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Background and Purpose: Inhibitors of voltage‐gated sodium channels (NaVs) are important anti‐epileptic drugs, but the contribution of specific channel isoforms is unknown since available inhibitors are non‐selective. We aimed to create novel, isoform selective inhibitors of Nav channels as a means of informing the development of improved antiseizure drugs. Experimental Approach: We created a series of compounds with diverse selectivity profiles enabling block of NaV1.6 alone or together with NaV1.2. These novel NaV inhibitors were evaluated for their ability to inhibit electrically evoked seizures in mice with a heterozygous gain‐of‐function mutation (N1768D/+) in Scn8a (encoding NaV1.6) and in wild‐type mice. Key Results: Pharmacologic inhibition of NaV1.6 in Scn8aN1768D/+ mice prevented seizures evoked by a 6‐Hz shock. Inhibitors were also effective in a direct current maximal electroshock seizure assay in wild‐type mice. NaV1.6 inhibition correlated with efficacy in both models, even without inhibition of other CNS NaV isoforms. Conclusions and Implications: Our data suggest NaV1.6 inhibition is a driver of efficacy for NaV inhibitor anti‐seizure medicines. Sparing the NaV1.1 channels of inhibitory interneurons did not compromise efficacy. Selective NaV1.6 inhibitors may provide targeted therapies for human Scn8a developmental and epileptic encephalopathies and improved treatments for idiopathic epilepsies. [ABSTRACT FROM AUTHOR]

Background This pooled analysis of patient-level data from trials evaluated the clinical outcomes of patients with metastatic renal cell carcinoma with or without cytoreductive nephrectomy before a combination of immune checkpoint inhibitor and antiangiogenic therapy. Methods Data from 5 trials of immune checkpoint inhibitors plus antiangiogenic therapy were pooled. Only patients with stage 4 disease at initial diagnosis were included to ensure that nephrectomy was performed for cytoreductive purposes and not to previously treat an earlier stage of disease. The effect of cytoreductive nephrectomy before immune checkpoint inhibitor therapy on outcomes was evaluated using the Kaplan-Meier method and a Cox proportional hazards regression model, adjusted for age, sex, risk group, performance status, and the presence of sarcomatoid differentiation. Results A total of 981 patients were included. The estimated median progression-free survival with and without nephrectomy was 15 and 11 months, respectively; the adjusted hazard ratio was 0.71 (95% confidence interval = 0.59 to 0.85). The estimated median overall survival with and without nephrectomy was 46 and 28 months, respectively; the adjusted hazard ratio was 0.63 (95% confidence interval = 0.51 to 0.77). Objective response was 60% of patients with vs 46% of patients without cytoreductive nephrectomy. Conclusions Patients with metastatic renal cell carcinoma who undergo cytoreductive nephrectomy before immune checkpoint inhibitor plus antiangiogenic therapy had improved outcomes compared with patients without cytoreductive nephrectomy. Selection factors for cytoreductive nephrectomy may be prognostic and could not be fully controlled for in this retrospective analysis. Prospective determination of and stratification by prior cytoreductive nephrectomy may be considered when designing clinical trials to assess the impact of this factor on prognosis. [ABSTRACT FROM AUTHOR]

Objective: The authors determined the prevalence of stress, depression, and burnout in medical students and the resources used by students in one school to alleviate psychological distress. Methods: A survey was administered to 526 students in the first 3 years of medical school (336 responders; response rate: 70%) at one institution, using a modified Maslach Burnout Inventory Human Services Survey (MBI-HSS), the two-question PRIME-MD depression screening survey, the Perceived Medical School Stress Scale, along with questions on demographics and helpful programs to cope with stress. Results: The percentage of respondents scoring in the High Burnout range was approximately 55% for all three subscales. Depressive symptoms were reported by 60% of respondents. The most helpful coping mechanisms reported were social support from peers and faculty, counseling services, and extracurricular activities. Conclusions: The prevalences of burnout, depression, and stress were higher in this sample of first- through third-year medical students when compared with other medical student groups previously studied. Important limitations of this research included the fact that it was cross-sectional in design and that the PRIME-MD tool is simply a screening tool and does not diagnose major depression. Medical educators, deans, and administrators should appreciate the possibility of higher levels of psychological distress among their own students than those previously reported. (Contains 1 table.)

This article discusses the role of upfront cytoreductive nephrectomy (CN) in the treatment of metastatic renal cell carcinoma. The authors present the results of their pooled analysis of three clinical trials, which showed that CN prior to systemic treatment with immune checkpoint inhibitors and anti-angiogenic therapy was associated with improved progression-free survival (PFS) and overall survival (OS). These findings support the use of CN as a first-line therapeutic option for metastatic renal cell carcinoma. The authors note that further research and data sharing are needed to fully understand the benefits of CN in this context. [Extracted from the article]

After previously discovering that the ion channel TRPA1 is used as an internal temperature sensor in Drosophila to control the slow response of flies to shallow thermal gradients, the authors show here that the rapid response of flies to steep warming gradients relies on a different protein, GR28B, providing the first example of a thermosensory role for a gustatory receptor. A novel thermosensor in Drosophila Flies use the TRPA1 ion channel as an internal temperature sensor to slowly adjust their response to shallow thermal gradients. Now Paul Garrity and colleagues show that the rapid response of flies exposed to steep warmth gradients does not require TRPA1, but instead relies on the gustatory receptor GR28B(D), acting in peripheral thermosensing cells. Gustatory receptors have been implicated in taste, olfaction and host-seeking by disease-vector insects, but have not previously been linked with thermosensation. Behavioural responses to temperature are critical for survival, and animals from insects to humans show strong preferences for specific temperatures.sup.1,2. Preferred temperature selection promotes avoidance of adverse thermal environments in the short term and maintenance of optimal body temperatures over the long term.sup.1,2, but its molecular and cellular basis is largely unknown. Recent studies have generated conflicting views of thermal preference in Drosophila, attributing importance to either internal.sup.3 or peripheral.sup.4 warmth sensors. Here we reconcile these views by showing that thermal preference is not a singular response, but involves multiple systems relevant in different contexts. We found previously that the transient receptor potential channel TRPA1 acts internally to control the slowly developing preference response of flies exposed to a shallow thermal gradient.sup.3. We now find that the rapid response of flies exposed to a steep warmth gradient does not require TRPA1; rather, the gustatory receptor GR28B(D) drives this behaviour through peripheral thermosensors. Gustatory receptors are a large gene family, widely studied in insect gustation and olfaction, and are implicated in host-seeking by insect disease vectors.sup.5,6,7, but have not previously been implicated in thermosensation. At the molecular level, GR28B(D) misexpression confers thermosensitivity upon diverse cell types, suggesting that it is a warmth sensor. These data reveal a new type of thermosensory molecule and uncover a functional distinction between peripheral and internal warmth sensors in this tiny ectotherm reminiscent of thermoregulatory systems in larger, endothermic animals.sup.2. The use of multiple, distinct molecules to respond to a given temperature, as observed here, may facilitate independent tuning of an animal's distinct thermosensory responses., Author(s): Lina Ni [sup.1] [sup.2] , Peter Bronk [sup.1] [sup.2] , Elaine C. Chang [sup.1] [sup.2] , April M. Lowell [sup.1] [sup.2] , Juliette O. Flam [sup.1] [sup.2] , Vincent [...]

Discriminating among sensory stimuli is critical for animal survival. This discrimination is particularly essential when evaluating whether a stimulus is noxious or innocuous. From insects to humans, transient receptor potential (TRP) channels are key transducers of thermal, chemical and other sensory cues (1,2). Many TRPs are multimodal receptors that respond to diverse stimuli (1-3), but how animals distinguish sensory inputs activating the same TRP is largely unknown. Here we determine how stimuli activating Drosophila TRPA1 are discriminated. Although Drosophila TRPA1 responds to both noxious chemicals (4) and innocuous warming (5), we find that TRPA1-expressing chemosensory neurons respond to chemicals but not warmth, a specificity conferred by a chemosensory-specific TRPA1 isoform with reduced thermosensitivity compared to the previously described isoform. At the molecular level, this reduction results from a unique region that robustly reduces the channel's thermosensitivity. Cell-type segregation of TRPA1 activity is critical: when the thermosensory isoform is expressed in chemosensors, flies respond to innocuous warming with regurgitation, a nocifensive response. TRPA1 isoform diversity is conserved in malaria mosquitoes, indicating that similar mechanisms may allow discrimination of host-derived warmth--an attractant--from chemical repellents. These findings indicate that reducing thermosensitivity can be critical for TRP channel functional diversification, facilitating their use in contexts in which thermal sensitivity can be maladaptive., Highly temperature-responsive TRP cation channels, thermoTRPs, mediate thermosensation from insects to mammals (1,2) and are important for human pain and inflammation (6). Like mammalian thermoTRPs, Drosophila melanogaster TRPA1 is both [...]

Chemical nociception, the detection of tissue-damaging chemicals, is important for animal survival and causes human pain and inflammation, but its evolutionary origins are largely unknown. Reactive electrophiles are a class of noxious compounds humans find pungent and irritating, such as allyl isothiocyanate (in wasabi) and acrolein (in cigarette smoke) (1-3). Diverse animals, from insects to humans, find reactive electrophiles aversive1-3, but whether this reflects conservation of an ancient sensory modality has been unclear. Here we identify the molecular basis of reactive electrophile detection in flies. We demonstrate that Drosophila TRPA1 (Transient receptor potential A1), the Drosophila melanogaster orthologue of the human irritant sensor, acts in gustatory chemosensors to inhibit reactive electrophile ingestion. We show that fly and mosquito TRPA1 orthologues are molecular sensors of electrophiles, using a mechanism conserved with vertebrate TRPA1s. Phylogenetic analyses indicate that invertebrate and vertebrate TRPA1s share a common ancestor that possessed critical characteristics required for electrophile detection. These findings support emergence of TRPA1-based electrophile detection in a common bilaterian ancestor, with widespread conservation throughout vertebrate and invertebrate evolution. Such conservation contrasts with the evolutionary divergence of canonical olfactory and gustatory receptors and may relate to electrophile toxicity. We propose that human pain perception relies on an ancient chemical sensor conserved across ~500 million years of animal evolution., Reactive electrophiles are tissue-damaging agents that modify nucleic acids, proteins and other biomolecules. They are aversive to both vertebrates and invertebrates (1-3); plants and animals use them as deterrents (3). [...]

Ion transporters of blood-brain barrier (BBB) endothelial cells play an important role in regulating the movement of ions between the blood and brain. During ischemic stroke, reduction in cerebral blood flow is accompanied by transport of Na and C1 from the blood into the brain, with consequent brain edema formation. We have shown previously that a BBB Na-K-Cl cotransporter (NKCC) participates in ischemia-induced brain Na and water uptake and that a BBB Na/H exchanger (NHE) may also participate. While the abrupt reduction of blood flow is a prominent component of ischemia, the effects of flow on BBB NKCC and NHE are not known. In the present study, we examined the effects of changes in shear stress on NKCC and NHE protein levels in cerebral microvascular endothelial cells (CMECs). We have shown previously that estradiol attenuates both ischemia-induced cerebral edema and CMEC NKCC activity. Thus, in the present study, we also examined the effects of estradiol on NKCC and NHE protein levels in CMECs. Exposing CMECs to steady shear stress (19 dyn/[cm.sup.2]) increased the abundance of both NKCC and NHE. Estradiol abolished the shear stress-induced increase in NHE but not NKCC. Abrupt reduction of shear stress did not alter NKCC or NHE abundance in the absence of estradiol, but it decreased NKCC abundance in estradiol-treated cells. Our results indicate that changes in shear stress modulate BBB NKCC and NHE protein levels. They also support the hypothesis that estradiol attenuates edema formation in ischemic stroke in part by reducing the abundance of BBB NKCC protein. estrogen; ischemia; mechanotransduction; flow reduction; endothelium

Background: To review and summarize all U.S. Food and Drug Administration (FDA) approvals of programmed death (PD)‐1 and PD‐ligand 1 blocking antibodies (collectively referred to as PD‐[L]1 inhibitors) over a 6‐year period and corresponding companion/complementary diagnostic assays. Materials and Methods: To determine the indications and pivotal trials eligible for inclusion, approval letters and package inserts available on Drugs@FDA were evaluated for approved PD‐[L]1 inhibitors to identify all new indications granted from the first approval of a PD‐[L]1 inhibitor on September 4, 2014, through September 3, 2020. The corresponding FDA drug and device reviews from the marketing applications for the approved indications were identified through FDA internal records. Two reviewers independently extracted information for the endpoints, efficacy data, basis for approval, type of regulatory approval, and corresponding in vitro diagnostic device test. The results were organized by organ system and tumor type. Results: Of 70 Biologic Licensing Application or supplement approvals that resulted in new indications, 32 (46%) were granted based on response rate (ORR) and durability of response, 26 (37%) on overall survival, 9 (13%) on progression‐free survival, 2 (3%) on recurrence‐free survival, and 1 (1%) on complete response rate. Most ORR‐based approvals were granted under the accelerated approval provisions and were supported with prolonged duration of response. Overall, 21% of approvals were granted with a companion diagnostic. Efficacy results according to tumor type are discussed. Conclusion: PD‐[L]1 inhibitors are an effective anticancer therapy in a subset of patients. This class of drugs has provided new treatment options for patients with unmet need across a wide variety of cancer types. Yet, the modest response rates in several tumor types signal a lack of understanding of the biology of these diseases. Further preclinical and clinical investigation may be required to identify a more appropriate patient population, particularly as drug development continues and additional treatment alternatives become available. Implications for Practice: The number of PD‐[L]1 inhibitors in drug development and the associated companion and complementary diagnostics have led to regulatory challenges and questions regarding generalizability of trial results. The interchangeability of PD‐L1 immunohistochemical assays between PD‐1/PD‐L1 drugs is unclear. Furthermore, robust responses in some patients with low levels of PD‐L1 expression have limited the use of PD‐L1 as a predictive biomarker across all cancers, particularly in the setting of diseases with few alternative treatment options. This review summarizes the biomarker thresholds and assays approved as complementary and companion diagnostics and provides regulatory perspective on the role of biomarkers in oncology drug development. This review provides a regulatory overview on the U.S. FDA approvals of PD‐1 and PD‐L1 inhibitors and highlights complementary and companion diagnostics within the context of each disease and indication. [ABSTRACT FROM AUTHOR]

The U.S. Food and Drug Administration (FDA) granted accelerated approval to rucaparib in May 2020 for the treatment of adult patients with deleterious BRCA mutation (germline and/or somatic)‐associated metastatic castrate‐resistant prostate cancer (mCRPC) who have been treated with androgen receptor‐directed therapy and a taxane. This approval was based on data from the ongoing multicenter, open‐label single‐arm trial TRITON2. The primary endpoint, confirmed objective response rate, in the 62 patients who met the above criteria, was 44% (95% confidence interval [CI]: 31%–57%). The median duration of response was not estimable (95% CI: 6.4 to not estimable). Fifty‐six percent of patients had a response duration of >6 months and 15% >12 months. The safety profile of rucaparib was generally consistent with that of the class of poly‐(ADP‐ribose) polymerase enzyme inhibitors and other trials of rucaparib in the treatment of ovarian cancer. Deaths due to adverse events (AEs) occurred in 1.7% of patients, and 8% discontinued rucaparib because of an AE. Grade 3–4 AEs occurred in 59% of patients. No patients with prostate cancer developed myelodysplastic syndrome or acute myeloid leukemia. The trial TRITON3 in patients with mCRPC is ongoing and is planned to verify the clinical benefit of rucaparib in mCRPC. This article summarizes the FDA thought process and data supporting this accelerated approval. Implications for Practice: The accelerated approval of rucaparib for the treatment of adult patients with deleterious BRCA mutation (germline and/or somatic)‐associated metastatic castrate‐resistant prostate cancer who have been treated with androgen receptor‐directed therapy and a taxane represents the first approved therapy for this selected patient population. This approval was based on a single‐arm trial demonstrating a confirmed objective response rate greater than that of available therapy with a favorable duration of response and an acceptable toxicity profile. The ongoing trial TRITON3 is verifying the clinical benefit of this drug. This article reviews the data and basis for FDA accelerated approval of rucaparib for the first‐line treatment of patients with deleterious BRCA‐mutated metastatic castrate‐resistant prostate cancer. [ABSTRACT FROM AUTHOR]

Background: Protease inhibitors (PIs) may inhibit Kaposi sarcoma (KS) carcinogenesis. However, PI-based antiretroviral therapy (ART) is rarely a first-line choice in people living with HIV (PLWH) because of cost and toxicities. This is the first systematic review to assess KS incidence stratified by ART type. Methods: We searched PubMed to identify original, full research reports of KS incidence in ART-treated adult PLWH, stratified by ART class, published between 1996 and 2017. For overlapping cohorts, we included only the most recent study and supplemented data with earlier relevant analyses. We described study design, sociodemographic characteristics, statistical adjustment factors, and KS incidence. Results: We identified 3 unique retrospective cohort studies, and supplemented one of the studies with results from 6 previous subgroup reports, which included 242,309 PLWH and 3570 incident KS cases. Overall, KS crude incidence decreased by a factor of 10 between untreated and ART-treated PLWH; CD4-adjusted KS incidence decreased by ;50%, with either non-nucleoside reverse transcriptase inhibitor- or PI-based ART. A single study measured a cumulative dose-/time-dependent effect of ART, which reported a relative risk reduction in only the cohort receiving boosted PI-based ART. Other studies defined ART categories by first-line therapy only. Conclusions: The risk of incident KS was significantly reduced, regardless of ART class even after adjusting for CD4 count. The quality of evidence (ie, most studies categorizing users by first-line ART) does not permit KS risk reduction comparisons across ART types. Given the limited number and retrospective nature of these studies, prospective data are indicated. [ABSTRACT FROM AUTHOR]

Summary Selective block of Na V 1.7 promises to produce non-narcotic analgesic activity without motor or cognitive impairment. Several Na V 1.7-selective blockers have been reported, but efficacy in animal pain models required high multiples of the IC 50 for channel block. Here, we report a target engagement assay using transgenic mice that has enabled the development of a second generation of selective Nav1.7 inhibitors that show robust analgesic activity in inflammatory and neuropathic pain models at low multiples of the IC 50. Like earlier arylsulfonamides, these newer acylsulfonamides target a binding site on the surface of voltage sensor domain 4 to achieve high selectivity among sodium channel isoforms and steeply state-dependent block. The improved efficacy correlates with very slow dissociation from the target channel. Chronic dosing increases compound potency about 10-fold, possibly due to reversal of sensitization arising during chronic injury, and provides efficacy that persists long after the compound has cleared from plasma. Graphical Abstract Highlights • Aconitine-induced pain in IEM mice enables assay for target engagement of hNa V 1.7 • Acylsulfonamides inhibit pain at low multiples of the IC 50 for inhibition of Na V 1.7 • Improvement versus arylsulfonamides correlates with longer residency time on Na V 1.7 • Repeat dosing of acylsulfonamides results in a 10-fold decrease in EC 50 for analgesia Bankar et al. show that acylsulfonamides produce analgesic activity at low multiples of the IC 50 for inhibition of Na V 1.7, in contrast to studies with arylsulfonamides that required >10 times the IC 50. The improvement correlates with longer residency time on the target channels. [ABSTRACT FROM AUTHOR]

Plasmablastic lymphoma (PBL) is a rare subtype of diffuse large B cell lymphoma (DLBCL), often associated with HIV infection. We present a case of a 53-year-old HIV-negative man with untreated hepatitis C viral infection who presented with abdominal pain and lymphadenopathy. Lymph node and bone marrow biopsies were consistent with plasmablastic lymphoma. He had partial response (PR) to 6 cycles of EPOCH but disease progressed seven weeks later. Repeat biopsy was consistent with plasmablastic lymphoma. Three cycles of bortezomib, ifosfamide, carboplatin, and etoposide (B-ICE) chemotherapy resulted in a partial response (PR). Five months later, he presented with widespread lymphadenopathy and tumor lysis syndrome with circulating blasts. Flow cytometry revealed a different population of lymphoma cells, this time positive for CD5, CD19, CD20, and CD22, with dim expression of CD45 and CD38. The patient died on the first day of ESHAP chemotherapy. There are no treatment recommendations or standard of care for plasmablastic lymphoma. A literature search yielded 10 cases in which bortezomib was administered in either HIV-positive or HIV-negative PBL. Six reported a partial response, 3 reported a complete response, and 1 was a near-complete response. Bortezomib, in combination with chemotherapy, may be an effective treatment option in PBL as reported here. [ABSTRACT FROM AUTHOR]