory B cell production and higher anti–Pneumocystis IgG antibody production. SPD1 is a potential vaccine candidate to prevent or treat pulmonary infection with Pneumocystis.



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Sequential administration of a MVA-based MUC1 cancer vaccine and the TLR9 ligand Litenimod (Li28) improves local immune defense against tumors

Publication date: Available online 21 December 2016
Source:Vaccine
Author(s): Emmanuelle Schaedler, Christelle Remy-Ziller, Julie Hortelano, Nadine Kehrer, Marie-Christine Claudepierre, Tanja Gatard, Christopher Jakobs, Xavier Préville, Antoine F. Carpentier, Karola Rittner
TG4010 is an immunotherapeutic vaccine based on Modified Vaccinia virus Ankara (MVA) encoding the human tumor-associated antigen MUC1 and human IL-2. In combination with first-line standard of care chemotherapy in advanced metastatic non-small-cell lung cancer (NSCLC), repeated subcutaneous injection of TG4010 improved progression-free survival in phase 2b clinical trials. In preclinical tumor models, MVATG9931, the research version of TG4010, conferred antigen-specific responses against the weak antigen human MUC1. The combination of a suboptimal dose of MVATG9931 and the type B TLR9 ligand Litenimod (Li28) markedly increased survival in a subcutaneous RMA-MUC1 tumor model compared to the treatment with MVATG9931 or Li28 alone. The requirements for this protection were (i) de novo synthesis of MUC1, (ii) Li28 delivered several hours after MVATG9931 at the same site, (iii) at least two vaccination cycles, and (iv) implantation of MUC1-positive tumor cells in the vicinity to the vaccination site. Subcutaneously injected MVATG9931 allowed transient local gene expression and induced the local accumulation of MCP-1, RANTES, M-CSF, IL-15/IL-15R and IP-10. After repeated injection, CD4⁺ and CD8⁺ T lymphocytes, B lymphocytes, NK cells, pDCs, neutrophils, and macrophages accumulated around the injection site, local RANTES levels remained high. Delayed injection of Li28 into this environment, led to further accumulation of macrophages, the secretion of IL-18 and IL-1 beta, and an increase of the percentage of activated CD69⁺ NK cell. Combination treatment augmented the number of activated CD86⁺ DCs in the draining lymph nodes and increased the percentage of KLRG1⁺ CD127⁻CD8⁺ T cells at the injection site. In vivo depletion of macrophages around the injection site by Clodronate liposomes reduced local IL-18 levels and diminished survival rates significantly. Thus, sequential administration of MVATG9931 and Li28 improves local innate and adaptive immune defense against tumors, arguing for intratumoral delivery of this peculiar sequential combination therapy.



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Vaccination of alpacas against Rift Valley fever virus: Safety, immunogenicity and pathogenicity of MP-12 vaccine

Publication date: Available online 21 December 2016
Source:Vaccine
Author(s): M. Rissmann, R. Ulrich, C. Schröder, B. Hammerschmidt, D. Hanke, C. Mroz, M.H. Groschup, M. Eiden
Rift Valley fever (RVF) is an emerging zoonosis of major public health concern in Africa and Arabia. Previous outbreaks attributed camelids a significant role in the epidemiology of Rift Valley fever virus (RVFV), making them an important target species for vaccination. Using three alpacas as model-organisms for dromedary camels, the safety, immunogenicity and pathogenicity of the MP-12 vaccine were evaluated in this study. To compare both acute and subacute effects, animals were euthanized at 3 and 31days post infection (dpi). Clinical monitoring, analysis of liver enzymes and hematological parameters demonstrated the tolerability of the vaccine, as no significant adverse effects were observed. Comprehensive analysis of serological parameters illustrated the immunogenicity of the vaccine, eliciting high neutralizing antibody titers and antibodies targeting different viral antigens. RVFV was detected in serum and liver of the alpaca euthanized 3dpi, whereas no virus was detectable at 31dpi. Viral replication was confirmed by detection of various RVFV-antigens in hepatocytes by immunohistochemistry and the presence of mild multifocal necrotizing hepatitis. In conclusion, results indicate that MP-12 is a promising vaccine candidate but still has a residual pathogenicity, which requires further investigation.



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Some Drinking-water Disinfectants and Contaminants, including Arsenic.

An IARC Monographs Working Group of 23 experts from 13 countries convened to evaluate the evidence of carcinogenicity of drinking-water disinfectants and of arsenic (mostly naturally occurring) as a contaminant of drinking-water, and of the water-disinfectant chloramine. The Working Group also evaluated or re-evaluated four chlorination by-products found in drinking-water, namely chloral hydrate, di- and trichloroacetic acids, and 3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone (also known as MX).

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Prostanoids counterbalance the synergism between endothelin-1 and angiotensin II in mesenteric veins of trained rats

Publication date: Available online 21 December 2016
Source:Peptides
Author(s): Agnaldo Bruno Chies, Priscilla Bianca de Oliveira Ledo, Patrícia de Souza Rossignoli, Rafaela de Fátima Ferreira Baptista, Roger William de Lábio, Spencer Luiz Marques Payão
Exercise-induced adaptations of the modulating mechanisms that influence the angiotensin (Ang II) responses assume different features depending on the venous bed. In femoral veins, exercise mobilizes vasodilator prostanoids to cooperate with NO in order to maintain reduced Ang II responses. On the other hand, exercise's influence on the Ang II responses in veins that drain blood from the mesenteric region has been poorly described. Therefore, the present study aimed to identify the effects of a single bout of exercise, as well as exercise training, on the Ang II responses in mesenteric veins. The present study also aimed to investigate the involvement of prostanoids, NO and ET-1 in eventual exercise-induced modifications in these veins. To this end, mesenteric veins taken from resting-sedentary, exercised-sedentary, resting-trained and exercised-trained animals were studied in organ baths. In addition, the mRNA expression of prepro-endothelin-1 (ppET-1), as well as that of the ETA and ETB receptors, were quantified by real-time PCR in these veins. The results show that, either in absence or in presence of L-NAME, the Ang II responses were not different between groups. In the presence of indomethacin, higher Ang II responses were observed in the resting-trained animals than in the resting-sedentary animals. This difference, however, disappeared when L-NAME, BQ-123 or BQ-788 were added during incubation. In addition, no differences in ppET-1, ETA or ETB mRNA expression were observed between groups. Furthermore, in the presence of PD123,319, the Ang II responses in the exercised-sedentary animals were higher than those in the resting-sedentary animals. In conclusion, exercise training mobilizes endothelin-1 (ET-1) to reinforce the Ang II-induced responses mainly through ETA activation. On the other hand, vasodilator prostanoids are mobilized to act in parallel with NO in order to counterbalance the Ang II responses that have been potentiated by ET-1 in these trained animals.



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Increased FNDC5/Irisin expression in human hepatocellular carcinoma

Publication date: Available online 21 December 2016
Source:Peptides
Author(s): Melania Gaggini, Manuela Cabiati, Serena Del Turco, Teresa Navarra, Paolo De Simone, Franco Filipponi, Silvia Del Ry, Amalia Gastaldelli, Giuseppina Basta
The fibronectin type III domain containing 5 (FNDC5)/Irisin, a novel energy-regulating hormone, is associated with lipid and carbohydrate metabolism. It is produced in low amounts by normal hepatic tissue, while in human hepatocellular carcinoma (HCC), in which aberrant de novo lipogenesis (DNL) occurs, the hepatic expression of FNDC5/Irisin is still unknown. The gene expression of FNDC5/Irisin, associated to key regulators of DNL, inflammation and cancer progression was evaluated in liver tissue of 18 patients with HCC undergoing liver transplantation and of 18 deceased donors.Hepatic mRNA expression of FNDC5/Irisin and stearoyl-CoA desaturase (SCD-1), main enzymatic regulator of DNL, were significantly higher in HCC patients than in donors (p<0.0001 and p=0.015, respectively). The hepatic mRNA expression of the neurogenic locus notch homolog protein 1 (NOTCH1) tended to be higher in HCC patients than in donors (p=0.06). Only in HCC patients, hepatic FNDC5/Irisin strongly correlated with the transcription factor sterol regulatory element–binding factor 1, SCD-1, NOTCH1, tumor necrosis factor-α and Interleukin-6 mRNA expression. Further, in HCC patients, FNDC5/Irisin mRNA tended to correlate to plasma lipid profile namely triglycerides, palmitic/linoleic acid and polyunsaturated fatty acid/saturated fatty acid ratios.In conclusion, HCC-liver tissue over-expressed FNDC5/Irisin in association with gene expression of mediators involved in lipogenesis, inflammation and cancer, suggesting a possible protective role of the hormone from the liver damage.



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Glucagon Increases Insulin Levels by Stimulating Insulin Secretion Without Effect on Insulin Clearance in Mice

Publication date: Available online 21 December 2016
Source:Peptides
Author(s): Gina Song, Giovanni Pacini, Bo Ahrén, David Z. D'Argenio
Circulating insulin is dependent on a balance between insulin appearance through secretion and insulin clearance. However, to what extent changes in insulin clearance contribute to the increased insulin levels after glucagon administration is not known. This study therefore assessed and quantified any potential effect of glucagon on insulin kinetics in mice. Prehepatic insulin secretion in mice was first estimated following glucose (0.35g/kg i.v.) and following glucose plus glucagon (10μg/kg i.v.) using deconvolution of plasma C-peptide concentrations. Plasma concentrations of glucose, insulin, and glucagon were then measured simultaneously in individual mice following glucose alone or glucose plus glucagon (pre dose and at 1, 5, 10, 20min post). Using the previously determined insulin secretion profiles and the insulin concentration-time measurements, a population modeling analysis was applied to estimate the one-compartment kinetics of insulin disposition with and without glucagon. Glucagon with glucose significantly enhanced prehepatic insulin secretion (Cmax and AUC0-20) compared to that with glucose alone (p<0.0001). From the modeling analysis, the population mean and between-animal SD of insulin clearance was 6.4±0.34mL/min for glucose alone and 5.8±1.5mL/min for glucagon plus glucose, with no significant effect of glucagon on mean insulin clearance. Therefore, we conclude that the enhancement of circulating insulin after glucagon administration is solely due to stimulated insulin secretion.



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A Study of SBRT for OligoMetastatic ESCC

Condition:   Esophageal Squamous Cell Carcinoma Metastatic
Intervention:   Radiation: SBRT
Sponsor:   Fudan University
Recruiting - verified December 2016

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Neutrophilic eccrine hidradenitis in 2 patients treated with BRAF inhibitors: a new cutaneous adverse event

Abstract

Neutrophilic eccrine hidradenitis (NEH) is a rare neutrophilic dermatosis, first described in patients undergoing chemotherapy for a malignant hemopathy. Clinical features are polymorphous. Association of clinical and histological features are necessary to make a diagnosis. We report the first two cases of NEH in patients treated with a BRAF inhibitor (BRAFi), either dabrafenib or vemurafenib, for a stage IV metastatic melanoma. Disseminated erythematous plaques associated with fever and polyarthralgia occurred early after initiation of treatment and were badly tolerated. Histological analyses confirmed the diagnosis of NEH. Symptoms disappeared a few days after interruption of treatment and introduction of topical steroids. Replacement of one BRAFi by the other is a therapeutic alternative as it is not necessarily associated with relapse of NEH. NEH can be added to the spectrum of neutrophilic dermatoses induced by BRAFi. It occurs earlier (3 to 4 days) than previously described drug-induced NEH (9 to 12 days) and might be an earlier stage of eccrine squamous syringometaplasia already reported in the context of BRAFi-treated melanoma patients.

This article is protected by copyright. All rights reserved.

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Cortical inhibitory and excitatory function in drug-naive generalized anxiety disorder

Publication date: Available online 21 December 2016
Source:Brain Stimulation
Author(s): Cheng-Ta Li, Chia-Feng Lu, Hui-Ching Lin, Ying-Zu Huang, Chi-Hung Juan, Tung-Ping Su, Ya-Mei Bai, Mu-Hong Chen, Wei-Chen Lin
BackgroundA growing body of evidence suggests that deficits in GABAergic inhibitory and glutamatergic excitatory neurotransmission may be involved in the core pathophysiology of generalized anxiety disorder (GAD), a disease characterized by pathological anxiety worrying. The aim of the present study was to measure motor cortical excitability by paired-pulse transcranial magnetic stimulation (ppTMS) in patients with GAD.MethodsppTMS measurements of excitation and inhibition from bilateral motor cortices were investigated in 26 right-handed GAD patients who were drug-naïve (half of them with a comorbidity of major depressive disorder) and 35 right-handed age- and sex-matched healthy controls. Short-interval intracortical inhibition (SICI), intracortical facilitation (ICF), and long-interval intracortical inhibition (LICI) were studied; evidence indicated that these are mainly mediated by GABA-A receptors, glutamate receptors, and GABA-B receptors, respectively.ResultsAfter correcting for multiple comparisons, GAD patients had significantly lower left ICF (p < 0.001, Cohen's d = 1.348) and right ICF (p = 0.001, Cohen's d = 0.963), but not SICI and LICI, than did healthy controls. No significant difference of the ICF values was found between GAD with and without depressive disorders. Multivariate linear regression analysis revealed that left ICF (B = −4.990, 95% CI = −8.821 to −1.039, p = 0.007) and group (B = 13.179, 95% CI = 10.208 to 16.149, p = 0.001) predicted anxiety symptoms significantly.ConclusionThe present study provided direct evidence to support that generalized anxiety disorder is characterized by impaired intra-cortical facilitation of motor cortex, suggesting glutamate-related excitatory dysfunction may play a key role in pathological anxiety.



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Determining the need and utilization of radiotherapy in cancers of the breast, cervical, lung, prostate and rectum: A population level study

Publication date: Available online 21 December 2016
Source:Radiotherapy and Oncology
Author(s): Lorraine Shack, Shuang Lu, Lee-Anne Weeks, Peter Craighead, Marc Kerba
PurposeDetermining the appropriate rate of radiotherapy (RT) utilization is important for health care planning and resource allocation. The difference between the observed and the appropriate RT rate is influenced by the choice of a criterion based benchmarking (CBB) or evidence-based estimates (EBEST) measure. Our primary objective was to determine the utilization of radiotherapy for cancers of the breast (B), cervix (C), lung (L), prostate (P) and rectum (R) in Alberta (AB) Canada and to compare the observed RT rates to estimates of need derived from the criterion based benchmarking (CBB) and evidence-based estimates (EBEST).Materials and methodsAll incident cases of B,C,L,P and R cancers diagnosed in AB during 2004-8 (prior to the decentralization of provincial RT capacity) were identified from the Alberta Cancer Registry. Patients receiving RT within one year (RT-1y) of diagnosis were identified and the proportion receiving RT-1y was then calculated. Factors associated with RT utilization were analysed by region. Estimates of the need for RT were derived from CBB and EBEST methods in the literature.ResultsA total of n=68,164 cancer cases were identified from the ACR. RT-1y rates (95% C.I.) were B: 51.5% (50.1–52.9), C: 48.9% (43.8–54.0), L: 37.1% (35.4–38.8), P: 26.9% (25.1–28.7) and R: 39.3% (36.5–42.1). Observed rates of RT in AB were lower than estimates derived using the CBB and EBEST estimates. Shortfalls varied across cancer sites according to whether a CBB or EBEST estimate was used ranging from a low of -0.3% in cancer of the cervix to a high of 30.3% in rectal cancer.ConclusionsRT shortfalls exist in the utilization of RT in AB, Canada despite centralized cancer care and a publically funded health care system. Decisions to address shortfalls need to be mindful of how model selection can impact on findings.



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PET imaging of zirconium-89 labelled cetuximab: A phase I trial in patients with head and neck and lung cancer

Publication date: Available online 21 December 2016
Source:Radiotherapy and Oncology
Author(s): Judith van Loon, Aniek J.G. Even, Hugo J.W.L. Aerts, Michel Öllers, Frank Hoebers, Wouter van Elmpt, Ludwig Dubois, Anne-Marie C. Dingemans, Roy I. Lalisang, Pascal Kempers, Boudewijn Brans, Véronique Winnepenninckx, Ernst-Jan Speel, Eric Thunnissen, Kim M. Smits, Ronald Boellaard, Danielle J. Vugts, Dirk De Ruysscher, Philippe Lambin
Background and purposePET imaging of cetuximab uptake may help selecting cancer patients with the highest chance of benefit. The aim of this phase I trial was to determine the safety of the tracer ⁸⁹Zr-cetuximab and to assess tumour uptake.MethodsTwo dose schedules were used; two consecutive doses of 60MBq ⁸⁹Zr-cetuximab or a single dose of 120MBq, both preceded by 400mg/m² of unlabelled cetuximab. Toxicity (CTCAE 3.0) was scored twice weekly. PET-CT scans were acquired on days 4, 5 and 6 (step 1) or 5, 6, 7 (step 2). Because tumour uptake could not be assessed satisfactorily, a third step was added including EGFR overexpressing tumours.ResultsNine patients were included (6 NSCLC; 3 HNC). No additional toxicity was associated with administration of ⁸⁹Zr-cetuximab compared to standard cetuximab. A tumour to blood ratio (TBR)>1 was observed in all but one patient, with a maximum of 4.56. TBR was not different between dose schedules. There was a trend for higher TBR at intervals>5days after injection.ConclusionsBoth presented ⁸⁹Zr-cetuximab administration schedules are safe. The recommended dose for future trials is 60MBq, with a minimum time interval for scanning of 6days.



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Improved overall survival with adjuvant radiotherapy for high-intermediate and high risk Stage I endometrial cancer

Publication date: Available online 21 December 2016
Source:Radiotherapy and Oncology
Author(s): Matthew M. Harkenrider, William Adams, Alec M. Block, Stephanie Kliethermes, William Small, Surbhi Grover
Background/purposeTo perform a large analysis of Stage I endometrioid-type endometrial cancer patients to determine the impact of adjuvant radiotherapy (ART) on survival.Material/methods132,976 FIGO Stage I endometrioid-type endometrial cancer patients treated surgically were identified within the National Cancer Database (NCDB) comprising Commission on Cancer facilities in the United States. Patients were categorized as observation (OBS) or ART (vaginal brachytherapy, external beam radiotherapy, or both). Univariable generalized linear mixed effects models were used to estimate the odds of receiving ART, and a multivariable frailty survival model was used to estimate the instantaneous hazard of death for those receiving OBS versus ART. Due to the presence of a significant interaction, these estimates were stratified by PORTEC-based low, low-intermediate, high-intermediate, and high risk groups.Results104,645 (79%) underwent OBS while 28,331 (21%) received ART. Of those receiving ART, 12,913 (46%) received VBT alone, 12,857 (45%) received EBRT alone, and 2561 (9%) received EBRT+VBT. On univariable analysis, increasing stage/myometrial invasion, higher grade, older age, presence of lymphovascular space invasion, and larger tumor size predicted poorer survival (all p<0.01). On multivariable analysis, patients at high-intermediate risk and high risk experienced improved survival with ART with a hazard ratio of 0.796 (95% CI: 0.731–0.867; p<0.001) and 0.783 (95% CI: 0.693–0.885; p<0.001), respectively. There was no survival benefit for ART among patients at low or low-intermediate risk.ConclusionsIn Stage I high-intermediate and high risk endometrioid-type endometrial cancer patients, ART significantly improves overall survival.



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Reply to Alongi et al.

Publication date: Available online 21 December 2016
Source:Radiotherapy and Oncology
Author(s): Jan Nyman, Andreas Hallqvist




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Mouse DNA polymerase ι lacking the forty-two amino acids encoded by exon-2 is catalytically inactive in vitro

Publication date: Available online 21 December 2016
Source:DNA Repair
Author(s): Ekaterina G. Frank, John P. McDonald, Wei Yang, Roger Woodgate
In 2003, we reported that 129-derived strains of mice carry a naturally occurring nonsense mutation at codon 27 of the Poli gene that would produce a polι peptide of just 26 amino acids, rather then the full-length 717 amino acid wild-type polymerase. In support of the genomic analysis, no polι protein was detected in testes extracts from 129×1/SvJ mice, where wild-type polι is normally highly expressed. The early truncation in polι occurs before any structural domains of the polymerase are synthesized and as a consequence, we reasoned that 129-derived strains of mice should be considered as functionally defective in polι activity. However, it has recently been reported that during the maturation of the Poli mRNA in 129-derived strains, exon- 2 is sometimes skipped and that an exon-2-less polι protein of 675 amino acids is synthesized that retains catalytic activity in vitro and in vivo. From a structural perspective, we found this idea untenable, given that the amino acids encoded by exon-2 include residues critical for the coordination of the metal ions required for catalysis, as well as the structural integrity of the DNA polymerase. To determine if the exon-2-less polι isoform possesses catalytic activity in vitro, we have purified a glutathione-tagged full-length exon-2-less (675 amino acid) polι protein from baculovirus infected insect cells and compared the activity of the isoform to full-length (717 amino acid) GST-tagged wild-type mouse polι in vitro. Reaction conditions were performed under a range of magnesium or manganese concentrations, as well as different template sequence contexts. Wild-type mouse polι exhibited robust characteristic properties previously associated with human polι's biochemical properties. However, we did not detect any polymerase activity associated with the exon-2-less polι enzyme under the same reaction conditions and conclude that exon-2-less polι is indeed rendered catalytically inactive in vitro.



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Embryonic Stem Cell–like Population in Dupuytren’s Disease

Background: Recent research has identified mesenchymal stem cells (MSCs) within Dupuytren's disease (DD) tissue and they have been proposed to give rise to the myofibroblasts, implicated in the progression of this condition. The aim of this study was to identify and characterize the primitive population that might be upstream of the MSC population, within DD. Methods: Formalin-fixed paraffin-embedded 4-µm-thick sections of DD cords and nodules obtained from 6 patients underwent 3,3-diaminobenzidine and immunofluorescent immunohistochemical staining for embryonic stem cell (ESC) markers OCT4, NANOG, SOX2, pSTAT3, and SALL4 and endothelial markers CD34 and ERG. NanoString gene expression analysis was performed to determine the transcriptional activation of these markers. Results: Immunohistochemical staining demonstrated the expression of ESC markers OCT4, NANOG, SOX2, pSTAT3, and SALL4 on the endothelium of the microvessels expressing CD34 and ERG, particularly those surrounding the DD nodules. NanoString analysis confirmed the transcriptional activation of OCT4, NANOG, STAT3, and SALL4, but not SOX2. Conclusion: This article demonstrates the novel finding of an ESC-like population expressing ESC markers OCT4, NANOG, SOX2, pSTAT3, and SALL4, localized to the endothelium of the microvessels within DD tissue, suggesting a potential therapeutic target for this condition.

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Divided and Sliding Superficial Temporal Artery Flap for Primary Donor-site Closure

Summary: Superficial temporal artery (STA) flaps are often used for reconstruction of hair-bearing areas. However, primary closure of the donor site is not easy when the size of the necessary skin island is relatively large. In such cases, skin grafts are needed at the donor site, resulting in baldness. We have solved this issue by applying the divided and sliding flap technique, which was first reported for primary donor-site closure of a latissimus dorsi musculocutaneous flap. We applied this technique to the hair-bearing STA flap, where primary donor-site closure is extremely beneficial for preventing baldness consequent to skin grafting. The STA flap was divided into 3, and creation of large flap was possible. Therefore, we concluded that the divided and sliding STA flap could at least partially solve the donor-site problem. Although further investigation is necessary to validate the maximum possible flap size, this technique may be applicable to at least small defects that are common after skin cancer ablation or trauma.

http://ift.tt/2h9QLLD

Comparison of 2D single-shot turbo-spin-echo and spin-echo echo-planar diffusion weighted brain MRI at 3.0 Tesla: preliminary experience in children

Publication date: March–April 2017
Source:Clinical Imaging, Volume 42
Author(s): Amber L. Pokorney, Jeffrey H. Miller, Houchun H. Hu
PurposeTo qualitatively compare a 2D single-shot turbo-spin-echo (ssTSE) diffusion-weighted imaging MRI technique with a spin-echo echo-planar imaging (SE-EPI) approach in pediatric neuroimaging.MethodsImages were acquired at 3T in 15 patients (10.6±6.0years). A neuroradiologist rated the data based on the severity of image artifacts from air-tissue interfaces and devices such as ventriculoperitoneal shunts and orthodontia, and whether their presence affected diagnostic image quality.ResultsssTSE was preferred over SE-EPI in diagnostic image quality and exhibited fewer clinically relevant artifacts (p<0.01).ConclusionssTSE provides superior diffusion-weighted brain images at 3T, particularly in the presence of orthodontia and shunts.

Graphical abstract

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Pressure Ulcer Reconstruction in Patients with Heterotopic Ossification After Spinal Cord Injury: A Case Series and Review of Literature

Heterotopic Ossification (HO) is widely recognized as a common occurrence among patients suffering from traumatic spinal cord injuries (SCI). The exact etiology of HO formation is still unknown. Published medical and surgical management strategies are often plagued with questionable effectiveness and frequent complications. There are minimal publications regarding management strategies of HO in spinal cord patients as it pertains to plastic surgery. We present a case series of patients treated at our institution who underwent treatment of pressure ulcers with underlying HO to highlight the vast spectrum of clinical phenotypes present in this population.

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Can Patient Variables Measured on Arrival to the Emergency Department Predict Disposition in Medium-acuity Patients?

Publication date: Available online 21 December 2016
Source:The Journal of Emergency Medicine
Author(s): John P. Riordan, Wayne L. Dell, James T. Patrie
BackgroundEmergency department crowding has led to innovative "front end" care models to safely and efficiently care for medium and lower acuity patients. In the United States, most treatment algorithms rely on the emergency severity index (ESI) triage tool to sort patients. However, there are no objective criteria used to differentiate ESI 3 patients.ObjectiveWe seek to derive and validate a model capable of predicting patient discharge disposition (DD) using variables present on arrival to the emergency department for ESI 3 patients.MethodsOur retrospective cohort study included adult patients with an ESI triage designation 3 treated in an academic emergency department over the course of 2 successive years (2013–2015). The main outcome was DD. Two datasets were used in the modeling process. One dataset, the derivation dataset (n = 25,119), was used to develop the statistical model, while the second dataset, the validation dataset (n = 24,639), was used to evaluate the statistical model's prediction performance.ResultsAll variables included in the derivation model were uniquely associated with DD status (p < 0.001). We assessed multivariate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for age (2.50 [95% CI 2.35–2.65]), arrival mode (1.85 [95% CI 1.74–1.96]), heart rate (1.31 [95% CI 1.26–1.37]), sex (1.35 [95% CI 1.28–1.43]), oxygen saturation (1.06 [95% CI 1.01–1.10]), temperature (1.10 [95% CI 1.06–1.15]), systolic blood pressure (1.18 [95% CI 1.12–1.25]), diastolic blood pressure (1.16 [95% CI 1.09–1.22]), respiratory rate (1.05 [95% CI 1.01–1.10]), and pain score (1.13 [95% CI 1.06–1.21]). The validation C-statistic was 0.73.ConclusionWe derived and validated a model and created a nomogram with acceptable discrimination of ESI 3 patients on arrival for purposes of predicting DD. Incorporating these variables into the care of these patients could improve patient flow by identifying patients who are likely to be discharged. © 2016 Elsevier Inc.



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Colonization pressure as a risk factor of ICU-acquired multidrug resistant bacteria: a prospective observational study.

Related Articles

Colonization pressure as a risk factor of ICU-acquired multidrug resistant bacteria: a prospective observational study.

Eur J Clin Microbiol Infect Dis. 2016 Dec 20;:

Authors: Masse J, Elkalioubie A, Blazejewski C, Ledoux G, Wallet F, Poissy J, Preau S, Nseir S

Abstract
The primary objective of this study was to evaluate the impact of colonization pressure on intensive care unit (ICU)-acquired multidrug resistant bacteria (MDRB). All patients hospitalized for more than 48 h in the ICU were included in this prospective observational study. MDRB were defined as methicillin resistant Staphylococcus aureus, Pseudomonas aeruginosa resistant to ceftazidime or imipenem, Gram-negative bacilli producing extended-spectrum beta-lactamases (ESBL), and all strains of Acinetobacter baumannii and Stenotrophomonas maltophilia. Colonization pressure was daily calculated in the three participating ICUs. Univariate and multivariate analyses were used to determine risk factors for ICU-acquired MDRB. Two hundreds and four (34%) of the 593 included patients acquired an MDRB during their ICU stay. Multivariate analysis identified colonization pressure as an independent risk factor for ICU-acquired MDRB (OR (95% CI) 4.18 (1.03-17.01), p = 0.046). Other independent risk factors for ICU-acquired MDRB were mechanical ventilation (3.08 (1.28-7.38), p = 0.012), and arterial catheter use (OR, 3.04 (1.38-6.68), p = 0.006). ICU-acquired MDRB were associated with increased mortality, duration of mechanical ventilation, and ICU stay. However, ICU-acquired MDRB was not independently associated with ICU-mortality. Colonization pressure is an independent risk factor for acquiring MDRB in the ICU.

PMID: 28000030 [PubMed - as supplied by publisher]

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NK Cells are Biologic and Biochemical Targets of 6-Mercaptopurine in Crohn's Disease patients

Publication date: Available online 21 December 2016
Source:Clinical Immunology
Author(s): Susy Yusung, Dermot McGovern, Lin Lin, Daniel Hommes, Venu Lagishetty, Jonathan Braun
NK cells, which contribute to immune defense against certain viral infections and neoplasia, are emerging as modifiers of chronic immunologic diseases including transplant rejection and autoimmune diseases. Immunobiology and genetic studies have implicated NK cells as a modifier of Crohn's disease, a condition often treated with thiopurine agents such as 6-mercaptopurine (6-MP). Here, we demonstrate that thiopurines mediate NK cell apoptosis via a caspase 3 and 9 inclusive pathway, and that this process is triggered by thiopurine-mediated inhibition of Rac1. We also show that CD patients in clinical remission maintained on 6-MP have decreased NK cell Rac1 activity, and decreased NK cell numbers in their intestinal biopsies. These observations suggest that thiopurine targeting of NK cells may be a previously unappreciated therapeutic action of these agents in IBD.



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Mucosal-associated invariant T cells are depleted and functionally altered in patients with common variable immunodeficiency

Publication date: Available online 21 December 2016
Source:Clinical Immunology
Author(s): Serena Arduini, Jean Dunne, Niall Conlon, Conleth Feighery, Derek G. Doherty
Common variable immunodeficiency (CVID) is a primary immunoglobulin deficiency characterized by recurrent infections and complications, including autoimmunity, enteropathy, polyclonal lymphocytic infiltration or lymphoid malignancy. Innate T cells can support B cell maturation and antibody production. We investigated the numbers, phenotypes and functions of circulating B cell, γδ T cell, invariant natural killer T (iNKT) cell and mucosal-associated invariant T (MAIT) cell subsets in 23 CVID patients and 27 healthy controls. Switched-memory B cells and plasmablasts were depleted in CVID patients (p<0.0001). γδ T cells were found at normal numbers, but iNKT and MAIT cells were depleted (p<0.0001 and p<0.002). MAIT cells were especially low in patients with complicated CVID (p<0.05). MAIT cells from patients appeared more activated and more frequently produced interleukin-17A, interleukin-22 and tumor necrosis factor-α than MAIT cells from healthy subjects in vitro. Thus, MAIT cells depletion and activation may contribute to immunodeficiency and complications associated with CVID.



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Quantitative assessment of breast cosmetic outcome following whole breast irradiation

Publication date: Available online 21 December 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Jay P. Reddy, Xiudong Lei, Sheng-Cheng Huang, Krista M. Nicklaus, Michelle C. Fingeret, Simona F. Shaitelman, Kelly K. Hunt, Thomas A. Buchholz, Fatima Merchant, Mia K. Markey, Benjamin D. Smith
PurposeClinical studies of breast radiation therapy typically assess breast cosmetic outcome using subjective scales which may lack reproducibility or ability to discriminate subtle changes. To overcome these limitations, quantitative measures of breast cosmesis have been proposed, but their clinical relevance remains unproven. We applied quantitative analysis of digital photographs to measure breast cosmetic outcome within the setting of a randomized trial of conventionally fractionated (CF) and hypofractionated (HF) whole breast irradiation (WBI). Our goals were to identify how quantitative cosmesis metrics were associated with patient- and physician-reported cosmesis and whether they differed by treatment arm.Materials/MethodsFrom 2011-2014, 287 women age>40 with DCIS or early invasive breast cancer were randomized to HF-WBI (42.56Gy/16fx+10-12.5Gy/4-5fx boost) or CF-WBI (50Gy/25fx+10-14Gy/5-7fx). At one year post-treatment, we collected digital photographs, patient-reported cosmesis using the Breast Cancer Treatment and Outcomes Scale (BCTOS), and physician-reported cosmesis using the Radiation Therapy Oncology Group (RTOG) scale. Six quantitative measures of breast symmetry, labeled M1-M6, were calculated from anteroposterior digital photographs. For each measure, values closer to 1 imply greater symmetry, and values closer to 0 imply greater asymmetry. Associations between M1-M6 and patient- and physician-reported cosmesis and treatment arm were evaluated using the Kruskal-Wallis test.ResultsAmong 245 evaluable patients, patient-reported cosmesis was strongly associated with M1 (vertical symmetry measure) (P<0.01). Physician-reported cosmesis was similarly correlated with M1 (P<0.01) and also with M2 (vertical symmetry, P=0.01) and M4 (horizontal symmetry, P=0.03). At one-year post-treatment, HF-WBI resulted in better values of M2 (P=0.02) and M3 (P<0.01) than CF-WBI; treatment arm was not significantly associated with M1, M4, M5, or M6 (P≥0.12).ConclusionsQuantitative assessment of breast photographs reveals similar to improved cosmetic outcome with HF-WBI compared to CF-WBI one year after treatment. Assessing cosmetic outcome using these measures could be useful for future comparative effectiveness studies and outcome reporting.



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Stereotactic Ablative Radiotherapy is a Highly Safe and Effective Treatment for Elderly Patients with Early Stage Non-Small Cell Lung Cancer

Publication date: Available online 21 December 2016
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Eric D. Brooks, Bing Sun, Lina Zhao, Ritsuko Komaki, Zhonxing Liao, Melenda Jeter, James W. Welsh, Michael S. O'Reilly, Daniel R. Gomez, Stephen M. Hahn, John V. Heymach, David C. Rice, Joe Y. Chang
PurposeTo discern the efficacy and toxicity of SABR in the elderly population (age ≥75), and to consider how it compares to surgical outcomes historically reported in the elderly.Methods and Materials772 patients with clinically early-stage I-II NSCLC (T1-T3 N0M0) were treated with SABR (50 Gy in 4 fractions or 70 Gy in 10 fractions) between 2004-2014 at our center (n=442 age <75, n=330 age ≥75). Primary end points included overall survival, time-to-progression, and grade ≥3 toxicity. Median follow-up time was approximately 55 months.ResultsCompared to patients age <75, patients age ≥75 had no difference in time-to-progression (p=0.419), lung cancer-specific survival (p=0.275), or toxicity (p=0.536). Overall survival was the same between both age groups at 2-years of follow-up but diverged thereafter, with patients aged <75 when treatment began having higher overall survival rates at 5 years. Median OS rates for patients age ≥75 were 86% at 1 year, 57.5% at 3 years, and 39.5% at 5 years. Median OS rates for patients age <75 were 87.3% at 1 year, 67.6% at 3 years, and 51.5% at 5 years. No patient ≥75 experienced any grade 4 or 5 toxicity.ConclusionsSABR's effectiveness is the same in the elderly as it is in the average age population based on lung cancer-specific survival and time-to-progression. It also poses no increased toxicity. Compared to historical outcomes with surgery in the elderly, SABR outcomes here are considered comparable for stage I-II disease but have less morbidity.



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Governing Council Page

Publication date: December 2016
Source:Medical Journal Armed Forces India, Volume 72, Supplement 1





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Magnetic resonance imaging based functional imaging in paediatric oncology

Publication date: Available online 21 December 2016
Source:European Journal of Cancer
Author(s): Karen A. Manias, Simrandip K. Gill, Lesley MacPherson, Katharine Foster, Adam Oates, Andrew C. Peet
Imaging is central to management of solid tumours in children. Conventional magnetic resonance imaging (MRI) is the standard imaging modality for tumours of the central nervous system (CNS) and limbs and is increasingly used in the abdomen. It provides excellent structural detail, but imparts limited information about tumour type, aggressiveness, metastatic potential or early treatment response. MRI based functional imaging techniques, such as magnetic resonance spectroscopy, diffusion and perfusion weighted imaging, probe tissue properties to provide clinically important information about metabolites, structure and blood flow. This review describes the role of and evidence behind these functional imaging techniques in paediatric oncology and implications for integrating them into routine clinical practice.



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Efficacy of Methylprednisolone Acetate Versus Triamcinolone Acetonide Intra-Articular Knee Injection in Patients With Chronic Inflammatory Arthritis: A 24-Week Randomized Controlled Trial

Publication date: Available online 21 December 2016
Source:Clinical Therapeutics
Author(s): Ashwani Kumar, Varun Dhir, Shefali Sharma, Aman Sharma, Surjit Singh
PurposeTriamcinolone hexacetonide (TH), triamcinolone acetonide (TA), and methylprednisolone acetate (MPA) are commonly used intra-articular steroid preparations. Studies suggest that intra-articular TH is more efficacious than MPA and TA in chronic inflammatory arthritis. However, it is unclear which of the latter two preparations has better efficacy. Thus, we compared intra-articular knee injections of MPA and TA in patients with chronic inflammatory arthritis.MethodsThis double-blind, randomized controlled trial included patients with rheumatoid arthritis or spondyloarthritis with an acutely swollen knee joint (≥1 week, <24 weeks). They were randomly assigned (1:1) to intra-articular knee injection with MPA or TA (80 mg, 2 mL of each). Evaluations were performed at 4, 12, and 24 weeks. Primary outcome was time to relapse (Kaplan-Meier) over 24 weeks, with relapse defined as return to baseline pain or swelling ≥1 week. Secondary outcomes were change in pain and swelling (using a numerical rating scale), range of movement, and occurrence of adverse effects. Primary analysis was intention to treat, with last observation carried forward.FindingsOne hundred patients (89 with rheumatoid arthritis) were randomly assigned in equal numbers to the MPA and TA groups. Nine patients relapsed in each group over 24 weeks. The mean time to relapse was not significantly different between the MPA and TA groups (20.8 [95% CI, 18.8–22.7] weeks and 20.9 [95% CI, 19.0–22.8] weeks, respectively; P = 0.9; hazard ratio = 1.0 [95% CI, 0.4–2.5]). In both groups, there was a significant decline in pain and swelling scores at all visits (P < 0.001); however, there were no significant intergroup differences. At 24 weeks, mean change in pain in the MPA (–4.4 [3.1]) and TA groups (–3.9 [2.8]) was not significantly different (P = 0.46). No infection, hematoma or hypopigmentation occurred in any patient. In addition, no significant intergroup differences were found in joint swelling, range of movement, modified (28 joint) Disease Activity Score using 3 variables, or Health Assessment Questionnaire over 24 weeks.ImplicationsNo significant differences were found in efficacy between intra-articular knee injections with MPA and TA in these patients with chronic inflammatory arthritis. However, results need to be extrapolated cautiously because of the small sample size. Three-quarters of the patients remained relapse free at 24 weeks. Clinical Trials Registry of India (www.ctri.nic.in) identifier: CTRI/2015/09/006187.



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Three-Dimensional Architecture of the Human BRCA1-A Histone Deubiquitinase Core Complex

Publication date: 20 December 2016
Source:Cell Reports, Volume 17, Issue 12
Author(s): Otto J.P. Kyrieleis, Pauline B. McIntosh, Sarah R. Webb, Lesley J. Calder, Janette Lloyd, Nisha A. Patel, Stephen R. Martin, Carol V. Robinson, Peter B. Rosenthal, Stephen J. Smerdon
BRCA1 is a tumor suppressor found to be mutated in hereditary breast and ovarian cancer and plays key roles in the maintenance of genomic stability by homologous recombination repair. It is recruited to damaged chromatin as a component of the BRCA1-A deubiquitinase, which cleaves K63-linked ubiquitin chains attached to histone H2A and H2AX. BRCA1-A contributes to checkpoint regulation, repair pathway choice, and HR repair efficiency through molecular mechanisms that remain largely obscure. The structure of an active core complex comprising two Abraxas/BRCC36/BRCC45/MERIT40 tetramers determined by negative-stain electron microscopy (EM) reveals a distorted V-shape architecture in which a dimer of Abraxas/BRCC36 heterodimers sits at the base, with BRCC45/Merit40 pairs occupying each arm. The location and ubiquitin-binding activity of BRCC45 suggest that it may provide accessory interactions with nucleosome-linked ubiquitin chains that contribute to their efficient processing. Our data also suggest how ataxia telangiectasia mutated (ATM)-dependent BRCA1 dimerization may stabilize self-association of the entire BRCA1-A complex.

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Teaser

Kyrieleis et al. have used negative stain electron microscopy along with mass spectrometry and binding assays to characterize one of the major BRCA1-interacting complexes, BRCA1-A, showing the overall architecture of the core four-protein assembly and how this relates to its role as a histone deubiquitinase in double-stranded DNA break signaling.


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Peroxiredoxin 1 Protects Telomeres from Oxidative Damage and Preserves Telomeric DNA for Extension by Telomerase

Publication date: 20 December 2016
Source:Cell Reports, Volume 17, Issue 12
Author(s): Eric Aeby, Wareed Ahmed, Sophie Redon, Viesturs Simanis, Joachim Lingner
Oxidative damage of telomeres can promote cancer, cardiac failure, and muscular dystrophy. Specific mechanisms protecting telomeres from oxidative damage have not been described. We analyzed telomeric chromatin composition during the cell cycle and show that the antioxidant enzyme peroxiredoxin 1 (PRDX1) is enriched at telomeres during S phase. Deletion of the PRDX1 gene leads to damage of telomeric DNA upon oxidative stress, revealing a protective function of PRDX1 against oxidative damage at telomeres. We also show that the oxidized nucleotide 8-oxo-2′deoxyguanosine-5′-triphosphate (8oxodGTP) causes premature chain termination when incorporated by telomerase and that some DNA substrates terminating in 8oxoG prevent extension by telomerase. Thus, PRDX1 safeguards telomeres from oxygen radicals to counteract telomere damage and preserve telomeric DNA for elongation by telomerase.

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Teaser

Aeby et al. analyze the protein composition of telomeres during the cell cycle. The antioxidant enzyme PRDX1 associates with telomeres during S and G2 phases of the cell cycle. Deletion studies reveal that PRDX1 protects telomeres from acute oxidative damage. Oxidized telomeric DNA cannot be extended by telomerase.


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Probabilistic Modeling of Reprogramming to Induced Pluripotent Stem Cells

Publication date: 20 December 2016
Source:Cell Reports, Volume 17, Issue 12
Author(s): Lin L. Liu, Justin Brumbaugh, Ori Bar-Nur, Zachary Smith, Matthias Stadtfeld, Alexander Meissner, Konrad Hochedlinger, Franziska Michor
Reprogramming of somatic cells to induced pluripotent stem cells (iPSCs) is typically an inefficient and asynchronous process. A variety of technological efforts have been made to accelerate and/or synchronize this process. To define a unified framework to study and compare the dynamics of reprogramming under different conditions, we developed an in silico analysis platform based on mathematical modeling. Our approach takes into account the variability in experimental results stemming from probabilistic growth and death of cells and potentially heterogeneous reprogramming rates. We suggest that reprogramming driven by the Yamanaka factors alone is a more heterogeneous process, possibly due to cell-specific reprogramming rates, which could be homogenized by the addition of additional factors. We validated our approach using publicly available reprogramming datasets, including data on early reprogramming dynamics as well as cell count data, and thus we demonstrated the general utility and predictive power of our methodology for investigating reprogramming and other cell fate change systems.

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Teaser

Liu et al. use probabilistic models to interrogate the dynamics of reprogramming from somatic cells to iPSCs. These studies demonstrate that the general two-type (or multi-type) birth-death transition process is a useful mathematical framework to investigate important biological questions, such as inferring the reprogramming rate and addressing whether cells are homogeneous in terms of properties including division rates, apoptosis rates, and reprogramming rates.


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Beyond Epilepsy and Autism: Disruption of GABRB3 Causes Ocular Hypopigmentation

Publication date: 20 December 2016
Source:Cell Reports, Volume 17, Issue 12
Author(s): Ryan J. Delahanty, Yanfeng Zhang, Terry Jo Bichell, Wangzhen Shen, Kelienne Verdier, Robert L. Macdonald, Lili Xu, Kelli Boyd, Janice Williams, Jing-Qiong Kang
Reduced ocular pigmentation is common in Angelman syndrome (AS) and Prader-Willi syndrome (PWS) and is long thought to be caused by OCA2 deletion. GABRB3 is located in the 15q11-13 region flanked by UBE3A, GABRA5, GABRG3, and OCA2. Mutations in GABRB3 have frequently been associated with epilepsy and autism, consistent with its role in neurodevelopment. We report here a robust phenotype in the mouse in which deletion of Gabrb3 alone causes nearly complete loss of retinal pigmentation due to atrophied melanosomes, as evidenced by electron microscopy. Using exome and RNA sequencing, we confirmed that only the Gabrb3 gene was disrupted while the Oca2 gene was intact. However, mRNA abundance of Oca2 and other genes adjacent to Gabrb3 is substantially reduced in Gabrb3^−/− mice, suggesting complex transcriptional regulation in this region. These results suggest that impairment in GABRB3 downregulates OCA2 and indirectly causes ocular hypopigmentation and visual defects in AS and PWS.

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Teaser

Hypopigmentation in Angelman syndrome is thought to stem from deletion of the pigment gene OCA2. Delahanty et al. now find that disruption of Gabrb3 alone causes profound loss of retinal pigmentation via downregulation of Oca2 transcription. This suggests unique complexities in gene regulation in the 15q11-13 imprinted region.


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Calcium Imaging Reveals Coordinated Simple Spike Pauses in Populations of Cerebellar Purkinje Cells

Publication date: 20 December 2016
Source:Cell Reports, Volume 17, Issue 12
Author(s): Jorge E. Ramirez, Brandon M. Stell
The brain's control of movement is thought to involve coordinated activity between cerebellar Purkinje cells. The results reported here demonstrate that somatic Ca²⁺ imaging is a faithful reporter of Na⁺-dependent "simple spike" pauses and enables us to optically record changes in firing rates in populations of Purkinje cells in brain slices and in vivo. This simultaneous calcium imaging of populations of Purkinje cells reveals a striking spatial organization of pauses in Purkinje cell activity between neighboring cells. The source of this organization is shown to be the presynaptic gamma-Aminobutyric acid producing (GABAergic) network, and blocking ionotropic gamma-Aminobutyric acid receptor (GABAARs) abolishes the synchrony. These data suggest that presynaptic interneurons synchronize (in)activity between neighboring Purkinje cells, and thereby maximize their effect on downstream targets in the deep cerebellar nuclei.

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Teaser

Ramirez and Stell use high-speed calcium imaging to monitor action potentials in populations of neurons and extract pauses in ongoing neuronal activity as well as changes in spiking rate. They see that presynaptic GABAergic interneurons organize Purkinje cell activity by simultaneously pausing spiking in neighboring Purkinje cells.


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Targeted Inactivation of Bax Reveals a Subtype-Specific Mechanism of Cajal-Retzius Neuron Death in the Postnatal Cerebral Cortex

Publication date: 20 December 2016
Source:Cell Reports, Volume 17, Issue 12
Author(s): Fanny Ledonne, David Orduz, Judith Mercier, Lisa Vigier, Elisabeth A. Grove, Fadel Tissir, Maria Cecilia Angulo, Alessandra Pierani, Eva Coppola
Cajal-Retzius cells (CRs), the first-born neurons in the developing cerebral cortex, coordinate crucial steps in the construction of functional circuits. CRs are thought to be transient, as they disappear during early postnatal life in both mice and humans, where their abnormal persistence is associated with pathological conditions. Embryonic CRs comprise at least three molecularly and functionally distinct subtypes: septum, ventral pallium/pallial-subpallial boundary (PSB), and hem. However, whether subtype-specific features exist postnatally and through which mechanisms they disappear remain unknown. We report that CR subtypes display unique distributions and dynamics of death in the postnatal mouse cortex. Surprisingly, although all CR subtypes undergo cell death, septum, but not hem, CRs die in a Bax-dependent manner. Bax-inactivated rescued septum-CRs maintain immature electrophysiological properties. These results underlie the existence of an exquisitely refined control of developmental cell death and provide a model to test the effect of maintaining immature circuits in the adult neocortex.

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Ledonne et al. report that Cajal-Retzius neuron subtypes display unique distributions and dynamics of death in the postnatal mouse cortex. Conditional inactivation of the pro-apoptotic factor Bax reveals that different pathways control subtype death. CRs that are prevented from dying maintain immature electrophysiological properties in an adult environment.


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A Mouse Model of Zika Virus Sexual Transmission and Vaginal Viral Replication

Publication date: 20 December 2016
Source:Cell Reports, Volume 17, Issue 12
Author(s): William Weihao Tang, Matthew Perry Young, Anila Mamidi, Jose Angel Regla-Nava, Kenneth Kim, Sujan Shresta
Case reports of Zika virus (ZIKV) sexual transmission and genital persistence are mounting. Venereal transmission and genital persistence threaten public health within and beyond the range of ZIKV's mosquito vectors. In this study, we administered ZIKV into the vaginas of AG129 mice and LysMCre⁺IFNAR^fl/fl C57BL/6 mice after hormonal treatments. Mice infected during estrus-like phase were resistant to vaginal infection. In contrast, when infected during diestrus-like phase, AG129 mice succumbed to infection, whereas LysMCre⁺IFNAR^fl/fl mice experienced transient illness. Patency of transgenital transmission (TGT) in diestrus-like mice was demonstrated by detection of viremia and ZIKV replication in spleen and brain, and viral RNA persisted in vaginal washes as late as 10 days post-infection. In these lethal and sublethal mouse models, this study indicates that intravaginal deposition of ZIKV can cause TGT, hormonal changes in the female reproductive tract (FRT) influence transmission, and ZIKV replication persists in the FRT for several days.

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Teaser

Tang et al. provide mouse models of Zika virus sexual transmission in which hormonal staging influences susceptibility to vaginal infection, transgenital transmission, and persistence of viral replication in the female reproductive tract. These models offer valuable tools to study the pathogenesis of, and preventative strategies against, Zika virus sexual transmission.


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Anabolism-Associated Mitochondrial Stasis Driving Lymphocyte Differentiation over Self-Renewal

Publication date: 20 December 2016
Source:Cell Reports, Volume 17, Issue 12
Author(s): William C. Adams, Yen-Hua Chen, Radomir Kratchmarov, Bonnie Yen, Simone A. Nish, Wen-Hsuan W. Lin, Nyanza J. Rothman, Larry L. Luchsinger, Ulf Klein, Meinrad Busslinger, Jeffrey C. Rathmell, Hans-Willem Snoeck, Steven L. Reiner
Regeneration requires related cells to diverge in fate. We show that activated lymphocytes yield sibling cells with unequal elimination of aged mitochondria. Disparate mitochondrial clearance impacts cell fate and reflects larger constellations of opposing metabolic states. Differentiation driven by an anabolic constellation of PI3K/mTOR activation, aerobic glycolysis, inhibited autophagy, mitochondrial stasis, and ROS production is balanced with self-renewal maintained by a catabolic constellation of AMPK activation, mitochondrial elimination, oxidative metabolism, and maintenance of FoxO1 activity. Perturbations up and down the metabolic pathways shift the balance of nutritive constellations and cell fate owing to self-reinforcement and reciprocal inhibition between anabolism and catabolism. Cell fate and metabolic state are linked by transcriptional regulators, such as IRF4 and FoxO1, with dual roles in lineage and metabolic choice. Instructing some cells to utilize nutrients for anabolism and differentiation while other cells catabolically self-digest and self-renew may enable growth and repair in metazoa.

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Activated lymphocytes use asymmetric cell division to couple differentiation and self-renewal. Adams et al. show that unequal elimination of aged mitochondria by sibling cells is part of a broader dichotomy of metabolic signaling, which instructs cells to use nutrients for division and differentiation or instead to catabolically self-digest for self-renewal.


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Cancer-Specific Synthetic Lethality between ATR and CHK1 Kinase Activities

Publication date: 20 December 2016
Source:Cell Reports, Volume 17, Issue 12
Author(s): Kumar Sanjiv, Anna Hagenkort, José Manuel Calderón-Montaño, Tobias Koolmeister, Philip M. Reaper, Oliver Mortusewicz, Sylvain A. Jacques, Raoul V. Kuiper, Niklas Schultz, Martin Scobie, Peter A. Charlton, John R. Pollard, Ulrika Warpman Berglund, Mikael Altun, Thomas Helleday




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The Ciliary Margin Zone of the Mammalian Retina Generates Retinal Ganglion Cells

Publication date: 20 December 2016
Source:Cell Reports, Volume 17, Issue 12
Author(s): Florencia Marcucci, Veronica Murcia-Belmonte, Qing Wang, Yaiza Coca, Susana Ferreiro-Galve, Takaaki Kuwajima, Sania Khalid, M. Elizabeth Ross, Carol Mason, Eloisa Herrera
The retina of lower vertebrates grows continuously by integrating new neurons generated from progenitors in the ciliary margin zone (CMZ). Whether the mammalian CMZ provides the neural retina with retinal cells is controversial. Live imaging of embryonic retina expressing eGFP in the CMZ shows that cells migrate laterally from the CMZ to the neural retina where differentiated retinal ganglion cells (RGCs) reside. Because Cyclin D2, a cell-cycle regulator, is enriched in ventral CMZ, we analyzed Cyclin D2^−/− mice to test whether the CMZ is a source of retinal cells. Neurogenesis is diminished in Cyclin D2 mutants, leading to a reduction of RGCs in the ventral retina. In line with these findings, in the albino retina, the decreased production of ipsilateral RGCs is correlated with fewer Cyclin D2⁺ cells. Together, these results implicate the mammalian CMZ as a neurogenic site that produces RGCs and whose proper generation depends on Cyclin D2 activity.

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Is the mammalian CMZ a source of retinal neurons? By live imaging of the mouse retina, Marcucci et al. chronicled cells translocating from the CMZ to the neural retina. In addition, genetic perturbations of CMZ cells implicate the CMZ as a neurogenic site for RGCs.


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Cdx and T Brachyury Co-activate Growth Signaling in the Embryonic Axial Progenitor Niche

Publication date: 20 December 2016
Source:Cell Reports, Volume 17, Issue 12
Author(s): Shilu Amin, Roel Neijts, Salvatore Simmini, Carina van Rooijen, Sander C. Tan, Lennart Kester, Alexander van Oudenaarden, Menno P. Creyghton, Jacqueline Deschamps
In vertebrate embryos, anterior tissues are generated early, followed by the other axial structures that emerge sequentially from a posterior growth zone. The genetic network driving posterior axial elongation in mice, and its disturbance in mutants with posterior truncation, is not yet fully understood. Here, we show that the combined expression of Cdx2 and T Brachyury is essential to establish the core signature of posterior axial progenitors. Cdx2 and T Brachyury are required for extension of a similar trunk portion of the axis. Simultaneous loss of function of these two genes disrupts axial elongation to a much greater extent than each single mutation alone. We identify and validate common targets for Cdx2 and T Brachyury in vivo, including Wnt and Fgf pathway components active in the axial progenitor niche. Our data demonstrate that integration of the Cdx/Hox and T Brachyury transcriptional networks controls differential axial growth during vertebrate trunk elongation.

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Vertebrate embryos elongate their body from a posterior growth zone containing tissue progenitors. Amin et al. find that two different transcription factors required for body elongation directly bind and activate the same growth-stimulating genes. The authors demonstrate the importance of these activation events for differential control of axial growth.


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Engineered Murine HSCs Reconstitute Multi-lineage Hematopoiesis and Adaptive Immunity

Publication date: 20 December 2016
Source:Cell Reports, Volume 17, Issue 12
Author(s): Yi-Fen Lu, Patrick Cahan, Samantha Ross, Julie Sahalie, Patricia M. Sousa, Brandon K. Hadland, Wenqing Cai, Erik Serrao, Alan N. Engelman, Irwin D. Bernstein, George Q. Daley
Hematopoietic stem cell (HSC) transplantation is curative for malignant and genetic blood disorders, but is limited by donor availability and immune-mismatch. Deriving HSCs from patient-matched embryonic/induced-pluripotent stem cells (ESCs/iPSCs) could address these limitations. Prior efforts in murine models exploited ectopic HoxB4 expression to drive self-renewal and enable multi-lineage reconstitution, yet fell short in delivering robust lymphoid engraftment. Here, by titrating exposure of HoxB4-ESC-HSC to Notch ligands, we report derivation of engineered HSCs that self-renew, repopulate multi-lineage hematopoiesis in primary and secondary engrafted mice, and endow adaptive immunity in immune-deficient recipients. Single-cell analysis shows that following engraftment in the bone marrow niche, these engineered HSCs further specify to a hybrid cell type, in which distinct gene regulatory networks of hematopoietic stem/progenitors and differentiated hematopoietic lineages are co-expressed. Our work demonstrates engineering of fully functional HSCs via modulation of genetic programs that govern self-renewal and lineage priming.

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Embryonic/induced pluripotent stem cells (ESCs/iPSCs) represent an unlimited source of hematopoietic stem cells (HSCs) for treating blood diseases. By modulating genetic programs governing self-renewal and lineage-guiding pathways, Lu et al. derive engineered HSCs with robust lymphoid potential and endow adaptive immunity in vivo.


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Blood Stage Malaria Disrupts Humoral Immunity to the Pre-erythrocytic Stage Circumsporozoite Protein

Publication date: 20 December 2016
Source:Cell Reports, Volume 17, Issue 12
Author(s): Gladys J. Keitany, Karen S. Kim, Akshay T. Krishnamurty, Brian D. Hondowicz, William O. Hahn, Nicholas Dambrauskas, D. Noah Sather, Ashley M. Vaughan, Stefan H.I. Kappe, Marion Pepper
Many current malaria vaccines target the pre-erythrocytic stage of infection in the liver. However, in malaria-endemic regions, increased blood stage exposure is associated with decreased vaccine efficacy, thereby challenging current vaccine efforts. We hypothesized that pre-erythrocytic humoral immunity is directly disrupted by blood stage infection. To investigate this possibility, we used Plasmodium-antigen tetramers to analyze B cells after infection with either late liver stage arresting parasites or wild-type parasites that progress to the blood stage. Our data demonstrate that immunoglobulin G (IgG) antibodies against the pre-erythrocytic antigen, circumsporozoite protein (CSP), are generated only in response to the attenuated, but not the wild-type, infection. Further analyses revealed that blood stage malaria inhibits CSP-specific germinal center B cell differentiation and modulates chemokine expression. This results in aberrant memory formation and the loss of a rapid secondary B cell response. These data highlight how immunization with attenuated parasites may drive optimal immunity to malaria.

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Individuals in malaria-endemic regions develop poor humoral immunity to pre-erythrocytic Plasmodium antigens. Keitany et al. demonstrate that immunization with genetically attenuated parasites leads to functional memory formation of B cells specific for the pre-erythrocytic antigen, circumsporozoite protein (CSP), yet exposure to blood stage infection suppresses this process.


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Inhibition of RORγT Skews TCRα Gene Rearrangement and Limits T Cell Repertoire Diversity

Publication date: 20 December 2016
Source:Cell Reports, Volume 17, Issue 12
Author(s): Yanxia Guo, Kenzie D. MacIsaac, Yi Chen, Richard J. Miller, Renu Jain, Barbara Joyce-Shaikh, Heidi Ferguson, I-Ming Wang, Razvan Cristescu, John Mudgett, Laura Engstrom, Kyle J. Piers, Gretchen A. Baltus, Kenneth Barr, Hongjun Zhang, Huseyin Mehmet, Laxminarayan G. Hegde, Xiao Hu, Laura L. Carter, Thomas D. Aicher, Gary Glick, Dennis Zaller, Abbas Hawwari, Craig C. Correll, Dallas C. Jones, Daniel J. Cua
Recent studies have elucidated the molecular mechanism of RORγT transcriptional regulation of Th17 differentiation and function. RORγT was initially identified as a transcription factor required for thymopoiesis by maintaining survival of CD4⁺CD8⁺ (DP) thymocytes. While RORγ antagonists are currently being developed to treat autoimmunity, it remains unclear how RORγT inhibition may impact thymocyte development. In this study, we show that in addition to regulating DP thymocytes survival, RORγT also controls genes that regulate thymocyte migration, proliferation, and T cell receptor (TCR)α selection. Strikingly, pharmacological inhibition of RORγ skews TCRα gene rearrangement, limits T cell repertoire diversity, and inhibits development of autoimmune encephalomyelitis. Thus, targeting RORγT not only inhibits Th17 cell development and function but also fundamentally alters thymic-emigrant recognition of self and foreign antigens. The analysis of RORγ inhibitors has allowed us to gain a broader perspective of the diverse function of RORγT and its impact on T cell biology.

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Guo et al. find that small-molecule RORγT antagonist treatment induces CD4⁺CD8⁺ thymocyte apoptosis, skews the T cell repertoire, prevents autoreactive T cell development, and delays autoimmune EAE progression. This work underscores the risk versus benefit of targeting RORγT in clinical testing of RORγT inhibitors.


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Myeloid-Derived Suppressor Cells Are Controlled by Regulatory T Cells via TGF-β during Murine Colitis

Publication date: 20 December 2016
Source:Cell Reports, Volume 17, Issue 12
Author(s): Cho-Rong Lee, Yewon Kwak, Taewoo Yang, Jung Hyun Han, Sang-Heon Park, Michael B. Ye, Wongeun Lee, Kyu-Young Sim, Jung-Ah Kang, Yong-Chul Kim, Sarkis K. Mazmanian, Sung-Gyoo Park
Myeloid-derived suppressor cells (MDSCs) are well known regulators of regulatory T cells (Treg cells); however, the direct regulation of MDSCs by Treg cells has not been well characterized. We find that colitis caused by functional deficiency of Treg cells leads to altered expansion and reduced function of MDSCs. During differentiation of MDSCs in vitro from bone marrow cells, Treg cells enhanced MDSC function and controlled their differentiation through a mechanism involving transforming growth factor-β (TGF-β). TGF-β-deficient Treg cells were not able to regulate MDSC function in an experimentally induced model of colitis. Finally, we evaluated the therapeutic effect of TGF-β-mediated in-vitro-differentiated MDSCs on colitis. Adoptive transfer of MDSCs that differentiated with TGF-β led to better colitis prevention than the transfer of MDSCs that differentiated without TGF-β. Our results demonstrate an interaction between Treg cells and MDSCs that contributes to the regulation of MDSC proliferation and the acquisition of immunosuppressive functions.

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Lee et al. find that, under pro-inflammatory conditions, Treg cells and MDSCs establish a positive feedback loop whereby MDSCs support the expansion of Treg cells while Treg cells modulate MDSC differentiation and function. This property of Treg cells is dependent upon Treg cell-derived TGF-β.


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Long-Term Optical Access to an Estimated One Million Neurons in the Live Mouse Cortex

Publication date: 20 December 2016
Source:Cell Reports, Volume 17, Issue 12
Author(s): Tony Hyun Kim, Yanping Zhang, Jérôme Lecoq, Juergen C. Jung, Jane Li, Hongkui Zeng, Cristopher M. Niell, Mark J. Schnitzer
A major technological goal in neuroscience is to enable the interrogation of individual cells across the live brain. By creating a curved glass replacement to the dorsal cranium and surgical methods for its installation, we developed a chronic mouse preparation providing optical access to an estimated 800,000–1,100,000 individual neurons across the dorsal surface of neocortex. Post-surgical histological studies revealed comparable glial activation as in control mice. In behaving mice expressing a Ca²⁺ indicator in cortical pyramidal neurons, we performed Ca²⁺ imaging across neocortex using an epi-fluorescence macroscope and estimated that 25,000–50,000 individual neurons were accessible per mouse across multiple focal planes. Two-photon microscopy revealed dendritic morphologies throughout neocortex, allowed time-lapse imaging of individual cells, and yielded estimates of >1 million accessible neurons per mouse by serial tiling. This approach supports a variety of optical techniques and enables studies of cells across >30 neocortical areas in behaving mice.

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Kim et al. present a preparation for long-term imaging in which a curved glass window replaces the mouse dorsal cranium. This method enables large-scale Ca²⁺ imaging of neuronal dynamics across neocortex in behaving mice and yields an estimated >1 million optically accessible neurons by two-photon microscopy.


http://ift.tt/2iiyGuv

TGF-β Signaling in Dopaminergic Neurons Regulates Dendritic Growth, Excitatory-Inhibitory Synaptic Balance, and Reversal Learning

Publication date: 20 December 2016
Source:Cell Reports, Volume 17, Issue 12
Author(s): Sarah X. Luo, Leah Timbang, Jae-Ick Kim, Yulei Shang, Kadellyn Sandoval, Amy A. Tang, Jennifer L. Whistler, Jun B. Ding, Eric J. Huang
Neural circuits involving midbrain dopaminergic (DA) neurons regulate reward and goal-directed behaviors. Although local GABAergic input is known to modulate DA circuits, the mechanism that controls excitatory/inhibitory synaptic balance in DA neurons remains unclear. Here, we show that DA neurons use autocrine transforming growth factor β (TGF-β) signaling to promote the growth of axons and dendrites. Surprisingly, removing TGF-β type II receptor in DA neurons also disrupts the balance in TGF-β1 expression in DA neurons and neighboring GABAergic neurons, which increases inhibitory input, reduces excitatory synaptic input, and alters phasic firing patterns in DA neurons. Mice lacking TGF-β signaling in DA neurons are hyperactive and exhibit inflexibility in relinquishing learned behaviors and re-establishing new stimulus-reward associations. These results support a role for TGF-β in regulating the delicate balance of excitatory/inhibitory synaptic input in local microcircuits involving DA and GABAergic neurons and its potential contributions to neuropsychiatric disorders.

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Luo et al. show that loss of TGF-β signaling in mature DA neurons leads to defects in axonal and dendritic growth and in the maintenance of balanced excitation-inhibition synaptic input in early postnatal life. Mice lacking TGF-β signaling in DA neurons exhibit hyperactivity and behavioral inflexibility in reversal learning.


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Ets Factors Regulate Neural Stem Cell Depletion and Gliogenesis in Ras Pathway Glioma

Publication date: 20 December 2016
Source:Cell Reports, Volume 17, Issue 12
Author(s): Joshua J. Breunig, Rachelle Levy, C. Danielle Antonuk, Jessica Molina, Marina Dutra-Clarke, Hannah Park, Aslam Abbasi Akhtar, Gi Bum Kim, Terrance Town, Xin Hu, Serguei I. Bannykh, Roel G.W. Verhaak, Moise Danielpour




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Calcium Release from Stores Inhibits GIRK

Publication date: 20 December 2016
Source:Cell Reports, Volume 17, Issue 12
Author(s): Paul F. Kramer, John T. Williams
Synaptic transmission is mediated by ionotropic and metabotropic receptors that together regulate the rate and pattern of action potential firing. Metabotropic receptors can activate ion channels and modulate other receptors and channels. The present paper examines the interaction between group 1 mGluR-mediated calcium release from stores and GABAB/D2-mediated GIRK currents in rat dopamine neurons of the Substantia Nigra. Transient activation of mGluRs decreased the GIRK current evoked by GABAB and D2 receptors, although less efficaciously for D2. The mGluR-induced inhibition of GIRK current peaked in 1 s and recovered to baseline after 5 s. The inhibition was dependent on release of calcium from stores, was larger for transient than for tonic currents, and was unaffected by inhibitors of PLC, PKC, PLA2, or calmodulin. This inhibition of GABAB IPSCs through release of calcium from stores is a postsynaptic mechanism that may broadly reduce GIRK-dependent inhibition of many central neurons.

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Kramer and Williams show that Gq-mediated calcium release from stores functionally inhibits Gi-coupled GIRK currents. This process occurs within milliseconds and lasts seconds and is not mediated through classical Gq modulators of GIRK such as PKC, PLC, or PLA2.


http://ift.tt/2iiCBHD

Synaptic Specializations Support Frequency-Independent Purkinje Cell Output from the Cerebellar Cortex

Publication date: 20 December 2016
Source:Cell Reports, Volume 17, Issue 12
Author(s): Josef Turecek, Skyler L. Jackman, Wade G. Regehr
The output of the cerebellar cortex is conveyed to the deep cerebellar nuclei (DCN) by Purkinje cells (PCs). Here, we characterize the properties of the PC-DCN synapse in juvenile and adult mice and find that prolonged high-frequency stimulation leads to steady-state responses that become increasingly frequency independent within the physiological firing range of PCs in older animals, resulting in a linear relationship between charge transfer and activation frequency. We used a low-affinity antagonist to show that GABAA-receptor saturation occurs at this synapse but does not underlie frequency-invariant transmission. We propose that PC-DCN synapses have two components of release: one prominent early in trains and another specialized to maintain transmission during prolonged activation. Short-term facilitation offsets partial vesicle depletion to produce frequency-independent transmission.

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Turecek et al. show that, at synapses between Purkinje cells and deep cerebellar nuclear neurons, synaptic transmission is frequency invariant. This frequency invariance is generated by a balance between short-term depression and facilitation.


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Processing of preceramic polymer to low density silicon carbide foam

Publication date: 15 February 2017
Source:Materials & Design, Volume 116
Author(s): Prasanta Jana, Emanuele Zera, Gian Domenico Sorarù
A method is described here for preparing lightweight and low cost polymer-derived silicon carbide foam by impregnation of preceramic polymer in polyurethane foam. A series of silicon carbide foams with various density (0.035–0.35g/cm³), porosity (87–98%) and thermal conductivity (0.05–0.12W/m·K) were prepared using allylhydropolycarbosilane as a base material. Surface analysis shows that the resultant foams have an open and interconnected porous structure. Phase analysis shows that it has cubic crystal structure. There was no evidence of cracks or damage even after treating the silicon carbide foam with concentrated hydrofluoric acid for 12days. From the oxidation resistance experiment, it can be concluded that the silicon carbide foam is stable up to 1500°C in air and 2000°C in argon.

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Tensile response of carbon-aramid hybrid 3D braided composites

Publication date: 15 February 2017
Source:Materials & Design, Volume 116
Author(s): Yuanyuan Zheng, Ying Sun, Jialu Li, Liu Limin, Li Chen, Junling Liu, Shuquan Tian
The effects of braided architecture and co-braided hybrid structure on the tensile response of carbon-aramid hybrid three-dimensional (3D) braided composites are investigated experimentally in this paper. Four kinds of specimens with different braided architectures or different co-braided hybrid structures were produced. The elastic properties and surface deformation of hybrid 3D braided composites were measured under axial tensile loading to failure utilizing the Digital Image Correlation (DIC) technique. The surface full-field strain contours indicate that the high strain aeras are distributed at the braiding yarns. Both the highest tensile strength and modulus of specimens are achieved by hybrid three-dimensional five-directional (3D5d) braided composites with carbon fibers as axial yarns. While, both the maximum ultimate tensile strain and Poisson's ratio are achieved by hybrid 3D5d braided composites with aramid fibers as axial yarns. The fracture morphologies of samples show that the fracture patterns of hybrid composites depend on both braided architecture and co-braided hybrid structure. The carbon-aramid co-braided hybrid 3D braided composites can be developed with strength and toughness properties far superior to those of their individual constituents.

Graphical abstract

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Oxidation and thermal shock resistant properties of Si/Yb2SiO5/NdMgAl11O19 coating deposited on Cf/SiC composites

Publication date: 15 February 2017
Source:Materials & Design, Volume 116
Author(s): Cunyan Fan, Binglin Zou, Ling Zhu, Wenjuan Fan, Xiaolong Cai, Ying Wang, Xueqiang Cao
Yb2SiO5 and NdMgAl11O19 (NMA) powders were synthesized by solid-state reactions. Triple-layer ceramic coatings based on the Si bond layer, Yb2SiO5 interlayer and NMA top layer were prepared on carbon fiber reinforced silicon carbide ceramic matrix (Cf/SiC) composites by atmospheric plasma spraying (APS). The coatings were subjected to thermal shock tests at 1300°C, 1400°C and 1450°C, respectively. The results showed that the Si/Yb2SiO5/NMA coating significantly improved the oxidation resistance of Cf/SiC composites. The failure mechanism of the Si/Yb2SiO5/NMA coating was closely related to the thermal shock temperature. Below 1400°C, the failure of the coating was connected with the mismatch of thermal expansion coefficient (CTE) between the coating and substrate, the reaction between Yb2SiO5 and NMA at the interface, the poor sintering property of Yb2SiO5 and NMA and the substrate itself. Above 1450°C, the coating failed after only one thermal shock cycle due to the temperature higher than the melting point of the silicon.

Graphical abstract

http://ift.tt/2iiosKu

Alloying effects of Ga on the Co-V-Si high-temperature shape memory alloys

Publication date: 15 February 2017
Source:Materials & Design, Volume 116
Author(s): Hengxing Jiang, Cuiping Wang, Weiwei Xu, Xiao Xu, Shuiyuan Yang, Ryosuke Kainuma, Xingjun Liu
Co64V15Si21−xGax (x=4, 6, 8, 10) alloys have been prepared to investigate the alloying effects of Ga on various properties of Co-V-Si high-temperature shape memory alloys, including crystal structure, transformation behavior, thermal cycle stability, microstructure evolution, mechanical property and shape memory behavior. Results show that the D022-type martensite single-phase is transformed from the L21-type parent phase in Co64V15Si17Ga4 alloys. With the increase of Ga content, R phase appears along grain boundaries of martensite and martensitic transformation temperatures decrease rapidly. Furthermore, the Co64V15Si17Ga4 alloy exhibits excellent thermal cycle stability and stable microstructure even after heated to high temperatures of ~800°C repeatedly. On the other hand, for the (martensite+R) dual-phase alloys (i.e., Co64V15Si15Ga6, Co64V15Si13Ga8 and Co64V15Si11Ga10), (εCo) phase precipitates during thermal cycle process, with respective thermal cycle stabilities enhanced at different temperatures simultaneously. In addition, although excess Ga addition deteriorates the mechanical property significantly, it is still concluded that the doping of Ga has a positive effect on the development of shape memory effect of Co-V-Si high-temperature shape memory alloys.

Graphical abstract

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Surface modification of carbon fibers and the selective laser sintering of modified carbon fiber/nylon 12 composite powder

Publication date: 15 February 2017
Source:Materials & Design, Volume 116
Author(s): Wu Jing, Chen Hui, Wu Qiong, Liu Hongbo, Luo Zhanjun
This work aims to study the surface modification and reinforcing effect in carbon fiber (CF)/nylon 12 (PA12) composites of CFs, and more importantly, resolves the practical application problems of modified CF/PA12 composite powder in selective laser sintering (SLS). CFs were surface modified by nitric acid (HNO3), the surface changes of CFs were characterized by SEM, FT-IR and XPS. Initially, the effects of the experimental factors on the properties of composites were investigated, and the CF/PA12 composite powder prepared with optimized technological parameters was subsequently adopted in SLS experiments. The sintering behavior and relationship between mechanical properties and porosity of sintered specimens were also discussed. The results indicated that the oxygen functional groups on HNO3 modified CFs were partly thermally decomposed and released as gas in the process of laser sintering, which caused high porosity and poor mechanical properties of sintered specimens. Treating CFs at 400°C (approximately the laser sintering temperature) after HNO3 modification was proposed as a solution. This treatment preserved part of the modified effect and reduced the porosity of the composites at the same time. Compared with the unmodified CF/PA12 sintered specimens, the tensile strength, tensile modulus, flexural strength, and flexural modulus were all increased to different degrees.

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Mode I delamination mechanism analysis on CFRP interference-fit during the installation process

Publication date: 15 February 2017
Source:Materials & Design, Volume 116
Author(s): Peng Zou, Yuan Li, Kaifu Zhang, Ping Liu, Heng Zhong
The wide application of composite materials in aerospace raises a new challenge for the joining technology. Though interference-fit can enhance joint strength, potential delamination damage also emerges for oversized percentage. A delamination analytical model during the interference-fit pin installation process is established in this paper. It consists of the critical delamination force (CDF) induced by mode I delamination and the pin-hole friction. The establishment of CDF model is based on fracture mechanics, classical bending plate theory and the mechanics of composites, and the friction model is built with classical anisotropic plate theory and friction law. Cohesive element (CE) based delamination simulation with bilinear softening constitutive law is made, and corresponding pin installation experiments are also conducted. The effect of interference-fit percentages and residual layers on CDF was analyzed and the critical interference percentage below which delamination-free hole can be obtained was also proposed. Finite-element delamination results and experimental delamination specimens were analyzed and the rationality of the model was testified.

Graphical abstract

http://ift.tt/2iioOkm