Inhibition of Phosphoinositide 3-Kinase p110delta Does Not Affect T Cell Driven Development of Type 1 Diabetes Despite Significant Effects on Cytokine Production.

Type 1 diabetes is caused by the destruction of insulin producing beta cells by the immune system. The p110δ isoform of PI3K is expressed primarily in cells of haematopoietic origin and the catalytic activity of p110δ is important for the activation of these cells. Targeting of this pathway offers an opportunity to reduce immune cell activity without unwanted side effects. We have explored the effects of a specific p110δ isoform inhibitor, IC87114, on diabetogenic T cells both in vitro and in vivo, and find that although pharmacological inhibition of p110δ has a considerable impact on the production of pro-inflammatory cytokines, it does not delay the onset of diabetes after adoptive transfer of diabetogenic cells. Further, we demonstrate that combination treatment with CTLA4-Ig does not improve the efficacy of treatment, but instead attenuates the protective effects seen with CTLA4-Ig treatment alone. Our results suggest that decreased IL-10 production by Foxp3+ CD4+ T cells in the presence of IC87114 negates individual anti-inflammatory effects of IC8114 and CTLA4-Ig.This work was supported by Grant number 09/0003840, Diabetes UK https://www.diabetes.org.uk/ (MW); Grant number 5-2006-229, Juvenile Diabetes Research Foundation https://www.jdrf.org.uk/ (KO); Grant number BBS/E/B/0000C236 Biotechnology and Biological Sciences Research Council (KO); Grant number health-f5-2009-241883 European Research Council 7th Frame Programme http://ec.europa.eu/research/fp7/index_en.cfm (AC); and Grant number 02BX12ACYD, the Britain Israel Research and Academic Exchange Partnership (BIRAX) http://www.britishcouncil.org.il/en/programmes/science/birax.This is the final version of the article. It first appeared from PLOS via http://dx.doi.org/10.1371/journal.pone.014651

The transcriptional coactivator MAML1 regulates p300 autoacetylation and HAT activity

MAML1 is a transcriptional coregulator originally identified as a Notch coactivator. MAML1 is also reported to interact with other coregulator proteins, such as CDK8 and p300, to modulate the activity of Notch. We, and others, previously showed that MAML1 recruits p300 to Notch-regulated genes through direct interactions with the DNA–CSL–Notch complex and p300. MAML1 interacts with the C/H3 domain of p300, and the p300–MAML1 complex specifically acetylates lysines of histone H3 and H4 tails in chromatin in vitro. In this report, we show that MAML1 potentiates p300 autoacetylation and p300 transcriptional activation. MAML1 directly enhances p300 HAT activity, and this coincides with the translocation of MAML1, p300 and acetylated histones to nuclear bodies

Feasibility of a self-help web-based intervention targeting young cancer patients with sexual problems and fertility distress

PURPOSE: The purpose of the study is to evaluate the feasibility of a self-help web-based intervention to alleviate sexual problems and fertility distress in adolescents and young adults with cancer. METHODS: Twenty-three persons with cancer (19 women and 4 men, age 18-43, 1-5 years post-diagnosis of lymphoma, breast, gynecologic, central nervous system, or testicular cancer) were recruited to test a 2-month web-based program targeting sexual problems or fertility distress. The programs were organized in modules with educational and behavior change content, including texts, illustrations, exercises, and video vignettes. The program also included a discussion forum and an "ask the expert" forum. In addition, the sexuality program offered two telephone consultations. Feasibility (regarding demand, acceptability, preliminary efficacy, and functionality) was evaluated with the website system data, telephone interviews, continuous online evaluations, and study-specific measures. RESULTS: Fifteen participants completed four modules or more. Most of the program features were used and well accepted by these "committed users." The web-based format enabled flexible use by participants with diverse needs. Preliminary efficacy was indicated by self-reported increased knowledge and skill in handling sexual problems and fertility distress. The website was easy to use and functioned well technically. CONCLUSIONS: The present study indicated that this web-based intervention was feasible for adolescents and young adults with cancer. The effectiveness of the intervention in decreasing sexual problems and fertility distress will be tested in a population-based randomized controlled trial for adolescents and young adults with cancer. TRIAL REGISTRATION: ISRCTN36621459

Regulation of Skeletal Muscle Glucose Transport and Glucose Metabolism by Exercise Training

Aerobic exercise training and resistance exercise training are both well-known for their ability to improve human health; especially in individuals with type 2 diabetes. However, there are critical differences between these two main forms of exercise training and the adaptations that they induce in the body that may account for their beneficial effects. This article reviews the literature and highlights key gaps in our current understanding of the effects of aerobic and resistance exercise training on the regulation of systemic glucose homeostasis, skeletal muscle glucose transport and skeletal muscle glucose metabolism

Hubungan Asupan Protein, Seng, Zat Besi, Dan Riwayat Penyakit Infeksi Dengan Z-score Tb/u Pada Balita

Latar Belakang : Masalah gizi yang paling banyak ditemukan pada anak di Indonesia adalah stunting, Indikator untuk menilai stunting berdasarkan pada Indeks Tinggi Badan menurut Umur (TB/U) dengan ambang batas (Z-score) <-2 Standart Deviasi (SD). Several micronutrients are required for adequate growth among children. However, it has been unclear as to which nutrient deficiencies contribute most often to growth faltering in populations at risk for poor nutrition and poor growth. Inadequate intakes of dietary energy and protein and frequent infections are well-known causes of growth retardation (3–5). However, the role of specific micronutrient deficiencies in the etiology of growth retardation has gained attention more recently (6–8). Tujuan : Mengetahui hubungan antara asupan protein, seng, zat besi, dan penyakit infeksi terhadap indeks z-score TB/U pada Balita usia 24-59 bulan.Metode : Penelitian observasional dengan pendekatan cross sectional di Kelurahan Jangli Semarang, jumlah sampel 61 Balita usia 24-59 bulan, dipilih dengan simple random sampling. Data yang dikumpulkan meliputi: identitas sampel, berat badan, tinggi badan, riwayat asupan makan, dan riwayat penyakit infeksi. Berat badan diukur menggunakan timbangan digital dan tinggi badan diukur menggunakan microtoise. Asupan protein, seng, zat besi, dan riwayat penyakit infeksi diperoleh dari food frequency questionairre semi-kuantitatif. Data dianalisis dengan uji analisis depskripsi, analisis bivariate menggunakan uji Chi Square, Pearson, dan Spearman.Hasil : Sebanyak 36,1 subjek mengalami stunting. Rerata z-score TB/U -1,25 ± 1,2. Rerata asupan protein, seng, dan zat besi subjek berturut-turut 34.8 ± 13 g, 5.2 ± 2.5 mg, 8.2 ± 6.5 mg dengan sebagian besar tingkat kecukupan protein, seng, dan zat besi subjek adalah cukup. Sebanyak 29.1% subjek memiliki riwayat infeksi. Terdapat hubungan antara protein dan penyakit infeksi dengan z-score TB/U pada Balita. Tidak terdapat hubungan antara asupan seng, dan zat besi dengan z-score TB/U pada Balita. Simpulan : Terdapat hubungan antara asupan protein dan riwayat penyakit infeksi terhadap indeks z-score TB/U pada Balita

GSK3β is a negative regulator of the transcriptional coactivator MAML1

Glycogen synthase kinase 3β (GSK3β) is involved in several cellular signaling systems through regulation of the activity of diverse transcription factors such as Notch, p53 and β-catenin. Mastermind-like 1 (MAML1) was originally identified as a Notch coactivator, but has also been reported to function as a transcriptional coregulator of p53, β-catenin and MEF2C. In this report, we show that active GSK3β directly interacts with the MAML1 N-terminus and decreases MAML1 transcriptional activity, suggesting that GSK3β might target a coactivator in its regulation of gene expression. We have previously shown that MAML1 increases global acetylation of histones, and here we show that the GSK3 inhibitor SB41, further enhances MAML1-dependent histone acetylation in cells. Finally, MAML1 translocates GSK3β to nuclear bodies; this function requires full-length MAML1 protein

Installing oncofertility programs for breast cancer in limited versus optimum resource settings: Empirical data from 39 surveyed centers in Repro-Can-OPEN Study Part I & II

Purpose: As a further step to elucidate the actual diverse spectrum of oncofertility practices for breast cancer around the globe, we present and discuss the comparisons of oncofertility practices for breast cancer in limited versus optimum resource settings based on data collected in the Repro-Can-OPEN Study Part I & II. Methods: We surveyed 39 oncofertility centers including 14 in limited resource settings from Africa, Asia & Latin America (Repro-Can-OPEN Study Part I), and 25 in optimum resource settings from the United States, Europe, Australia and Japan (Repro-Can-OPEN Study Part II). Survey questions covered the availability of fertility preservation and restoration options offered to young female patients with breast cancer as well as the degree of utilization. Results: In the Repro-Can-OPEN Study Part I & II, responses for breast cancer and calculated oncofertility scores showed the following characteristics: (1) higher oncofertility scores in optimum resource settings than in limited resource settings especially for established options, (2) frequent utilization of egg freezing, embryo freezing, ovarian tissue freezing, GnRH analogs, and fractionation of chemo- and radiotherapy, (3) promising utilization of oocyte in vitro maturation (IVM), (4) rare utilization of neoadjuvant cytoprotective pharmacotherapy, artificial ovary, and stem cells reproductive technology as they are still in preclinical or early clinical research settings, (5) recognition that technical and ethical concerns should be considered when offering advanced and innovative oncofertility options. Conclusions: We presented a plausible oncofertility best practice model to guide oncofertility teams in optimizing care for breast cancer patients in various resource settings

Non-muscle Myosin II reactivation and cytoskeletal remodelling as a new vulnerability in therapy-resistant melanoma

Trabajo presentado en el 3rd ASEICA Educational Symposium, celebrado en modalidad virtual del 23 al 25 de noviembre de 2021.MAPK-targeted therapies (MAPKi) and immune checkpoint blockers (ICB) improve survival of subsets of melanoma patients. However, therapy resistance is a persistent problem. Cross-resistance to MAPKi and ICB may be driven by common transcriptomic alterations in pathways controlling invasion and metastasis. Using phosphoproteomic and transcriptomic analyses, we find that adaptation to treatment and acquisition of resistance to MAPKi involve cytoskeletal remodelling and changes in levels in the ROCK-non-muscle Myosin II (NMII) pathway, which is essential for cancer invasion and metastasis. NMII activity is decreased shortly after MAPK is blocked. However, persister cells promptly restore NMII activity to increase survival, and this becomes a vulnerability, since survival of MAPKi- and ICB-resistant cells is highly dependent on ROCK-NMII. Efficacy of MAPKi and ICB can be improved by combination with ROCK inhibitors, which have a dual action by impairing melanoma cell survival (through induction of lethal reactive oxygen species and unresolved DNA damage) and reducing myeloid- and lymphoid-driven immunosuppression, ultimately overcoming cross-resistance in vivo. In human tumours, high ROCK-NMII levels identify MAPKi-, ICB-resistant melanomas, and treatment-naïve melanomas with worse prognosis. Therefore, a subset of MAPKi- and ICB-resistant melanomas is more susceptible to ROCK-NMII blockade, suggesting clinical opportunities for combination therapies