Summary
In our systematic review and meta-analysis, we comprehensively evaluated menatetrenone in the management of osteoporosis. We found that menatetrenone decreased the ratio of undercarboxylated ...osteocalcin to osteocalcin (ucOC/OC) and improved lumbar BMD compared with placebo based on the 18 studies assessed. However, its benefit in fracture risk control was uncertain.
Introduction
We performed a systematic review and meta-analysis of the efficacy and safety of menatetrenone in managing osteoporosis.
Methods
PubMed, Cochrane Library, Embase,
ClinicalTrials.gov
, and three Chinese literature databases (CNKI, CBM, Wanfang) were searched for relevant randomized controlled trials (RCTs) published before October 5, 2017, comparing menatetrenone with other anti-osteoporotic drugs or placebo in treating osteoporosis. The pooled risk ratio (RR) or mean difference (MD) and 95% confidence interval (CI) were calculated using fixed-effects or random-effects meta-analysis.
Results
Eighteen RCTs (8882 patients) were included. Pooled analyses showed that menatetrenone was more effective than placebo in improving lumbar bone mineral density (BMD) (five studies,
N
= 658, MD = 0.05 g/cm
2
, 95% CI 0.01 to 0.09 g/cm
2
) and decreasing ucOC/OC (two studies,
N
= 75, MD = − 21.78%, 95% CI − 33.68 to − 9.87%). Compared with placebo, menatetrenone was associated with a nonsignificantly decreased risk of vertebral fracture (five studies,
N
= 5508, RR = 0.87, 95% CI 0.64 to 1.20). Evidence on other anti-osteoporotic drugs as comparators was limited and revealed no significantly different effects of menatetrenone on BMD or fracture risks. Furthermore, compared with placebo, menatetrenone significantly increased the incidence of adverse events (AEs) (two studies,
N
= 1949, RR = 1.47, 95% CI 1.07 to 2.02) and adverse drug reactions (four studies,
N
= 6102, RR = 1.29, 95% CI 1.07 to 1.56). However, no significant difference in the incidence of serious AEs was found between menatetrenone and placebo.
Conclusions
Menatetrenone significantly decreases ucOC and might improve lumbar BMD in osteoporotic patients. However, its benefit in fracture risk control is uncertain.
Summary
Most adherence studies only consider treatment following a first prescription. Using an extended follow-up, we found that 60% of seniors starting oral bisphosphonate therapy were exposed for ...≥ 3 years (48% for ≥ 5 years). Studies are needed to examine the benefits and harms of continuing bisphosphonate therapy beyond 3 years.
Introduction
The purpose of this study was to identify and describe patterns of long-term oral bisphosphonate use among seniors using a novel methodological approach that considers extended follow-up.
Methods
Among Ontarians aged 66 years or older, we identified subjects with a first dispensing of alendronate or risedronate between November 2000 and December 2016. We followed them until death or December 2019 to identify patients with ≥ 3 years of bisphosphonate use, defined as a proportion of days covered ≥ 80%, using 3-year rolling windows. We calculated the proportion of patients with long-term therapy (≥ 3 years of use) using Kaplan-Meier estimates. We described patterns of long-term use and compared patient characteristics between patients with and without long-term therapy.
Results
We identified 260,784 eligible seniors initiating bisphosphonate therapy. Of these, 60% continued therapy ≥ 3 years (77% women), and 48% continued ≥ 5 years. Characteristics did not meaningfully differ between patients with or without long-term therapy. The median length of long-term therapy was 7.0 (IQR 5.1) years for women and 6.1 (IQR 4.3) years for men. Only 20% experienced a treatment gap before long-term therapy, yet 50% experienced a treatment gap of ≥ 120 days after a median 5.3 years of therapy. Eighty-one percent who returned to therapy following a treatment gap re-initiated an oral bisphosphonate, with 18% switching to denosumab.
Conclusions
Among seniors initiating oral bisphosphonates, we found that 60% receive at least 3 years of therapy when using an extended follow-up. Studies are needed to examine the benefits and harms of continuing bisphosphonate therapy beyond 3 years.
Bacterial blight (BB) is currently considered one of the most serious rice diseases and is caused by Xanthomonas oryzae pv. oryzae (Xoo). Numerous studies have shown that breeding resistant rice ...varieties is one of the most effective methods to prevent BB, and it is important to identify and isolate more BB resistance (R) genes from different rice resources.
Using a map‐based approach, we identified a new QTL/gene, Xa43(t), from ZhangPu wild rice, which was highly resistant to the BB isolate PX099. We performed bulked segregant analysis combined with candidate gene prediction to identify the candidate gene.
The Xa43(t) gene was narrowed down to a 29‐kb region containing four putative genes. More importantly, the candidate gene Xa43(t) did not affect the main agronomic traits of rice. We also identified a widely applicable molecular marker, namely Inde1‐18, which co‐segregates with the Xa43(t) gene.
The Xa43(t) gene is a new broad‐spectrum BB resistance gene without identified alleles and has good application prospects for rice disease resistance breeding.
Xa43(t), identified from Zhangpu wild rice (Oryza rufipogon), was a new BB resistance gene.
We evaluated the utility of optical redox imaging (ORI) to identify the therapeutic response of triple-negative breast cancers (TNBC) under various drug treatments. Cultured HCC1806 and MDA-MB-231 ...cells treated with FK866 (nicotinamide phosphoribosyltransferase (Nampt) inhibitor), FX11 (lactate dehydrogenase A inhibitor), paclitaxel, and their combinations were subjected to ORI, followed by imaging fluorescently labeled reactive oxygen species (ROS). Cell growth inhibition was measured by a cell viability assay. We found that both cell lines experienced significant NADH decrease and redox ratio (Fp/(NADH+Fp)) increase due to FK866 treatment; however, HCC1806 was much more responsive than MDA-MB-231. We further studied HCC1806 with the main findings: (i) nicotinamide riboside (NR) partially restored NADH in FK866-treated cells; (ii) FX11 induced an over 3-fold NADH increase in FK866 or FK866+NR pretreated cells; (iii) FK866 combined with paclitaxel caused synergistic increases in both Fp and the redox ratio; (iv) FK866 sensitized cells to paclitaxel treatments, which agrees with the redox changes detected by ORI; (v) Fp and the redox ratio positively correlated with cell growth inhibition; and (vi) Fp and NADH positively correlated with ROS level. Our study supports the utility of ORI for detecting the treatment responses of TNBC to Nampt inhibition and the sensitization effects on standard chemotherapeutics.
Co-enzyme nicotinamide adenine dinucleotide NAD(H) regulates hundreds of biochemical reactions within the cell. We previously reported that NAD(H) redox status may have prognostic value for ...predicting breast cancer metastasis. However, the mechanisms of NAD(H) involvement in metastasis remain elusive. Given the important roles of TGFβ signalling in metastatic processes, such as promoting the epithelial-to-mesenchymal transition, we aimed to investigate the involvement of the mitochondrial NAD(H) redox status in TGFβ receptor signalling. Here we present the initial evidence that NAD(H) redox status is responsive to TGFβ receptor signalling in triple-negative breast cancer cells in culture. The mitochondrial NAD(H) redox status was determined by the optical redox imaging (ORI) technique. Cultured HCC1806 (less aggressive) and MDA-MB-231 (more aggressive) cells were subjected to ORI after treatment with exogenous TGFβ1 or LY2109761, which stimulates or inhibits TGFβ receptor signalling, respectively. Cell migration was determined with the transwell migration assay. Global averaging quantification of the ORI images showed that 1) TGFβ1 stimulation resulted in differential responses between HCC1806 and MDA-MB-231 lines, with HCC1806 cells having a significant change in the mitochondrial redox status, corresponding to a larger increase in cell migration; 2) HCC1806 cells acutely treated with LY2109761 yielded immediate increases in ORI signals. These preliminary data are the first evidence that suggests the existence of a cell line-dependent shift of the mitochondrial NAD(H) redox status in the TGFβ receptor signalling induced migratory process of breast cancer cells. Further research should be conducted to confirm these results as improved understanding of the underlying mechanisms of metastatic process may contribute to the identification of prognostic biomarkers and therapeutic targets.
Significance: Stratification of malignancy is valuable for cancer treatment. Both optical redox imaging (ORI) indices and nuclear-to-cytoplasmic volume/area ratio (N:C ratio) have been investigated ...to differentiate between cancers with varying aggressiveness, but these two methods have not been directly compared. The redox status in the cell nucleus has not been studied by ORI, and it remains unknown whether nuclear ORI indices add new biological information.
Aim: We sought to compare the capacity of whole-cell and subcellular ORI indices and N:C ratio to differentiate between breast cancer subtypes with varying aggressiveness and between mitotic and nonmitotic cells.
Approach: ORI indices for whole cell, cytoplasm, and nucleus as well as the N:C area ratio were generated for two triple-negative (more aggressive) and two receptor-positive (less aggressive) breast cancer cell lines by fluorescence microscopy.
Results: We found positive correlations between nuclear and cytoplasmic ORI indices within individual cells. On average, a nuclear redox status was found to be more oxidized than cytoplasm in triple-negative cells but not in receptor-positive cells. Whole-cell and subcellular ORI indices distinguished between the receptor statuses better than the N:C ratio. However, N:C ratio was a better differentiator between nonmitotic and mitotic triple-negative cells.
Conclusions: Subcellular ORI analysis differentiates breast cancer subtypes with varying aggressiveness better than N:C area ratio.
The lung macrophages play a crucial role in health and disease. Sexual dimorphism significantly impacts the phenotype and function of tissue-resident macrophages. The primary mechanisms responsible ...for sexually dimorphic outcomes in bronchopulmonary dysplasia (BPD) remain unidentified. We tested the hypothesis that biological sex plays a crucial role in the transcriptional state of alveolar macrophages, using neonatal murine hyperoxia-induced lung injury as a relevant model for human BPD. The effects of neonatal hyperoxia exposure (95 % FiO2, PND1-5: saccular stage) on the lung myeloid cells acutely after injury and during normoxic recovery were measured. Alveolar macrophages (AM) from room air- and hyperoxia exposed from male and female neonatal murine lungs were subjected to bulk-RNA Sequencing. AMs are significantly depleted in the hyperoxia-exposed lung acutely after injury, with subsequent recovery in both sexes. The transcriptome of the alveolar macrophages is impacted by neonatal hyperoxia exposure and by sex as a biological variable. Pathways related to DNA damage and interferon-signaling were positively enriched in female AMs. Metabolic pathways related to glucose and carbohydrate metabolism were positively enriched in the male AMs, while oxidative phosphorylation was negatively enriched. These pathways were shared with monocytes and airway macrophages from intubated male and female human premature neonates.
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•Alveolar macrophages (AM) are depleted after neonatal hyperoxia exposure.•Sex modulates the AM transcriptional state after hyperoxia exposure.•Sex-specific pathways in human neonatal airway myeloid cells with lung injury.
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