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Efficacy and Safety of Oral Small Molecule Glucagon-Like Peptide 1 Receptor Agonist Danuglipron for Glycemic Control Among Patients With Type 2 Diabetes: A Randomized Clinical Trial.
Saxena, AR, Frias, JP, Brown, LS, Gorman, DN, Vasas, S, Tsamandouras, N, Birnbaum, MJ
JAMA network open. 2023;(5):e2314493
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Abstract
IMPORTANCE Currently available glucagon-like peptide 1 receptor (GLP-1R) agonists for treating type 2 diabetes (T2D) are peptide agonists that require subcutaneous administration or strict fasting requirements before and after oral administration. OBJECTIVE To investigate the efficacy, safety, and tolerability of multiple dose levels of the novel, oral, small molecule GLP-1R agonist danuglipron over 16 weeks. DESIGN, SETTING, AND PARTICIPANTS A phase 2b, double-blind, placebo-controlled, parallel-group, 6-group randomized clinical trial with 16-week double-blind treatment period and 4-week follow-up was conducted from July 7, 2020, to July 7, 2021. Adults with T2D inadequately controlled by diet and exercise, with or without metformin treatment, were enrolled from 97 clinical research sites in 8 countries or regions. INTERVENTIONS Participants received placebo or danuglipron, 2.5, 10, 40, 80, or 120 mg, all orally administered twice daily with food for 16 weeks. Weekly dose escalation steps were incorporated to achieve danuglipron doses of 40 mg or more twice daily. MAIN OUTCOMES AND MEASURES Change from baseline in glycated hemoglobin (HbA1c, primary end point), fasting plasma glucose (FPG), and body weight were assessed at week 16. Safety was monitored throughout the study period, including a 4-week follow-up period. RESULTS Of 411 participants randomized and treated (mean [SD] age, 58.6 [9.3] years; 209 [51%] male), 316 (77%) completed treatment. For all danuglipron doses, HbA1c and FPG were statistically significantly reduced at week 16 vs placebo, with HbA1c reductions up to a least squares mean difference vs placebo of -1.16% (90% CI, -1.47% to -0.86%) for the 120-mg twice daily group and FPG reductions up to a least squares mean difference vs placebo of -33.24 mg/dL (90% CI, -45.63 to -20.84 mg/dL). Body weight was statistically significantly reduced at week 16 compared with placebo in the 80-mg twice daily and 120-mg twice daily groups only, with a least squares mean difference vs placebo of -2.04 kg (90% CI, -3.01 to -1.07 kg) for the 80-mg twice daily group and -4.17 kg (90% CI, -5.15 to -3.18 kg) for the 120-mg twice daily group. The most commonly reported adverse events were nausea, diarrhea, and vomiting. CONCLUSIONS AND RELEVANCE In adults with T2D, danuglipron reduced HbA1c, FPG, and body weight at week 16 compared with placebo, with a tolerability profile consistent with the mechanism of action. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT03985293.
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The Role of Fecal Microbiota Transplantation in the Allogeneic Stem Cell Transplant Setting.
Metafuni, E, Di Marino, L, Giammarco, S, Bellesi, S, Limongiello, MA, Sorà, F, Frioni, F, Maggi, R, Chiusolo, P, Sica, S
Microorganisms. 2023;(9)
Abstract
Microbiota changes during allogeneic hematopoietic stem cell transplantation has several known causes: conditioning chemotherapy and radiation, broad-spectrum antibiotic administration, modification in nutrition status and diet, and graft-versus-host disease. This article aims to review the current knowledge about the close link between microbiota and allogeneic stem cell transplantation setting. The PubMed search engine was used to perform this review. We analyzed data on microbiota dysbiosis related to the above-mentioned affecting factors. We also looked at treatments aimed at modifying gut dysbiosis and applications of fecal microbiota transplantation in the allogeneic stem cell transplant field, with particular interest in fecal microbiota transplantation for graft-versus-host disease (GvHD), multidrug-resistant and clostridium difficile infections, and microbiota restoration after chemotherapy and antibiotic therapy.
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Lifestyle Factors and Development and Natural Course of Gastroenteropancreatic Neuroendocrine Tumors: A Review of the Literature.
Bogaards, M, May, AM, Hassan, FA, Valk, GD, van Leeuwaarde, RS
Neuroendocrinology. 2023;(4):381-394
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Abstract
INTRODUCTION The rarity of neuroendocrine tumors (NETs) and their heterogeneous presentation complicate the identification of risk factors for their development and natural course. Several tumor-specific prognostic factors have been identified, but less attention has been given to lifestyle factors as risk and prognostic factors. This review aimed to identify studies on smoking, alcohol use, physical activity, diet, body mass index (BMI), and diabetes and their association with the development and course of gastroenteropancreatic (GEP-) NETs. METHODS The literature was systematically searched for articles on lifestyle factors and NETs available via PubMed and Embase. Study quality was assessed using the Newcastle-Ottawa scale. RESULTS A total of 25 eligible studies out of 3,021 screened articles were included. Most studies reported on smoking and alcohol, reporting conflicting results. Diet seems to have an influence on NET development, but few studies were published. Articles reporting on BMI were not unanimous on the effect on GEP-NETs. Diabetes was reported as a risk factor for NETs, while a protective effect was observed with metformin use. CONCLUSION Different tissues, i.e., the pancreas and small intestine, may respond differently to exposure to alcohol and smoking. Evidence for diet so far is too limited to draw conclusions. Diabetes seems to be an important risk factor for the development of pancreatic NETs with a protective role in disease progression, while BMI is not unequivocally associated with the development and prognosis of NETs. Hence, our findings suggest that lifestyle factors play an important role in NET development as a disease course. Future research should consider lifestyle as an influence on disease progression and treatment response.
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Relationship between hyperuricemia, HSP70 and NLRP3 inflammasome in arterial hypertension.
Rodríguez-Iturbe, B, Johnson, RJ, Sánchez-Lozada, LG
Archivos de cardiologia de Mexico. 2023;(4):458-463
Abstract
Arterial hypertension is the most important cardiovascular risk factor in chronic non-communicable diseases and is estimated to be responsible for 10.4 million deaths annually. The global prevalence of hypertension is 30% and the majority of people with hypertension do not have a clear identifiable cause and are considered to have primary hypertension. Experimental and clinical investigations from several research groups, including ours, have established that inflammation and autoimmune reactivity play a role in the sodium retention and hemodynamic responses that drive primary hypertension. Hyperuricemia and heat stress proteins (HSP), particularly HSP70, are both associated with the activation of innate immunity that plays a role in the development of inflammatory reactivity in the hypertensive patient. Clinical studies have shown an association between the expression of HSP70 and anti-HSP70 antibodies and primary hypertension. This brief review aims to examine the interrelation between hyperuricemia and extracellular overexpression of HSP70 in the activation of the inflammasome that may have a central role in the pathophysiology of primary hypertension.
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Vitamin C reduces the severity of common colds: a meta-analysis.
Hemilä, H, Chalker, E
BMC public health. 2023;(1):2468
Abstract
BACKGROUND Randomized trials have shown that vitamin C shortens the duration of common colds. Some trials reported greater effects on severe cold symptoms compared with mild symptoms. This review systematically compares the effects of vitamin C on severe and mild common cold symptoms. METHODS We included all placebo-controlled trials of orally administered vitamin C in doses of at least 1 g/day for the common cold for people in good health at baseline. The analysis was restricted to trials which reported both the total duration of the common cold, and the severity of the common cold measured using severity scales, the duration of more severe stages of the cold, or proxies for severe colds such as days indoors. Findings were pooled using the inverse variance, fixed effect options of the metacont function of the R package meta to calculate the ratio of means estimate. RESULTS Fifteen comparisons from 10 trials which reported both mild and severe symptoms were identified. All trials were randomized and double-blind. Compared to placebo, vitamin C significantly decreased the severity of the common cold by 15% (95% CI 9-21%). The direct comparison of the effect of vitamin C on mild and severe symptoms was limited to five comparisons which found that vitamin C had a significant benefit on the duration of severe symptoms. In this subset, there was a significant difference in the size of the effect of vitamin C on the overall duration of colds versus the duration of severe colds (P = 0.002), and vitamin C had no significant effect on the duration of mild symptoms. CONCLUSIONS The common cold is the leading cause of acute morbidity and a major cause of absenteeism from work and school. However, absenteeism is dependent on the severity of symptoms. The finding that vitamin C may have a greater effect on more severe measures of the common cold is therefore important. Further research on the therapeutic effects of vitamin C on the common cold should measure outcomes of differing levels of severity.
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Neurodevelopmental Outcome in Very Preterm Infants Randomised to Receive Two Different Standardised, Concentrated Parenteral Nutrition Regimens.
Morgan, C, Parry, S, Park, J, Tan, M
Nutrients. 2023;(22)
Abstract
We have previously shown that increasing parenteral protein (target: 3.8 versus 2.8 g/kg/d) and energy (12% versus 10% glucose; 3.8 versus 2.8 g/kg/d) intake using a Standardised, Concentrated with Added Macronutrients Parenteral (SCAMP) nutrition regimen ameliorates early head growth failure in very-preterm infants (VPIs). We hypothesised that the SCAMP nutrition regimen would also improve neurodevelopmental outcome. The original double-blind randomised, controlled study (ISRCTN 76597892) received ethical approval. VPIs were randomised to either start SCAMP or remain on the control regimen. The consent process included neurodevelopmental assessments (Bayley III), all of which were performed (blinded) at 2-3.5 years of corrected gestational age. Bayley III assessments were performed for 38/60 SCAMP survivors and 41/63 control survivors at means of (sd) 29.2 (3.7) and 20.0 (3.9) months, respectively. Motor, cognitive, language, and combined scores were all higher in the SCAMP intervention group, but none of the differences were statistically significant. Nutrient intake and biochemical monitoring data confirmed that protein/energy ratios were maintained in the SCAMP intervention group without increasing the incidence of hyperglycaemia, insulin treatment, or the derangement of plasma mineral/electrolyte levels. This study did not show a statistically significant improvement in neurodevelopmental outcome when administering higher parenteral protein/energy intakes despite optimal energy and mineral intakes.
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The evolving landscape of COVID-19 and post-COVID condition in patients with chronic lymphocytic leukemia: A study by ERIC, the European research initiative on CLL.
Visentin, A, Chatzikonstantinou, T, Scarfò, L, Kapetanakis, A, Demosthenous, C, Karakatsoulis, G, Minga, E, Chamou, D, Allsup, D, Cabrero, AA, et al
American journal of hematology. 2023;(12):1856-1868
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Abstract
In this retrospective international multicenter study, we describe the clinical characteristics and outcomes of patients with chronic lymphocytic leukemia (CLL) and related disorders (small lymphocytic lymphoma and high-count monoclonal B lymphocytosis) infected by SARS-CoV-2, including the development of post-COVID condition. Data from 1540 patients with CLL infected by SARS-CoV-2 from January 2020 to May 2022 were included in the analysis and assigned to four phases based on cases disposition and SARS-CoV-2 variants emergence. Post-COVID condition was defined according to the WHO criteria. Patients infected during the most recent phases of the pandemic, though carrying a higher comorbidity burden, were less often hospitalized, rarely needed intensive care unit admission, or died compared to patients infected during the initial phases. The 4-month overall survival (OS) improved through the phases, from 68% to 83%, p = .0015. Age, comorbidity, CLL-directed treatment, but not vaccination status, emerged as risk factors for mortality. Among survivors, 6.65% patients had a reinfection, usually milder than the initial one, and 16.5% developed post-COVID condition. The latter was characterized by fatigue, dyspnea, lasting cough, and impaired concentration. Infection severity was the only risk factor for developing post-COVID. The median time to resolution of the post-COVID condition was 4.7 months. OS in patients with CLL improved during the different phases of the pandemic, likely due to the improvement of prophylactic and therapeutic measures against SARS-CoV-2 as well as the emergence of milder variants. However, mortality remained relevant and a significant number of patients developed post-COVID conditions, warranting further investigations.
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Possible Side Effects of Polyphenols and Their Interactions with Medicines.
Duda-Chodak, A, Tarko, T
Molecules (Basel, Switzerland). 2023;(6)
Abstract
Polyphenols are an important component of plant-derived food with a wide spectrum of beneficial effects on human health. For many years, they have aroused great interest, especially due to their antioxidant properties, which are used in the prevention and treatment of many diseases. Unfortunately, as with any chemical substance, depending on the conditions, dose, and interactions with the environment, it is possible for polyphenols to also exert harmful effects. This review presents a comprehensive current state of the knowledge on the negative impact of polyphenols on human health, describing the possible side effects of polyphenol intake, especially in the form of supplements. The review begins with a brief overview of the physiological role of polyphenols and their potential use in disease prevention, followed by the harmful effects of polyphenols which are exerted in particular situations. The individual chapters discuss the consequences of polyphenols' ability to block iron uptake, which in some subpopulations can be harmful, as well as the possible inhibition of digestive enzymes, inhibition of intestinal microbiota, interactions of polyphenolic compounds with drugs, and impact on hormonal balance. Finally, the prooxidative activity of polyphenols as well as their mutagenic, carcinogenic, and genotoxic effects are presented. According to the authors, there is a need to raise public awareness about the possible side effects of polyphenols supplementation, especially in the case of vulnerable subpopulations.
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Effect of positive emotion intervention during late pregnancy on improving colostrum secretion: a randomised control trial protocol.
Xu, K, Xie, Y, Han, X, Yu, Y, Liu, S, Wu, S, Yang, Q, Zhang, Q
BMJ open. 2023;(6):e066601
Abstract
INTRODUCTION Though evidence has revealed the beneficial effects of cognitive improvement interventions on breastfeeding, the effect of psychological interventions has rarely been studied. This study aims to test whether promoting a positive emotion intervention, 'Three Good Things' intervention, during the last trimester of pregnancy can enhance early colostrum secretion and breastfeeding behaviours by modulating the hormones associated with lactation (prolactin and insulin-like growth factor I). We will attempt to promote exclusive breastfeeding by using physiological behavioural measures. METHODS AND ANALYSIS This study is designed as a randomised controlled trial conducted in the Women's Hospital School of Medicine at Zhejiang University and the Wuyi First People's Hospital. The participants will be randomly divided into two groups using stratified random grouping: the intervention group will receive 'Three Good Things' intervention, while the control group will write about three things that come to mind first. These interventions will be continued from enrolment until the day of delivery. Maternal blood hormone levels will be tested approaching delivery and the following day after birth. Behavioural information about breastfeeding will be collected 1 week afterwards. ETHICS AND DISSEMINATION The study has been approved by the Ethics Committees of the Women's Hospital School of Medicine at Zhejiang University and the Wuyi First People's Hospital. Results will be disseminated through peer-reviewed journals or international academic conferences. TRIAL REGISTRATION NUMBER ChiCTR2000038849.
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Vitamin D3 promotes gastric cancer cell autophagy by mediating p53/AMPK/mTOR signaling.
Wang, Y, He, Q, Rong, K, Zhu, M, Zhao, X, Zheng, P, Mi, Y
Frontiers in pharmacology. 2023;:1338260
Abstract
Objective: Vitamin D3 has the general properties of a lipid-soluble vitamin, but is also an active steroid hormone that can regulate the proliferation, apoptosis and differentiation of many tumor cells, and exerts anticancer activity against numerous malignancies. However, the mechanism underlying the effects of vitamin D3 on tumors is not fully understood. Here, we used network pharmacology and in vitro experimental approaches to explore the mechanism of vitamin D3 activity in the context of gastric cancer. Methods: The Targetnet, SuperPred, SwissTargetPrediction, and PharmMapper databases were screened for potential drug-related targets, while we used data from the PharmGKB, Drugbank, OMIM, DisGeNET, CTD, and GeneCards databases to identify potential targets associated with gastric cancer. Disease-drug crossover genes were obtained by constructing Venn diagrams. Gene ontology and Kyoto Encyclopedia of Genomes (KEGG) enrichment analyses of crossover genes were conducted and STRING was used to generate protein interaction networks and identify core targets. CCK-8 experiments were performed and apoptosis detected to assess the effect of vitamin D3 on gastric cancer cells. Western blotting was applied to detect p53/AMPK/mTOR signaling, as well as autophagy-, cell cycle-, and apoptosis-related proteins. Results: A total of 485 targets of vitamin D3 activity were obtained and 1200 gastric cancer disease-related targets discovered. Further, 60 potential targets for vitamin D3 in gastric cancer treatment were identified. KEGG analysis indicated that potential targets were mainly involved in the cell cycle, HIF-1 signaling, and the AMPK pathway, among other pathways. These findings were validated using cellular experiments, which demonstrated that the viability of AGS and SGC-7901 cells was impeded by vitamin D3. Further, vitamin D3 promoted apoptosis and inhibited the cell cycle in those cell lines, as well as activating the p53/AMPK/mTOR pathway, which promotes autophagy and inhibits tumor development. Conclusion: Our network pharmacological analyses provide preliminarily data supporting a role for vitamin D3 in promoting autophagy and apoptosis in gastric cancer cells, and in activating the p53/AMPK/mTOR pathway, which inhibits gastric cancer cell proliferation. Our findings demonstrate the molecular mechanism underlying the effect of vitamin D3 in cure of gastric cancer.