Hypoxia-induced TPC2 transcription and glycosylation aggravates pulmonary arterial hypertension by blocking autophagy flux.

Pulmonary arterial hypertension (PAH) is a serious medical condition that causes a failure in the right heart. Two-pore channel 2 (TPC2) is upregulated in PAH, but its roles in PAH remain largely unknown. Our investigation aims at the mechanisms by which TPC2 regulates PAH development.

Dual Immune Checkpoint Inhibition in Patients With Aggressive Thyroid Carcinoma: A Phase 2 Nonrandomized Clinical Trial.

Importance: Aggressive thyroid carcinoma, including radioiodine refractory (RAIR) differentiated thyroid carcinoma (DTC), medullary thyroid carcinoma (MTC), and anaplastic thyroid carcinoma (ATC), are associated with significant morbidity and mortality and have limited therapeutic options. Distinct immune profiles have been identified in thyroid cancer subtypes suggesting they may be susceptible to immune checkpoint inhibition.

Objective: To evaluate the efficacy of anti-programmed cell death 1 nivolumab and anti-cytotoxic lymphocyte-associated protein 4 ipilimumab in patients with aggressive thyroid carcinoma.

A phase I/II trial of sapanisertib in advanced anaplastic and radioiodine refractory differentiated thyroid carcinoma.

Background: There are limited therapeutic options for patients with recurrent/metastatic anaplastic thyroid carcinoma (ATC), and radioiodine refractory (RAIR) differentiated thyroid carcinoma (DTC) refractory to multi-kinase inhibitors. This multi-center trial evaluated sapanisertib, a next generation oral kinase inhibitor of mTOR complexes 1/2, in ATC and RAIR DTC.

Methods: A safety run-in phase I was followed by non-randomized phase II trial in ATC, with an exploratory cohort in RAIR DTC.

Patterns of initial distant metastases in 151 patients undergoing surveillance for treated Merkel cell carcinoma.

Background: Merkel cell carcinoma (MCC) is associated with high rates of recurrence and distant metastatic progression. Current guidelines for surveillance imaging are not evidence based. Better characterization of the pattern of distant metastatic spread will better inform surveillance and facilitate earlier detection of metastases.

Pancreatitis and Hyperlipasemia in the Setting of Immune Checkpoint Inhibitor Therapy.

Background: Immune checkpoint inhibitor-induced pancreatic injury (ICI-PI) ranges from asymptomatic hyperlipasemia to symptomatic acute pancreatitis (AP). The proportion of pancreatic injury while receiving ICIs that is attributable to therapy remains unclear. We evaluated the etiology of hyperlipasemia in patients receiving ICIs, and the clinical characteristics, management, and outcomes of ICI-PI.

Bavituximab Decreases Immunosuppressive Myeloid-Derived Suppressor Cells in Newly Diagnosed Glioblastoma Patients.

Purpose: We evaluated the efficacy of bavituximab-a mAb with anti-angiogenic and immunomodulatory properties-in newly diagnosed patients with glioblastoma (GBM) who also received radiotherapy and temozolomide. Perfusion MRI and myeloid-related gene transcription and inflammatory infiltrates in pre-and post-treatment tumor specimens were studied to evaluate on-target effects (NCT03139916).

Patients And Methods: Thirty-three adults with IDH--wild-type GBM received 6 weeks of concurrent chemoradiotherapy, followed by 6 cycles of temozolomide (C1-C6).

Report on the PET/CT Image-Based Radiation Dosimetry of [F]FDHT in Women, a Validated Imaging Agent with New Applications for Evaluation of Androgen Receptor Status in Women with Metastatic Breast Cancer.

In a prospective clinical trial, [F]fluoro-5α-dihydrotestosterone ([F]FDHT), the radiolabeled analog of the androgen dihydrotestosterone, was used as a PET/CT imaging agent for in vivo assessment of metastatic androgen receptor-positive breast cancer in postmenopausal women. To our knowledge, this article presents the first report of PET/CT image-based radiation dosimetry of [F]FDHT in women. [F]FDHT PET/CT imaging was performed on a cohort of 11 women at baseline before the start of therapy and at 2 additional time points during selective androgen receptor modulator (SARM) therapy for androgen receptor-positive breast cancer.

Structural optimization of tetrahydroisoquinoline-hydroxamate hybrids as potent dual ERα degraders and HDAC inhibitors.

Both estrogen receptor α (ERα) and histone deacetylases (HDACs) are valid therapeutic targets for anticancer drug development. Combination therapies using diverse ERα antagonists or degraders and HDAC inhibitors have been proven effective in endocrine-resistant ER + breast cancers based on the crosstalk between ERα and HDAC pathway. In this study, we reported the optimization of a series of methoxyphenyl- or pyridinyl- substituted tetrahydroisoquinoline-hydroxamates, which were optimized from 31, a dual ERα degrader/HDAC inhibitor previously reported by our group.

YAP1 and WWTR1 expression inversely correlates with neuroendocrine markers in Merkel cell carcinoma.

BackgroundMerkel cell carcinoma (MCC) is an aggressive neuroendocrine (NE) skin cancer caused by severe UV-induced mutations or expression of Merkel cell polyomavirus (MCPyV) large and small T antigens (LT and ST). Despite deep genetic differences between MCPyV-positive and -negative subtypes, current clinical diagnostic markers are indistinguishable, and the expression profile of MCC tumors is, to our knowledge, unexplored.MethodsHere, we leveraged bulk and single-cell RNA-Seq of patient-derived tumor biopsies and cell lines to explore the underlying transcriptional environment of MCC.

Performance of a Triage Protocol for Monoclonal Antibodies in a Mixed Vaccinated and Unvaccinated Cohort of COVID-19 Patients Treated With Intravenous Infusion or Subcutaneous Injection.

Background: Several monoclonal antibodies (mAbs) have been shown to reduce rates of hospitalization in patients with coronavirus disease 2019 (COVID-19) who have risk factors for severe disease. Due to capacity constraints, many health systems have been unable to provide mAbs to all eligible patients. There is little evidence regarding the performance of triage protocols for allocation or the relative effectiveness of subcutaneous administration vs intravenous infusion.

Bamlanivimab Efficacy in Older and High-BMI Outpatients With COVID-19 Selected for Treatment in a Lottery-Based Allocation Process.

Background: Given the challenges associated with timely delivery of monoclonal antibody (mAb) therapy to outpatients with coronavirus disease 2019 (COVID-19) who are most likely to benefit, it is critical to understand the effectiveness of such therapy outside the context of clinical trials.

Methods: This was a case-control study of 1257 adult outpatients with COVID-19, ≥65 years of age or with body mass index (BMI) ≥35, who were entered into a lottery for mAb therapy.

Results: Patients who were called to be offered mAb therapy had a statistically significant 44% reduction in the odds of hospitalization within 30 days of a positive severe acute respiratory syndrome coronavirus 2 test compared with those who were not called (odds ratio [OR], 0.

Imaging Androgen Receptors in Breast Cancer with F-Fluoro-5α-Dihydrotestosterone PET: A Pilot Study.

Most breast cancers express androgen receptors (ARs). This prospective imaging substudy explored imaging of ARs with F-fluoro-5α-dihydrotestosterone (F-FDHT) PET in patients with metastatic breast cancer (MBC) receiving selective AR modulation (SARM) therapy (GTx-024). Eleven postmenopausal women with estrogen receptor-positive MBC underwent F-FDHT PET/CT at baseline and at 6 and 12 wk after starting SARM therapy.

Feasibility of Auricular Field Stimulation in Fibromyalgia: Evaluation by Functional Magnetic Resonance Imaging, Randomized Trial.

Objective: To evaluate the feasibility of recruitment, preliminary efficacy, and acceptability of auricular percutaneous electrical nerve field stimulation (PENFS) for the treatment of fibromyalgia in veterans, using neuroimaging as an outcome measure and a biomarker of treatment response.

Design: Randomized, controlled, single-blind.

Setting: Government hospital.

Adverse Outcomes Associated With Inpatient Administration of Beers List Medications Following Total Knee Replacement.

Purpose: Beers List drugs are potentially harmful in older adults and are grouped by level of risk. Over 9000 total knee arthroplasties (TKAs) are performed each year Veterans Affairs (VA) hospitals, primarily on older adults. Minimal data on the administration of Beers List drugs following arthroplasty currently exists in the literature.

A patient with multiple paradoxical emboli.

We present a case report of simultaneous pulmonary emboli and paradoxical embolism to the cerebellum causing a stroke and severe ischemia to the left leg. This patient had risk factors for thromboembolic events that included autoimmune disease, cancer, and recent pelvic surgery. The presence of a perforate foramen ovale was suspected on his initial presentation and confirmed with echocardiography.