Diabetes Mellitus Inhibits Hair Follicle Regeneration by Inducing Macrophage Reprogramming-Mediated Pyroptosis.

Background: Diabetes mellitus (DM) is known to inhibit skin self-renewal and hair follicle stem cell (HFSC) activation, which may be key in the formation of chronic diabetic wounds. This study aimed to investigate the reasons behind the suppression of HFSC activation in DM mice. Methods: Type 1 DM (T1DM) was induced in 6-week-old mice via streptozotocin, and hair follicle growth was subsequently monitored. RNA sequencing, bioinformatics analyses, qRT‒PCR, immunostaining, and cellular experiments were carried out to investigate the underlying mechanisms involved. Results: T1DM inhibited HFSC activation, which correlated with an increase in caspase-dependent programmed cell death. Additionally, T1DM triggered apoptosis and pyroptosis, predominantly in HFSCs and epidermal regions, with pyroptosis being more pronounced in the inner root sheath of hair follicles. Notably, significant cutaneous immune imbalances were observed, particularly in macrophages. Cellular experiments demonstrated that M1 macrophages inhibited HaCaT cell proliferation and induced cell death, whereas high-glucose environments alone did not have the same effect. Conclusion: T1DM inhibits HFSC activation via macrophage reprogramming-mediated caspase-dependent pyroptosis, and there is a significant regional characterization of cell death. Moreover, T1DM-induced programmed cell death in the skin may be more closely related to immune homeostasis imbalance than to hyperglycemia itself. These findings shed light on the pathogenesis of diabetic ulcers and provide a theoretical basis for the use of hair follicle grafts in wound repair.

Enhancing subsurface multiphase flow simulation with Fourier neural operator.

Accurate numerical modeling of multiphase flow in subsurface oil and gas reservoirs is critical for optimizing hydrocarbon recovery. However, traditional physics-based algorithms face substantial computational hurdles due to the need for fine grid resolution and the inherent geological heterogeneity. To overcome these challenges, data-driven surrogate models solving the flow governing partial differential equations (PDEs) offer a promising alternative to enhance the efficiency of hydrocarbon production operations. In this study, we employ the Fourier Neural Operator (FNO) to extract spectral information from the reservoir properties, thereby facilitating the solution of coupled porous flow PDEs. Our focus is on two-phase flow dynamics, specifically exploring how water injection enhances reservoir pressure and displaces oil. This scenario involves solving a set of nonlinearly coupled PDEs with highly heterogeneous coefficients. Numerical results demonstrate that the developed FNO accurately predicts the reservoir pressure distributions. We further observe that the FNO's zero-shot super-resolution capability is sensitive to abrupt local changes in the reservoir pressure near injection and production wells. To enhance its accuracy, we propose a multi-fidelity FNO model that exhibits better adaptability across various grid configurations. After moderate training on graphics processing units (GPUs), the FNO achieves a speedup of three orders of magnitude compared to traditional numerical PDE solvers. Our experiments confirm the FNO's potential to replace repetitive physics-based simulations, significantly advancing computational efficiency in the uncertainty quantification of reservoir performance.

Cell-type-specific splicing of transcription regulators and Ptbp1 by Rbfox1/2/3 in the developing neocortex.

How master splicing regulators crosstalk with each other and to what extent transcription regulators are differentially spliced remain unclear in the developing brain. Here, cell-type-specific RNA-Seq of the developing neocortex uncover that transcription regulators are enriched for differential splicing, altering protein isoforms or inducing nonsense-mediated mRNA decay. Transient expression of Rbfox proteins in radial glia progenitors induces neuronal splicing events preferentially in transcription regulators such as Meis2 and Tead1. Surprisingly, Rbfox proteins promote the inclusion of a mammal-specific alternative exon and a previously undescribed poison exon in Ptbp1. Simultaneous ablation of Rbfox1/2/3 in the neocortex downregulates neuronal isoforms and disrupts radial neuronal migration. Furthermore, the progenitor isoform of Meis2 promotes Tgfb3 transcription, while the Meis2 neuron isoform promotes neuronal differentiation. These observations indicate that transcription regulators are differentially spliced between cell types in the developing neocortex.

The Difference in Ir-Catalyzed C(sp2)-H and C(sp3)-H Bond Activation Assisted by a Directing Group: Cyclometalation via Cis- or Trans-Chelation?

Iridium-catalyzed C-H borylation of aromatic and aliphatic hydrocarbons assisted by a directing group was theoretically investigated. Density functional theory (DFT) calculations revealed both Ir-catalyzed C(sp2)-H and C(sp3)-H borylations via an IrIII/IrV catalytic cycle, where the tetra-coordinated (C, N)IrIII(Bpin)2 complex with two vacant sites is an active species. Dramatically, the orientation of cyclometalation for C(sp2)-H bond activation assisted by a directing group is different from the C(sp3)-H one. The activation energy (ΔG°‡ = 28.5 kcal mol-1) of the C(sp2)-H bond via trans-chelation to form cyclometalation is lower than that (41.4 kcal mol-1) via cis-chelation. In contrast, the ΔG°‡ (26.6 kcal mol-1) of the C(sp3)-H bond via cis-chelation to form cyclometalation is lower than that (34.3 kcal mol-1) via trans-chelation. In addition, the rate-determining step of Ir-catalyzed C(sp2)-H borylation is oxidative addition of the C(sp2)-H bond, while that of C(sp3)-H analogues is hydride migration. Such differences arise from not only the differences in the steric hindrance of the C(sp2) and secondary C(sp3) atoms but also the differences in the trans effect and steric effect of the two vacant sites of active species. These findings were expected to facilitate further studies on the design and synthesis of innovative ligands for Ir-catalyzed C-H borylation.

PDCD10 Is a Key Player in TMZ-Resistance and Tumor Cell Regrowth: Insights into Its Underlying Mechanism in Glioblastoma Cells.

Overcoming temozolomide (TMZ)-resistance is a major challenge in glioblastoma therapy. Therefore, identifying the key molecular player in chemo-resistance becomes urgent. We previously reported the downregulation of PDCD10 in primary glioblastoma patients and its tumor suppressor-like function in glioblastoma cells. Here, we demonstrate that the loss of PDCD10 causes a significant TMZ-resistance during treatment and promotes a rapid regrowth of tumor cells after treatment. PDCD10 knockdown upregulated MGMT, a key enzyme mediating chemo-resistance in glioblastoma, accompanied by increased expression of DNA mismatch repair genes, and enabled tumor cells to evade TMZ-induced cell-cycle arrest. These findings were confirmed in independent models of PDCD10 overexpressing cells. Furthermore, PDCD10 downregulation led to the dedifferentiation of glioblastoma cells, as evidenced by increased clonogenic growth, the upregulation of glioblastoma stem cell (GSC) markers, and enhanced neurosphere formation capacity. GSCs derived from PDCD10 knockdown cells displayed stronger TMZ-resistance and regrowth potency, compared to their parental counterparts, indicating that PDCD10-induced stemness may independently contribute to tumor malignancy. These data provide evidence for a dual role of PDCD10 in tumor suppression by controlling both chemo-resistance and dedifferentiation, and highlight PDCD10 as a potential prognostic marker and target for combination therapy with TMZ in glioblastoma.

Hongjin Xiaojie Capsule, a Chinese patent medicine, for treating moderate to severe cyclical breast pain: A single-blind randomized controlled trial.

BACKGROUND: Moderate to severe breast pain has major effects on the quality of life for patients. Patent Chinese medicines are widely used in the treatment of breast pain due to their stable dosage form and good efficacy. OBJECTIVE: To evaluate the beneficial effects and safety of Hongjin Xiaojie Capsule (HJXJC), a Chinese patent medicine, for the treatment of cyclical breast pain. DESIGN, SETTING, PARTICIPANTS AND INTERVENTION: This is a multicenter, single-blind randomized controlled trial conducted in 3 medical centers in China from 2019 to 2021. Patients with moderate to severe cyclic breast pain were randomly divided into the intervention group (who took HJXJC, four capsules per dose, three times a day for 12 weeks) and the control group (waiting for the treatment) in a 1:1 ratio. MAIN OUTCOME MEASURES: The primary outcome was pain duration, and the patients recorded measurements at baseline and at the end of weeks 4, 8, 12 and 16 on a patient log card. RESULTS: The full analysis set (FAS) population included 298 participants (intervention group, n = 150; control group, n = 148), while the per-protocol analysis set (PPS) included 274 participants. After 12 weeks, the duration of breast pain was significantly shorter in the intervention group (FAS: mean difference, -6.69; 95% CI, -7.58 to -5.80; P < 0.01, vs control. PPS: mean difference, -7.09; 95% CI, -8.01 to -6.16; P < 0.01, vs control). The Short-form McGill Pain Questionnaire (SF-MPQ) scores were significantly lower in the intervention group (FAS: mean difference, -12.55; 95% CI, -13.90 to -11.21; P < 0.01, vs control. PPS: mean difference, -13.07; 95% CI, -14.48 to -11.66; P < 0.01, vs control). The above indicators continued to be significantly different through week 16. Moreover, in the intervention group, breast lumps shrank after 12 weeks and the size of breast lumps was statistically smaller than that in the control group (P < 0.05), whereas the sizes of breast nodules and uterine fibroid showed no statistically significant difference compared with the control group (P > 0.05). At weeks 8 and 12, the dysmenorrhea scores in the intervention group were lower than those in the control group (P < 0.05). No obvious adverse reactions were observed in any group. CONCLUSION: HJXJC can significantly shorten the duration of breast pain, reduce breast pain, reduce the size of breast lumps, and relieve dysmenorrhea. However, it has no significant effect on the size of breast nodules or uterine fibroid. TRIAL REGISTRATION: This trial has been registered at the ISRCTN Registry. Number: ISRCTN44184398. PLEASE CITE THIS ARTICLE AS: Zhang Q, Fan YY, Wu XQ, Huo YD, Wang CH, Liang SB, Wang T, Zhong R, Wang X, Lai BY, Pei XH, Liu JP. Hongjin Xiaojie Capsule, a Chinese patent medicine, for treating moderate to severe cyclical breast pain: A single-blind randomized controlled trial. J Integr Med. 2024; 22(5): 552-560.

Dynamic Control of Asymmetric Charge Distribution for Electrocatalytic Urea Synthesis.

Constructing dual catalytic sites with charge density differences is an efficient way to promote urea electrosynthesis from parallel NO 3 - ${\mathrm{NO}}_3^ - $ and CO2 reduction yet still challenging in static system. Herein, a dynamic system is constructed by precisely controlling the asymmetric charge density distribution in an Au-doped coplanar Cu7 clusters-based 3D framework catalyst (Au@cpCu7CF). In Au@cpCu7CF, the redistributed charge between Au and Cu atoms changed periodically with the application of pulse potentials switching between -0.2 and -0.6 V and greatly facilitated the electrosynthesis of urea. Compared with the static condition of pristine cpCu7CF (FEurea = 5.10%), the FEurea of Au@cpCu7CF under pulsed potentials is up to 55.53%. Theoretical calculations demonstrated that the high potential of -0.6 V improved the adsorption of *HNO2 and *NH2 on Au atoms and inhibited the reaction pathways of by-products. While at the low potential of -0.2 V, the charge distribution between Au and Cu atomic sites facilitated the thermodynamic C-N coupling step. This work demonstrated the important role of asymmetric charge distribution under dynamic regulation for urea electrosynthesis, providing a new inspiration for precise control of electrocatalysis.

A real-world study on the treatment of extremely preterm infants: a multi-center study in southwest area of Fujian Province in China.

BACKGROUND: Due to regional and cultural differences, the current status of extremely preterm infants(EPIs) treatment across different areas of mainland China remains unclear. This study investigated the survival rate and incidence of major diseases among EPIs in the southwest area of Fujian province. METHOD: This retrospective and multicenter study collected perinatal data from EPIs with gestational ages between 22-27+ 6w and born in the southwest area of Fujian province. The study population was divided into 6 groups based on gestational age at delivery. The primary outcome was the survival status at ordered hospital discharge or correct gestational age of 40 weeks, and the secondary outcome was the incidence of major diseases. The study analyzed the actual survival status of EPIs in the area. RESULT: A total of 2004 preterm infants with gestational ages of 22-27+ 6 weeks were enrolled in this study. Among them, 1535 cases (76.6%) were born in the delivery room but did not survive, 469 cases (23.4%) were transferred to the neonatal department for treatment, 101 cases (5.0%) received partial treatment, and 368 cases (18.4%) received complete treatment. The overall all-cause mortality rate was 84.4% (1691/2004). The survival rate and survival rate without major serious disease for EPIs who received complete treatment were 85.1% (313/368) and 31.5% (116/318), respectively. The survival rates for gestational ages 22-22+ 6w, 23-23+ 6w, 24-24+ 6w, 25-25+ 6w, 26-26+ 6w, and 27-27+ 6w were 0%, 0%, 59.1% (13/22), 83% (39/47), 88.8% (87/98), and 89.7% (174/198), respectively. The survival rates without major serious disease were 0%, 0%, 9.1% (2/22), 19.1% (9/47), 27.6% (27/98), and 40.2% (78/194), respectively. CONCLUSION: The all-cause mortality of EPIs in the southwest area of Fujian Province remains high, with a significant number of infants were given up after birth in the delivery room being the main influencing factor. The survival rate of EPIs who received complete treatment at 25-27 weeks in the NICU was similar to that in developed countries. However, the survival rate without major serious disease was significantly lower compared to high-income countries.

Causality of genetically determined metabolites on susceptibility to prevalent urological cancers: a two-sample Mendelian randomization study and meta-analysis.

Background: Prevalent urological cancers, including kidney, prostate, bladder, and testicular cancers, contribute significantly to global cancer incidence and mortality. Metabolomics, focusing on small-molecule intermediates, has emerged as a tool to understand cancer etiology. Given the knowledge gap in this field, we employ a two-sample Mendelian randomization (MR) analysis to investigate the causal relationships between genetically determined metabolites (GDMs) and the susceptibility to four common urological cancers. Methods: The study employs genome-wide association studies (GWAS) data from European populations, featuring the most extensive case count available for both blood metabolites and four prevalent urological cancers. Preliminary and secondary MR analyses were separately conducted, employing inverse variance weighted (IVW) as the primary method. Multiple statistical analyses, including the MR-Steiger test, Cochran's Q test, leave-one-out analysis, MR-Egger intercept analysis, and MR-PRESSO analysis, were executed to ensure robustness. Additionally, a meta-analysis was carried out to consolidate findings. The weighted median (WM) method was utilized for a relatively lenient correction (PWM < 0.05). Results: After rigorous genetic variation filtering, 645 out of 1,400 metabolites were included in both preliminary and secondary MR analyses. Preliminary MR analysis identified 96 potential causal associations between 94 distinct metabolites and four urological cancers. Secondary analysis based on Finnish outcome data revealed 93 potential causal associations. Cross-database meta-analysis identified 68 blood metabolites associated with four urological cancers. Notably, 31 metabolites remained significant after using WM for correction, with additional 37 suggestive causal relationships. Reverse MR analysis revealed a significant causal association between genetically predicted prostate cancer and elevated 4-hydroxychlorothalonil levels (IVW, combined OR: 1.039, 95% CI 1.014-1.064, p = 0.002; WM, combined OR: 1.052, 95% CI 1.010-1.095, p = 0.014). Conclusion: This comprehensive MR study provides insights into the causal relationships between blood metabolites and urological cancers, revealing potential biomarkers and therapeutic targets, thereby addressing gaps in understanding and laying the foundation for targeted interventions in urological cancer research and treatment.

Evaluating the efficacy of percutaneous puncture biopsy guided by contrast-enhanced ultrasound for peripheral pulmonary lesions.

BACKGROUND: The incidence and mortality of lung cancer have increased annually. Accurate diagnosis can help improve therapeutic efficacy of interventions and prognosis. Percutaneous lung biopsy is a reliable method for the clinical diagnosis of lung cancer. Ultrasound-guided percutaneous lung biopsy technology has been widely promoted and applied in recent years. AIM: To investigate the diagnostic value of contrast-enhanced ultrasound (CEUS)-guided percutaneous biopsy in peripheral pulmonary lesions. METHODS: We retrospectively collected data on 237 patients with peripheral thoracic focal lesions who underwent puncture biopsy at Wuxi People's Hospital. The patients were randomly divided into two groups: The CEUS-guided before lesion puncture group (contrast group) and conventional ultrasound-guided group (control group). Analyze the diagnostic efficacy of the puncture biopsy, impact of tumor size, and number of puncture needles and complications were analyzed and compared between the two groups. RESULTS: Accurate pathological results were obtained for 92.83% (220/237) of peripheral lung lesions during the first biopsy, with an accuracy rate of 95.8% (113/118) in the contrast group and 89.9% (107/119) in the control group. The difference in the area under the curve (AUC) between the contrast and the control groups was not statistically significant (0.952 vs 0.902, respectively; P > 0.05). However, when the lesion diameter ≥ 5 cm, the diagnostic AUC of the contrast group was higher than that of the control group (0.952 vs 0.902, respectively; P < 0.05). In addition, the average number of puncture needles in the contrast group was lower than that in the control group (2.58 ± 0.53 vs 2.90 ± 0.56, respectively; P < 0.05). CONCLUSION: CEUS guidance can enhance the efficiency of puncture biopsy of peripheral pulmonary lesions, especially for lesions with a diameter ≥ 5 cm. Therefore, CEUS guidance has high clinical diagnostic value in puncture biopsy of peripheral focal lung lesions.

Satellite observations reveal anthropogenic pressure significantly affects the suspended particulate matter concentrations in coastal waters of Hainan Island.

Suspended particulate matter (SPM) plays a crucial role in assessing the health status of coastal ecosystems. Satellite remote sensing offers an effective approach to investigate the variations and distribution patterns of SPM, with the performance of various satellite retrieval models exhibiting significant spatial heterogeneity. However, there is still limited information on precise remote sensing retrieval algorithms specifically designed for estimating SPM in tropical areas, hindering our ability to monitor the health status of valuable tropical ecological resources. A relatively accurate empirical algorithm (root mean square error = 2.241 mg L-1, mean absolute percentage error = 42.527%) was first developed for the coastal SPM of Hainan Island based on MODIS images and over a decade of field SPM data, which conducted comprehensive comparisons among empirical models, semi-analytical models, and machine learning models. Long-term monitoring from 2003 to 2022 revealed that the average SPM concentration along the coastal wetlands of Hainan Island was 6.848 mg L-1, which displayed a decreasing trend due to government environmental protection regulations (average rate of change of -0.009 mg L-1/year). The seasonal variations in coastal SPM were primarily influenced by sea surface temperature (SST). Spatially, the concentrations of SPM along the southwest coast of Hainan Island were higher in comparison to other waters, which was attributable to sediment types and ocean currents. Further, anthropogenic pressure (e.g., agricultural waste input, vegetation cover) was the main influence on the long-term changes of coastal SPM in Hainan Island, particularly evident in typical tropical ecosystems affected by aquaculture, coastal engineering, and changes in coastal green vegetation. Compared to other typical ecosystems around the globe, the overall health status of SPM along the coast wetlands of Hainan is considered satisfactory. These findings not only establish a robust remote sensing model for long-term SPM monitoring along the coast of Hainan Island, but also provide comprehensive insights into SPM dynamics, thereby contributing to the formulation of future coastal zone management policies.

Membranous aplasia cutis congenita: A rare case report highlighting clinical presentation, genetic insights, and the need for comprehensive evaluation.

Introduction: Membranous aplasia cutis congenita (MACC) is the most common clinical subtype of aplasia cutis congenita (ACC). It is typified by a localized skin lesion devoid of hair and features a membranous surface. While most MACC individuals do not present with concurrent abnormalities, it can sometimes co-occur with additional physical anomalies and various malformation syndromes. Moreover, the underlying causes of MACC remain elusive. Case presentation: We describe a case of a 6-month-old female infant diagnosed with MACC. The patient presented with a midline skin lesion on the occipital scalp, characterized by a glistening surface and a hair collar sign. Dermoscopic examination revealed specific features, including translucency, telangiectasia, and hypertrichosis. The infant had a history of patent foramen ovale, and further examination uncovered an asymptomatic ventricular septal defect. Whole exome sequencing revealed 20 gene variants relevant to the clinical phenotype of the patient, suggesting a possible association with MACC. Conclusion: MACC is a rare and underreported condition, primarily diagnosed based on its distinctive clinical features. It is imperative to emphasize the significance of thorough evaluations in MACC patients, encompassing developmental, cardiac, neurological, and genetic assessments to facilitate early detection and the exclusion of potentially life-threatening comorbidities. Importantly, genetic characterization, as demonstrated in this case, contributes to our understanding of MACC's etiology and highlights the need for further research in this field.

Sleep patterns, genetic susceptibility, and risk of cirrhosis among individuals with nonalcoholic fatty liver disease.

BACKGROUND: The associations between sleep patterns or behaviors and the risk of cirrhosis and the influence of genetic susceptibility on these associations among NAFLD participants remain inadequately elucidated. METHODS: This study conducted a prospective follow-up of 112,196 NAFLD participants diagnosed at baseline from the UK Biobank cohort study. Five sleep behaviors were collected to measure a healthy sleep score. Five genetic variants were used to construct a polygenic risk score. We used Cox proportional hazard model to assess hazard ratios (HR) and 95% confidence intervals (CIs) for incidence of cirrhosis. RESULTS: During the follow-up, 592 incident cirrhosis cases were documented. Healthy sleep pattern was associated with reduced risk of cirrhosis in a dose-response manner (ptrend < 0.001). Participants with favourable sleep score (versus unfavourable sleep score) had an HR of 0.55 for cirrhosis risk (95% CI 0.39-0.78). Multivariable-adjusted HRs (95% CIs) of cirrhosis incidence for NAFLDs with no frequent insomnia, sleeping for 7-8 h per day, and no excessive daytime dozing behaviors were 0.73 (0.61-0.87), 0.79 (0.66-0.93), and 0.69 (0.50-0.95), respectively. Compared with participants with favourable sleep pattern and low genetic risk, those with unfavourable sleep pattern and high genetic risk had higher risks of cirrhosis incidence (HR 3.16, 95% CI 1.88-5.33). In addition, a significant interaction between chronotype and genetic risk was detected for the incidence of cirrhosis (p for multiplicative interaction = 0.004). CONCLUSION: An association was observed between healthy sleep pattern and decreased risk of cirrhosis among NAFLD participants, regardless of low or high genetic risk.

Diagnosis of cervical lymphoma using a YOLO-v7-based model with transfer learning.

To investigate the ability of an auxiliary diagnostic model based on the YOLO-v7-based model in the classification of cervical lymphadenopathy images and compare its performance against qualitative visual evaluation by experienced radiologists. Three types of lymph nodes were sampled randomly but not uniformly. The dataset was randomly divided into for training, validation, and testing. The model was constructed with PyTorch. It was trained and weighting parameters were tuned on the validation set. Diagnostic performance was compared with that of the radiologists on the testing set. The mAP of the model was 96.4% at the 50% intersection-over-union threshold. The accuracy values of it were 0.962 for benign lymph nodes, 0.982 for lymphomas, and 0.960 for metastatic lymph nodes. The precision values of it were 0.928 for benign lymph nodes, 0.975 for lymphomas, and 0.927 for metastatic lymph nodes. The accuracy values of radiologists were 0.659 for benign lymph nodes, 0.836 for lymphomas, and 0.580 for metastatic lymph nodes. The precision values of radiologists were 0.478 for benign lymph nodes, 0.329 for lymphomas, and 0.596 for metastatic lymph nodes. The model effectively classifies lymphadenopathies from ultrasound images and outperforms qualitative visual evaluation by experienced radiologists in differential diagnosis.

Developing and validating a nomogram for early predicting the need for intestinal resection in pediatric intussusception.

Purpose: Develop and validate a nomogram for predicting intestinal resection in pediatric intussusception suspecting intestinal necrosis. Patients & methods: Children with intussusception were retrospectively enrolled after a failed air-enema reduction in the outpatient setting and divided into two groups: the intestinal resection group and the non-intestinal resection group. The enrolled cases were randomly selected for training and validation sets with a split ratio of 3:1. A nomogram for predicting the risk of intestinal resection was visualized using logistic regression analysis with calibration curve, C-index, and decision curve analysis to evaluate the model. Results: A total of 547 cases were included in the final analysis, of which 414 had non-intestinal necrosis and 133 had intestinal necrosis and underwent intestinal resection. The training set consisted of 411 patients and the validation cohort included 136 patients. Through forward stepwise regression, four variables (duration of symptoms, C-reaction protein, white blood cells, ascites) were selected for inclusion in the nomogram with a concordance index 0.871 (95% confidence interval: 0.834-0.908). Conclusion: We developed a nomogram for predicting intestinal resection in children with intussusception suspecting intestinal necrosis after a failed air-enema based on multivariate regression. This nomogram could be directly applied to facilitate predicting intestinal resection in pediatric intussusception suspecting necrosis.

Alcohol and colorectal cancer risk, subclassified by mutational signatures of DNA mismatch repair deficiency.

BACKGROUND: We examined whether the association between alcohol consumption and colorectal cancer (CRC) incidence was stronger for tumors with higher contributions of defective mismatch repair (dMMR)-related tumor mutational signatures. METHODS: We used data from 227 916 men and women who participated in the Nurses' Health Study (1980-2016), the Nurses' Health Study II (1991-2017), and the Health Professionals Follow-Up Study (1986-2016). Dietary data were collected every 4 years through validated food frequency questionnaires. Relative contributions of 2 defective mismatch repair-related tumor mutational signatures with single-based substitutions (c-dMMRa/SBS15 and c-dMMRb/SBS26) were quantified using whole-exome sequencing data in a subset of incident CRC patients. Duplication-method Cox proportional hazards regression models were used to assess the association between alcohol consumption and the risk of CRC subtypes according to different contributions of the tumor mutational signatures. All statistical tests were 2-sided. RESULTS: We documented 825 incident CRC patients with available tumor mutational signature data over 26 to 36 years of follow-up. The association between alcohol consumption and CRC incidence was stronger for tumors with higher contributions of c-dMMRb/SBS26 (Ptrend = .02 for heterogeneity) compared with tumors with lower contributions of this tumor mutational signature. Compared with nondrinkers, drinkers who imbibed 15 g/d or more of alcohol had a high risk of c-dMMRb/SBS26-high CRC (multivariable-adjusted hazard ratio = 2.43, 95% confidence interval = 1.55 to 3.82) but not c-dMMRb/SBS26-low CRC (multivariable-adjusted hazard ratio = 0.86, 95% confidence interval = 0.57 to 1.28) or c-dMMRb/SBS26-moderate CRC (multivariable-adjusted hazard ratio = 1.14, 95% confidence interval = 0.76 to 1.71). No significant differential associations were observed for c-dMMRa/SBS15 (Ptrend = .41 for heterogeneity). CONCLUSIONS: High alcohol consumption was associated with an increased incidence of CRC containing higher contributions of c-dMMRb/SBS26, suggesting that alcohol consumption may be involved in colorectal carcinogenesis through the DNA mismatch repair pathway.

Intestinal epithelial Krüppel-like factor 4 alleviates endotoxemia and atherosclerosis through improving NF-κB/miR-34a-mediated intestinal permeability.

Maintenance of intestinal barrier function contributes to gastrointestinal homeostasis and therefore cardiovascular diseases. A number of studies show that intestinal permeability is affected by excessive inflammatory responses. Krüppel-like factor (KLF) 4 is one of the critical transcriptional factors, which controls multiple immune responses. In this study we investigated the role of KLF4 in regulating intestinal inflammation and permeability during the atherosclerotic process. Atherosclerotic model was established in ApoE-/- mice by feeding a high fat high cholesterol (HFHC) diet. We showed that colon expression levels of KLF4 and tight junction proteins were significantly decreased whereas inflammatory responses increased in atherosclerotic mice. Overexpression of colon epithelial Klf4 decreased atherosclerotic plaque formation and vascular inflammation in atherosclerotic mice, accompanied by remarkable suppression of intestinal NF-κB activation. We found that overexpression of epithelial Klf4 in atherosclerotic mice significantly increased intestinal tight junction expression and ameliorated endotoxemia, whereas replenishment of LPS abolished these benefits. Overexpression of Klf4 reversed LPS-induced permeability and downregulation of ZO-1 and Occludin in Caco-2 cells in vitro. HFHC diet stimulated the expression of epithelial microRNA-34a, whereas silence of epithelial Klf4 abolished the benefits of microRNA-34a sponge, a specific miR-34a inhibitor, on intestinal permeability and atherosclerotic development. A clinical cohort of 24 atherosclerotic patients supported colon KLF4/NF-κB/tight junction protein axis mediated intestine/cardiovascular interaction in patients with atherosclerosis. Taken together, intestinal epithelial KLF4 protects against intestinal inflammation and barrier dysfunction, ameliorating atherosclerotic plaque formation.

Targeting the IRE1α-XBP1s axis confers selective vulnerability in hepatocellular carcinoma with activated Wnt signaling.

Liver-specific Ern1 knockout impairs tumor progression in mouse models of hepatocellular carcinoma (HCC). However, the mechanistic role of IRE1α in human HCC remains unclear. In this study, we show that XBP1s, the major downstream effector of IRE1α, is required for HCC cell survival both in vitro and in vivo. Mechanistically, XBP1s transactivates LEF1, a key co-factor of ß-catenin, by binding to its promoter. Moreover, XBP1s physically interacts with LEF1, forming a transcriptional complex that enhances classical Wnt signaling. Consistently, the activities of XBP1s and LEF1 are strongly correlated in human HCC and with disease prognosis. Notably, selective inhibition of XBP1 splicing using an IRE1α inhibitor significantly repressed the viability of tumor explants as well as the growth of tumor xenografts derived from patients with distinct Wnt/LEF1 activities. Finally, machine learning algorithms developed a powerful prognostic signature based on the activities of XBP1s/LEF1. In summary, our study uncovers a key mechanistic role for the IRE1α-XBP1s pathway in human HCC. Targeting this axis could provide a promising therapeutic strategy for HCC with hyperactivated Wnt/LEF1 signaling.

Post-diagnostic multivitamin supplement use and colorectal cancer survival: A prospective cohort study.

BACKGROUND: Use of multivitamin supplements has been associated with lower incidence of colorectal cancer (CRC). However, its influence on CRC survival remains unknown. METHODS: Among 2424 patients with stage I-III CRC who provided detailed information about multivitamin supplements in the Nurses' Health Study and Health Professionals Follow-up Study, the authors calculated multivariable hazard ratios (HRs) of multivitamin supplements for all-cause and CRC-specific mortality according to post-diagnostic use and dose of multivitamin supplements. RESULTS: During a median follow-up of 11 years, the authors documented 1512 deaths, among which 343 were of CRC. Compared to non-users, post-diagnostic users of multivitamin supplements at a dose of 3-5 tablets/week had lower CRC-specific mortality (HR, 0.55; 95% confidence interval [CI], 0.36-0.83, p = .005), and post-diagnostic users at doses of 3-5 and 6-9 tablets/week had lower all-cause mortality (HR, 0.81; 95% CI, 0.67-0.99, p = .04; HR, 0.79; 95% CI, 0.70-0.88), p < .001). The dose-response analysis showed a curvilinear relationship for both CRC-specific (pnonlinearity < .001) and all-cause mortality (pnonlinearity = .004), with the maximum risk reduction observed at 3-5 tablets/week and no further reduction at higher doses. Compared to non-users in both pre- and post-diagnosis periods, new post-diagnostic users at dose of <10 tablets/week had a lower all-cause mortality (HR, 0.81; 95% CI, 0.71-0.94, p = .005), whereas new users at a dose of ≥10 tablets/week (HR, 1.58; 95% CI, 1.07-2.33) and discontinued users (HR, 1.35; 95% CI, 1.14-1.59) had a higher risk of mortality. CONCLUSIONS: Use of multivitamin supplements at a moderate dose after a diagnosis of nonmetastatic CRC is associated with lower CRC-specific and overall mortality, whereas a high dose (≥10 tablets/week) use is associated with higher CRC-specific mortality.

Development of Inverse-Opal-Structured Charge-Deficient Co9S8@nitrogen-Doped-Carbon to Catalytically Enable High Energy and High Power for the Two-Electron Transfer I+/I- Electrode.

The iodine (I) electrode involving two-electron transfer chemistry by converting between I+ and I-, has the potential to deliver theoretically doubled capacity and higher working voltage platforms, thus achieving higher energy density. However, owing to the slow kinetics of the cascade two-electron transfer reactions, the system suffers from large overpotentials and low power density, especially at high working currents and low temperatures. Here, an inverse-opal-structured cobalt sulfide@nitrogen-doped-carbon (Co9S8@NC) catalyst with unique charge-deficient states is developed to promote the reaction kinetics of the I-/I+ electrode. The charge-deficient Co9S8@NC catalyst not only enables strong physicochemical adsorption with the iodine species but also significantly reduces the activation energy and interfacial charge transfer resistance of the cascade I+/I0/I- conversion reaction. Consequently, the prototypical Zn‖I+/I0/I- battery equipped with the Co9S8@NC catalyst can deliver a high energy density of 554 Wh kg-1 and a stable cycle life of 5000 cycles at 30 °C. Moreover, at a subzero temperature of -30 °C, the battery can exhibit enhanced kinetics and a high power density of 1514 W kg-1, high energy density of 485 Wh kg-1.