BRAF Expression Research Articles

IMG-15. Radiomic Profiling of Pediatric Low-Grade Glioma Improves Risk Stratification Beyond Clinical Measures

Abstract PURPOSE: Treatment response is heterogeneous among patients with pediatric low-grade glioma (pLGG), the most frequent childhood brain tumor. Upfront prediction of progression-free survival (PFS) may facilitate more personalized treatment planning and improve outcomes for the pLGG patients. In this work, we explored the additive value of radiomics to clinical measures for prediction of PFS in pLGGs. We further sought associations between the derived risk groups and underlying alterations in key genomic and transcriptomic variables. METHODS: Quantitative radiomic features were extracted from pre-operative multi-parametric MRI scans (T1, T1-post, T2, T2-FLAIR) of 96 patients with newly diagnosed pLGG (median age, 8.59, range, 0.35-18.87 years; median PFS, 25.23, range, 3.03-124.83 months). Multivariate Cox proportional hazard’s (Cox-PH) regression models were fitted using 5-fold cross-validation on a training cohort of 68 subjects and tested on 28 patients. Three models were generated using (1) only clinical variables (age, sex, and extent of tumor resection), (2) radiomic features, and (3) clinical and radiomic variables. The dimensionality of radiomic features in Cox-PH models was reduced by applying Elastic Net regularization penalty to identify a subset of variables that are most predictive of PFS. The patients were then stratified into three groups of high, medium, and low-risk based on model predictions. RESULTS: Cox-PH modeling resulted in a concordance index (c-index) of 0.55 for clinical data, 0.65 for radiomics, and 0.73 for a combination of clinical and radiomic variables, highlighting the additive value of radiomics to the readily available clinical information in prediction of PFS. Radiogenomic assessments revealed significant differences in expression of BRAF, NF1, TSC1, ALK (p<0.01), and RB1 (p<0.05) genes in the high-risk group, compared to the medium and low-risk groups. CONCLUSION: Our results demonstrate the value of integrating radiomics with clinical measures to improve risk assessment of patients with pLGG through improved pretreatment prediction of PFS.

BRAF V600E Expression in Primary Melanoma and Its Association With Death: A Population-Based, Retrospective, Cross-Sectional Study.

Approximately 50% of melanomas contain BRAF mutations; the effects on survival are unclear. We aimed to determine whether mutant BRAF expression in melanoma differs according to age, sex, and melanoma-specific survival. A total of 638 patients who resided in Olmsted County, Minnesota, with a first lifetime diagnosis of melanoma between 1970 and 2009 were identified from the Rochester Epidemiology Project (REP). Available tissue was analyzed for a BRAF V600E mutation with immunohistochemistry.

Detection of BRAFV600E Biomarker In Patients With Colorectal Cancer Using Immunohistochemical Techniques / Clinico-Pathological Study

Background : Colorectal cancer (CRC) is the 4th common gastrointestinal cancer. (BRAFV600E) is a member of RAF family of serine/threonine protein kinases that function to regulate the (MAPK) / (ERK) pathway. BRAFV600E mutated CRC are associated with right-sided primary tumors, older women and high-grade tumors. Aims of the study: Study the immunohistochemical expression of BRAFV600E biomarker in a sample of Iraqi patients with colorectal cancer and the correlation of BRAFV600E expression with other clinicopathological variables such as patient's age and tumor grade. Materials and Methods : in this prospective study a total of 90 colorectal cases of a sample of Iraqi patients were collected from teaching labs of AL-Yarmouk Teaching Hospital including 60 cases of colorectal carcinoma and 30 cases of colorectal adenoma. Result: BRAFV600E biomarker was positive in 16.6% of colorectal carcinoma group and negative in colorectal adenoma group. Conclusions: BRAF expression was higher in older patients ages & higher tumor stages and there is no expression of BRAFV600E in adenoma cases.

BRAF Modulates Lipid Use and Accumulation.

Simple SummaryBRAF is a serine/threonine kinase that is commonly mutated across cancers. The BRAF V600E mutation is targetable with kinase inhibitors; however, many patients eventually develop resistance. Recent evidence suggests that tumors harboring BRAF mutations may oxidize fatty acids for energy rather than utilizing aerobic glycolysis (the Warburg effect). Understanding the metabolism of cells harboring BRAF mutations may uncover targets to improve therapy response. We studied the effects of BRAF mutation and expression on metabolism. We found that cell expressing BRAF V600E were enriched with immunomodulatory lipids and have a metabolism that is distinct from cells expressing wild type BRAF. We also found that patients with melanoma who did not respond to BRAF-targeted therapy had plasma lipid profiles that were different from patients who responded to this therapy. Overall, our findings indicate that targeting lipid metabolism may be a potential alternative strategy to improve patient responses to BRAF-targeted therapies.There is increasing evidence that oxidative metabolism and fatty acids play an important role in BRAF-driven tumorigenesis, yet the effect of BRAF mutation and expression on metabolism is poorly understood. We examined how BRAF mutation and expression modulates metabolite abundance. Using the non-transformed NIH3T3 cell line, we generated cells that stably overexpressed BRAF V600E or BRAF WT. We found that cells expressing BRAF V600E were enriched with immunomodulatory lipids. Further, we found a unique transcriptional signature that was exclusive to BRAF V600E expression. We also report that BRAF V600E mutation promoted accumulation of long chain polyunsaturated fatty acids (PUFAs) and rewired metabolic flux for non-Warburg behavior. This cancer promoting mutation further induced the formation of tunneling nanotube (TNT)-like protrusions in NIH3T3 cells that preferentially accumulated lipid droplets. In the plasma of melanoma patients harboring the BRAF V600E mutation, levels of lysophosphatidic acid, sphingomyelin, and long chain fatty acids were significantly increased in the cohort of patients that did not respond to BRAF inhibitor therapy. Our findings show BRAF V600 status plays an important role in regulating immunomodulatory lipid profiles and lipid trafficking, which may inform future therapy across cancers.

Comparative BRAF V600E immunohistochemical expression in differentiated thyroid tumors with papillary features.

Differentiated thyroid tumors (DTC) are the most common indolent tumors associated with a good prognosis compared with other tumors. Its incidence during the last few decades has increased. DTC includes papillary carcinoma and follicular carcinoma. The BRAF is the most prevalent genetic mutation in thyroid carcinoma, occurring in more than 50% of papillary thyroid cancers (PTCs). The study aimed to evaluate BRAF expression in differentiated thyroid tumors with papillary-like nuclear features. Formalin-fixed paraffin-embedded blocks (FFPE) were collected from archival samples of patients in private histopathology labs in Al-Najaf city from 55 cases, which included 27 papillary thyroid carcinoma (PTC) cases, 10 cases of NIFTP, 13 FVPTC cases, 2 papillary microcarcinoma cases, and 3 NIFTP coexist with papillary microcarcinoma cases. All samples were stained using the immunohistochemistry method in the Middle Euphrates unit for cancer research at the University of Kufa/Faculty of Medicine. 15/55 (27.3%) of cases increased BRAF expression. The BRAF expression was statistically significant with tumor type (p=0.008). The higher expression was associated with 13 (48.15%) of PTC cases. However, the BRAF expression did not correlate with gender (p=0.2), tumor size (p=0.07), and tumor focality (p=0.09). BRAF V600E has prognostic value as it correlates with tumor progression.

The expression of VISTA on CD4+ T cells associate with poor prognosis and immune status in non-small cell lung cancer patients.

V-domain immunoglobulin suppressor of T-cell activation (VISTA) is a novel negative immune checkpoint considered to be relevant to immunotherapy resistance and a potential target for immunotherapy. In this study, we investigated the relevance of VISTA expression on CD4+ T cells and clinical prognosis in non-small cell lung cancer (NSCLC) patients. Tumor tissue samples from 140 NSCLC patients were organized into a tissue microarray. The prognostic value of CD4+ VISTA+ T cells was analyzed through immunohistochemistry and multicolor fluorescence immunostaining. Fresh tumor tissue samples from 33 NSCLC patients were collected and similarly analyzed to confirm the immune state of patients with VISTA expression on CD4+ T cells by flow cytometry. CD4+ VISTA+ T cells were significantly more infiltrated in tumor tissues. The expression of VISTA on CD4+ T cells was correlated with the reduced overall survival of patients with NSCLC and presented a high rate of lymphocyte metastasis. The expression of VISTA on CD4+ T cells in tumor tissue showed low secretion of cytokines including IFN-γ, IL-2, IL-4, IL-10, IL-17, and IL-12p70. The expression of VISTA on CD4+ T cells could regulate tumor immunity and serve as a prognostic indicator for survival outcomes.

Evaluation of lung cancer biomarkers profile for the decision of targeted therapy in EBUS-TBNA cytological samples.

Guidelines recommend performing biomarker tests for epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), BRAF and ROS proto-oncogene-1(ROS1) genes and protein expression of programmed death ligand-1(PD-L1) in patients with non-small lung cell carcinoma (NSCLC). Studies reported that endobronchial ultrasound-transbronchial needle aspiration (EBUS-TBNA) can provide sufficient material for cancer biomarker analyses, but there are still concerns about the subject. The purpose of the study was to assess the adequacy of EBUS-TBNA for testing lung cancer biomarkers. We retrospectively reviewed patients with NSCLC whose EBUS-TBNA was analysed for EGFR, ALK, ROS-1, BRAF and PD-L1 expression between December 2011 and December 2020. A total of 394 patients were enrolled in the study. EGFR mutation and ALK fusion were the most common studied biomarkers. EBUS-TBNA adequacy rate for biomarker tests was found 99.0% for EGFR, 99.1 for ALK, 97.2% for ROS1, 100% for BRAF and 99.3% for PD-L1 testing. Multivariate analysis revealed the histological type, history of treatment for NSCL, size, or 18-fluorodeoxyglucose uptake of sampled lesion did not show any association with TBNA adequacy for biomarker testing. EBUS-TBNA can provide adequate material for biomarker testing for EGFR, ALK, ROS-1, BRAF and PD-L1 expression.

MOB3A Bypasses BRAF and RAS Oncogene-Induced Senescence by Engaging the Hippo Pathway.

These results suggest that MOB3 targeting to re-engage the Hippo pathway, or direct targeting of YAP/TAZ, may be viable therapeutic strategies potential for RAS-pathway driven tumours.

Association between BRAF expression in circulating tumor cells and the clinical feature of patients with multiple myeloma

Multiple myeloma (MM) is the most common hematological malignancy with uncontrolled proliferation of monoclonal plasma cells. Despite treatment improvements, MM remains an incurable disease for most patients. Therefore, promising molecular markers are required for MM treatment decisions. In the present study, we explored the relationship between the BRAF expression in circulating tumor cells (CTCs) and the clinical features of patients with MM. The results showed that CTCs were associated with MM staging, and the expression of BRAF was associated with different CTCs. Moreover, the BRAF gene was correlated with patients' white blood cells, blood albumin levels, and Eastern Cooperative Oncology Group (ECOG) score. BRAF expression positively correlated with total CTCs, hybrid CTCs, and mesenchymal CTCs. Taken together, CTCs tightly correlated with the clinical stages and characteristics of MM. Our findings may provide a promising prognosis biomarker for MM treatment decisions.

Expression and Prognostic Significance of c-Myc, ALK, ROS1, BRAF, and PD-L1 Among Patients With Non-Small Cell Lung Cancer.

Background:Non-small cell lung cancer (NSCLC) remains a leading cause of cancer death worldwide, for which better knowledge in molecular prognostic factors is needed to improve clinical outcome. This study aimed to investigate the clinical significance of c-Myc, ALK, ROS1, BRAF, and PD-L1 in NSCLC patients.Methods:Formalin-fixed paraffin-embedded tissue specimens were obtained from 124 NSCLC patients. Of these, 66 matched specimens of normal respiratory epithelial and tumor tissue from patients with stages I-III, who underwent surgical resection, and 58 NSCLC specimens from stage IV patients were recruited into this analysis. Immunohistochemistry staining along with semiquantitative criteria were used to evaluate the expression of the interested proteins.Results:Of the 66 patients with stages I-III, positive expression of c-Myc was detected in 12 specimens (18.2%) of NSCLC tissue, whereas none of the normal respiratory epithelial tissue was found to have c-Myc expression (P < .001). Of the 66 NSCLC patients, 28 (43.8%) had PD-L1-positive staining on 1%-49% tumor cells and 7 (10.9%) patients expressed PD-L1 in ⩾50% tumor cells. One (2.3%) adenocarcinoma patient was found to have ROS1 rearrangement. Patients with no expression of c-Myc and PD-L1 (co-negative expression) tended to have a better prognosis than other subgroups.Conclusions:NSCLC tissue significantly expressed more c-Myc and PD-L1, compared with the matched normal respiratory epithelium, emphasizing the important role of these key drivers in tumorigenesis. Therapeutic approach to precisely inhibit the targetable molecular pathways should be considered on an individual patient basis to improve survival outcome.

Three-dimensional telomere profiles in papillary thyroid cancer variants: A pilot study.

Besides the two main histologic types of papillary thyroid carcinoma (PTC), the classical PTC (CL-PTC) and the follicular variant PTC (FV-PTC), several other variants are described. The encapsulated FV-PTC variant was recently reclassified as non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) due to its similarities to benign lesions. Specific molecular signatures, however, are still unavailable. It is well known that improper DNA repair of dysfunctional telomeres may cause telomere-related genome instability. The mechanisms involved in the damaged telomere repair processing may lead to detrimental outcomes, altering the three-dimensional (3D) nuclear telomere and genome organization in cancer cells. This pilot study aimed to evaluate whether specific 3D nuclear telomere architecture might characterize NIFTP, potentially distinguishing it from other PTC histologic variants. Our findings demonstrate that 3D telomere profiles of CL-PTC and FV-PTC were different from NIFTP and that NIFTP more closely resembles follicular thyroid adenoma (FTA). NIFTP has longer telomeres than CL-PTC and FV-PTC samples, and the telomere length of NIFTP overlaps with that of the FTA histotype. In contrast, there was no association between BRAF expression and telomere length in all tested samples. These preliminary findings reinforce the view that NIFTP is closer to non-malignant thyroid nodules and confirm that PTC features short telomeres.

Relevance of BRAF Subcellular Localization and Its Interaction with KRAS and KIT Mutations in Skin Melanoma.

Although skin melanoma (SKM) represents only one-quarter of newly diagnosed skin malignant tumors, it presents a high mortality rate. Hence, new prognostic and therapeutic tools need to be developed. This study focused on investigating the prognostic value of the subcellular expression of BRAF, KRAS, and KIT in SKM in correlation with their gene-encoding interactions. In silico analysis of the abovementioned gene interactions, along with their mRNA expression, was conducted, and the results were validated at the protein level using immunohistochemical (IHC) stains. For IHC expression, the encoded protein expressions were checked on 96 consecutive SKMs and 30 nevi. The UALCAN database showed no prognostic value for the mRNA expression level of KRAS and BRAF and demonstrated a longer survival for patients with low mRNA expression of KIT in SKMs. IHC examinations of SKMs confirmed the UALCAN data and showed that KIT expression was inversely correlated with ulceration, Breslow index, mitotic rate, and pT stage. KRAS expression was also found to be inversely correlated with ulceration and perineural invasion. When the subcellular expression of BRAF protein was recorded (nuclear vs. cytoplasmatic vs. mixed nucleus + cytoplasm), a direct correlation was emphasized between nuclear positivity and lymphovascular or perineural invasion. The independent prognostic value was demonstrated for mixed expression of the BRAF protein in SKM. BRAF cytoplasmic predominance, in association with KIT’s IHC positivity, was more frequently observed in early-stage nonulcerated SKMs, which displayed a low mitotic rate and a late death event. The present study firstly verified the possible prognostic value of BRAF subcellular localization in SKMs. A low mRNA expression or IHC cytoplasmic positivity for KIT and BRAF might be used as a positive prognostic parameter of SKM. SKM’s BRAF nuclear positivity needs to be evaluated in further studies as a possible indicator of perineural and lymphovascular invasion.

High-throughput virtual screening and preclinical analysis identifies CB-1, a novel potent dual B-Raf/c-Raf inhibitor, effective against wild and mutant variants of B-Raf expression in colorectal carcinoma.

Paradoxical Raf activation via Raf dimerization is a major drawback of wild/mutant B-Raf inhibitors. Herein, we report that CB-1 a novel, potent B-Raf/c-Raf dual inhibitor, effective against colon cancer cells, irrespective of their genetic status. High-throughput virtual screening of the ChemBridge library against wild B-Raf (B-RafWT), mutant B-Raf (B-RafV600E), and c-Raf was performed using an automated protocol with the AutoDock-VINA. Caco-2 and HT-29 cells were used. Of the 23,365 compounds screened computationally, CB-1 showed the highest binding energy towards B-RafWT with a ΔGbinding score of -13.0kcal/mol. The compound was also predicted to be effective against B-RafV600E and c-Raf molecules with ΔGbinding energies of -10.6 and -10.1kcal/mol, respectively. The compound inhibited B-RafWT, B-RafV600E and c-Raf kinases with IC50 values of 27.13, 51.70, and 40.23 nM, respectively. The GI50 value of CB-1 was 247.9 nM in B-RafWT-expressing Caco-2 cells and 352.4 nM in B-RafV600E-expressing HT-29 cells. Dose-dependent increases in total apoptosis and G1 cell cycle phase arrest was observed in CB-1-treated colon cancer cells. The compound decreased B-Raf expression in both wild and mutant colon cancer cells. CB-1, a novel, potent dual B-Raf/c-Raf inhibitor was effective against colon cancer cells bearing wild-type and mutant variants of B-Raf expression.

Reprogramming NK cells and macrophages via combined antibody and cytokine therapy primes tumors for elimination by checkpoint blockade.

SUMMARYTreatments aiming to augment immune checkpoint blockade (ICB) in cancer often focus on T cell immunity, but innate immune cells may have important roles to play. Here, we demonstrate a single-dose combination treatment (termed AIP) using a pan-tumor-targeting antibody surrogate, half-life-extended interleukin-2 (IL-2), and anti-programmed cell death 1 (PD-1), which primes tumors to respond to subsequent ICB and promotes rejection of large established tumors in mice. Natural killer (NK) cells and macrophages activated by AIP treatment underwent transcriptional reprogramming; rapidly killed cancer cells; governed the recruitment of cross-presenting dendritic cells (DCs) and other leukocytes; and induced normalization of the tumor vasculature, facilitating further immune infiltration. Thus, innate cell-activating therapies can initiate critical steps leading to a self-sustaining cycle of T cell priming driven by ICB.

B-RAF PROTEIN IMMUNOEXPRESSION IN HEPATOCELLULAR CARCINOMA DUE TO HEPATITIS C VIRUS RELATED CIRRHOSIS.

Hepatocarcinogenesis is a multistep process that lead to genetic changes in hepatocytes resulting in neoplasia. However, the mechanisms of malignant transformation seem to differ widely. To know carcinogenesis mechanisms is essential to develop new treatment and prevention methods. The aim of this study is to analyze B-Raf protein immunoexpression in explants with hepatocellular carcinoma (HCC) related to hepatitis C (HCV), in adjacent cirrhotic tissue and in normal livers. We also associated the immunoexpression with known HCC related histopathogical prognostic features. Livers from 35 patients with HCV related cirrhosis and HCC that underwent liver transplantation or hepatectomy at Clinical Hospital &ndash; UFMG and 25 normal livers from necropsy archives were studied. Tumors were classified according to: tumor size, vascular invasion and differentiation grade. B-Raf protein expression was determined by immunohistochemistry. B-Raf was strongly expressed in the HCV cirrhotic parenchyma cytoplasm of 17.1% cases and in 62.9% of HCC samples. Strong B-Raf protein staining was associated with tumor tissue (P<0.0001; OR=8.18 (2.62&ndash;26.63)). All normal livers showed weak or negative expression for B-Raf. There was no significant association among B-Raf scores and tumor differentiation grade (P=0.9485), tumor size (P=0.4427) or with vascular invasion (P=0.2666). We found B-Raf protein immunostaining difference in normal livers, in the areas of HCV cirrhosis and in the hepatocarcinoma. We did not find association between B-Raf expression and histopathological markers of tumor progression. Our data suggests that B-Raf may play an important role in initial HCC carcinogenesis. Larger studies are needed to validate these observations.

Tissue architecture delineates field cancerization in BRAFV600E-induced tumor development.

ABSTRACTCancer cells hijack developmental growth mechanisms but whether tissue morphogenesis and architecture modify tumorigenesis is unknown. Here, we characterized a new mouse model of sporadic thyroid carcinogenesis based on inducible expression of BRAF carrying a Val600 Glu (V600E) point mutation (BRAFV600E) from the thyroglobulin promoter (TgCreERT2). Spontaneous activation of this Braf-mutant allele due to leaky activity of the Cre recombinase revealed that intrinsic properties of thyroid follicles determined BRAF-mutant cell fate. Papillary thyroid carcinomas developed multicentrically within a normal microenvironment. Each tumor originated from a single follicle that provided a confined space for growth of a distinct tumor phenotype. Lineage tracing revealed oligoclonal tumor development in infancy and early selection of BRAFV600E kinase inhibitor-resistant clones. Somatic mutations were few, non-recurrent and limited to advanced tumors. Female mice developed larger tumors than males, reproducing the gender difference of human thyroid cancer. These data indicate that BRAFV600E-induced tumorigenesis is spatiotemporally regulated depending on the maturity and heterogeneity of follicles. Moreover, thyroid tissue organization seems to determine whether a BRAF-mutant lineage becomes a cancerized lineage. The TgCreERT2;BrafCA/+ sporadic thyroid cancer mouse model provides a new tool to evaluate drug therapy at different stages of tumor evolution.

Chronic Exercise Protects against the Progression of Renal Cyst Growth and Dysfunction in Rats with Polycystic Kidney Disease.

ABSTRACTIntroductionPolycystic kidney disease (PKD) is a genetic disorder characterized by the progressive enlargement of renal epithelial cysts and renal dysfunction. Previous studies have reported the beneficial effects of chronic exercise on chronic kidney disease. However, the effects of chronic exercise have not been fully examined in PKD patients or models. The effects of chronic exercise on the progression of PKD were investigated in a polycystic kidney (PCK) rat model.MethodsSix-week-old male PCK rats were divided into a sedentary group and an exercise group. The exercise group underwent forced treadmill exercise for 12 wk (28 m·min−1, 60 min·d−1, 5 d·wk−1). After 12 wk, renal function and histology were examined, and signaling cascades of PKD progression, including arginine vasopressin (AVP), were investigated.ResultsChronic exercise reduced the excretion of urinary protein, liver-type fatty acid–binding protein, plasma creatinine, urea nitrogen, and increased plasma irisin and urinary AVP excretion. Chronic exercise also slowed renal cyst growth, glomerular damage, and interstitial fibrosis and led to reduced Ki-67 expression. Chronic exercise had no effect on cAMP content but decreased the renal expression of B-Raf and reduced the phosphorylation of extracellular signal-regulated kinase (ERK), mammalian target of rapamycin (mTOR), and S6.ConclusionChronic exercise slows renal cyst growth and damage in PCK rats, despite increasing AVP, with the downregulation of the cAMP/B-Raf/ERK and mTOR/S6 pathways in the kidney of PCK rats.

Neuronal cells from bipolar individuals are more susceptible to glutamate induced apoptosis than cells from non-bipolar subjects

BackgroundBipolar disorder (BD) is associated with marked parenchymal brain loss in a significant fraction of patients. The lack of necrosis in postmortem examination suggests an apoptotic process. Emerging evidence suggests that mood stabilizers, like lithium, have antiapoptotic actions. Glutamatergic abnormalities have been associated with BD. MethodsOlfactory neuroepithelial progenitors (ONPs) harvested by biopsy from type I bipolar patients (BD-ONPs, n = 3) and non-bipolar controls (non-BD-ONPs, n = 6), were treated with glutamate at concentrations sufficient to mimic the observed doubling of intracellular sodium known to occur in both mania and bipolar depression, to investigate potential differential lithium effect on both BD-ONPs and non-BD-ONPs. ResultsApoptosis was detected in BP-ONPs exposed to 0.1 M glutamate for 6 h but in non-BD-ONPs at 24 h. Moreover, after treatment with 0.1 M glutamate treated for 6 h the levels of the pro-apoptotic cleaved-caspase-3 and cleaved-PARP proteins were significantly higher in BD-ONPs compare to non-BD-ONPs. Pretreatment with a therapeutic concentration of 1 mM lithium for 3 days attenuated the glutamate induced apoptosis. Lithium pretreatment 3 days also prevented the DNA fragmentation induced by glutamate, and significantly increased the antiapoptotic phospho-B-Raf and Bcl-2 proteins in BD-ONPs compared to non-BD-ONPs. LimitationsONPs are obtained from subjects with and without bipolar illness, but outcome of their study may still not reflect the biology of the illness. ConclusionsONPs derived from BD are more susceptible to glutamate-induced apoptosis. Lithium is associated with a greater increase of anti-apoptotic B-Raf and Bcl-2 expression in BD-ONPs.

PD-L1 Expression in colorectal carcinoma and its correlation with clinicopathological parameters, microsatellite instability and BRAF mutation.

: Programmed cell death ligand-1 (PD-L1) is the key inhibitor of the cytotoxic immune response thus causing progression of tumors and adverse prognosis in many malignancies. The current study investigates PD-L1 expression in colorectal carcinoma and its correlation with clinicopathological parameters, microsatellite instability, and BRAF mutation. 110 cases of colorectal carcinoma were evaluated for PD-L1 expression using SP263 clone in tissue microarray. Clinico-pathological characteristics and survival data were correlated with PD-L1 expression analyzed at different cut-offs of ≥1%, ≥10% and ≥50% in tumor cells and tumor infiltrating lymphocytes along with its correlation with BRAF expression and microsatellite instability status in these cases. Mean age was 49 years with male to female ratio of 1.5:1. 52.7% cases presented with stage 3/4 disease and 14.7% with >10 cm tumor size. Tumor cells expressed PD-L1 in 40% and TILs in 45.4% cases at a cut off of ≥1% was 17.3%, at ≥10% was 15.5% and at ≥50% was 7.3%. Significant association was seen between tumor proportion score (TPS) and increasing age, histological type, histological grade, tumor size, higher T stage (p = 0.03), TILs (p = 0.04), lymph vascular invasion, and perineural invasion. PDL-1 correlated with BRAF expression and microsatellite instability (MLH-1/PMS-2 expression loss). The overall survival was significantly higher (p < 0.001) with negative PDL1 expression in cases of colorectal carcinoma. Immunotherapy may be used as potential therapeutic option in colorectal carcinoma cases showing microsatellite instability and BRAF mutations which show poor response to conventional chemotherapy regimen and anti-EGFR therapy.

Targeted Deep Sequencing in Untreated Progressive CLL Helps to Better Dissect the Genomic Landscape and Shows Novel Associations between Mutations, Prognostic and Clinical Parameters: Data from E1912, a Randomized Phase III Study of the ECOG-ACRIN Cancer Research Group

Targeted Deep Sequencing in Untreated Progressive CLL Helps to Better Dissect the Genomic Landscape and Shows Novel Associations between Mutations, Prognostic and Clinical Parameters: Data from E1912, a Randomized Phase III Study of the ECOG-ACRIN Cancer Research Group