The Role of Aging and Senescence in Immune Checkpoint Inhibitor Response and Toxicity.

Cellular senescence accumulates with age and has been shown to impact numerous physiological and pathological processes, including immune function. The role of cellular senescence in cancer is multifaceted, but the impact on immune checkpoint inhibitor response and toxicity has not been fully evaluated. In this review, we evaluate the impact of cellular senescence in various biological compartments, including the tumor, the tumor microenvironment, and the immune system, on immune checkpoint inhibitor efficacy and toxicity.

Circulating, cell-free methylated DNA indicates cellular sources of allograft injury after liver transplant.

Post-transplant complications reduce allograft and recipient survival. Current approaches for detecting allograft injury non-invasively are limited and do not differentiate between cellular mechanisms. Here, we monitor cellular damages after liver transplants from cell-free DNA (cfDNA) fragments released from dying cells into the circulation.

Cell-type Deconvolution and Age Estimation Using DNA Methylation Reveals NK Cell Deficiency in the Hepatocellular Carcinoma Microenvironment.

Hepatocellular carcinoma (HCC) has been an approved indication for the administration of immunotherapy since 2017, but biomarkers that predict therapeutic response have remained limited. Understanding and characterizing the tumor immune microenvironment enables better classification of these tumors and may reveal biomarkers that predict immunotherapeutic efficacy. In this paper, we applied a cell-type deconvolution algorithm using DNA methylation array data to investigate the composition of the tumor microenvironment in HCC.

Deconvolution of immune cell composition and biological age of hepatocellular carcinoma using DNA methylation.

Hepatocellular carcinoma (HCC) has been an approved indication for the administration of immunotherapy since 2017, but biomarkers that predict therapeutic response have remained limited. Understanding and characterizing the tumor immune microenvironment enables better classification of these tumors and may reveal biomarkers that predict immunotherapeutic efficacy. In this paper, we applied a cell-type deconvolution algorithm using DNA methylation array data to investigate the composition of the tumor microenvironment in HCC.

Circulating cell-free methylated DNA reveals tissue-specific, cellular damage from radiation treatment.

Radiation therapy is an effective cancer treatment, although damage to healthy tissues is common. Here we analyzed cell-free, methylated DNA released from dying cells into the circulation to evaluate radiation-induced cellular damage in different tissues. To map the circulating DNA fragments to human and mouse tissues, we established sequencing-based, cell-type-specific reference DNA methylation atlases.

Low Dose Chronic Angiotensin II Induces Selective Senescence of Kidney Endothelial Cells.

Angiotensin II can cause oxidative stress and increased blood pressure that result in long term cardiovascular pathologies. Here we evaluated the contribution of cellular senescence to the effect of chronic exposure to low dose angiotensin II in a model that mimics long term tissue damage. We utilized the INK-ATTAC (p16-Apoptosis Through Targeted Activation of Caspase 8) transgenic mouse model that allows for conditional elimination of p16 -dependent senescent cells by administration of AP20187.

Paralog knockout profiling identifies DUSP4 and DUSP6 as a digenic dependence in MAPK pathway-driven cancers.

Although single-gene perturbation screens have revealed a number of new targets, vulnerabilities specific to frequently altered drivers have not been uncovered. An important question is whether the compensatory relationship between functionally redundant genes masks potential therapeutic targets in single-gene perturbation studies. To identify digenic dependencies, we developed a CRISPR paralog targeting library to investigate the viability effects of disrupting 3,284 genes, 5,065 paralog pairs and 815 paralog families.

Integrative Analysis of DNA Methylation and microRNA Expression Reveals Mechanisms of Racial Heterogeneity in Hepatocellular Carcinoma.

Pathologic alterations in epigenetic regulation have long been considered a hallmark of many cancers, including hepatocellular carcinoma (HCC). In a healthy individual, the relationship between DNA methylation and microRNA (miRNA) expression maintains a fine balance; however, disruptions in this harmony can aid in the genesis of cancer or the propagation of existing cancers. The balance between DNA methylation and microRNA expression and its potential disturbance in HCC can vary by race.

Molecular basis for substrate recruitment to the PRMT5 methylosome.

PRMT5 is an essential arginine methyltransferase and a therapeutic target in MTAP-null cancers. PRMT5 uses adaptor proteins for substrate recruitment through a previously undefined mechanism. Here, we identify an evolutionarily conserved peptide sequence shared among the three known substrate adaptors (CLNS1A, RIOK1, and COPR5) and show that it is necessary and sufficient for interaction with PRMT5.

Immune characterization and profiles of SARS-CoV-2 infected patients reveals potential host therapeutic targets and SARS-CoV-2 oncogenesis mechanism.

The spread of SARS-CoV-2 and the increasing mortality rates of COVID-19 create an urgent need for treatments, which are currently lacking. Although vaccines have been approved by the FDA for emergency use in the U.S.

Immune characterization and profiles of SARS-CoV-2 infected patients reveals potential host therapeutic targets and SARS-CoV-2 oncogenesis mechanism.

The spread of SARS-CoV-2 and the increasing mortality rates of COVID-19 create an urgent need for treatments, which are currently lacking. Although vaccines have been approved by the FDA for emergency use in the U.S.

GEMINI: a variational Bayesian approach to identify genetic interactions from combinatorial CRISPR screens.

Systems for CRISPR-based combinatorial perturbation of two or more genes are emerging as powerful tools for uncovering genetic interactions. However, systematic identification of these relationships is complicated by sample, reagent, and biological variability. We develop a variational Bayes approach (GEMINI) that jointly analyzes all samples and reagents to identify genetic interactions in pairwise knockout screens.

TCF7L1 Modulates Colorectal Cancer Growth by Inhibiting Expression of the Tumor-Suppressor Gene EPHB3.

Dysregulation of the Wnt pathway leading to accumulation of β-catenin (CTNNB1) is a hallmark of colorectal cancer (CRC). Nuclear CTNNB1 acts as a transcriptional coactivator with TCF/LEF transcription factors, promoting expression of a broad set of target genes, some of which promote tumor growth. However, it remains poorly understood how CTNNB1 interacts with different transcription factors in different contexts to promote different outcomes.

To evaluate the effect of various surface treatments on the shear bond strength of three different intraoral ceramic repair systems: an in vitro study.

Fractures of metal-ceramic restoration pose an esthetic and functional dilemma both for patient and the dentist. Intraoral repair systems eliminate the remake and removal of restoration. Many intraoral repair materials and surface treatments are available to repair intraorally fractured metal-ceramic restoration.

Attenuation of the side effect profile of regadenoson: a randomized double-blinded placebo-controlled study with aminophylline in patients undergoing myocardial perfusion imaging. "The ASSUAGE trial".

Background: It is unknown whether the standardized intravenous aminophylline administration following regadenoson-stress can prevent the gastrointestinal and other adverse effects associated with regadenoson.

Methods: In a randomized, double-blinded, placebo-controlled clinical trial we compared the frequency and severity of regadenoson adverse effects in those who received 75 mg of intravenous aminophylline versus a matching placebo administered 2 minutes after regadenoson or 90 seconds post-radioisotope injection.

Results: 248 patients [44.

Patient and provider delays in breast cancer patients attending a tertiary care centre: a prospective study.

Objectives: To find out factors that are responsible for the patient or provider delays in the diagnosis of breast cancer in India.

Design: This prospective study was designed to be conducted over a period of two years including a cohort of 100 patients with locally advanced breast cancer. The delays were assessed using questionnaires prepared according to the Indian scenario.

Prosthetic rehabilitation of ocular defect using digital photography: a case report.

The fundamental objective in restoring a congenital as well as acquired defect of eye with an ocular prosthesis is to enable the patient to cope better with the difficult process of rehabilitation after an enucleation or evisceration. A cosmetically acceptable prosthesis is that reproduces the color, form and orientation of iris and allows the patient to return to accustomed lifestyle. A sequence of steps for construction of custom-made ocular prostheses is outlined in this case report using the advantages of digital imaging technique.

The correlation of anxiety and depression levels with response to neoadjuvant chemotherapy in patients with breast cancer.

Background: The aim was to evaluate and correlate anxiety and depression levels with response to neoadjuvant chemotherapy in patients with breast cancer. The study also assessed the effects of family support on distress levels.

Design: It was a prospective study in a cohort of 84 patients with locally advanced breast cancer.

Vulval elephantiasis as a result of tubercular lymphadenitis: two case reports and a review of the literature.

Introduction: Elephantiasis as a result of chronic lymphedema is characterized by gross enlargement of the arms, legs or genitalia, and occurs due to a variety of obstructive diseases of the lymphatic system. Genital elephantiasis usually follows common filariasis and lymphogranuloma venereum. It may follow granuloma inguinale, carcinomas, lymph node dissection or irradiation and tuberculosis but this happens rarely.