The efficacy and safety of monoclonal antibody therapies for interstitial cystitis/bladder pain syndrome: A meta-analysis of randomized controlled trials.

OBJECTIVES: This study aimed to assess the efficacy and safety of monoclonal antibody therapies (MATs) for interstitial cystitis/bladder pain syndrome (IC/BPS). METHODS: A systematic search was conducted across databases including PubMed, Embase, clinicalTrial.gov, and the Cochrane Library Central Register of Controlled Trials. Randomized controlled trials (RCTs) comparing MATs versus placebo were included. Primary outcomes comprised the Global Response Assessment (GRA) scale and the O'Leary-Sant Interstitial Cystitis Symptom Index (ICSI). Additional analyses encompassed mean daily frequency of voids, the O'Leary-Sant Interstitial Cystitis Problem Index, pain scores, and complications. Statistical analyses were performed using Review Manager 5.3. RESULTS: Five high-quality RCTs, comprising 263 patients with IC/BPS, were ultimately selected. MATs were generally effective in treating IC/BPS. Patients receiving MATs exhibited a higher satisfaction rate (odds ratio [OR]: 2.7, confidence interval [CI]: 1.31-5.58, p = 0.007) and lower ICSI scores (mean difference [MD]: -1.44, CI: -2.36 to -0.52, p = 0.002). Moreover, MAT recipients experienced reduced pain (MD: -0.53, CI: -0.79 to -0.26, p < 0.0001) and decreased frequency of urination (MD: -1.91, CI: -2.55 to -1.27, p < 0.00001). Importantly, there were no disparities regarding complication incidence in the MAT and control groups. CONCLUSIONS: The current findings indicate that MATs are effective and safe for treating IC/BPS. Nonetheless, future RCTs with larger sample sizes and long-term follow-up are warranted.

The Role of Gut Microbiota in the Neuroprotective Effects of Selenium in Alzheimer's Disease.

The objective of the present review was to provide a timely update on the molecular mechanisms underlying the beneficial role of Se in Alzheimer's disease pathogenesis, and discuss the potential role of gut microbiota modulation in this neuroprotective effect. The existing data demonstrate that selenoproteins P, M, S, R, as well as glutathione peroxidases and thioredoxin reductases are involved in regulation of Aß formation and aggregation, tau phosphorylation and neurofibrillary tangles formation, as well as mitigate the neurotoxic effects of Aß and phospho-tau. Correspondingly, supplementation with various forms of Se in cellular and animal models of AD was shown to reduce Aß formation, tau phosphorylation, reverse the decline in brain antioxidant levels, inhibit neuronal oxidative stress and proinflammatory cytokine production, improve synaptic plasticity and neurogenesis, altogether resulting in improved cognitive functions. In addition, most recent findings demonstrate that these neuroprotective effects are associated with Se-induced modulation of gut microbiota. In animal models of AD, Se supplementation was shown to improve gut microbiota biodiversity with a trend to increased relative abundance of Lactobacillus, Bifidobacterium, and Desulfivibrio, while reducing that of Lachnospiracea_NK4A136, Rikenella, and Helicobacter. Moreover, the relative abundance of Se-affected taxa was significantly associated with Aß accumulation, tau phosphorylation, neuronal oxidative stress, and neuroinflammation, indicative of the potential role of gut microbiota to mediate the neuroprotective effects of Se in AD. Hypothetically, modulation of gut microbiota along with Se supplementation may improve the efficiency of the latter in AD, although further detailed laboratory and clinical studies are required.

Plasma metabolites and inflammatory proteins profiling predict outcome of Fufang Duzhong Jiangu granules treating Kashin-Beck disease.

To investigate predictive biomarkers that could be used to identify patients' response to treatment, plasma metabolomics and proteomics analyses were performed in Kashin-Beck disease (KBD) patients treated with Fufang Duzhong Jiangu Granules (FDJG). Plasma was collected from 12 KBD patients before treatment and 1 month after FDJG treatment. LC-MS and olink proteomics were employed for obtaining plasma metabolomics profiling and inflammatory protein profiles. Patients were classified into responders and non-responders based on drug efficacy. Enrichment analyses of differential metabolites and proteins of the responders at baseline and after treatment were conducted to study the mechanism of drug action. Differential metabolites and proteins between the two groups were screened as biomarkers to predict the drug efficacy. The receiver operating characteristic curve was used to evaluate the prediction accuracy of biomarkers. The changes in metabolites and inflammatory proteins in responders after treatment reflected the mechanism of FDJG treatment for KBD, which may act on glycerophospholipid metabolism, d-glutamine and d-glutamate metabolism, nitrogen metabolism and NF-kappa B signaling pathway. Three metabolites were identified as potential predictors: N-undecanoylglycine, ß-aminopropionitrile and PC [18:3(6Z,9Z,12Z)/20:4(8Z,11Z,14Z,17Z)]. For inflammatory protein, interleukin-8 was identified as a predictive biomarker to detect responders. Combined use of these four biomarkers had high predictive ability (area under the curve = 0.972).

Feasibility of a modified hybrid glubran-supported single-proglide technique for access closure during endovascular aneurysm repair.

Objective: This study aimed to evaluate the feasibility of a hybrid Glubran-supported single-Proglide technique for large bore femoral access closure during percutaneous access endovascular aneurysm repair (EVAR). Methods: A retrospective cohort study was performed for all percutaneous EVARs at our center from January 2023 to June 2023. All patients received the hybrid Glubran-supported single-Proglide technique involving a mixture of surgical glue and Lipiodol injection after single suture placement for femoral access closure. Technical success was defined as achieving complete hemostasis without a bailout strategy. Vascular complications and bleeding were defined by Valve Academic Research Consortium-3 (VARC-3) criteria. Vascular access changes and 30-day mortality were recorded. Results: The technique success rate for the entire study population was 100% (55 femoral access in 37 patients; median age: 72; 78% males). The mean sheath size was 20.4 ± 2.3F. The mean manual compression time was 3.5 ± 1.4 min, the mean hemostasis time was 9.0 ± 2.5 min, and the mean procedural time was 103.9 ± 34.7 min. One patient (1.6%) developed an access site infection and recovered conservatively. No VARC-3 vascular complications and access changes were observed. No 30-day mortality happened. Conclusions: The hybrid Glubran-supported single-Proglide technique is feasible for large bore access closure during EVAR and may be a viable alternative; however, larger prospective studies are required to confirm its efficacy.

Intense interaction between biochar/g-C3N4 promotes the photocatalytic performance of heterojunction catalysts.

In recent decades, environmental protection and energy issues have gained significant attention, and the development of efficient, environmentally friendly catalysts has become especially crucial for the advancement of photocatalytic technology. This study employs the sintering method to produce biochar. A hybrid photocatalyst for the degradation of RHB under visible light was prepared by loading varying proportions of biochar onto g-C3N4 using ultrasonic technology. Among them, 2% CGCD (2% biochar/g-C3N4) achieved a degradation rate of 91.3% for RHB after 30 minutes of visible light exposure, which was more than 25% higher than GCD (g-C3N4), and exhibited a higher photocurrent intensity and lower impedance value. The enhancement in photocatalytic activity is primarily attributed to the increased utilization efficiency of visible light and the electron transfer channel effect from a minor amount of biochar, effectively reducing the recombination of photo-generated charge carriers on the g-C3N4 surface, thereby significantly improving photocatalytic activity. The degradation of RHB is synergistically mediated by O2 -, h+ (photo-generated holes), and ˙OH. The free radical capture experiment indicates that O2 - and ˙OH are the primary active components, followed by h+.

Estimation of Hair Toxic and Essential Trace Element and Mineral Profiles of Patients with Chronic Gout.

The objective of the present study was to evaluate hair levels of toxic and essential trace elements and minerals in male and female patients with chronic gout. A total of 223 examinees aged from 27 to 82 years old including 116 healthy controls (64 women and 52 men) and 107 patients with gout (56 women and 51 men) were enrolled in the current cross-sectional study. Analysis of hair toxic and essential trace element and mineral content was performed using inductively-coupled plasma mass-spectrometry. The obtained data demonstrate that hair B, Fe, I, and Mo levels in gout patients were 67%, 8%, 46%, and 21% higher in comparison to the respective control values. Hair Cr and V content in patients was more than twofold higher than in the controls. Hair Mg and Zn levels were found to be 34% and 11% lower when compared to the respective control values. Hair toxic metal and metalloid content was also significantly affected in gout patients. Specifically, hair Al, As, and Pb levels were 24%, 43%, and 33% higher in gout patients than in healthy controls, respectively. Analysis of covariance demonstrated that sex also had a significant influence on hair trace element and mineral levels in gout patients. Specifically, gout-associated overaccumulation of hair trace elements including was more profound in male than in female patients. It is assumed that trace element dysregulation may contribute to gout development and progression, especially in men. However, further studies are required to elucidate this association and the underlying molecular mechanisms.

Modulation of Ras signaling pathway by exosome miRNAs in T-2 toxin-induced chondrocyte injury.

This study aims to investigate the impact of T-2 toxin on the regulation of downstream target genes and signaling pathways through exosome-released miRNA in the development of cartilage damage in Kashin-Beck disease (KBD). Serum samples from KBD patients and supernatant from C28/I2 cells treated with T-2 toxin were collected for the purpose of comparing the differential expression of exosomal miRNA using absolute quantitative miRNA-seq. Target genes of differential exosomal miRNAs were identified using Targetscan and Miranda databases, followed by GO and KEGG enrichment analyses. Validation of key indicators of chondrocyte injury in KBD was conducted using Real-time quantitative PCR (RT-qPCR) and Immunohistochemical staining (IHC). A total of 20 exosomal miRNAs related to KBD were identified in serum, and 13 in chondrocytes (C28/I2). The identified exosomal miRNAs targeted 48,459 and 60,612 genes, primarily enriched in cell organelles and membranes, cell differentiation, and cytoskeleton in the serum, and the cytoplasm and nucleus, metal ion binding in chondrocyte (C28/I2). The results of the KEGG enrichment analysis indicated that the Ras signaling pathway may play a crucial role in the pathogenesis of KBD. Specifically, the upregulation of hsa-miR-181a-5p and hsa-miR-21-3p, along with the downregulation of hsa-miR-152-3p and hsa-miR-186-5p, were observed. Additionally, T-2 toxin intervention led to a significant downregulation of RALA, REL, and MAPK10 expression. Furthermore, the protein levels of RALA, REL, and MAPK10 were notably decreased in the superficial and middle layers of cartilage tissues from KBD. The induction of differential expression of chondrocyte exosomal miRNAs by T-2 toxin results in the collective regulation of target genes RALA, REL, and MAPK10, ultimately mediating the Ras signaling pathway and causing a disruption in chondrocyte extracellular matrix metabolism, leading to chondrocyte injury.

HT-2 mycotoxin and selenium deficiency: Effects on Femur development and integrity in Young mice.

Kashin-Beck Disease (KBD), an osteoarticular disorder, is potentially influenced by several factors, among which selenium deficiency and HT-2 mycotoxin exposure are considered significant. However, the combined effect of these factors on femoral development remains unclear, Conducted over eight weeks on forty-eight male mice categorized into control, selenium-deficient, and HT-2 toxin-exposed groups, including dual-exposure sets, this study comprehensively monitored body weight, bone metabolism markers, and cellular health. Employing biomechanical analysis, micro-computed tomography (micro-CT), and transmission electron microscopy (TEM), we unearthed a reduction in body weight due to HT-2 toxin alone, with selenium deficiency exacerbating these effects synergistically. Our results unveil that both factors independently affect bone metabolism, yet their confluence leads to a pronounced degradation of bone health parameters, including alterations in calcium, phosphorus, and vitamin D levels, alongside marked changes in osteoblast and osteoclast activity and bone cell structures. The notable damage to femoral cortical and trabecular architectures underscores the perilous interplay between dietary selenium absence and HT-2 toxin presence, necessitating a deeper understanding of their separate and joint effects on bone integrity. These discoveries underscore the imperative for a nuanced approach to toxicology research and public health policy, highlighting the pivotal influence of environmental and nutritional factors on skeletal well-being.

Activation of Notch Signaling Pathway is involved in Extracellular Matrix Degradation in human induced pluripotent stem cells chondrocytes induced by HT-2 toxin.

Notch signaling regulates cartilage formation and homeostasis. Kashin-Beck Disease (KBD), an endemic osteochondropathy, is characterized by severe cartilage degradation. The etiology of KBD is related to the exposure of HT-2 toxin, a mycotoxin and primary metabolite of T-2 toxin. This study aims to explore the role of HT-2 toxin in the Notch signaling regulation and extracellular matrix (ECM) metabolism of hiPSCs-Chondrocytes. Immunohistochemistry and qRT-PCR were employed to investigate the expression of Notch pathway molecules in KBD articular cartilage and primary chondrocytes. hiPSCs-Chondrocytes, derived from hiPSCs, were treated with 100 ng/mL HT-2 toxin and the γ-secretase inhibitor (DAPT) for 48h, respectively. The markers related to the Notch signaling pathway and ECM were assessed using qRT-PCR and Western blot. Notch pathway dysregulation was prominent in KBD cartilage. HT-2 toxin exposure caused cytotoxicity in hiPSCs-Chondrocytes, and activated Notch signaling by increasing the mRNA and protein levels of NOTCH1 and HES1. HT-2 toxin also upregulated ECM catabolic enzymes and downregulated ECM components (COL2A1 and ACAN), indicating ECM degradation. DAPT-mediated Notch signaling inhibition suppressed the mRNA and protein level of ADAMTS5 expression while enhancing ECM component expression in hiPSCs-Chondrocytes. This study suggests that HT-2 toxin may induce ECM degradation in hiPSCs-Chondrocytes through activating Notch signaling.

Divergent Synthesis of Scabrolide A and Havellockate via an exo-exo-endo Radical Cascade.

Here we report a concise and divergent synthesis of scabrolide A and havellockate, representative members of polycyclic marine natural product furano(nor)cembranoids. The synthesis features a highly efficient exo-exo-endo radical cascade. Through the generation of two rings, three C-C bonds, and three contiguous stereocenters in one step, this remarkable transformation not only assembles the bowl-shaped, common 6-5-5 fused ring system from simple building blocks but also precisely installs the functionalities at desired positions and sets the stage for further divergent preparation of both target molecules. Further studies reveal that the robust and unusual 6-endo radical addition in the cascade is likely facilitated by the rigidity of the substrate.

Molecular mechanisms of environmental pollutant-induced cartilage damage: from developmental disorders to osteoarthritis.

The objective of the present study was to review the molecular mechanisms of the adverse effects of environmental pollutants on chondrocytes and extracellular matrix (ECM). Existing data demonstrate that both heavy metals, including cadmium (Cd), lead (Pb), and arsenic (As), as well as organic pollutants, including polychlorinated dioxins and furans (PCDD/Fs) and polychlorinated biphenyls (PCB), bisphenol A, phthalates, polycyclic aromatic hydrocarbons (PAH), pesticides, and certain other organic pollutants that target cartilage ontogeny and functioning. Overall, environmental pollutants reduce chondrocyte viability through the induction apoptosis, senescence, and inflammatory response, resulting in cell death and impaired ECM production. The effects of organic pollutants on chondrocyte development and viability were shown to be mediated by binding to the aryl hydrocarbon receptor (AhR) signaling and modulation of non-coding RNA expression. Adverse effects of pollutant exposures were observed in articular and growth plate chondrocytes. These mechanisms also damage chondrocyte precursors and subsequently hinder cartilage development. In addition, pollutant exposure was shown to impair chondrogenesis by inhibiting the expression of Sox9 and other regulators. Along with altered Runx2 signaling, these effects also contribute to impaired chondrocyte hypertrophy and chondrocyte-to-osteoblast trans-differentiation, resulting in altered endochondral ossification. Several organic pollutants including PCDD/Fs, PCBs and PAHs, were shown to induce transgenerational adverse effects on cartilage development and the resulting skeletal deformities. Despite of epidemiological evidence linking human environmental pollutant exposure to osteoarthritis or other cartilage pathologies, the data on the molecular mechanisms of adverse effects of environmental pollutant exposure on cartilage tissue were obtained from studies in laboratory rodents, fish, or cell cultures and should be carefully extrapolated to humans, although they clearly demonstrate that cartilage should be considered a putative target for environmental pollutant toxicity.

Differential analysis of serum immunology and gut microbiota in patients with gastrointestinal diseases.

Objective: Gastric and intestinal diseases possess distinct characteristics although they are interconnected. The primary objective of this study was to investigate the pathogenesis of gastrointestinal diseases through different analyses of clinical characteristics, serum immunology, and gut microbiota in patients with gastrointestinal diseases. Methods: We collected serum samples from 89 patients with gastrointestinal diseases and 9 healthy controls for immunological assessment, stool samples for DNA extraction, library construction, sequencing, as well as clinical data for subsequent analysis. Results: Regarding clinical characteristics, there were significant differences between the disease group and the healthy control (HC) group, particularly in terms of age, cancer antigen 125 (CA125), cancer antigen 199 (CA199), alpha-fetoprotein (AFP), total bilirubin (TBIL) and indirect bilirubin (IBIL). The intestinal disease (ID) group exhibited the highest IL-6 level, which significantly differed from the stomach disease (SD) group (p < 0.05). In comparing the HC with the ID groups, significant differences in abundance were detected across 46 species. The HC group displayed a greater abundance of Clostridiales, Clostridia, Firmicutes, Bifidobacterium, Bifidobacteriaceae, Bifidobacteriales, Actinobacteria, Veillonellaceae, Longum, Copri, Megamonas and Callidus than other species. Similarly, when comparing the HC with the SD groups, significant differences in abundance were identified among 49 species, with only one species that the Lachnospiraceae in the HC group exhibited a higher abundance than others. Furthermore, certain clinical characteristics, such as CA125, CA199, glucose (Glu), creatine kinase-MB (CKMB) and interleukin-22 (IL-22), displayed positive correlations with enriched gut species in the ID and SD groups, while exhibiting a negative correlation with the HC group. Conclusion: The disturbance in human gut microbiota is intimately associated with the development and progression of gastrointestinal diseases. Moreover, the gut microbiota in the HC group was found more diverse than that in the ID and SD groups, and there were significant differences in microbial species among the three groups at different classification levels. Notably, a correlation was identified between specific clinical characteristics (e.g., CA125, CA199, Glu, CKMB and IL-22) and gut microbiota among patients with gastrointestinal diseases.

Oxalisxishuiensis (Oxalidaceae), a new species from Danxia landforms in Guizhou, China.

Oxalisxishuiensis, a new species of Oxalidaceae from Danxia landforms of Xishui County, Guizhou, China, is described and illustrated. It is morphologically similar to O.wulingensis by the two lateral leaflets arranged at about 180° angle and oblong pink petals with lilac veins, but clearly differs from the latter by leaflets almost as long as wide, obliquely obcordate lateral leaflets, shorter peduncles, longer capsule (1.2-1.5 cm vs. 0.5-0.7 cm) and alveolate seeds.

Modulatory interactions of T-2 and deoxynivalenol mycotoxins on murine femoral development and osteological integrity.

In this study, we conducted a systematic assessment of the effectsof deoxynivalenol (DON) and T-2 mycotoxins (T-2) on the developmental processes and structural integrity of murine femurs, considering both the isolated and synergistic effects of these toxins. To this end, we divided 72 male mice into nine groups, each subjected to varying dosages of T-2, DON, or their combinations. Over a four-week experimental period, meticulous monitoring was undertaken regarding the mice's body weight, biochemical markers of bone formation and resorption, and the activity of relevant cells. To comprehensively evaluate alterations in bone structure, we employed biomechanical analysis, micro-computed tomography (micro-CT), and transmission electron microscopy.Our findings unveiled a significant revelation: the mice exhibited a dose-dependent decrease in body weight upon exposure to individual mycotoxins, while the combined use of these toxins manifested an atypical antagonistic effect. Furthermore, we observed variations in the levels of calcium, phosphorus, and vitamin D, as well as adjustments in the activities of osteoblasts and osteoclasts, all intricately linked to the dosage and ratio of the toxins. Alterations in biomechanical properties were also noted to correlate with the dosage and combination of toxins. Analyses via micro-CT and transmission electron microscopy further corroborated the substantial impact of toxin dosage and combinations on both cortical and trabecular bone structures.In summation, our research unequivocally demonstrates the dose- and ratio-dependent detrimental effects of DON and T-2 mycotoxins on the growth and structural integrity of murine femurs. These insights accentuate the importance of a profound understanding of the potential risks these toxins pose to bone health, offering pivotal guidance for future toxicological research and public health preventative strategies.

Rectifying METTL4-Mediated N6-Methyladenine Excess in Mitochondrial DNA Alleviates Heart Failure.

BACKGROUND: Myocardial mitochondrial dysfunction underpins the pathogenesis of heart failure (HF), yet therapeutic options to restore myocardial mitochondrial function are scarce. Epigenetic modifications of mitochondrial DNA (mtDNA), such as methylation, play a pivotal role in modulating mitochondrial homeostasis. However, their involvement in HF remains unclear. METHODS: Experimental HF models were established through continuous angiotensin II and phenylephrine (AngII/PE) infusion or prolonged myocardial ischemia/reperfusion injury. The landscape of N6-methyladenine (6mA) methylation within failing cardiomyocyte mtDNA was characterized using high-resolution mass spectrometry and methylated DNA immunoprecipitation sequencing. A tamoxifen-inducible cardiomyocyte-specific Mettl4 knockout mouse model and adeno-associated virus vectors designed for cardiomyocyte-targeted manipulation of METTL4 (methyltransferase-like protein 4) expression were used to ascertain the role of mtDNA 6mA and its methyltransferase METTL4 in HF. RESULTS: METTL4 was predominantly localized within adult cardiomyocyte mitochondria. 6mA modifications were significantly more abundant in mtDNA than in nuclear DNA. Postnatal cardiomyocyte maturation presented with a reduction in 6mA levels within mtDNA, coinciding with a decrease in METTL4 expression. However, an increase in both mtDNA 6mA level and METTL4 expression was observed in failing adult cardiomyocytes, suggesting a shift toward a neonatal-like state. METTL4 preferentially targeted mtDNA promoter regions, which resulted in interference with transcription initiation complex assembly, mtDNA transcriptional stalling, and ultimately mitochondrial dysfunction. Amplifying cardiomyocyte mtDNA 6mA through METTL4 overexpression led to spontaneous mitochondrial dysfunction and HF phenotypes. The transcription factor p53 was identified as a direct regulator of METTL4 transcription in response to HF-provoking stress, thereby revealing a stress-responsive mechanism that controls METTL4 expression and mtDNA 6mA. Cardiomyocyte-specific deletion of the Mettl4 gene eliminated mtDNA 6mA excess, preserved mitochondrial function, and mitigated the development of HF upon continuous infusion of AngII/PE. In addition, specific silencing of METTL4 in cardiomyocytes restored mitochondrial function and offered therapeutic relief in mice with preexisting HF, irrespective of whether the condition was induced by AngII/PE infusion or myocardial ischemia/reperfusion injury. CONCLUSIONS: Our findings identify a pivotal role of cardiomyocyte mtDNA 6mA and the corresponding methyltransferase, METTL4, in the pathogenesis of mitochondrial dysfunction and HF. Targeted suppression of METTL4 to rectify mtDNA 6mA excess emerges as a promising strategy for developing mitochondria-focused HF interventions.

Comparison of three frailty scales for prediction of prolonged postoperative ileus following major abdominal surgery in elderly patients: a prospective cohort study.

BACKGROUND: To determine whether frailty can predict prolonged postoperative ileus (PPOI) in older abdominal surgical patients; and to compare predictive ability of the FRAIL scale, the five-point modified frailty index (mFI-5) and Groningen Frailty Indicator (GFI) for PPOI. METHODS: Patients (aged ≥ 65 years) undergoing major abdominal surgery at our institution between April 2022 to January 2023 were prospectively enrolled. Frailty was evaluated with FRAIL, mFI-5 and GFI before operation. Data on demographics, comorbidities, perioperative management, postoperative recovery of bowel function and PPOI occurrence were collected. RESULTS: The incidence of frailty assessed with FRAIL, mFI-5 and GFI was 18.2%, 38.4% and 32.5% in a total of 203 patients, respectively. Ninety-five (46.8%) patients experienced PPOI. Time to first soft diet intake was longer in patients with frailty assessed by the three scales than that in patients without frailty. Frailty diagnosed by mFI-5 [Odds ratio (OR) 3.230, 95% confidence interval (CI) 1.572-6.638, P = 0.001] or GFI (OR 2.627, 95% CI 1.307-5.281, P = 0.007) was related to a higher risk of PPOI. Both mFI-5 [Area under curve (AUC) 0.653, 95% CI 0.577-0.730] and GFI (OR 2.627, 95% CI 1.307-5.281, P = 0.007) had insufficient accuracy for the prediction of PPOI in patients undergoing major abdominal surgery. CONCLUSIONS: Elderly patients diagnosed as frail on the mFI-5 or GFI are at an increased risk of PPOI after major abdominal surgery. However, neither mFI-5 nor GFI can accurately identify individuals who will develop PPOI. TRIAL REGISTRATION: This study was registered in Chinese Clinical Trial Registry (No. ChiCTR2200058178). The date of first registration, 31/03/2022, https://www.chictr.org.cn/ .

FTO promotes gastric cancer progression by modulating MAP4K4 expression via demethylation in an m6A-dependent manner.

Gastric cancer (GC) is a serious malignant tumour with a high mortality rate and a poor prognosis. Recently, emerging evidence has suggested that N6-methyladenosine (m6A) modification plays a crucial regulatory role in cancer progression. However, the exact role of m6A regulatory factors FTO in GC is unclear. First, the expression of m6A methylation-related regulatory factors in clinical samples and the clinical data of the corresponding patients were obtained from The Cancer Genome Atlas (TCGA-STAD) dataset, and correlation analysis between FTO expression and patient clinicopathological parameters was subsequently performed. qRT-PCR, immunohistochemistry (IHC) and western blotting (WB) were used to verify FTO expression in GC. CCK-8, EdU, flow cytometry and transwell assays were used to evaluate the effect of FTO on the behaviour of GC cells. Transcriptome sequencing and RNA immunoprecipitation analysis were used to explore the potential regulatory mechanisms mediated by FTO. FTO was highly expressed in GC tissues and cells, and high expression of FTO predicted a worse prognosis than low expression. Functionally, overexpression of FTO promoted the proliferation, migration and invasion of GC cells but inhibited cell apoptosis. Mechanistically, we found that FTO is upregulated in GC and promotes GC progression by modulating the expression of MAP4K4. Taken together, our findings provide new insights into the effects of FTO-mediated m6A demethylation and could lead to the development of new strategies for GC monitoring and aggressive treatment.

YTHDF1 Promotes Proliferation and Inhibits Apoptosis of Gastric Cancer Cells via Upregulating TCF7 mRNA Translation.

BACKGROUND: N6-methyladenosine (m6A) modification is one of the most common RNA modifications in mammals. m6A modification, and associated abnormal gene expression, occur during various biological processes, most notably tumorigenesis. YTH domain-containing family protein 1 (YTHDF1), a m6A reader, bind to messenger RNAs (mRNAs) containing a m6A modification and this enhances its interaction with the ribosome and promotes translation. The function of YTHDF1 in gastric cancer (GC) has been the subject of earlier studies; however, the precise mechanism underlying YTHDF1's role in GC has not been fully elucidated. METHODS: The expression of YTHDF1 was evaluated using quantitative real time polymerase chain reaction (qRT-PCR), immunohistochemistry and western blotting. CCK-8, 5-Ethynyl-2'-deoxyuridine (EdU) and flow cytometry assays were utilized to explore the effect of YTHDF1 on GC cell viability and proliferation. Transcriptome sequencing and RNA immunoprecipitation assays were utilized to explore the underlying mechanisms mediated by YTHDF1. RESULTS: We observed that YTHDF1 is upregulated in GC cancer tissues. Knockdown of YTHDF1 in GC cells significantly inhibited proliferation and promoted apoptosis, suggesting that YTHDF1 increases proliferation and blocks apoptosis in GC cells. Mechanistically, data gathered suggest that YTHDF1 promotes the translation of the transcription factor TCF7 and this results in activation of the WNT signaling axis. CONCLUSIONS: We found that YTHDF1 was upregulated in GC and that YTHDF1 could promote GC progression through modulating the translational efficiency of TCF7. Taken together, these findings may provide a novel therapeutic target for GC.

Changes in disease burden and global inequalities in bladder, kidney and prostate cancers from 1990 to 2019: a comparative analysis based on the global burden of disease study 2019.

BACKGROUND: Bladder, kidney and prostate cancers make significant contributors to cancer burdens. Exploring their cross-country inequalities may inform equitable strategies to meet the 17 sustainable development goals before 2030. METHODS: We analyzed age-standardized disability-adjusted life-years (ASDALY) rates for the three cancers based on Global Burden of Diseases Study 2019. We quantified the inequalities using slope index of inequality (SII, absolute measure) and concentration index (relative measure) associated with national sociodemographic index. RESULTS: Varied ASDALY rates were observed in the three cancers across 204 regions. The SII decreased from 35.15 (95% confidence interval, CI: 29.34 to 39.17) in 1990 to 15.81 (95% CI: 7.99 to 21.79) in 2019 for bladder cancers, from 78.94 (95% CI: 75.97 to 81.31) in 1990 to 59.79 (95% CI: 55.32 to 63.83) in 2019 for kidney cancer, and from 192.27 (95% CI: 137.00 to 241.05) in 1990 to - 103.99 (95% CI: - 183.82 to 51.75) in 2019 for prostate cancer. Moreover, the concentration index changed from 12.44 (95% CI, 11.86 to 12.74) in 1990 to 15.72 (95% CI, 15.14 to 16.01) in 2019 for bladder cancer, from 33.88 (95% CI: 33.35 to 34.17) in 1990 to 31.13 (95% CI: 30.36 to 31.43) in 2019 for kidney cancer, and from 14.61 (95% CI: 13.89 to 14.84) in 1990 to 5.89 (95% CI: 5.16 to 6.26) in 2019 for prostate cancer. Notably, the males presented higher inequality than females in both bladder and kidney cancer from 1990 to 2019. CONCLUSIONS: Different patterns of inequality were observed in the three cancers, necessitating tailored national cancer control strategies to mitigate disparities. Priority interventions for bladder and kidney cancer should target higher socioeconomic regions, whereas interventions for prostate cancer should prioritize the lowest socioeconomic regions. Additionally, addressing higher inequality in males requires more intensive interventions among males from higher socioeconomic regions.

Unveiling inflammatory and prehypertrophic cell populations as key contributors to knee cartilage degeneration in osteoarthritis using multi-omics data integration.

OBJECTIVES: Single-cell and spatial transcriptomics analysis of human knee articular cartilage tissue to present a comprehensive transcriptome landscape and osteoarthritis (OA)-critical cell populations. METHODS: Single-cell RNA sequencing and spatially resolved transcriptomic technology have been applied to characterise the cellular heterogeneity of human knee articular cartilage which were collected from 8 OA donors, and 3 non-OA control donors, and a total of 19 samples. The novel chondrocyte population and marker genes of interest were validated by immunohistochemistry staining, quantitative real-time PCR, etc. The OA-critical cell populations were validated through integrative analyses of publicly available bulk RNA sequencing data and large-scale genome-wide association studies. RESULTS: We identified 33 cell population-specific marker genes that define 11 chondrocyte populations, including 9 known populations and 2 new populations, that is, pre-inflammatory chondrocyte population (preInfC) and inflammatory chondrocyte population (InfC). The novel findings that make this an important addition to the literature include: (1) the novel InfC activates the mediator MIF-CD74; (2) the prehypertrophic chondrocyte (preHTC) and hypertrophic chondrocyte (HTC) are potentially OA-critical cell populations; (3) most OA-associated differentially expressed genes reside in the articular surface and superficial zone; (4) the prefibrocartilage chondrocyte (preFC) population is a major contributor to the stratification of patients with OA, resulting in both an inflammatory-related subtype and a non-inflammatory-related subtype. CONCLUSIONS: Our results highlight InfC, preHTC, preFC and HTC as potential cell populations to target for therapy. Also, we conclude that profiling of those cell populations in patients might be used to stratify patient populations for defining cohorts for clinical trials and precision medicine.