Haddad syndrome novel association with BRAF mutation

BACKGROUND Coronavirus disease (COVID-19) is a budding infectious disease that has affected various countries globally. OBJECTIVE The aim of this study was to analyze the effect of COVID-19 disease on liver and kidney functions and to determine their association with the severity and mortality of disease METHODS A total of 100 confirmed COVID-19 adult patients from Madinah city of Saudi Arabia hospitalized between April 28, and June 30, 2020 were included,and categorized into asymptomatic,mild to moderate and severely ill patients.We analyzed the clinical status of liver and renal functioning in all of the three groups. RESULTS The majority of patients (51%) were diagnosed with mild to moderate disease, 27% of patients were severely ill and 22% of patients were asymptomatic.The liver and renal functional analysis showed that the severity of the COVID-19 patients were significantly associated with the kidney and renal impairments exhibiting higher levels of ALT, AST, Creatinine, Urea levels (P < 0.05). Furthermore, in this study, a novel association is found between high Na and Cl levels with the severely ill COVID-19 patients. CONCLUSIONS We concluded from the present study that a significant percentage of COVID-19 patients continued to have a normal liver and renal function during the course of their disease. Nevertheless, severely ill COVID-19 patients were more prone to have abnormal liver and renal functions. During the course of treatment, the patients had a gradual normalization of their liver and kidney parameters and subsequently achieved a complete normal liver and renal functions upon discharge with no mortality.

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EGFRvIII Promotes Cell Survival during Endoplasmic Reticulum Stress through a Reticulocalbin 1-Dependent Mechanism

Cancers ◽

10.3390/cancers13061198 ◽

2021 ◽

Vol 13 (6) ◽

pp. 1198

Author(s):

Juliana Gomez ◽

Zammam Areeb ◽

Sarah F. Stuart ◽

Hong P. T. Nguyen ◽

Lucia Paradiso ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Cell Viability ◽

Er Stress ◽

Cell Survival ◽

Glioblastoma Cells ◽

Over Expression ◽

Stress Markers ◽

Apoptotic Protein ◽

Novel Association ◽

Reduced Activity

Reticulocalbin 1 (RCN1) is an endoplasmic reticulum (ER)-residing protein, involved in promoting cell survival during pathophysiological conditions that lead to ER stress. However, the key upstream receptor tyrosine kinase that regulates RCN1 expression and its potential role in cell survival in the glioblastoma setting have not been determined. Here, we demonstrate that RCN1 expression significantly correlates with poor glioblastoma patient survival. We also demonstrate that glioblastoma cells with expression of EGFRvIII receptor also have high RCN1 expression. Over-expression of wildtype EGFR also correlated with high RCN1 expression, suggesting that EGFR and EGFRvIII regulate RCN1 expression. Importantly, cells that expressed EGFRvIII and subsequently showed high RCN1 expression displayed greater cell viability under ER stress compared to EGFRvIII negative glioblastoma cells. Consistently, we also demonstrated that RCN1 knockdown reduced cell viability and exogenous introduction of RCN1 enhanced cell viability following induction of ER stress. Mechanistically, we demonstrate that the EGFRvIII-RCN1-driven increase in cell survival is due to the inactivation of the ER stress markers ATF4 and ATF6, maintained expression of the anti-apoptotic protein Bcl-2 and reduced activity of caspase 3/7. Our current findings identify that EGFRvIII regulates RCN1 expression and that this novel association promotes cell survival in glioblastoma cells during ER stress.

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752 The impact of grade of differentiation and BRAF mutation status on neoantigen and immune landscape in papillary thyroid cancer

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0752 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A800-A800

Author(s):

Myungwoo Nam ◽

Woojung Yang ◽

Ju Young Lee ◽

Jaeyoun Choi ◽

...

Keyword(s):

T Cells ◽

Regulatory T Cells ◽

Braf Mutation ◽

Cytolytic Activity ◽

Activity Score ◽

Cyt B ◽

Mutation Status ◽

Poorly Differentiated ◽

Immune Traits ◽

Well Differentiated

BackgroundThe use of immune checkpoint inhibitors (ICIs) in cancer treatment has been approved by the FDA, but its application is experimental in the treatment of papillary thyroid cancer (PTC). Induction of immune response via recognition of neoantigens is considered to be the basis for the treatment mechanism of ICIs.1 However, the neoantigen landscape has not been explored in PTC. Our aim is to investigate the immune landscape of PTC in relation to neoantigens, taking into account the BRAF mutation status and grade of differentiation as contributing factors.MethodsBRAF V600E mutation status and thyroid differentiation scores (TDSs) were gathered from the PTC cohort of The Cancer Genome Atlas (TCGA). TDS was derived from the mRNA expression levels of 16 thyroid function genes to quantify the grade of differentiation. Tumors with TDSs in the 1st quartile and 4th quartile were defined as poorly differentiated and well differentiated, respectively. The neoantigen burden for each sample was predicted using CloudNeo pipeline. The infiltration of immune cells was calculated through CIBERSORT.ResultsAmong 400 patients with predicted neoantigen data, 187 (47%) had BRAF mutations. The BRAF mutated tumors showed increased cytolytic activity score (CYT, p=0.001), increased infiltration of regulatory T cells (Treg, p<0.001), and higher PD-L1 expression (p<0.001) compared to BRAF wild-type tumors (figure 1). In regard to grade of differentiation, poorly differentiated tumors showed increased CYT (p=0.002), increased infiltration of Treg (p<0.001), and higher PD-L1 expression (p<0.001) compared to well differentiated tumors (figure 2). However, BRAF mutation status or grade of differentiation did not correlate with the neoantigen burden. Also, the neoantigen burden did not show any correlations with immune landscape features such as infiltration of CD8+ T cells or Treg, CYT, and PD-L1 expression.Abstract 752 Figure 1Immune traits according to BRAF mutation status. (a) Cytolytic activity score(CYT). (b) Infiltration of regulatory T cells(Tregs). (c) PD-L1 expression.Abstract 752 Figure 2Immune traits according to grade of differentiation. (a) Cytolytic activity score(CYT). (b) Infiltration of regulatory T cells(Tregs). (c) PD-L1 expression.ConclusionsIncreased CYT and higher expression of PD-L1 in the BRAF mutated or the poorly differentiated tumors imply the possible role of ICI use in these subgroups of patients. However, the immune response to these subgroups does not seem to be mediated through the increase in neoantigen formation. Further studies are warranted to explore markers for immunotherapy implication.ReferencesSchumacher TN, Schreiber RD, Neoantigens in cancer immunotherapy. Science 2015; 348:69–74.

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