Insulin Directs Dichotomous Translational Regulation to Control Human Pluripotent Stem Cell Survival, Proliferation and Pluripotency.

Insulin is essential for diverse biological processes in human pluripotent stem cells (hPSCs). However, the underlying mechanism of insulin's multitasking ability remains largely unknown. Here, we show that insulin controls hPSC survival and proliferation by modulating RNA translation via distinct pathways. It activates AKT signaling to inhibit RNA translation of pro-apoptotic proteins such as NOXA/PMAIP1, thereby promoting hPSC survival. At the same time, insulin acts via the mTOR pathway to enhance another set of RNA translation for cell proliferation. Consistently, mTOR inhibition by rapamycin results in eIF4E phosphorylation and translational repression. It leads to a dormant state with sustained pluripotency but reduced cell growth. Together, our study uncovered multifaceted regulation by insulin in hPSC survival and proliferation, and highlighted RNA translation as a key step to mediate mitogenic regulation in hPSCs.

Successful administration of chimeric antigen receptor (CAR) T-cell therapy in patients requiring hemodialysis.

Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment of relapsed/refractory B-cell malignancies. However, there is no data on the safety and efficacy of CAR T-cell therapy in patients with end stage renal disease (ESRD) requiring dialysis. In this report, we present two patients with DLBCL and ESRD who were successfully treated with different CAR T-cell products. Patient #1 is a 66 year-old woman with a history of HIV who was treated to complete response with axicabtagene ciloleucel with treatment complicated by grade 1 cytokine release syndrome (CRS) and grade 2 immune effector cell-associated neurolotoxicity syndrome (ICANS). Patient #2 is 52 year old woman whose ESRD was caused by ifosphamide toxicity and was treated to complete response with lisocabtagene maraleucel and did not experience either CRS or ICANS. Both patients received lymphodepletion chemotherapy with fludarabine and cyclophosphamide, which was dose-adjusted for ESRD with scheduled dialysis 12 h after each dose of lymphodepletion chemotherapy. Patients with DLBCL and ESRD can be safely administered both lymphodepletion chemotherapy and CAR T-cell therapy. Additionally, the fact that both patients achieved complete response to therapy suggests that CAR T-cell therapy should be strongly considered in patients with ESRD. Long-term follow up is needed to determine if therapy in this setting is of curative intent.

The Impact of Prior Salvage Treatment With Immune Checkpoint Inhibitors on Hodgkin Lymphoma Patients Undergoing Autologous Hematopoietic Stem Cell Transplantation: A Single-Center Experience.

INTRODUCTION: The objective of the study was to assess the impact of the previous use of immune-checkpoint inhibitors (ICIs) on the clinical course of Hodgkin Lymphoma (HL) patients undergoing autologous hematopoietic stem cell transplantation (ASCT). METHODS: A single-center, retrospective chart review of adult HL patients who received ASCT from January 1, 2014, to December 31, 2019, was conducted. Primary endpoints included the length of stay (LOS) and the composite outcome of late-onset noninfectious fever (LONIF) or late-onset hypotension (LOH) requiring intravenous fluid (IVF) resuscitation. Secondary endpoints included number of days until neutrophil engraftment, documented infections, and corticosteroid use. RESULTS: A total of 52 HL patients were included. Nine (17%) received ICI before ASCT, and 43 (83%) patients underwent standard salvage chemotherapy. The composite outcome of LONIF or LOH requiring IVF resuscitation was significantly higher in patients previously treated with ICIs compared with those who received standard non-ICI salvage chemotherapy (78% vs. 33%; P = .022). The differences between the median LOS and time to neutrophil engraftment were not statistically significant (P = .94 and P = .083, respectively). All LONIF patients received systemic corticosteroids with symptom resolution. CONCLUSION: The composite outcome of LONIF or LOH requiring IVF resuscitation was significantly higher in patients who received prior ICI salvage therapy. LOS and time to neutrophil engraftment were not affected by prior ICI therapy. Early institution of steroids may prevent the evolution of additional sequelae associated with engraftment or engraftment-like syndrome that can complicate ASCT.

Pomalidomide desensitization for hypersensitivity: A case report.

INTRODUCTION: Pomalidomide is an immunomodulating agent that is used to treat relapsed and/or refractory multiple myeloma. Although the incidence of hypersensitivity with pomalidomide is not well documented, the most common type of hypersensitivity involves a cutaneous reaction. Previous reports have successfully utilized a desensitization protocol in patients who developed hypersensitivity to pomalidomide. Here we describe a case of a patient who developed urticaria on pomalidomide and successfully underwent a desensitization using the previously reported method in a case report. CASE REPORT: A 68-year-old woman with relapsed multiple myeloma and no known drug allergies developed urticaria a day after taking the first dose of pomalidomide. MANAGEMENT AND OUTCOME: The patient underwent a 10-step desensitization process in the medical intensive care unit without any reported adverse events. The following day in the medical intensive care unit, the patient was able to tolerate a full dose of pomalidomide with no further reactions and was discharged with instructions to take a full dose of pomalidomide daily for 21 days out of a 28-day cycle. The patient was followed up in the outpatient clinic and noted no further reactions from pomalidomide at the three-month visit. DISCUSSION: The 10-step desensitization protocol with pomalidomide was well tolerated in the patient with hypersensitivity to pomalidomide. Whether this approach would work in patients with more severe reactions such as anaphylaxis and angioedema is still unknown.

Acupuncture therapies for chronic obstructive pulmonary disease: a systematic review of randomized, controlled trials.

CONTEXT: Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality and is projected to be the third leading cause of death by 2030. Acupuncture, a traditional Chinese therapy, has been used for more than 2000 years to treat respiratory conditions and may treat COPD effectively. In previous literature reviews, researchers have noted significant heterogeneity among the included studies, and none of the reviewers found convincing evidence to recommend routine use of acupuncture therapies for COPD. OBJECTIVE: This literature review examined the efficacy and safety of acupuncture therapies for patients with COPD in improving lung function, increasing exercise capacity, creating positive subjective changes in symptoms, and enhancing health-related quality of life (QoL). DESIGN: The research team searched the following electronic databases from inception to April 2013: PubMed, the Cochrane Central Register of Controlled Trials (CENTRAL), the Cumulative Index to Nursing and Allied Health Literature (CINAHL), the Allied and Complementary Medicine Database (AMED), Embase (Elsevier), the China National Knowledge Infrastructure (CNKI), Chongqing VIP Information Company (CQVIP), the Chinese Biomedical Literature Database (CBM), and Wanfang Data. The review included randomized, controlled trials (RCTs) that examined the benefits of acupuncture or other related therapies for treatment of COPD. Data were extracted into a predefined form; risk of bias was assessed according to the Cochrane Risk of Bias tool; and statistical analyses were made. RESULTS: In total, 16 studies were included in the review. The research team found that the acupuncture therapies used in these studies improved health-related QoL. The team's conclusions, comparing results from the interventions with placebo, were based on data from 3 questionnaires that the studies used: (1) the St George's Respiratory Questionnaire (SGRQ), with a mean difference (MD) of -8.33 units (95% CI, -13.13 to -3.53); (2) dyspnea on the Medical Research Council's (MRC's) dyspnea scale, with an MD of -0.34 units (95% CI, -0.38 to -0.30); and (3) the Dyspnea Visual Analogue Scale (DVAS), with an MD of -8.85 mm (95% CI, -11.81 to -5.89). Compared with placebo, acupuncture therapies also increased the distance walked in 6 min (6MWT), with an MD of -28.14 (95% CI, 23.92 to 32.36) compared with placebo. No benefit was seen on measures of lung function when acupuncture therapies were compared with either placebo or drug therapy. CONCLUSION: Acupuncture therapies may result in clinically important improvements in QoL and dyspnea. Future high-quality RCTs should be undertaken to provide conclusive evidence concerning the benefits of acupuncture therapies in the treatment of COPD.

Interactions of antimicrobial compounds with cross-linking agents of alginate dressings.

OBJECTIVES: The aim of this study was to investigate the antimicrobial activities of calcium ions and other cross-linking agents of alginate dressings, as well as their compatibility with commonly used topical antimicrobials. METHODS: The antimicrobial activities of cross-linking agents and antimicrobials (five antibiotics and four antiseptics) were evaluated by the broth dilution method. The interactions between individual cross-linking agents and antimicrobials were evaluated using the chequerboard test against common skin pathogens, Staphylococcus aureus and Pseudomonas aeruginosa. RESULTS: From the MIC determined, antibiotics were the most active, followed by the antiseptics and cross-linking agents. Calcium ions, which are commonly used to cross-link alginate, exhibited very weak antimicrobial activity and higher fractional inhibitory concentration than the other cross-linking agents. The use of calcium and gentamicin resulted in antagonism against S. aureus. In contrast, aluminium, zinc and copper ions exhibited higher antimicrobial activities but insignificant interactions with the antimicrobials. CONCLUSIONS: Commonly used topical antimicrobials that are active against the skin pathogens S. aureus and P. aeruginosa could be potentially incompatible with calcium alginate dressings. Copper, zinc and aluminium ions are more suitable cross-linking agents for alginate as they do not show antagonism with the antimicrobials and could impart antimicrobial property to the resultant dressing.