Mechanistic Insights into the Successful Development of Combination Therapy of Enfortumab Vedotin and Pembrolizumab for the Treatment of Locally Advanced or Metastatic Urothelial Cancer.

Antibody-drug conjugates (ADCs) consist of an antibody backbone that recognizes and binds to a target antigen expressed on tumor cells and a small molecule chemotherapy payload that is conjugated to the antibody via a linker. ADCs are one of the most promising therapeutic modalities for the treatment of various cancers. However, many patients have developed resistance to this form of therapy.

Germline variant profiling of CHEK2 sequencing variants in breast cancer patients.

The cell cycle checkpoint kinase 2 (CHEK2) is a tumor suppressor gene coding for a protein kinase with a role in the cell cycle and DNA repair pathways. Variants within CHEK2 are associated with an increased risk of developing breast, colorectal, prostate and several other types of cancer. Comprehensive genetic risk assessment leads to early detection of hereditary cancer and provides an opportunity for better survival.

Challenges and the Evolving Landscape of Assessing Blood-Based PD-L1 Expression as a Biomarker for Anti-PD-(L)1 Immunotherapy.

While promising, PD-L1 expression on tumor tissues as assessed by immunohistochemistry has been shown to be an imperfect biomarker that only applies to a limited number of cancers, whereas many patients with PD-L1-negative tumors still respond to anti-PD-(L)1 immunotherapy. Recent studies using patient blood samples to assess immunotherapeutic responsiveness suggests a promising approach to the identification of novel and/or improved biomarkers for anti-PD-(L)1 immunotherapy. In this review, we discuss the advances in our evolving understanding of the regulation and function of PD-L1 expression, which is the foundation for developing blood-based PD-L1 as a biomarker for anti-PD-(L)1 immunotherapy.

IL-10 Signaling Elicited by Nivolumab-Induced Activation of the MAP Kinase Pathway Does Not Fully Contribute to Nivolumab-Modulated Heterogeneous T Cell Responses.

Immune checkpoint inhibitor (ICI) therapy has revolutionized anti-cancer treatment for many late-stage cancer patients. However, ICI therapy has thus far demonstrated limited efficacy for most patients, and it remains unclear why this is so. Interleukin 10 (IL-10) is a cytokine that has been recognized as a central player in cancer biology with its ability to inhibit anti-tumor T cell responses.

Deciphering the Dynamic Complexities of the Liver Microenvironment - Toward a Better Understanding of Immune-Mediated liver Injury Caused by Immune Checkpoint Inhibitors (ILICI).

Immune checkpoint inhibitors (ICIs) represent a promising therapy for many types of cancer. However, only a portion of patients respond to this therapy and some patients develop clinically significant immune-mediated liver injury caused by immune checkpoint inhibitors (ILICI), an immune-related adverse event (irAE) that may require the interruption or termination of treatment and administration of systemic corticosteroids or other immunosuppressive agents. Although the incidence of ILICI is lower with monotherapy, the surge in combining ICIs with chemotherapy, targeted therapy, and combination of different ICIs has led to an increase in the incidence and severity of ILICI - a major challenge for development of effective and safe ICI therapy.

Exploring the Potential Use of a PBMC-Based Functional Assay to Identify Predictive Biomarkers for Anti-PD-1 Immunotherapy.

The absence of reliable, robust, and non-invasive biomarkers for anti- Programmed cell death protein 1 (PD-1) immunotherapy is an urgent unmet medical need for the treatment of cancer patients. No predictive biomarkers have been established based on the direct assessment of T cell functions, the primary mechanism of action of anti-PD-1 therapy. In this study, we established a model system to test T cell functions modulated by Nivolumab using anti-CD3 monoclonal antibody (mAb)-stimulated peripheral blood mononuclear cells (PBMCs), and characterized T cell functions primarily based on the knowledge gained from retrospective observations of patients treated with anti-PD-1 immunotherapy.

Training the next generation of genomic medicine providers: trends in medical education and national assessment.

Purpose: To assess the utilization of genetics on the United States Medical Licensing Examination (USMLE®).

Methods: A team of clinical genetics educators performed an analysis of the representation of genetics content on a robust sample of recent Step 1, Step 2 Clinical Knowledge (CK), and Step 3 examination forms. The content of each question was mapped to curriculum recommendations from the peer reviewed Association of Professors of Human and Medical Genetics white paper, Medical School Core Curriculum in Genetics, and the USMLE Content Outline.

High-Dose IV Administration of Rasburicase Suppresses Anti-rasburicase Antibodies, Depletes Rasburicase-Specific Lymphocytes, and Upregulates Treg Cells.

Therapeutic proteins can be potent agents for treating serious diseases, but in many patients these proteins provoke antibody responses that blunt therapeutic efficacy. Intravenous administration of high doses of some proteins induces immune tolerance, but the mechanisms underlying this effect are poorly understood. As a model to study tolerance induction in mice, we used rasburicase, a commercial recombinant uricase used for the treatment of hyperuricemia.

Defining the right diluent for intravenous infusion of therapeutic antibodies.

Therapeutic monoclonal antibodies (mAbs) are commonly administered to patients through intravenous (IV) infusion, which involves diluting the medication into an infusion solution (e.g., saline and 5% dextrose).

Molecular classification of endometrial carcinoma applied to endometrial biopsy specimens: Towards early personalized patient management.

Background: The current risk stratification systems used to guide management of endometrial cancer are based on irreproducible post surgical pathological information, hence the need for more reliable classification systems. Using microarray and sequencing technologies, TCGA recently identified four prognostically significant endometrial carcinoma subtypes, which subsequently proved reproducible using clinically applicable surrogate tests. Using these tests, we sought to determine the level of concordance between endometrial biopsies and subsequent hysterectomy specimens in assessing the molecular classification of endometrial carcinoma.

The Current State of Newborn Screening in the United States.

Newborn screening has evolved since its introduction in 1963. The disorders that are being screened for continue to evolve as new treatments and new technologies advance. In this review, the authors discuss the current state of newborn screening in the United States, including the disorders currently being screened for and how newborn screening is performed.

BRAF and MEK inhibitors differentially affect nivolumab-induced T cell activation by modulating the TCR and AKT signaling pathways.

Immune checkpoint inhibitors (ICIs) such as the anti-PD-1 antibody Nivolumab, achieve remarkable clinical efficacy in patients with late stage cancers. However, only a small subset of patients benefit from this therapy. Numerous clinical trials are underway testing whether combining ICIs with other anti-cancer therapies can increase this response rate.

Recognition of preclinical signs of dementia: A qualitative study exploring the experiences of family carers and professional care assistants.

Aims And Objectives: To identify preclinical signs of dementia by exploring the experiences of family caregivers and professional care assistants.

Background: Dementia results in disability, emotional strain and financial loss for people with dementia, family members and nations. Informal identification of social and behavioural risk signifiers could facilitate timely interventions with potential to delay onset of serious disability.

Medical genetics and genomics training in obstetrics and gynecology residencies: are we ready for the future?

Objective: The primary objective of this study is to evaluate the availability and duration of formal medical genetics and genomics (MGG) education during obstetrics and gynecology (OB/GYN) residency training in the United States compared to other noncore OB/GYN rotations.

Methods: We performed a review of rotation schedules published in all American Council for Graduate Medical Education (ACGME)-accredited OB/GYN residency programs' websites during the month of December 2016. Information regarding availability and duration of MGG rotation and other noncore OB/GYN rotations (ultrasound, breast health, and family planning) were collected.

Primary ovarian insufficiency in classic galactosemia: current understanding and future research opportunities.

Classic galactosemia is an inborn error of the metabolism with devastating consequences. Newborn screening has been successful in markedly reducing the acute neonatal symptoms from this disorder. The dramatic response to dietary treatment is one of the major success stories of newborn screening.

Cell-free DNA results lead to unexpected diagnosis.

Maternal cell-free DNA (cfDNA) results that are discordant with the diagnostic fetal karyotype should prompt further investigation. If deeper analysis of the cfDNA results demonstrates a "saw-tooth" pattern characteristic of genome-wide imbalance, maternal malignancy is suggested. Identifying the maternal malignancy can, however, be difficult.

PP2A inhibition with LB100 enhances cisplatin cytotoxicity and overcomes cisplatin resistance in medulloblastoma cells.

The protein phosphatase 2A (PP2A) inhibitor, LB100, has been shown in pre-clinical studies to be an effective chemo- and radio-sensitizer for treatment of various cancers. We investigated effects associated with LB100 treatment alone and in combination with cisplatin for medulloblastoma (MB) in vitro and in vivo in an intracranial xenograft model. We demonstrated that LB100 had a potent effect on MB cells.

The macrophage: Switches from a passenger to a driver during anticancer therapy.

We have recently discovered that BRAF inhibitors induce potent macrophage responses that confer melanoma resistance to therapy. Our studies lay a foundation for the hypothesis that macrophages switch their role from a passenger to a driver for tumor survival during therapeutic treatment, suggesting that agents that target macrophages can be an important component of "cocktail" anticancer therapy.

The many faces of FcγRI: implications for therapeutic antibody function.

Fcγ receptor I (FcγRI or CD64) is the sole human Fc receptor with high affinity for monovalent IgG. While it contains an immunoreceptor tyrosine-based activation motif in its cytoplasmic domain, binding of FcγRI can result in a complex array of activating and inhibitory outcomes. For instance, binding of monomeric IgG provides a low-intensity tonic signal through FcγRI that is necessary for full interferon γ receptor signaling in the same cell.