Associations Among Optimal Lung Cancer Treatment, Clinical Outcomes, and Health Care Utilization in Patients Who Underwent Comprehensive Genomic Profiling.

Background: Although immune checkpoint inhibitor immunotherapies are contraindicated as first-line treatment of advanced non-small cell lung cancer (NSCLC) in patients with ALK rearrangement and EGFR mutation, many receive them. The purpose of this study was to examine the association between optimal first-line treatment in this population and clinical outcomes.

Methods: Claims and genomic data from patients with advanced or metastatic NSCLC were extracted from a nationally representative GuardantINFORM dataset.

Resistance to ATR Inhibitors Is Mediated by Loss of the Nonsense-Mediated Decay Factor UPF2.

Unlabelled: Over one million cases of gastric cancer are diagnosed each year globally, and the metastatic disease continues to have a poor prognosis. A significant proportion of gastric tumors have defects in the DNA damage response pathway, creating therapeutic opportunities through synthetic lethal approaches. Several small-molecule inhibitors of ATR, a key regulator of the DNA damage response, are now in clinical development as targeted agents for gastric cancer.

Lithium Toxicity With Lasting Mental Status Impairment.

A 49-year-old female taking lithium for bipolar affective disorder for over 20 years presented with lithium toxicity resulting in declining mentation. Lithium poisoning has been well documented to cause acute gastrointestinal, cardiac, and neurological side effects, along with long-term neurologic sequelae. There has, however, been scant discussion on the potential long-term effects on mentation.

BRAF induces reversible mitotic arrest in human melanocytes via microrna-mediated suppression of AURKB.

Benign melanocytic nevi frequently emerge when an acquired mutation triggers unchecked proliferation and subsequent arrest in melanocytes. Recent observations have challenged the role of oncogene-induced senescence in melanocytic nevus formation, necessitating investigations into alternative mechanisms for the establishment and maintenance of proliferation arrest in nevi. We compared the transcriptomes of melanocytes from healthy human skin, nevi, and melanomas arising from nevi and identified a set of microRNAs as highly expressed nevus-enriched transcripts.

Reverse Takotsubo cardiomyopathy: a comprehensive review.

Takotsubo cardiomyopathy (TTC) was first described in Japan in the 1980s. It is described as an acute but often reversible left ventricular (LV) dysfunction mainly triggered by emotional or physical stress. Multiple variants of TTC have been reported including reverse Takotsubo cardiomyopathy (rTTC) which is a variant characterized by the basal akinesis/hypokinesis associated with apical hyperkinesis that resolves spontaneously.

Bi-allelic Loss of CDKN2A Initiates Melanoma Invasion via BRN2 Activation.

Loss of the CDKN2A tumor suppressor is associated with melanoma metastasis, but the mechanisms connecting the phenomena are unknown. Using CRISPR-Cas9 to engineer a cellular model of melanoma initiation from primary human melanocytes, we discovered that a lineage-restricted transcription factor, BRN2, is downstream of CDKN2A and directly regulated by E2F1. In a cohort of melanocytic tumors that capture distinct progression stages, we observed that CDKN2A loss coincides with both the onset of invasive behavior and increased BRN2 expression.

Core Clinical Data Elements for Cancer Genomic Repositories: A Multi-stakeholder Consensus.

The Center for Medical Technology Policy and the Molecular Evidence Development Consortium gathered a diverse group of more than 50 stakeholders to develop consensus on a core set of data elements and values essential to understanding the clinical utility of molecularly targeted therapies in oncology.

Intrarater and interrater reliability of a hand-held dynamometric technique to quantify palmar thumb abduction strength in individuals with and without carpal tunnel syndrome.

Study Design: Clinical measurement.

Introduction: Individuals with carpal tunnel syndrome (CTS) sometimes exhibit weakness of palmar abduction strength (TAS). Reliable assessment of this strength in both subjects with and without CTS with the commonly available Microfet 2 is not known.

Cooperativity Enables Non-neutralizing Antibodies to Neutralize Ebolavirus.

Drug combinations are synergistic when their combined efficacy exceeds the sum of the individual actions, but they rarely include ineffective drugs that become effective only in combination. We identified several "enabling pairs" of neutralizing and non-neutralizing anti-ebolavirus monoclonal antibodies, whose combination exhibited new functional profiles, including transforming a non-neutralizing antibody to a neutralizer. Sub-neutralizing concentrations of antibodies 2G4 or m8C4 enabled non-neutralizing antibody FVM09 (IC >1 μM) to exhibit potent neutralization (IC 1-10 nM).

Selective Vulnerability of Cancer Cells by Inhibition of Ca(2+) Transfer from Endoplasmic Reticulum to Mitochondria.

In the absence of low-level ER-to-mitochondrial Ca(2+) transfer, ATP levels fall, and AMPK-dependent, mTOR-independent autophagy is induced as an essential survival mechanism in many cell types. Here, we demonstrate that tumorigenic cancer cell lines, transformed primary human fibroblasts, and tumors in vivo respond similarly but that autophagy is insufficient for survival, and cancer cells die while their normal counterparts are spared. Cancer cell death is due to compromised bioenergetics that can be rescued with metabolic substrates or nucleotides and caused by necrosis associated with mitotic catastrophe during their proliferation.

CDKN2B Loss Promotes Progression from Benign Melanocytic Nevus to Melanoma.

Unlabelled: Deletion of the entire CDKN2B-CDKN2A gene cluster is among the most common genetic events in cancer. The tumor-promoting effects are generally attributed to loss of CDKN2A-encoded p16 and p14ARF tumor suppressors. The degree to which the associated CDKN2B-encoded p15 loss contributes to human tumorigenesis is unclear.

IQGAP1 and IQGAP3 Serve Individually Essential Roles in Normal Epidermal Homeostasis and Tumor Progression.

IQ motif-containing GTPase-activating protein (IQGAP) scaffolding proteins regulate many essential cellular processes including growth factor receptor signaling, cytoskeletal rearrangement, adhesion, and proliferation and are highly expressed in many cancers. Using genetically engineered human skin tissue in vivo, we demonstrate that diminished, sub-physiologic expression of IQGAP1 or IQGAP3 is sufficient to maintain normal epidermal homeostasis, whereas significantly higher levels are required to support tumorigenesis. To target this tumor-specific IQGAP requirement in vivo, we engineered epidermal keratinocytes to express individual IQGAP protein domains designed to compete with endogenous IQGAPs for effector protein binding.

Activating FGFR3 mutations cause mild hyperplasia in human skin, but are insufficient to drive benign or malignant skin tumors.

Fibroblast growth factor receptor 3 (FGFR3) activating mutations are drivers of malignancy in several human tissues, including bladder, lung, cervix, and blood. However, in skin, these mutations are associated predominantly with benign, common epidermal growths called seborrheic keratoses (SKs). How epidermis resists FGFR3 mediated transformation is unclear, but previous studies have suggested that FGFR3 activation in skin keratinocytes may serve a tumor-suppressive role by driving differentiation and antagonizing Ras signaling.

Drug dependent sex-differences in periaqueducatal gray mediated antinociception in the rat.

Mu-opioid receptor (MOPr) agonists, such as morphine, produce greater antinociception in male compared to female rats. The ventolateral periaqueductal gray (vlPAG) appears to contribute to this sex-difference despite fewer vlPAG output neurons projecting to the rostral ventromedial medulla in male compared to female rats. This greater projection in female rats suggests that non-opioid activation of vlPAG output neurons should produce greater antinociception in female compared to male rats.

Prevalence of HCV risk factors in Hispanic-American sub populations.

To assess the prevalence of HCV risk factors among Hispanic-American subpopulations in Philadelphia. Patients from four primary care practices in Philadelphia were enrolled. Demographics and HCV risk factors were ascertained using a self-administered questionnaire.

Ginkgo biloba extract EGb 761 has anti-inflammatory properties and ameliorates colitis in mice by driving effector T cell apoptosis.

Ulcerative colitis is a dynamic, chronic inflammatory condition of the colon associated with an increased colon cancer risk. Ginkgo biloba is a putative antioxidant and has been used for thousands of years to treat a variety of ailments. The aim of this study was to test whether the standardized G.

Hepatitis C risk assessment, testing and referral for treatment in urban primary care: role of race and ethnicity.

Aim: To determine rates of hepatitis C (HCV) risk factor ascertainment, testing, and referral in urban primary care practices, with particular attention to the effect of race and ethnicity.

Methods: Retrospective chart review from four primary care sites in Philadelphia; two academic primary care practices and two community clinics was performed. Demographics, HCV risk factors, and other risk exposure information were collected.

Involving students in experimental design: three approaches.

Many faculty want to involve students more actively in laboratories and in experimental design. However, just "turning them loose in the lab" is time-consuming and can be frustrating for both students and faculty. We describe three different ways of providing structures for labs that require students to design their own experiments but guide the choices.

Teaching critical thinking skills in physiology.

This is a report of a workshop presented at Experimental Biology '99 on April 18, 1999, in Washington, DC.

Massive nerve root hypertrophy in chronic inflammatory demyelinating polyradiculoneuropathy.

In the course of investigating severe, shooting leg pains in a patient with chronic inflammatory demyelinating polyradiculoneuropathy, we observed massive nerve root enlargement on magnetic resonance imaging. Clinical evaluation ruled out other possible etiologies. Lumbar laminectomy was performed in an attempt to alleviate the pain, with poor results.