Effect of olmesartan and amlodipine on serum angiotensin-(1–7) levels and kidney and vascular function in patients with type 2 diabetes and hypertension

Background Recent studies suggest that angiotensin-converting enzyme 2 (ACE2) and angiotensin-(1–7) [Ang-(1–7)] might have beneficial effects on the cardiovascular system. We investigated the effects of olmesartan on the changes in serum ACE2 and Ang-(1–7) levels as well as kidney and vascular function in patients with type 2 diabetes and hypertension. Methods This was a prospective, randomized, active comparator-controlled trial. Eighty participants with type 2 diabetes and hypertension were randomized to receive 20mg of olmesartan (N = 40) or 5mg of amlodipine (N = 40) once daily. The primary endpoint was changes of serum Ang-(1–7) from baseline to week 24. Results Both olmesartan and amlodipine treatment for 24weeks decreased systolic and diastolic blood pressures significantly by > 18mmHg and > 8mmHg, respectively. Serum Ang-(1–7) levels were more significantly increased by olmesartan treatment (25.8 ± 34.5pg/mL → 46.2 ± 59.4pg/mL) than by amlodipine treatment (29.2 ± 38.9pg/mL → 31.7 ± 26.0pg/mL), resulting in significant between-group differences (P = 0.01). Serum ACE2 levels showed a similar pattern (6.31 ± 0.42ng/mL → 6.74 ± 0.39ng/mL by olmesartan treatment vs. 6.43 ± 0.23ng/mL → 6.61 ± 0.42ng/mL by amlodipine treatment; P < 0.05). The reduction in albuminuria was significantly associated with the increases in ACE2 and Ang-(1–7) levels (r =  − 0.252 and r =  − 0.299, respectively). The change in Ang-(1–7) levels was positively associated with improved microvascular function (r = 0.241, P < 0.05). Multivariate regression analyses showed that increases in serum Ang-(1–7) levels were an independent predictor of a reduction in albuminuria. Conclusions These findings suggest that the beneficial effects of olmesartan on albuminuria may be mediated by increased ACE2 and Ang-(1–7) levels. These novel biomarkers may be therapeutic targets for the prevention and treatment of diabetic kidney disease. Trial registration: ClinicalTrials.gov NCT05189015.This research was funded by Daiichi Sankyo Co., Seoul, South Korea through a subcontract with SNUBH (Seongnam, Republic of Korea). The funding agency had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript

Brigatinib Versus Crizotinib in ALK Inhibitor–Naive Advanced ALK-Positive NSCLC: Final Results of Phase 3 ALTA-1L Trial

ALK tyrosine kinase inhibitor; Brigatinib; Non–small cell lung cancerInhibidor de la tirosina quinasa ALK; Brigatinib; Cáncer de pulmón de células no pequeñasInhibidor de la tirosina cinasa ALK; Brigatinib; Càncer de pulmó de cèl·lules no petitesIntroduction In the phase 3 study entitled ALK in Lung cancer Trial of brigAtinib in 1st Line (ALTA-1L), which is a study of brigatinib in ALK inhibitor–naive advanced ALK-positive NSCLC, brigatinib exhibited superior progression-free survival (PFS) versus crizotinib in the two planned interim analyses. Here, we report the final efficacy, safety, and exploratory results. Methods Patients were randomized to brigatinib 180 mg once daily (7-d lead-in at 90 mg once daily) or crizotinib 250 mg twice daily. The primary end point was a blinded independent review committee–assessed PFS. Genetic alterations in plasma cell-free DNA were assessed in relation to clinical efficacy. Results A total of 275 patients were enrolled (brigatinib, n = 137; crizotinib, n = 138). At study end, (brigatinib median follow-up = 40.4 mo), the 3-year PFS by blinded independent review committee was 43% (brigatinib) versus 19% (crizotinib; median = 24.0 versus 11.1 mo, hazard ratio [HR] = 0.48, 95% confidence interval [CI]: 0.35–0.66). The median overall survival was not reached in either group (HR = 0.81, 95% CI: 0.53–1.22). Posthoc analyses suggested an overall survival benefit for brigatinib in patients with baseline brain metastases (HR = 0.43, 95% CI: 0.21–0.89). Detectable baseline EML4-ALK fusion variant 3 and TP53 mutation in plasma were associated with poor PFS. Brigatinib exhibited superior efficacy compared with crizotinib regardless of EML4-ALK variant and TP53 mutation. Emerging secondary ALK mutations were rare in patients progressing on brigatinib. No new safety signals were observed. Conclusions In the ALTA-1L final analysis, with longer follow-up, brigatinib continued to exhibit superior efficacy and tolerability versus crizotinib in patients with or without poor prognostic biomarkers. The suggested survival benefit with brigatinib in patients with brain metastases warrants future study

Efficacy and Safety of Brigatinib Compared With Crizotinib in Asian vs. Non-Asian Patients With Locally Advanced or Metastatic ALK–Inhibitor-Naive ALK+ Non–Small Cell Lung Cancer: Final Results From the Phase III ALTA-1L Study

Anaplastic lymphoma kinase; First line; Tyrosine kinase inhibitorCinasa del linfoma anaplásico; Primera línea; Inhibidor de la tirosina quinasaQuinasa del limfoma anaplàsic; Primera línia; Inhibidor de la tirosina quinasaBackground Brigatinib is a next-generation anaplastic lymphoma kinase (ALK) inhibitor with demonstrated efficacy in locally advanced and metastatic non–small cell lung cancer (NSCLC) in crizotinib-refractory and ALK inhibitor-naive settings. This analysis assessed brigatinib in Asian vs. non-Asian patients from the first-line ALTA-1L trial. Patients and Methods This was a subgroup analysis from the phase III ALTA-1L trial of brigatinib vs. crizotinib in ALK inhibitor–naive ALK+ NSCLC. The primary endpoint was progression-free survival (PFS) as assessed by blinded independent review committee (BIRC). Secondary endpoints included confirmed objective response rate (ORR) and overall survival (OS) in the overall population and BIRC-assessed intracranial ORR and PFS in patients with brain metastases. Results Of the 275 randomized patients, 108 were Asian. Brigatinib showed consistent superiority in BIRC-assessed PFS vs. crizotinib in Asian (hazard ratio [HR]: 0.35 [95% CI: 0.20-0.59]; log-rank P = .0001; median 24.0 vs. 11.1 months) and non-Asian (HR: 0.56 [95% CI: 0.38-0.84]; log-rank P = .0041; median 24.7 vs. 9.4 months) patients. Results were consistent with investigator-assessed PFS and BIRC-assessed intracranial PFS. Brigatinib was well tolerated. Toxicity profiles and dose modification rates were similar between Asian and non-Asian patients. Conclusion Efficacy with brigatinib was consistently better than with crizotinib in Asian and non-Asian patients with locally advanced or metastatic ALK inhibitor-naive ALK-+ NSCLC. There were no clinically notable differences in overall safety in Asian vs. non-Asian patients.This study was supported by ARIAD Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. The sponsor designed and conducted the study and collected the data together with the authors. The sponsor managed and analyzed the data. Data were interpreted by the authors and the sponsor. The sponsor together with the authors prepared, reviewed, and approved the manuscript and made the decision to submit the manuscript for publication

Atrophic Gastritis: A Related Factor for Osteoporosis in Elderly Women

Purpose Osteoporosis poses a great threat to the aging society. Hypochlorhydric or achlorhydric conditions are risk factors for osteoporosis. Atrophic gastritis also decreases gastric acid production; however, the role of atrophic gastritis as a related factor for osteoporosis is unclear. We investigated the relationship between atrophic gastritis and osteoporosis in postmenopausal women over 60 years of age. Subjects and Methods A total of 401 postmenopausal women were included in this cross-sectional study, which was conducted during their medical check-ups. Bone mineral densitometry was measured using a dual energy X-ray absorptiometry. Atrophic gastritis was defined endoscopically if gastric mucosa in the antrum and the body were found to be atrophied and thinned and submucosal vessels could be well visualized. Results: The proportion of people with atrophic gastritis was higher in the osteoporotic group than in the group without osteoporosis. A linear relationship was observed in the proportion of atrophic gastritis according to the categories of normal, osteopenia, and osteoporosis at the lumbar spine (p for trend = 0.039) and femur (p for trend = 0.001). A multiple logistic regression analysis revealed that the presence of atrophic gastritis was associated with an increased odds of osteoporosis after adjusting for age, body mass index, triglyceride, high-density lipoprotein cholesterol, alcohol consumption, and smoking status (odds ratio 1.89, 95% confidence interval 1.15–3.11). Conclusions: Atrophic gastritis is associated with an increased likelihood of osteoporosis in Korean elderly women

Identification of a novel ubiquitin binding site of STAM1 VHS domain by NMR spectroscopy

AbstractInteraction between the signal-transducing adapter molecule 1 (STAM1) Vps27/Hrs/Stam (VHS) domain and ubiquitin was investigated by nuclear magnetic resonance (NMR) spectroscopy. NMR evidence showed that the structure of STAM1 VHS domain resembles that of other VHS domains, especially the homologous domain of STAM2. We found that the VHS domain binds to ubiquitin via its hydrophobic patch consisting of N-terminus of helix 2 and C-terminus of helix 4 in which Trp26 on helix 2 plays a pivotal role in the binding. The binding between VHS and ubiquitin seems to be very similar to that between ubiquitin associated domain (UBA) and ubiquitin, however, the direction of α-helices involved in the ubiquitin binding is opposite. Here, we propose a novel ubiquitin binding site and the manner of ubiquitin recognition of the STAM1 VHS domain.Structured summaryMINT-6804185:STAM1 (uniprotkb:Q92783) binds (MI:0407) to ubiquitin (uniprotkb:P62988) by nuclear magnetic resonance (MI:0077

Stemness Evaluation of Mesenchymal Stem Cells from Placentas According to Developmental Stage: Comparison to Those from Adult Bone Marrow

This study was done to evaluate the stemness of human mesenchymal stem cells (hMSCs) derived from placenta according to the development stage and to compare the results to those from adult bone marrow (BM). Based on the source of hMSCs, three groups were defined: group I included term placentas, group II included first-trimester placentas, and group III included adult BM samples. The stemness was evaluated by the proliferation capacity, immunophenotypic expression, mesoderm differentiation, expression of pluripotency markers including telomerase activity. The cumulative population doubling, indicating the proliferation capacity, was significantly higher in group II (P<0.001, 31.7±5.8 vs. 15.7±6.2 with group I, 9.2±4.9 with group III). The pattern of immunophenotypic expression and mesoderm differentiation into adipocytes and osteocytes were similar in all three groups. The expression of pluripotency markers including ALP, SSEA-4, TRA-1-60, TRA-1-81, Oct-4, and telomerase were strongly positive in group II, but very faint positive in the other groups. In conclusions, hMSCs from placentas have different characteristics according to their developmental stage and express mesenchymal stemness potentials similar to those from adult human BMs

Gyejigachulbu-Tang Relieves Oxaliplatin-Induced Neuropathic Cold and Mechanical Hypersensitivity in Rats via the Suppression of Spinal Glial Activation

Activation of spinal glial cells plays a crucial role in the pathogenesis of neuropathic pain. An administration of oxaliplatin, an important anticancer drug, often induces acute neuropathic cold hypersensitivity and/or mechanical hypersensitivity in patients. Gyejigachulbu-tang (GBT), a herbal formula comprising Cinnamomi Cortex, Paeoniae Radix, Atractylodis Lanceae Rhizoma, Zizyphi Fructus, Glycyrrhizae Radix, Zingiberis Rhizoma, and Aconiti Tuber, has been used in East Asia to treat various pain symptoms, especially in cold patients. This study investigated whether and how GBT alleviates oxaliplatin-induced cold and mechanical hypersensitivity in rats. The behavioral signs of cold and mechanical hypersensitivity were evaluated by a tail immersion test in cold water (4°C) and a von Frey hair test, respectively. The significant cold and mechanical hypersensitivity were observed 3 days after an oxaliplatin injection (6 mg/kg, i.p.). Daily oral administration of GBT (200, 400, and 600 mg/kg) for 5 days markedly attenuated cold and mechanical hypersensitivity. Immunoreactivities of glial fibrillary acidic protein (GFAP, astrocyte marker) and OX-42 (microglia marker) in the spinal dorsal horn were significantly increased by an oxaliplatin injection, which were restored by GBT administration. These results indicate that GBT relieves oxaliplatin-induced cold and mechanical hypersensitivity in rats possibly through the suppression of spinal glial activation

Sequential magnetic resonance spectroscopic changes in a patient with nonketotic hyperglycinemia

Nonketotic hyperglycinemia (NKH) is a rare inborn error of amino acid metabolism. A defect in the glycine cleavage enzyme system results in highly elevated concentrations of glycine in the plasma, urine, cerebrospinal fluid, and brain, resulting in glycine-induced encephalopathy and neuropathy. The prevalence of NKH in Korea is very low, and no reports of surviving patients are available, given the scarcity and poor prognosis of this disease. In the current study, we present a patient with NKH diagnosed on the basis of clinical features, biochemical profiles, and genetic analysis. Magnetic resonance spectroscopy (MRS) allowed the measurement of absolute glycine concentrations in different parts of the brain that showed a significantly increased glycine peak, consolidating the diagnosis of NKH. In additional, serial MRS follow-up showed changes in the glycine/creatinine ratios in different parts of the brain. In conclusion, MRS is an effective, noninvasive diagnostic tool for NKH that can be used to distinguish this disease from other glycine metabolism disorders. It may also be useful for monitoring NKH treatment