المؤلفون: Casselini, Carolina M, Parson, Henri K, Frizzi, Katie E, Marquez, Alex, Smith, Darrell R, Guernsey, Lucie, Nemmani, Rakesh, Tayarani, Alireza, Jolivalt, Corinne G, Weaver, Jessica, Fernyhough, Paul, Vinik, Aaron I, Calcutt, Nigel A

المصدر: Acta Neuropathologica. 147(1)

مصطلحات موضوعية: Pharmacology and Pharmaceutical Sciences, Biomedical and Clinical Sciences, Neurosciences, Clinical Sciences, Neurodegenerative, Peripheral Neuropathy, Clinical Research, Chronic Pain, Diabetes, Clinical Trials and Supportive Activities, Pain Research, Development of treatments and therapeutic interventions, 6.1 Pharmaceuticals, 5.2 Cellular and gene therapies, Evaluation of treatments and therapeutic interventions, 5.1 Pharmaceuticals, Metabolic and endocrine, Neurological, Diabetic neuropathy, Epidermal nerve fibres, Muscarinic antagonist, Neuropathic pain, Oxybutynin, Randomized clinical trial, Animals, Humans, Mice, Rats, Diabetic Neuropathies, Diabetes Mellitus, Experimental, Diabetes Mellitus, Type 2, Mandelic Acids, Receptors, Muscarinic, Muscarinic Antagonists, Quality of Life, Adult, Diabetes Mellitus, Type 1, Neurology & Neurosurgery

الوصف: Preclinical studies indicate that diverse muscarinic receptor antagonists, acting via the M1 sub-type, promote neuritogenesis from sensory neurons in vitro and prevent and/or reverse both structural and functional indices of neuropathy in rodent models of diabetes. We sought to translate this as a potential therapeutic approach against structural and functional indices of diabetic neuropathy using oxybutynin, a muscarinic antagonist approved for clinical use against overactive bladder. Studies were performed using sensory neurons maintained in vitro, rodent models of type 1 or type 2 diabetes and human subjects with type 2 diabetes and confirmed neuropathy. Oxybutynin promoted significant neurite outgrowth in sensory neuron cultures derived from adult normal rats and STZ-diabetic mice, with maximal efficacy in the 1-100 nmol/l range. This was accompanied by a significantly enhanced mitochondrial energetic profile as reflected by increased basal and maximal respiration and spare respiratory capacity. Systemic (3-10 mg/kg/day s.c.) and topical (3% gel daily) oxybutynin reversed paw heat hypoalgesia in the STZ and db/db mouse models of diabetes and reversed paw tactile allodynia in STZ-diabetic rats. Loss of nerve profiles in the skin and cornea of db/db mice was also prevented by daily topical delivery of 3% oxybutynin for 8 weeks. A randomized, double-blind, placebo-controlled interventional trial was performed in subjects with type 2 diabetes and established peripheral neuropathy. Subjects received daily topical treatment with 3% oxybutynin gel or placebo for 6 months. The a priori designated primary endpoint, significant change in intra-epidermal nerve fibre density (IENFD) in skin biopsies taken before and after 20 weeks of treatments, was met by oxybutynin but not placebo. Secondary endpoints showing significant improvement with oxybutynin treatment included scores on clinical neuropathy, pain and quality of life scales. This proof-of-concept study indicates that muscarinic antagonists suitable for long-term use may offer a novel therapeutic opportunity for treatment of diabetic neuropathy. Trial registry number: NCT03050827.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/8jf8v1cqTest

المؤلفون: Devineni, Divya, Akbarpour, Meleeka, Gong, Yufan, Wong, Nathan

المصدر: Cardiovascular Drugs and Therapy. 38(2)

مصطلحات موضوعية: Cardiovascular risk, Diabetes, GLP-1 receptor agonists, SGLT2-inhibitors, Adult, Male, Humans, Glycemic Control, Precision Medicine, Cardiovascular Diseases, Sodium-Glucose Transporter 2, Risk Factors, Population Health, Diabetes Mellitus, Heart Disease Risk Factors, Atherosclerosis, Glucagon-Like Peptide 1, Glucose, Diabetes Mellitus, Type 2, Glucagon-Like Peptide-1 Receptor, Hypoglycemic Agents

الوصف: PURPOSE: Data are limited on sodium glucose co-transport 2 inhibitors (SGLT2-is) and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) among real-world cohorts of underrepresented patients. We examined these therapies and glycemic control in US adults with diabetes mellitus (DM) by atherosclerotic cardiovascular disease (ASCVD) risk and sociodemographic factors. METHODS: In the NIH Precision Medicine Initiative All of Us Research Program, we categorized DM as (1) moderate risk, (2) high risk, and (3) with ASCVD. We examined proportions on DM therapies, including SGLT2-i or GLP-1 RA, and at glycemic control by sociodemographic factors and CVD risk groups. RESULTS: Our 81,332 adults aged ≥ 18 years with DM across 340 US sites included 22.3% non-Hispanic Black, 17.2% Hispanic, and 1.8% Asian participants; 31.1%, 30.3%, and 38.6% were at moderate risk, high risk, or with ASCVD, respectively. Those with DM and ASCVD were most likely on SGLT2-i (8.6%) or GLP-1 RA (11.9%). SGLT2-i use was

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/4qr8161gTest

المؤلفون: Faggionato, Edoardo, Schiavon, Michele, Ekhlaspour, Laya, Buckingham, Bruce, Dalla Man, Chiara

المصدر: IEEE Transactions on Biomedical Engineering. 71(3)

مصطلحات موضوعية: Humans, Adult, Middle Aged, Glucose, Diabetes Mellitus, Type 1, Insulin Resistance, Blood Glucose, Blood Glucose Self-Monitoring, Bayes Theorem, Insulin, Hypoglycemic Agents

الوصف: OBJECTIVE: Modeling the effect of meal composition on glucose excursion would help in designing decision support systems (DSS) for type 1 diabetes (T1D) management. In fact, macronutrients differently affect post-prandial gastric retention (GR), rate of appearance (R[Formula: see text]), and insulin sensitivity (S[Formula: see text]). Such variables can be estimated, in inpatient settings, from plasma glucose (G) and insulin (I) data using the Oral glucose Minimal Model (OMM) coupled with a physiological model of glucose transit through the gastrointestinal tract (reference OMM, R-OMM). Here, we present a model able to estimate those quantities in daily-life conditions, using minimally-invasive (MI) technologies, and validate it against the R-OMM. METHODS: Forty-seven individuals with T1D (weight =78±13 kg, age =42±10 yr) underwent three 23-hour visits, during which G and I were frequently sampled while wearing continuous glucose monitoring (CGM) and insulin pump (IP). Using a Bayesian Maximum A Posteriori estimator, R-OMM was identified from plasma G and I measurements, and MI-OMM was identified from CGM and IP data. RESULTS: The MI-OMM fitted the CGM data well and provided precise parameter estimates. GR and R[Formula: see text] model parameters were not significantly different using the MI-OMM and R-OMM (p 0.05) and the correlation between the two S[Formula: see text] was satisfactory ( ρ =0.77). CONCLUSION: The MI-OMM is usable to estimate GR, R[Formula: see text], and S[Formula: see text] from data collected in real-life conditions with minimally-invasive technologies. SIGNIFICANCE: Applying MI-OMM to datasets where meal compositions are available will allow modeling the effect of each macronutrient on GR, R[Formula: see text], and S[Formula: see text]. DSS could finally exploit this information to improve diabetes management.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/4zm3c05sTest

المؤلفون: Patel, Sandip, Alonso-Gordoa, Teresa, Banerjee, Susana, Wang, Ding, Naidoo, Jarushka, Standifer, Nathan, Palmer, Doug, Cheng, Lin-Yang, Kourtesis, Panagiotis, Ascierto, Maria, Das, Mayukh, Diamond, Jennifer, Hellmann, Matthew, Carneiro, Benedito

المصدر: Journal for ImmunoTherapy of Cancer. 12(2)

مصطلحات موضوعية: Adaptive Immunity, Immunity, Innate, Natural Killer T-Cells, Programmed Cell Death 1 Receptor, Tumor Microenvironment, Female, Humans, Adolescent, Adult, Carcinoma, Non-Small-Cell Lung, Ligands, Lung Neoplasms, Tumor Microenvironment, Antibodies, Monoclonal, Antibodies, Monoclonal, Humanized

الوصف: BACKGROUND: The combination of monalizumab (anti-NKG2A/CD94) and durvalumab (anti-programmed death ligand-1) may promote antitumor immunity by targeting innate and adaptive immunity. This phase 1/2 study of monalizumab and durvalumab evaluated safety, antitumor activity, and pharmacodynamics in patients with advanced solid tumors. MAIN BODY: Immunotherapy-naïve patients aged ≥18 years with advanced disease, Eastern Cooperative Oncology Group performance status of 0-1, and 1-3 prior lines of systemic therapy in the recurrent/metastatic setting were enrolled. In part 1 (dose escalation), patients received durvalumab 1500 mg every 4 weeks (Q4W) with increasing doses of monalizumab Q2W/Q4W (n=15). Dose expansion in part 1 included patients with cervical cancer (n=15; durvalumab 1500 mg Q4W and monalizumab 750 mg Q2W) or metastatic microsatellite stable (MSS)-colorectal cancer (CRC) (n=15; durvalumab 1500 mg Q4W and monalizumab 750 mg Q4W). In part 2 (dose expansion), patients with MSS-CRC (n=40), non-small cell lung cancer (NSCLC; n=20), MSS-endometrial cancer (n=40), or ovarian cancer (n=40) received durvalumab 1500 mg Q4W and monalizumab 750 mg Q2W. The primary endpoint was safety. Secondary endpoints included antitumor activity per Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1). Exploratory analyses included assessment of T-cell and natural killer (NK) cell activation and proliferation in peripheral blood and the tumor microenvironment (TME). The study enrolled 185 patients (part 1, 45; part 2, 140). No dose-limiting toxicities were observed and the maximum tolerated dose was not reached. In part 2, the most common treatment-related adverse events were fatigue (12.1%), asthenia (9.3%), diarrhea (9.3%), pruritus (7.9%), and pyrexia (7.1%). In the expansion cohorts, response rates were 0% (cervical), 7.7% (MSS-CRC), 10% (NSCLC), 5.4% (ovarian), and 0% (MSS-endometrial). Sustained NK cell activation, CD8+ T-cell proliferation, increased serum levels of CXCL10 (C-X-C motif chemokine ligand 10) and CXCL11, and increased tumor infiltration of CD8+ and granzyme B+ cells were observed. CONCLUSIONS: Although efficacy was modest, monalizumab plus durvalumab was well tolerated and encouraging immune activation was observed in the peripheral blood and TME. TRIAL REGISTRATION NUMBER: NCT02671435.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/2888m63bTest

المؤلفون: Jiang, Wei, De Belly, Henry, Wang, Bingying, Wong, Andrew, Kim, Minseo, Oh, Fiona, DeGeorge, Jason, Huang, Xinya, Guang, Shouhong, Weiner, Orion, Ma, Dengke

المصدر: Science Advances. 10(4)

مصطلحات موضوعية: Adult, Humans, Animals, Longevity, Thrombospondin 1, Adverse Childhood Experiences, Caenorhabditis elegans, Resilience, Psychological, Tetraspanins, Transcription Factors, Caenorhabditis elegans Proteins, Histone Acetyltransferases

الوصف: Early-life stress experiences can produce lasting impacts on organismal adaptation and fitness. How transient stress elicits memory-like physiological effects is largely unknown. Here, we show that early-life thermal stress strongly up-regulates tsp-1, a gene encoding the conserved transmembrane tetraspanin in C. elegans. TSP-1 forms prominent multimers and stable web-like structures critical for membrane barrier functions in adults and during aging. Increased TSP-1 abundance persists even after transient early-life heat stress. Such regulation requires CBP-1, a histone acetyltransferase that facilitates initial tsp-1 transcription. Tetraspanin webs form regular membrane structures and mediate resilience-promoting effects of early-life thermal stress. Gain-of-function TSP-1 confers marked C. elegans longevity extension and thermal resilience in human cells. Together, our results reveal a cellular mechanism by which early-life thermal stress produces long-lasting memory-like impact on organismal resilience and longevity.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/5fw4s85pTest

المؤلفون: Cardona-Hernandez, Roque, Dôvc, Klemen, Biester, Torben, Macedoni, Maddalena, Tauschmann, Martin, Mameli, Chiara, Ekhlaspour, Laya

مصطلحات موضوعية: Automated insulin delivery, Children, Technology, Time in range, Type 1 diabetes, Youths, Young Adult, Humans, Adolescent, Child, Adult, Diabetes Mellitus, Type 1, Hypoglycemic Agents, Glycemic Control, Blood Glucose Self-Monitoring, Blood Glucose, Insulin, Insulin Infusion Systems

الوصف: Type 1 diabetes (T1D) is the most frequent form of diabetes in pediatric age, affecting more than 1.5 million people younger than age 20 years worldwide. Early and intensive control of diabetes provides continued protection against both microvascular and macrovascular complications, enhances growth, and ensures normal pubertal development. In the absence of definitive reversal therapy for this disease, achieving and maintaining the recommended glycemic targets is crucial. In the last 30 years, enormous progress has been made using technology to better treat T1D. In spite of this progress, the majority of children, adolescents and young adults do not reach the recommended targets for glycemic control and assume a considerable burden each day. The development of promising new therapeutic advances, such as more physiologic insulin analogues, pioneering diabetes technology including continuous glucose monitoring and closed loop systems as well as new adjuvant drugs, anticipate a new paradigm in T1D management over the next few years. This review presents insights into current management of T1D in youths.

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الوصول الحر: https://escholarship.org/uc/item/7s31w37tTest

المؤلفون: Sińska, Beata I.¹ (AUTHOR) alicja.kucharska@wum.edu.pl, Rzońca, Ewa² (AUTHOR) erzonca@wum.edu.pl, Kucharska, Alicja¹ (AUTHOR) iwona.traczyk@wum.edu.pl, Gałązkowski, Robert³ (AUTHOR) robert.galazkowski@wum.edu.pl, Traczyk, Iwona¹ (AUTHOR), Rzońca, Patryk⁴ (AUTHOR) patryk.rzonca@wum.edu.pl

المصدر: European Journal of Investigation in Health, Psychology & Education (EJIHPE). Oct2023, Vol. 13 Issue 10, p2035-2045. 11p.

مصطلحات موضوعية: *GLYCOSYLATED hemoglobin, *TYPE 1 diabetes, *GLYCEMIC control, *DIABETES, *ADULTS, *COMPULSIVE eating

مستخلص: Numerous complications of type 1 diabetes (T1D) may be prevented through suitable glycemic control. Glycated hemoglobin (HbA1c) may be one of the markers for the early detection of the metabolic imbalance characteristic of the disease. However, optimal control of diabetes is not achieved in a large group of patients. It was demonstrated that numerous factors (sociodemographic, psychological, and clinical) contributed to this condition. The aim of the study was to identify factors influencing the control of diabetes measured via glycated hemoglobin concentrations in people with T1D. Independent factors influencing better diabetes control measured via HbA1c in the study group included higher disease acceptance, higher nutritional adherence, lower BMI, and a lower risk of eating disorders. Describing the determinants will allow for the improvement of the system of care provided to people with T1D and for it to comprise important psychological variables related to self-care and acceptance of the disease. [ABSTRACT FROM AUTHOR]

المؤلفون: Berg, Cynthia, Munion, Ascher, Loyola, Maria, Mello, Daniel, Butner, Jonathan, Suchy, Yana, Marino, Jessica, Wiebe, Deborah

المصدر: Annals of Behavioral Medicine. 57(8)

مصطلحات موضوعية: Daily diary, Diabetes self-management, Emerging adulthood, Executive functioning, Self-regulation, Type 1 diabetes, Humans, Female, Adult, Male, Diabetes Mellitus, Type 1, Executive Function, Self Report, Self-Control

الوصف: BACKGROUND: Executive functioning (EF) predicts better Type 1 diabetes (T1D) management in the high-risk years after high school, but the daily self-regulation processes involved are unclear. PURPOSE: To examine whether EF is associated with daily self-regulation that minimizes ones exposure or buffers adverse reactions to daily diabetes problems, and to determine whether these patterns become stronger during the transition out of high school. METHODS: A measurement burst design with convenience sampling was used. Seniors in high school with T1D (N = 207; 66% female) completed self-report (i.e., Behavioral Rating Inventory of Executive Functioning) and performance measures of EF (i.e., Delis-Kaplan Executive Function System). A 14-day daily diary assessing self-regulation failures, diabetes problems, affect, and indicators of diabetes management was completed at baseline and 1 year later. RESULTS: Correlations and multilevel modeling were conducted. Lower self-reported EF problems were associated with lower average levels of daily self-regulation failures, and these variables were associated with fewer daily diabetes problems. In contrast, better EF performance was unrelated to average daily self-regulation failures, and was unexpectedly associated with more frequent diabetes problems in year 2. Equally across years, on days participants reported lower than their average levels of daily self-regulation failures, they had fewer diabetes problems, regardless of EF. On days with lower than average diabetes problems, participants reported better diabetes management indicators. EF generally did not buffer daily associations in either year. CONCLUSIONS: Regardless of EF, promoting daily self-regulation may prevent diabetes problems and promote T1D management in daily life at this high-risk transitional time.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/03f4h7d5Test

المؤلفون: Ly, Ina, Romo, Carlos G, Gottesman, Sally, Kelly, Kristen M, Kornacki, Deanna, York, Zachary, Lee, Sang Y, Rhodes, Steven D, Staedtke, Verena, Steensma, Matthew R, Blakeley, Jaishri O, Wolkenstein, Pierre

المصدر: The Journal of investigative dermatology. 143(8)

مصطلحات موضوعية: Humans, Neurofibroma, Neurofibromatosis 1, Skin Neoplasms, Pruritus, Quality of Life, Adult, Clinical Trials and Supportive Activities, Clinical Research, Cancer, Rare Diseases, Clinical Sciences, Oncology and Carcinogenesis, Dermatology & Venereal Diseases

الوصف: Cutaneous neurofibromas (cNFs) are benign tumors of the skin that affect >95% of adults with neurofibromatosis type 1. Despite their benign histology, cNFs can significantly impact QOL due to disfigurement, pain, and pruritus. There are no approved therapies for cNFs. Existing treatments are limited to surgery or laser-based treatments that have had mixed success and cannot be readily applied to a large number of tumors. We review cNF treatment options that are currently available and under investigation, discuss the regulatory considerations specific to cNFs, and propose strategies to improve cNF clinical trial design and standardize clinical trial endpoints.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/2j02s0htTest

المؤلفون: Wright, Davene, Williams, Adrienne, Divers, Jasmin, Pihoker, Catherine, Liese, Angela, Bellatorre, Anna, Kahkoska, Anna, Bell, Ronny, Mendoza, Jason, Mayer-Davis, Elizabeth, Wisk, Lauren, Everett, Estelle

المصدر: Diabetes Technology and Therapeutics. 25(2)

مصطلحات موضوعية: Diabetes disparities, Insulin pump, Insurance coverage, Socioeconomic status, Type 1 diabetes, Humans, Adolescent, Young Adult, Adult, Diabetes Mellitus, Type 1, Cross-Sectional Studies, Ethnicity, Hispanic or Latino, Insulins, Healthcare Disparities

الوصف: Objective: To evaluate changes in insulin pump use over two decades in a national U.S. sample. Research Design and Methods: We used data from the SEARCH for Diabetes in Youth study to perform a serial cross-sectional analysis to evaluate changes in insulin pump use in participants

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/3fh8c384Test