The Effectiveness of Clinician-Led Community-Based Group Exercise Interventions on Health Outcomes in Adults with Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis.

This systematic review and meta-analysis evaluated the combined effects of clinician-led and community-based group exercise interventions on a range of health outcomes in adults with type 2 diabetes mellitus. Our literature search spanned Medline, Scopus, PubMed, Embase, and CINAHL databases, focusing on peer-reviewed studies published between January 2003 and January 2023. We included studies involving participants aged 18 years and older and articles published in English, resulting in a dataset of eight studies with 938 participants. Spanning eight peer-reviewed studies with 938 participants, the analysis focused on the interventions' impact on glycemic control, physical fitness, and anthropometric and hematological measurements. Outcomes related to physical fitness, assessed through the six-minute walk test, the 30 s sit-to-stand test, and the chair sit-and-reach test, were extracted from five studies, all of which reported improvements. Anthropometric outcomes from seven studies highlighted positive changes in waist circumference and diastolic blood pressure; however, measures such as body mass index, systolic blood pressure, weight, and resting heart rate did not exhibit significant changes. Hematological outcomes, reviewed in four studies, showed significant improvements in fasting blood glucose, triglycerides, and total cholesterol, with glycemic control evidenced by reductions in HbA1c levels, yet LDL and HDL cholesterol levels remained unaffected. Ten of the fifteen outcome measures assessed showed significant enhancement, indicating that the intervention strategies implemented may offer substantial health benefits for managing key type 2 diabetes mellitus-related health parameters. These findings in combination with further research, could inform the refinement of physical activity guidelines for individuals with type 2 diabetes mellitus, advocating for supervised group exercise in community settings.

The Effect of Community-Based Exercise on Health Outcomes for Indigenous Peoples with Type 2 Diabetes: A Systematic Review.

Indigenous peoples globally experience a high burden of type 2 diabetes in comparison to non-Indigenous peoples. While community-based exercise interventions designed for type 2 diabetes (T2D) management have garnered success in non-Indigenous populations, they likely require adjustments to meet the needs of Indigenous people. This systematic review aims to determine if health outcomes in Indigenous peoples with T2D could be improved by community-based exercise programmes and the features of those programmes that best meet their needs. The CINAHL, Embase, Informit Indigenous Collection, Medline, PubMed, Scopus, SportDiscus, and Web of Science databases have been searched to identify peer-reviewed literature with original outcome data that report on the health effects of community-based exercise interventions for the management of T2D among Indigenous peoples. The Mixed Methods Appraisal Tool and Indigenous Community Engagement Tool were implemented to assess methodological quality. Three moderate-to-high-quality studies were selected for review, including participants of Polynesian or Native American Zuni Indian descent. Results indicated positive effects of group exercise on glycated haemoglobin (HbA1c), body mass index, body weight, total cholesterol, blood pressure, quality of life, and patient activation levels in high-adhering participants. This review concludes that community-based exercise interventions may improve health outcomes for Indigenous adults with T2D when conducted with strong community engagement.

Characterizing Ventilatory Muscle Dysfunction in Inclusion Body Myositis.

OBJECTIVE: Investigation of the frequency and progression of ventilatory muscle dysfunction in patients with inclusion body myositis, the most common myopathy after age of 50 yrs. Prior research is limited to case series and cross-section studies. DESIGN: This is a retrospective review of pulmonary function tests, respiratory symptoms, and muscle strength testing. RESULTS: Of the 54 patients reviewed (mean age: 65 ± 9 yrs and disease duration: 7 ± 7 yrs), the majority ( n = 32, 59%) had restrictive forced vital capacity deficits at initial visit. Patients with reduced forced vital capacity showed higher prevalence of respiratory symptoms; but age, body mass index, and limb strength were similar when compared with patients without restrictive forced vital capacity. Mean rate of forced vital capacity decline of 0.108 l/yr in inclusion body myositis patients. Lower baseline limb strength correlated with longer disease duration and future forced vital capacity decline (eg, weaker patients experienced faster decline). CONCLUSIONS: Based on forced vital capacity, there is a high frequency of ventilatory pump muscle weakness in inclusion body myositis, which is associated with a higher burden of respiratory symptoms. Baseline strength may indicate risk of respiratory decline and need for vigilant screening. Importantly, ventilatory and limb muscle decline may not progress in a corresponding manner, highlighting the importance of pulmonary function surveillance.

Targeting Ribonucleotide Reductase Induces Synthetic Lethality in PP2A-Deficient Uterine Serous Carcinoma.

Uterine serous carcinoma (USC) is a highly aggressive endometrial cancer subtype with limited therapeutic options and a lack of targeted therapies. While mutations to PPP2R1A, which encodes the predominant protein phosphatase 2A (PP2A) scaffolding protein Aα, occur in 30% to 40% of USC cases, the clinical actionability of these mutations has not been studied. Using a high-throughput screening approach, we showed that mutations in Aα results in synthetic lethality following treatment with inhibitors of ribonucleotide reductase (RNR). In vivo, multiple models of Aα mutant uterine serous tumors were sensitive to clofarabine, an RNR inhibitor (RNRi). Aα-mutant cells displayed impaired checkpoint signaling upon RNRi treatment and subsequently accumulated more DNA damage than wild-type (WT) cells. Consistently, inhibition of PP2A activity using LB-100, a catalytic inhibitor, sensitized WT USC cells to RNRi. Analysis of The Cancer Genome Atlas data indicated that inactivation of PP2A, through loss of PP2A subunit expression, was prevalent in USC, with 88% of patients with USC harboring loss of at least one PP2A gene. In contrast, loss of PP2A subunit expression was rare in uterine endometrioid carcinomas. While RNRi are not routinely used for uterine cancers, a retrospective analysis of patients treated with gemcitabine as a second- or later-line therapy revealed a trend for improved outcomes in patients with USC treated with RNRi gemcitabine compared with patients with endometrioid histology. Overall, our data provide experimental evidence to support the use of ribonucleotide reductase inhibitors for the treatment of USC. SIGNIFICANCE: A drug repurposing screen identifies synthetic lethal interactions in PP2A-deficient uterine serous carcinoma, providing potential therapeutic avenues for treating this deadly endometrial cancer.

The SRG rat, a Sprague-Dawley Rag2/Il2rg double-knockout validated for human tumor oncology studies.

We have created the immunodeficient SRG rat, a Sprague-Dawley Rag2/Il2rg double knockout that lacks mature B cells, T cells, and circulating NK cells. This model has been tested and validated for use in oncology (SRG OncoRat®). The SRG rat demonstrates efficient tumor take rates and growth kinetics with different human cancer cell lines and PDXs. Although multiple immunodeficient rodent strains are available, some important human cancer cell lines exhibit poor tumor growth and high variability in those models. The VCaP prostate cancer model is one such cell line that engrafts unreliably and grows irregularly in existing models but displays over 90% engraftment rate in the SRG rat with uniform growth kinetics. Since rats can support much larger tumors than mice, the SRG rat is an attractive host for PDX establishment. Surgically resected NSCLC tissue from nine patients were implanted in SRG rats, seven of which engrafted and grew for an overall success rate of 78%. These developed into a large tumor volume, over 20,000 mm3 in the first passage, which would provide an ample source of tissue for characterization and/or subsequent passage into NSG mice for drug efficacy studies. Molecular characterization and histological analyses were performed for three PDX lines and showed high concordance between passages 1, 2 and 3 (P1, P2, P3), and the original patient sample. Our data suggest the SRG OncoRat is a valuable tool for establishing PDX banks and thus serves as an alternative to current PDX mouse models hindered by low engraftment rates, slow tumor growth kinetics, and multiple passages to develop adequate tissue banks.

Protein phosphatase 2A activation as a therapeutic strategy for managing MYC-driven cancers.

The tumor suppressor protein phosphatase 2A (PP2A) is a serine/threonine phosphatase whose activity is inhibited in most human cancers. One of the best-characterized PP2A substrates is MYC proto-oncogene basic helix-loop-helix transcription factor (MYC), whose overexpression is commonly associated with aggressive forms of this disease. PP2A directly dephosphorylates MYC, resulting in its degradation. To explore the therapeutic potential of direct PP2A activation in a diverse set of MYC-driven cancers, here we used biochemical assays, recombinant cell lines, gene expression analyses, and immunohistochemistry to evaluate a series of first-in-class small-molecule activators of PP2A (SMAPs) in Burkitt lymphoma, KRAS-driven non-small cell lung cancer, and triple-negative breast cancer. In all tested models of MYC-driven cancer, the SMAP treatment rapidly and persistently inhibited MYC expression through proteasome-mediated degradation, inhibition of MYC transcriptional activity, decreased cancer cell proliferation, and tumor growth inhibition. Importantly, we generated a series of cell lines expressing PP2A-dependent phosphodegron variants of MYC and demonstrated that the antitumorigenic activity of SMAPs depends on MYC degradation. Collectively, the findings presented here indicate a pharmacologically tractable approach to drive MYC degradation by using SMAPs for the management of a broad range of MYC-driven cancers.