By serving as intermediaries between cellular metabolism and the bioenergetic demands of proliferation, endolysosomes allow cancer cells to thrive under normally detrimental conditions. Here, we show that an endolysosomal TRP channel, TRPML1, is necessary for the proliferation of cancer cells that bear activating mutations in HRAS. Expression of MCOLN1, which encodes TRPML1, is significantly elevated in HRAS‐positive tumors and inversely correlated with patient prognosis. Concordantly, MCOLN1 knockdown or TRPML1 inhibition selectively reduces the proliferation of cancer cells that express oncogenic, but not wild‐type, HRAS. Mechanistically, TRPML1 maintains oncogenic HRAS in signaling‐competent nanoclusters at the plasma membrane by mediating cholesterol de‐esterification and transport. TRPML1 inhibition disrupts the distribution and levels of cholesterol and thereby attenuates HRAS nanoclustering and plasma membrane abundance, ERK phosphorylation, and cell proliferation. These findings reveal a selective vulnerability of HRAS‐driven cancers to TRPML1 inhibition, which may be leveraged as an actionable therapeutic strategy.

Mitochondrial ATP production is a well-known regulator of neuronal excitability. The reciprocal influence of plasma-membrane potential on ATP production, however, remains poorly understood. Here, we describe a mechanism by which depolarized neurons elevate the somatic ATP/ADP ratio in Drosophila glutamatergic neurons. We show that depolarization increased phospholipase-Cβ (PLC-β) activity by promoting the association of the enzyme with its phosphoinositide substrate. Augmented PLC-β activity led to greater release of endoplasmic reticulum Ca2+ via the inositol trisphosphate receptor (IP3R), increased mitochondrial Ca2+ uptake, and promoted ATP synthesis. Perturbations that decoupled membrane potential from this mode of ATP synthesis led to untrammeled PLC-β–IP3R activation and a dramatic shortening of Drosophila lifespan. Upon investigating the underlying mechanisms, we found that increased sequestration of Ca2+ into endolysosomes was an intermediary in the regulation of lifespan by IP3Rs. Manipulations that either lowered PLC-β/IP3R abundance or attenuated endolysosomal Ca2+ overload restored animal longevity. Collectively, our findings demonstrate that depolarization-dependent regulation of PLC-β–IP3R signaling is required for modulation of the ATP/ADP ratio in healthy glutamatergic neurons, whereas hyperactivation of this axis in chronically depolarized glutamatergic neurons shortens animal lifespan by promoting endolysosomal Ca2+ overload.

Purpose The social vulnerability index (SVI), developed by the Centers for Disease Control and Prevention, is a novel composite measure encompassing multiple variables that correspond to key social determinants of health. The objective of this review was to investigate innovative applications of the SVI to oncology research and to employ the framework of the cancer care continuum to elucidate further research opportunities. Methods A systematic search for relevant articles was performed in five databases from inception to 13 May 2022. Included studies applied the SVI to analyze outcomes in cancer patients. Study characteristics, patent populations, data sources, and outcomes were extracted from each article. This review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Results In total, 31 studies were included. Along the cancer care continuum, five applied the SVI to examine geographic disparities in potentially cancer-causing exposures; seven in cancer diagnosis; fourteen in cancer treatment; nine in treatment recovery; one in survivorship care; and two in end-of-life care. Fifteen examined disparities in mortality. Conclusion In highlighting place-based disparities in patient outcomes, the SVI represents a promising tool for future oncology research. As a reliable geocoded dataset, the SVI may inform the development and implementation of targeted interventions to prevent cancer morbidity and mortality at the neighborhood level.

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Spiny keratoderma (SpK) is a rare skin condition characterized by spine‐like papules on the palms and soles. The condition is identified under several names such as “music box spine keratosis” and “palmoplantar filiform hyperkeratosis,” creating ambiguity in the diagnostic and histopathologic features of the disease. In this study, we reviewed 84 cases of SpK to examine patient demographics, medical history, clinical and histopathological descriptions, and sporadic versus hereditary onset. Notably, the most used histopathological terms were “parakeratosis” and “hypogranulosis,” and the most used clinical terms were “spine” and “hyperpigmented.” The average age at presentation was 60.1 years with the majority of cases in males. Only 29.8% of cases were associated with a family history of SpK and underlying malignancies were present in 28.6% of cases. This review investigates the frequency of histopathologic and clinical terms used to describe SpK to provide insight into the clinical and histopathological characteristics of this rarely reported condition.

Linear lichen planus (LLP), also known as blaschkolinear or blaschkoid lichen planus, is a rare subtype of lichen planus that presents along the lines of Blaschko. While LLP has been associated with vaccinations, neoplasms, medications, and successive pregnancies, we present a case of LLP following a primary pregnancy. A 29-year-old G1P1 female presented to dermatology for the evaluation of an intensely pruritic, whorled rash confined to her left lower leg that appeared shortly after the birth of her first child. A biopsy of the lesion and subsequent histopathology confirmed the diagnosis of LLP. The patient was treated with topical steroids with minimal response to therapy and declined further treatment.

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