Discovery of a Neuroprotective Chemical, ( S )- N -(3-(3,6-Dibromo-9 H -carbazol-9-yl)-2-fluoropropyl)-6-methoxypyridin-2-amine [(−)-P7C3-S243], with Improved Druglike Properties

(−)-P7C3-S243 is a neuroprotective aminopropyl carbazole with improved druglike properties compared with previously reported compounds in the P7C3 class. It protects developing neurons in a mouse model of hippocampal neurogenesis and protects mature neurons within the substantia nigra in a mouse model of Parkinson’s disease. A short, enantioselective synthesis provides the neuroprotective agent in optically pure form. It is nontoxic, orally bioavailable, metabolically stable, and able to cross the blood–brain barrier. As such, it represents a valuable lead compound for the development of drugs to treat neurodegenerative diseases and traumatic brain injury

Allogeneic Hematopoietic Cell Transplantation for Blastic Plasmacytoid Dendritic Cell Neoplasm: A CIBMTR Analysis

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematological malignancy with a poor prognosis and considered incurable with conventional chemotherapy. Small observational studies reported allogeneic hematopoietic cell transplantation (allo-HCT) offers durable remissions in patients with BPDCN. We report an analysis of patients with BPDCN who received an allo-HCT, using data reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). We identified 164 patients with BPDCN from 78 centers who underwent allo-HCT between 2007 and 2018. The 5-year overall survival (OS), disease-free survival (DFS), relapse, and nonrelapse mortality (NRM) rates were 51.2% (95% confidence interval [CI], 42.5-59.8), 44.4% (95% CI, 36.2-52.8), 32.2% (95% CI, 24.7-40.3), and 23.3% (95% CI, 16.9-30.4), respectively. Disease relapse was the most common cause of death. On multivariate analyses, age of ≥60 years was predictive for inferior OS (hazard ratio [HR], 2.16; 95% CI, 1.35-3.46; P = .001), and higher NRM (HR, 2.19; 95% CI, 1.13-4.22; P = .02). Remission status at time of allo-HCT (CR2/primary induction failure/relapse vs CR1) was predictive of inferior OS (HR, 1.87; 95% CI, 1.14-3.06; P = .01) and DFS (HR, 1.75; 95% CI, 1.11-2.76; P = .02). Use of myeloablative conditioning with total body irradiation (MAC-TBI) was predictive of improved DFS and reduced relapse risk. Allo-HCT is effective in providing durable remissions and long-term survival in BPDCN. Younger age and allo-HCT in CR1 predicted for improved survival, whereas MAC-TBI predicted for less relapse and improved DFS. Novel strategies incorporating allo-HCT are needed to further improve outcomes

Clinical Outcomes after Immunotherapies in Cancer Setting during COVID-19 Era: A Systematic Review and Meta-Regression

Background: This study aims to describe COVID-19–related clinical outcomes after immunotherapies (ICIs) for cancer patients. Methods: In this meta-analysis, we searched databases to collect data that addressed outcomes after immunotherapies (ICIs) during the COVID-19 pandemic. The primary endpoint was COVID-19–related mortality. Secondary endpoints included COVID-related hospital readmission, emergency room (ER) visits, opportunistic infections, respiratory complications, need for ventilation, and thrombo-embolic events. Pooled event rates (PERs) were calculated and a meta-regression analysis was performed. Results: A total of 262 studies were identified. Twenty-two studies with a total of forty-four patients were eligible. The PER of COVID-19–related mortality was 39.73%, while PERs of COVID-19–related ER visits, COVID-19–related pulmonary complications, and COVID-19–related ventilator needs were 40.75%, 40.41%, and 34.92%, respectively. The PER of opportunistic infections was 34.92%. The PERs of the use of antivirals, antibiotics, steroids, prophylactic anticoagulants, and convalescent plasma were 62.12%, 57.12%, 51.36%, 41.90%, and 26.48%, respectively. There was a trend toward an association between previous respiratory diseases and COVID-19–related mortality. Conclusion: The rates of COVID-19–related mortality, ER visits, pulmonary complications, need for a ventilator, and opportunistic infections are still high after ICIs during the COVID-19 pandemic. There was a trend toward an association between previous respiratory diseases and COVID-19–related mortality

Clinical Outcomes after Immunotherapies in Cancer Setting during COVID-19 Era: A Systematic Review and Meta-Regression

Background: This study aims to describe COVID-19–related clinical outcomes after immunotherapies (ICIs) for cancer patients. Methods: In this meta-analysis, we searched databases to collect data that addressed outcomes after immunotherapies (ICIs) during the COVID-19 pandemic. The primary endpoint was COVID-19–related mortality. Secondary endpoints included COVID-related hospital readmission, emergency room (ER) visits, opportunistic infections, respiratory complications, need for ventilation, and thrombo-embolic events. Pooled event rates (PERs) were calculated and a meta-regression analysis was performed. Results: A total of 262 studies were identified. Twenty-two studies with a total of forty-four patients were eligible. The PER of COVID-19–related mortality was 39.73%, while PERs of COVID-19–related ER visits, COVID-19–related pulmonary complications, and COVID-19–related ventilator needs were 40.75%, 40.41%, and 34.92%, respectively. The PER of opportunistic infections was 34.92%. The PERs of the use of antivirals, antibiotics, steroids, prophylactic anticoagulants, and convalescent plasma were 62.12%, 57.12%, 51.36%, 41.90%, and 26.48%, respectively. There was a trend toward an association between previous respiratory diseases and COVID-19–related mortality. Conclusion: The rates of COVID-19–related mortality, ER visits, pulmonary complications, need for a ventilator, and opportunistic infections are still high after ICIs during the COVID-19 pandemic. There was a trend toward an association between previous respiratory diseases and COVID-19–related mortality

Inhibitors of 15-Prostaglandin Dehydrogenase To Potentiate Tissue Repair

The enzyme 15-prostaglandin dehydrogenase (15-PGDH) catalyzes the first step in the degradation of prostaglandins including PGE2. It is a negative regulator of tissue repair and regeneration in multiple organs. Accordingly, inhibitors of 15-PGDH are anticipated to elevate in vivo levels of PGE2 and to promote healing and tissue regeneration. The small molecule SW033291 (<b>1</b>) inhibits 15-PGDH with <i>K</i>_i = 0.1 nM in vitro, doubles PGE2 levels in vivo, and shows efficacy in mouse models of recovery from bone marrow transplantation, ulcerative colitis, and partial hepatectomy. Here we describe optimized variants of <b>1</b> with improved solubility, druglike properties, and in vivo activity

Discovery of a Neuroprotective Chemical, (<i>S</i>)‑<i>N</i>‑(3-(3,6-Dibromo‑9<i>H</i>‑carbazol-9-yl)-2-fluoropropyl)-6-methoxypyridin-2-amine [(−)-P7C3-S243], with Improved Druglike Properties

(−)-P7C3-S243 is a neuroprotective aminopropyl carbazole with improved druglike properties compared with previously reported compounds in the P7C3 class. It protects developing neurons in a mouse model of hippocampal neurogenesis and protects mature neurons within the substantia nigra in a mouse model of Parkinson’s disease. A short, enantioselective synthesis provides the neuroprotective agent in optically pure form. It is nontoxic, orally bioavailable, metabolically stable, and able to cross the blood–brain barrier. As such, it represents a valuable lead compound for the development of drugs to treat neurodegenerative diseases and traumatic brain injury

Monitor Tumor pHe and Response Longitudinally during Treatment Using CEST MRI-Detectable Alginate Microbeads

Imaging pHe of the tumor microenvironment has paramount importance for characterizing aggressive, invasive tumors, as well as therapeutic responses. Here, a robust approach to image pH changes in the tumor microenvironment longitudinally and during sodium bicarbonate treatment was reported. The pH-sensing microbeads were designed and prepared based on materials approved for clinical use, i.e., alginate microbead-containing computed tomography (CT) contrast-agent (iopamidol)-loaded liposomes (Iop-lipobeads). This Iop-lipobead prepared using a customized microfluidic device generated a CEST contrast of 10.6% at 4.2 ppm at pH 7.0, which was stable for 20 days in vitro. The CEST contrast decreased by 11.8% when the pH decreased from 7.0 to 6.5 in vitro. Optimized Iop-lipobeads next to tumors showed a significant increase of 19.7 ± 6.1% (p < 0.01) in CEST contrast at 4.2 ppm during the first 3 days of treatment and decreased to 15.2 ± 4.8% when treatment stopped. Notably, percentage changes in Iop-lipobeads were higher than that of amide CEST (11.7% and 9.1%) in tumors during and after treatment. These findings demonstrated that the Iop-lipobead could provide an independent and sensitive assessment of the pHe changes for a noninvasive and longitudinal monitoring of the treatment effects using multiple CEST contrast