Dual-functional single-atomic Mo/Fe clusters-decorated C3N5 via three electron-pathway in oxygen reduction reaction for tandemly removing contaminants from water.

Inspired by the development of single-atom catalysts (SACs), the fabrication of multimetallic SACs can be a promising technical approach for the in situ electro-Fenton (EF) process. Herein, dual-functional atomically dispersed Mo-Fe sites embedded in carbon nitride (C3N5) (i.e., MoFe/C3N5) were synthesized via a facile SiO2 template method. The atomically isolated bimetallic configuration in MoFe/C3N5 was identified by combining the microscopic and spectroscopic techniques. The MoFe/C3N5 catalyst on the cathode exhibited a remarkable catalytic activity toward the three electron-dominated oxygen reduction reaction in sodium sulfate, leading to a highly effective EF reaction with a low overpotential for the removal of organic contaminants from wastewater. The new catalyst showed a superior performance over its conventional counterparts, owing to the dual functions of the dual-metal active sites. Density functional theory (DFT) analysis revealed that the dual-functional 50-MoFe/C3N5 catalyst enabled a synergistic action of the Mo-Fe dual single atomic centers, which can alter the adsorption/dissociation behavior and decrease the overall reaction barriers for effective organic oxidation during the EF process. This study not only sheds light on the controlled synthesis of atomically isolated catalyst materials but also provides deeper understanding of the structure-performance relationship of the nanocatalysts with dual active sites for the catalytic EF process. Additionally, the findings will promote the advanced catalysis for the treatment of emerging organic contaminants in water and wastewater.

Upregulation of proBDNF/p75NTR signaling in immune cells and its correlation with inflammatory markers in patients with major depression.

ProBDNF is the precursor protein of brain-derived neurotrophic factor (BDNF) expressed in the central nervous system and peripheral tissues. Previous studies showed that the blood levels of both proBDNF and p75 neurotrophic receptors (p75NTR) in major depressive disorder (MDD) were increased, but which blood cell types express proBDNF and its receptors is not known. Furthermore, the relationship between proBDNF/p75NTR and inflammatory cytokines in peripheral blood of MDD is unclear. Peripheral blood mononuclear cells (PBMCs) and serum were obtained from depressive patients (n = 32) and normal donors (n = 20). We examined the expression of proBDNF and inflammatory markers and their correlative relationship in patients with major depression. Using flow cytometry analysis, we examined which blood cells express proBDNF and its receptors. Finally, the role of proBDNF/p75NTR signal in inflammatory immune activity of PBMCs was verified in vitro experiments. Inflammatory cytokines in PBMC from MDD patients were increased and correlated with the major depression scores. The levels of IL-1ß and IL-10 were also positively correlated with the major depression scores, while the levels of TNF-α and IL-6 were negatively correlated with the major depression scores. Intriguingly, the levels of sortilin were positively correlated with IL-1ß. Q-PCR and Western blots showed proBDNF, p75NTR, and sortilin levels were significantly increased in PBMCs from MDD patients compared with that from the normal donors. Flow cytometry studies showed that proBDNF and p75NTR were present mainly in CD4+ and CD8+ T cells. The number of proBDNF and p75NTR positive CD4+ and CD8+ T cells from MDD patients was increased and subsequently reversed after therapeutic management. Exogenous proBDNF protein or p75ECD-Fc treatment of cultured PBMC affected the release of inflammatory cytokines in vitro. ProBDNF promoted the expression of inflammatory cytokines, while p75ECD-Fc inhibited the expression of inflammatory cytokines. Given there was an inflammatory response of lymphocytes to proBDNF, it is suggested that proBDNF/p75NTR signaling may upstream inflammatory cytokines in MDD. Our data suggest that proBDNF/p75NTR signaling may not only serve as biomarkers but also may be a potential therapeutic target for MDD.

DNMT3a-mediated methylation of PPARγ promote intervertebral disc degeneration by regulating the NF-κB pathway.

Intervertebral disc degeneration (IVDD) is a common chronic musculoskeletal disease that causes chronic low back pain and imposes an immense financial strain on patients. The pathological mechanisms underlying IVDD have not been fully elucidated. The development of IVDD is closely associated with abnormal epigenetic changes, suggesting that IVDD progression may be controlled by epigenetic mechanisms. Consequently, this study aimed to investigate the role of epigenetic regulation, including DNA methyltransferase 3a (DNMT3a)-mediated methylation and peroxisome proliferator-activated receptor γ (PPARγ) inhibition, in IVDD development. The expression of DNMT3a and PPARγ in early and late IVDD of nucleus pulposus (NP) tissues was detected using immunohistochemistry and western blotting analyses. Cellularly, DNMT3a inhibition significantly inhibited IL-1ß-induced apoptosis and extracellular matrix (ECM) degradation in rat NP cells. Pretreatment with T0070907, a specific inhibitor of PPARγ, significantly reversed the anti-apoptotic and ECM degradation effects of DNMT3a inhibition. Mechanistically, DNMT3a modified PPARγ promoter hypermethylation to activate the nuclear factor-κB (NF-κB) pathway. DNMT3a inhibition alleviated IVDD progression. Conclusively, the results of this study show that DNMT3a activates the NF-κB pathway by modifying PPARγ promoter hypermethylation to promote apoptosis and ECM degradation. Therefore, we believe that the ability of DNMT3a to mediate the PPARγ/NF-κB axis may provide new ideas for the potential pathogenesis of IVDD and may become an attractive target for the treatment of IVDD.

PCK2 maintains intestinal homeostasis and prevents colitis by protecting antibody-secreting cells from oxidative stress.

Maintaining intracellular redox balance is essential for the survival, antibody secretion, and mucosal immune homeostasis of immunoglobulin A (IgA) antibody-secreting cells (ASCs). However, the relationship between mitochondrial metabolic enzymes and the redox balance in ASCs has yet to be comprehensively studied. Our study unveils the pivotal role of mitochondrial enzyme PCK2 in regulating ASCs' redox balance and intestinal homeostasis. We discover that PCK2 loss, whether globally or in B cells, exacerbates dextran sodium sulphate (DSS)-induced colitis due to increased IgA ASC cell death and diminished antibody production. Mechanistically, the absence of PCK2 diverts glutamine into the TCA cycle, leading to heightened TCA flux and excessive mitochondrial reactive oxygen species (mtROS) production. In addition, PCK2 loss reduces glutamine availability for glutathione (GSH) synthesis, resulting in a decrease of total glutathione level. The elevated mtROS and reduced GSH expose ASCs to overwhelming oxidative stress, culminating in cell apoptosis. Crucially, we found that the mitochondria-targeted antioxidant Mitoquinone (Mito-Q) can mitigate the detrimental effects of PCK2 deficiency in IgA ASCs, thereby alleviating colitis in mice. Our findings highlight PCK2 as a key player in IgA ASC survival and provide a potential new target for colitis treatment.

Cetuximab plus FOLFOXIRI versus cetuximab plus FOLFOX as conversion regimen in RAS/BRAF wild-type patients with initially unresectable colorectal liver metastases (TRICE trial): A randomized controlled trial.

BACKGROUND: It remains unclear whether intensification of the chemotherapy backbone in tandem with an anti-EGFR can confer superior clinical outcomes in a cohort of RAS/BRAF wild-type colorectal cancer (CRC) patients with initially unresectable colorectal liver metastases (CRLM). To that end, we sought to comparatively evaluate the efficacy and safety of cetuximab plus FOLFOXIRI (triplet arm) versus cetuximab plus FOLFOX (doublet arm) as a conversion regimen (i.e., unresectable to resectable) in CRC patients with unresectable CRLM. METHODS AND FINDINGS: This open-label, randomized clinical trial was conducted from April 2018 to December 2022 in 7 medical centers across China, enrolling 146 RAS/BRAF wild-type CRC patients with initially unresectable CRLM. A stratified blocked randomization method was utilized to assign patients (1:1) to either the cetuximab plus FOLFOXIRI (n = 72) or cetuximab plus FOLFOX (n = 74) treatment arms. Stratification factors were tumor location (left versus right) and resectability (technically unresectable versus ≥5 metastases). The primary outcome was the objective response rate (ORR). Secondary outcomes included the median depth of tumor response (DpR), early tumor shrinkage (ETS), R0 resection rate, progression-free survival (PFS), overall survival (not mature at the time of analysis), and safety profile. Radiological tumor evaluations were conducted by radiologists blinded to the group allocation. Primary efficacy analyses were conducted based on the intention-to-treat population, while safety analyses were performed on patients who received at least 1 line of chemotherapy. A total of 14 patients (9.6%) were lost to follow-up (9 in the doublet arm and 5 in the triplet arm). The ORR was comparable following adjustment for stratification factors, with 84.7% versus 79.7% in the triplet and doublet arms, respectively (odds ratio [OR] 0.70; 95% confidence intervals [CI] [0.30, 1.67], Chi-square p = 0.42). Moreover, the ETS rate showed no significant difference between the triplet and doublet arms (80.6% (58/72) versus 77.0% (57/74), OR 0.82, 95% CI [0.37, 1.83], Chi-square p = 0.63). Although median DpR was higher in the triplet therapy group (59.6%, interquartile range [IQR], [50.0, 69.7] versus 55.0%, IQR [42.8, 63.8], Mann-Whitney p = 0.039), the R0/R1 resection rate with or without radiofrequency ablation/stereotactic body radiation therapy was comparable with 54.2% (39/72) of patients in the triplet arm versus 52.7% (39/74) in the doublet arm. At a median follow-up of 26.2 months (IQR [12.8, 40.5]), the median PFS was 11.8 months in the triplet arm versus 13.4 months in the doublet arm (hazard ratio [HR] 0.74, 95% CI [0.50, 1.11], Log-rank p = 0.14). Grade ≥ 3 events were reported in 47.2% (35/74) of patients in the doublet arm and 55.9% (38/68) of patients in the triplet arm. The triplet arm was associated with a higher incidence of grade ≥ 3 neutropenia (44.1% versus 27.0%, p = 0.03) and diarrhea (5.9% versus 0%, p = 0.03). The primary limitations of the study encompass the inherent bias in subjective surgical decisions regarding resection feasibility, as well as the lack of a centralized assessment for ORR and resection. CONCLUSIONS: The combination of cetuximab with FOLFOXIRI did not significantly improve ORR compared to cetuximab plus FOLFOX. Despite achieving an enhanced DpR, this improvement did not translate into improved R0 resection rates or PFS. Moreover, the triplet arm was associated with an increase in treatment-related toxicity. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03493048.

Hyperfractionation compared with standard fractionation in intensity-modulated radiotherapy for patients with locally advanced recurrent nasopharyngeal carcinoma: a multicentre, randomised, open-label, phase 3 trial.

BACKGROUND: Reirradiation in standard fractionation for locally advanced recurrent nasopharyngeal carcinoma after a previous course of high-dose radiotherapy is often associated with substantial late toxicity, negating its overall benefit. We therefore aimed to investigate the efficacy and safety of hyperfractionation compared with standard fractionation in intensity-modulated radiotherapy. METHODS: This multicentre, randomised, open-label, phase 3 trial was done in three centres in Guangzhou, China. Eligible patients were aged 18-65 years with histopathologically confirmed undifferentiated or differentiated, non-keratinising, advanced locally recurrent nasopharyngeal carcinoma. Participants were randomly assigned (1:1) to either receive hyperfractionation (65 Gy in 54 fractions, given twice daily with an interfractional time interval of at least 6 h) or standard fractionation (60 Gy in 27 fractions, given once a day). Intensity-modulated radiotherapy was used in both groups. A computer program generated the assignment sequence and randomisation was stratified by treatment centre, recurrent tumour stage (T2-T3 vs T4), and recurrent nodal stage (N0 vs N1-N2), determined at the time of randomisation. The two primary endpoints were the incidence of severe late complications defined as the incidence of grade 3 or worse late radiation-induced complications occurring 3 months after the completion of radiotherapy until the latest follow-up in the safety population, and overall survival defined as the time interval from randomisation to death due to any cause in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02456506. FINDINGS: Between July 10, 2015, and Dec 23, 2019, 178 patients were screened for eligibility, 144 of whom were enrolled and randomly assigned to hyperfractionation or standard fractionation (n=72 in each group). 35 (24%) participants were women and 109 (76%) were men. After a median follow-up of 45·0 months (IQR 37·3-53·3), there was a significantly lower incidence of grade 3 or worse late radiation-induced toxicity in the hyperfractionation group (23 [34%] of 68 patients) versus the standard fractionation group (39 [57%] of 68 patients; between-group difference -23% [95% CI -39 to -7]; p=0·023). Patients in the hyperfractionation group had better 3-year overall survival than those in the standard fractionation group (74·6% [95% CI 64·4 to 84·8] vs 55·0% [43·4 to 66·6]; hazard ratio for death 0·54 [95% CI 0·33 to 0·88]; p=0·014). There were fewer grade 5 late complications in the hyperfractionation group (five [7%] nasal haemorrhage) than in the standard fractionation group (16 [24%], including two [3%] nasopharyngeal necrosis, 11 [16%] nasal haemorrhage, and three [4%] temporal lobe necrosis). INTERPRETATION: Hyperfractionated intensity-modulated radiotherapy could significantly decrease the rate of severe late complications and improve overall survival among patients with locally advanced recurrent nasopharyngeal carcinoma. Our findings suggest that hyperfractionated intensity-modulated radiotherapy could be used as the standard of care for these patients. FUNDING: Key-Area Research and Development of Guangdong Province, the National Natural Science Foundation of China, the Special Support Program for High-level Talents in Sun Yat-sen University Cancer Center, the Guangzhou Science and Technology Plan Project, and the National Ten Thousand Talents Program Science and Technology Innovation Leading Talents, Sun Yat-Sen University Clinical Research 5010 Program.

Oxygen and Electron Storage Effects in W-Modified Ceria Catalysts for Ammonia Conversion.

Tungsten-modified CeO2 is an excellent catalyst for the catalytic conversion of ammonia. However, the geometric and electronic properties of this catalyst and the detailed reaction mechanisms are not well understood. In this work, the potential configurations of various monomer tungsten oxides supported on the CeO2(111) surface (WOX(x = 0-4)/CeO2(111)) are systematically studied and their relative stabilities are evaluated by using on-site Coulomb interaction corrected density functional theory calculations. Their performances are also investigated in enhancing the catalytic efficiency of NH3 adsorption and activation. It is found that the WOx clusters can always form tetrahedron-like structures on the CeO2(111) surface, and the CeO2(111) can exhibit both oxygen- and electron-storage roles to help the WOX maintain such tetrahedron-like WO4 structures and keep the W species at the highest 6+ state. Moreover, the flexibility of the tetrahedral WO4 structure leads to the preferential heterolytic NH3 dissociation at the WO sites, forming stable WNH2 and OH species. This study deepens the understanding of the unique oxygen- and electron-storage effects of the CeO2 support, it also provides valuable insights into the extraordinary catalytic properties of the W-modified CeO2 in NH3 conversion, paving the way for the rational design of more efficient CeO2-based NH3 treatment catalysts.

TGF-ß signaling pathway in spinal cord injury: Mechanisms and therapeutic potential.

Spinal cord injury (SCI) is a highly disabling central nervous system injury with a complex pathological process, resulting in severe sensory and motor dysfunction. The current treatment modalities only alleviate its symptoms and cannot effectively intervene or treat its pathological process. Many studies have reported that the transforming growth factor (TGF)-ß signaling pathway plays an important role in neuronal differentiation, growth, survival, and axonal regeneration after central nervous system injury. Furthermore, the TGF-ß signaling pathway has a vital regulatory role in SCI pathophysiology and neural regeneration. Following SCI, regulation of the TGF-ß signaling pathway can suppress inflammation, reduce apoptosis, prevent glial scar formation, and promote neural regeneration. Due to its role in SCI, the TGF-ß signaling pathway could be a potential therapeutic target. This article reported the pathophysiology of SCI, the characteristics of the TGF-ß signaling pathway, the role of the TGF-ß signaling pathway in SCI, and the latest evidence for targeting the TGF-ß signaling pathway for treating SCI. In addition, the limitations and difficulties in TGF-ß signaling pathway research in SCI are discussed, and solutions are provided to address these potential challenges. We hope this will provide a reference for the TGF-ß signaling pathway and SCI research, offering a theoretical basis for targeted therapy of SCI.

A 3-Year Survival Update from a Phase 2 Study of Paclitaxel Plus Cisplatin and 5-Fuorouracil Induction Chemotherapy for Locally Advanced Borderline-Resectable Esophageal Squamous Cell Carcinoma: The NEOCRTEC-1601 Clinical Trial.

BACKGROUND: This study updated 3-year analyses to further characterize the impact of docetaxel, cisplatin, and fluorouracil (TPF) chemotherapy followed by surgery. METHODS: This study was a single-center phase 2 clinical trial. Patients with a diagnosis of borderline resectable esophageal squamous cell carcinoma (BR-ESCC) because of the primary tumor or bulky lymph node that potentially invaded adjacent organs were eligible. The treatment started with TPF chemotherapy followed by surgery if the cancer was resectable, or by concurrent chemoradiation if it was unresectable. This updated report presents the 3-year overall survival (OS) and progression-free survival (PFS) rates. RESULTS: Surgery was performed for 27 patients (57.4%), and R0 resection was confirmed in 25 patients (53.2%). Pathologic complete response was confirmed in four patients (8.5%). The median follow-up time for the surviving patients was 44.8 months (range, 3.4-74.6 months). The median OS for all the patients was 41.9 months (95% confidence interval [CI], 18.6-65.3 months), with a median PFS of 38.7 months (95% CI, 23.5-53.9 months). The 3-year survival rate for all the patients was 54.4%. The 3-year survival rate for the R0 patients was 65.4%. CONCLUSION: Long-term follow-up evaluation confirmed that TPF followed by surgery is feasible and promising in terms of survival for BR-ESCC patients. Trial Registration ClinicalTrials.gov identifer: NCT02976909.

Patterns and correlates of potential range shifts of bat species in China in the context of climate change.

Climate change may diminish biodiversity; thus, it is urgent to predict how species' ranges may shift in the future by integrating multiple factors involving more taxa. Bats are particularly sensitive to climate change due to their high surface-to-volume ratio. However, few studies have considered geographic variables associated with roost availability and even fewer have linked the distributions of bats to their thermoregulation and energy regulation traits. We used species distribution models to predict the potential distributions of 12 bat species in China under current and future greenhouse gas emission scenarios (SSP1-2.6 and SSP5-8.5) and examined factors that could affect species' range shifts, including climatic, geographic, habitat, and human activity variables and wing surface-to-mass ratio (S-MR). The results suggest that Ia io, Rhinolophus ferrumequinum, and Rhinolophus rex should be given the highest priority for conservation in future climate conservation strategies. Most species were predicted to move northward, except for I. io and R. rex, which moved southward. Temperature seasonality, distance to forest, and distance to karst or cave were the main environmental factors affecting the potential distributions of bats. We found significant relationships between S-MR and geographic distribution, current potential distribution, and future potential distribution in the 2050s. Our work highlights the importance of analyzing range shifts of species with multifactorial approaches, especially for species traits related to thermoregulation and energy regulation, to provide targeted conservation strategies.

Patrones y correlaciones de los cambios potenciales en la distribución de las especies de murciélago de China en el contexto del cambio climático Resumen El cambio climático puede disminuir la biodiversidad, por lo que es urgente pronosticar cómo puede cambiar en el futuro la distribución de las especies mediante la integración de múltiples factores que involucren a más taxones. Los murciélagos son particularmente sensibles al cambio climático debido a que tienen una gran proporción superficie­volumen. Sin embargo, hay pocos estudios que han considerado las variables asociadas con la disponibilidad de nidos y son todavía menos los que han conectado la distribución de los murciélagos con sus rasgos de termorregulación y regulación de energía. Usamos modelos de distribución de especies para pronosticar la distribución potencial de doce especies de murciélago en China bajo escenarios actuales y futuros de emisión de gases de efecto invernadero (SSP1­2.6 y SSP5­8.5) y analizamos los factores que podrían afectar el cambio en la distribución de las especies, incluyendo las variables climáticas, geográficas, de hábitat y de actividad humana y la proporción entre la superficie del ala y la masa (P S­M). Los resultados sugieren que Ia io, Rhinolophus ferrumequinum y R. rex deberían ser la mayor prioridad de conservación para las estrategias de conservación climáticas en el futuro. Pronosticamos que la mayoría de las especies se desplazarían al norte, a excepción de I. io y R. rex, que se desplazarían hacia el sur. Los principales factores que afectaron la distribución potencial de los murciélagos fueron la estacionalidad de la temperatura, la distancia al bosque y la distancia a la cueva o al karst. Encontramos una relación significativa entre la P S­M y la distribución geográfica, la distribución potencial actual y la distribución potencial para la década de 2050. Nuestra investigación destaca la importancia del análisis de los cambios de distribución de las especies con enfoques multifactoriales, especialmente para los rasgos de especie relacionados con la termorregulación y la regulación de energía, para proporcionar estrategias de conservación focalizadas.

Transhiatal bilateral cervical approach for mediastinoscopy-assisted esophagectomy: A retrospective cohort study.

BACKGROUND: The McKeown minimally invasive esophagectomy (McMIE) procedure has various limitations, including surgical contraindications and a high rate of postoperative pulmonary complications. A novel mediastinoscopic esophagectomy procedure was described in this study by using esophageal invagination and a transhiatal and bilateral cervical approach (EITHBC). METHODS: According to the mode of operation, a total of 259 patients were divided into two groups, among which 106 underwent EITHBC and 153 underwent McMIE. The number of lymph nodes dissected, intraoperative outcomes, and postoperative outcomes were compared between the two groups of patients. RESULTS: The results revealed that the average number of resected lymph node in the EITHBC group was significantly higher in the recL106 and TbL106 stations (recL106: 1.75 vs. 1.51, p = 0.016, TbL106: 1.53 vs. 1.19, p = 0.016) and significantly lower in the 107 stations (1. 74 vs. 2. 07, p < 0.001) than in the McMIE group. The intraoperative blood loss in the EITHBC group was significantly lower than that in the McMIE group (63.30 vs. 80.45 mL, p < 0.001). The incidence of postoperative pulmonary complications in the EITHBC group was lower than that in the McMIE group (14.15% vs. 27.45%, p = 0.008). The incidence of recurrent laryngeal nerve paralysis in the EITHBC group was significantly higher than that in the McMIE group (26.41% vs. 10.46%, p = 0.003). CONCLUSION: Compared with the McMIE procedure, the EITHBC procedure has advantages in terms of removing the upper mediastinal lymph nodes and reducing postoperative pulmonary complications.

Histogenetic insights and genetic landscape of fibromatosis-like undifferentiated gastric carcinoma: a focused study.

BACKGROUND: The aim of this study was to elucidate the histogenesis and genetic underpinnings of fibromatosis-like undifferentiated gastric carcinoma (FLUGC), a rare pathological entity. METHOD: Through a detailed analysis of seven cases, including histopathological evaluation, CTNNB1 gene mutation screening, human epidermal growth factor receptor 2 (HER2) protein level quantification, and HER2 gene amplification assessment to identify the pathological and molecular characteristics of FLUGC. RESULTS: Of the seven patients in this study, five were male and two were female (age: 39-73 years). Four patients presented with lesions in the gastric antrum and three had lesions in the lateral curvature of the stomach. Histopathologically, over 90% of the tumor consisted of aggressive fibromatosis-like tissue, including proliferating spindle fibroblasts and myofibroblasts and varying amounts of collagenous fibrous tissues. Undifferentiated cancer cells, accounting for less than 10%, were dispersed among the aggressive fibromatosis-like tissues. These cells were characterized by their small size and were relatively sparse without glandular ducts or nested mass-like structures. Immunophenotyping results showed positive expression of CKpan, CDX2, villin, and p53 in undifferentiated cancer cells; positive expression of vimentin in aggressive fibromatosis-like tissue; positive cytoplasmic expression of ß-catenin; and focal cytoplasmic positive expression of smooth muscle actin (SMA). Genetic analysis did not reveal any mutations in the CTNNB1 gene test, nor was there amplification in the HER2 gene fluorescence in situ hybridization (FISH) test. Additionally, the Epstein-Barr encoding region (EBER) of in situ hybridization was negative; and the mismatch repair (MMR) protein was positive. Programmed cell death-1 (PD-1) was < 1-5%; programmed cell death ligand 1 (PD-L1): TPS = 1-4%, CPS = 3-8. CONCLUSION: The study highlights the significance of CTNNB1, HER2, EBER, and MMR as pivotal genetic markers in FLUGC, underscoring their relevance for diagnosis and clinical management. The rarity and distinct pathological features of FLUGC emphasize the importance of accurate diagnosis to prevent underdiagnosis or misdiagnosis and to raise awareness within the medical community.

Safety and Clinical Activity of SHR7390 Monotherapy or Combined With Camrelizumab for Advanced Solid Tumor: Results From Two Phase I Trials.

BACKGROUND: SHR7390 is a novel, selective MEK1/2 inhibitor. Here, we report results from two phase I trials conducted to evaluate the tolerability, safety and antitumor activity of SHR7390 monotherapy for advanced solid tumors and SHR7390 plus camrelizumab for treatment-refractory advanced or metastatic colorectal cancer (CRC). PATIENTS AND METHODS: Patients received SHR7390 alone or combined with fixed-dose camrelizumab (200 mg every 2 weeks) in an accelerated titration scheme to determine the maximum tolerated dose (MTD). A recommended dose for expansion was determined based on the safety and tolerability of the dose-escalation stage. The primary endpoints were dose limiting toxicity (DLT) and MTD. RESULTS: In the SHR7390 monotherapy trial, 16 patients were enrolled. DLTs were reported in the 1.0 mg cohort, and the MTD was 0.75 mg. Grade ≥3 treatment-related adverse events (TRAEs) were recorded in 4 patients (25.0%). No patients achieved objective response. In the SHR7390 combination trial, 22 patients with CRC were enrolled. One DLT was reported in the 0.5 mg cohort and the MTD was not reached. Grade ≥3 TRAEs were observed in 8 patients (36.4%), with the most common being rash (n=4). One grade 5 TRAE (increased intracranial pressure) occurred. Five patients (22.7%) achieved partial response, including one of 3 patients with MSS/MSI-L and BRAF mutant tumors, one of 15 patients with MSS/MSI-L and BRAF wild type tumors, and all 3 patients with MSI-H tumors. CONCLUSIONS: SHR7390 0.5 mg plus camrelizumab showed a manageable safety profile. Preliminary clinical activity was reported regardless of MSI and BRAF status.

GGC Repeat Expansion of RILPL1 is Associated with Oculopharyngodistal Myopathy.

OBJECTIVE: Oculopharyngodistal myopathy (OPDM) is an adult-onset neuromuscular disease characterized by progressive ptosis, dysarthria, ophthalmoplegia, and distal muscle weakness. Recent studies revealed that GGC repeat expansions in 5'-UTR of LRP12, GIPC1, and NOTCH2NLC are associated with OPDM. Despite these advances, approximately 30% of OPDM patients remain genetically undiagnosed. Herein, we aim to investigate the genetic basis for undiagnosed OPDM patients in two unrelated Chinese Han families. METHODS: Parametric linkage analysis was performed. Long-read sequencing followed by repeat-primed polymerase chain reaction and amplicon length polymerase chain reaction were used to determine the genetic cause. Targeted methylation sequencing was implemented to detect epigenetic changes. The possible pathogenesis mechanism was investigated by quantitative polymerase chain reaction, immunoblotting, RNA fluorescence in situ hybridization, and immunofluorescence staining of muscle biopsy samples. RESULTS: The disease locus was mapped to 12q24.3. Subsequently, GGC repeat expansion in the promoter region of RILPL1 was identified in six OPDM patients from two families, findings consistent with a founder effect, designated as OPDM type 4. Targeted methylation sequencing revealed hypermethylation at the RILPL1 locus in unaffected individuals with ultralong expansion. Analysis of muscle samples showed no significant differences in RILPL1 mRNA or RILPL1 protein levels between patients and controls. Public CAGE-seq data indicated that alternative transcription start sites exist upstream of the RefSeq-annotated RILPL1 transcription start site. Strand-specific RNA-seq data revealed bidirectional transcription from the RILPL1 locus. Finally, fluorescence in situ hybridization/immunofluorescence staining showed that both sense and antisense transcripts formed RNA foci, and were co-localized with hnRNPA2B1 and p62 in the intranuclear inclusions of OPDM type 4 patients. INTERPRETATION: Our findings implicate abnormal GGC repeat expansions in the promoter region of RILPL1 as a novel genetic cause for OPDM, and suggest a methylation mechanism and a potential RNA toxicity mechanism are involved in OPDM type 4 pathogenesis. ANN NEUROL 2022;92:512-526.

Downregulated calmodulin expression contributes to endothelial cell impairment in diabetes.

Endothelial dysfunction, a central hallmark of cardiovascular pathogenesis in diabetes mellitus, is characterized by impaired endothelial nitric oxide synthase (eNOS) and NO bioavailability. However, the underlying mechanisms remain unclear. Here in this study, we aimed to identify the role of calmodulin (CaM) in diabetic eNOS dysfunction. Human umbilical vein endothelial cells and murine endothelial progenitor cells (EPCs) treated with high glucose (HG) exhibited downregulated CaM mRNA/protein and vascular endothelial growth factor (VEGF) expression with impeded eNOS phosphorylation and cell migration/tube formation. These perturbations were reduplicated in CALM1-knockdown cells but prevented in CALM1-overexpressing cells. EPCs from type 2 diabetes animals behaved similarly to HG-treated normal EPCs, which could be rescued by CALM1-gene transduction. Consistently, diabetic animals displayed impaired eNOS phosphorylation, endothelium-dependent dilation, and CaM expression in the aorta, as well as deficient physical interaction of CaM and eNOS in the gastrocnemius. Local CALM1 gene delivery into a diabetic mouse ischemic hindlimb improved the blunted limb blood perfusion and gastrocnemius angiogenesis, and foot injuries. Diabetic patients showed insufficient foot microvascular autoregulation, eNOS phosphorylation, and NO production with downregulated CaM expression in the arterial endothelium, and abnormal CALM1 transcription in genome-wide sequencing analysis. Therefore, our findings demonstrated that downregulated CaM expression is responsible for endothelium dysfunction and angiogenesis impairment in diabetes, and provided a novel mechanism and target to protect against diabetic endothelial injury.

[Diurnal differences in acute gout attacks: A clinical study of male gout patients].

OBJECTIVE: To observe the diurnal difference of acute gout attacks in men, and provide reference for accurate clinical prevention and treatment. METHODS: Using a single-center, cross-sectional study design, the patients diagnosed with gout in the outpatient department of Rheumatology and Immuno-logy of PLA Joint Logistic Support Force No.980 Hospital from October 2021 to April 2022 were selected. The information about the patient's current/last acute gout attacks (less than 2 weeks from visit), date and time of attacks, joint symptoms and signs, medication use, and relevant biochemical tests on the day of visit was recorded. The diurnal time difference of acute gout attacks in male patients was analyzed, and univariate comparison and multivariate Logistic regression analyses were conducted to compare the diurnal difference of acute gout attacks with clinical characteristics and biochemical indicators. RESULTS: A total of 100 male gout patients were included, and 100 acute attacks were recorded. Diurnal distribution of acute gout attacks: morning (6:00~11:59, 18, 18%), afternoon (12:00~17:59, 11, 11%), the first half of the night (18:00~23:59, 22, 22%), the second half of the night (0:00~05:59, 49, 49%); During the day (included morning and afternoon, 29, 29%) and at night (included the first half of the night and the second half of the night, 71, 71%). The rate of acute gout attack was significantly higher at night than in the day (about 2.5 ∶1). No matter the first or recurrent gout, no matter the duration of the disease, the number of acute gout attacks had the difference of less in the day and more in the night. Serum urate (SU) level was higher in the patients with nocturnal attack than in those with daytime attack (P=0.044). Comorbidities were significantly different in the day-night ratio of the number of acute gout attack (P=0.028). Multiple Logistic regression analysis showed that SU level (OR=1.005, 95%CI: 1.001-1.009) and comorbidities (OR=3.812, 95%CI: 1.443-10.144) were the correlative factors of nocturnal acute gout attacks. CONCLUSION: No matter the first or recurrent gout, no matter the duration of the disease, it has a diurnal variation characterized by multiple attacks at night, increased SU level and comorbidities are correlative factors for nocturnal acute attack of gout.

Acid-catalyzed Disulfide-mediated Reversible Polymerization for Recyclable Dynamic Covalent Materials.

Poly(1,2-dithiolane)s are a family of intrinsically recyclable polymers due to their dynamic covalent disulfide linkages. Despite the common use of thiolate-initiated anionic ring-opening polymerization (ROP) under basic condition, cationic ROP is still not exploited. Here we report that disulfide bond can act as a proton acceptor, being protonated by acids to form sulfonium cations, which can efficiently initiate the ROP of 1,2-dithiolanes and result in high-molecular-weight (over 1000 kDa) poly(disulfide)s. The reaction can be triggered by adding catalytic amounts of acids and non-coordinating anion salts, and completed in few minutes at room temperature. The acidic conditions allow the applicability for acidic monomers. Importantly, the reaction condition can be under open air without inert protection, enabling the nearly quantitative chemical recycling from bulk materials to original monomers.

CRISPR/Cas9-based genome editing for the modification of multiple duplications that cause Duchenne muscular dystrophy.

With the development of basic research, some genetic-based methods have been found to treat Duchenne muscular dystrophy (DMD) with large deletion mutations and nonsense mutations. Appropriate therapeutic approaches for repairing multiple duplications are limited. We used the CRISPR (clustered regularly interspaced short palindromic repeat)/Cas9 system with patient-derived primary myoblasts to correct multiple duplications of the dystrophin gene. Muscle tissues from a patient carrying duplications of dystrophin were obtained, and tissue-derived primary cells were cultured. Myoblasts were purified with an immunomagnetic sorting system using CD56 microbeads. After transduction by lentivirus with a designed single guide RNA (sgRNA) targeting a duplicated region, myoblasts were allowed to differentiate for 7 days. Copy number variations in the exons of the patient's myotubes were quantified by real-time PCR before and after genetic editing. Western blot analysis was performed to detect the full-length dystrophin protein before and after genetic editing. The ten sequences predicted to be the most likely off-targets were determined by Sanger sequencing. The patient carried duplications of exon 18-25, dystrophin protein expression was completely abrogated. Real-time PCR showed that the copy number of exon 25 in the patient's myotubes was 2.015 ± 0.079 compared with that of the healthy controls. After editing, the copy number of exon 25 in the patient's modified myotubes was 1.308 ± 0.083 compared with that of the healthy controls (P < 0.001). Western blot analysis revealed no expression of the dystrophin protein in the patient's myotubes before editing. After editing, the patient's myotubes expressed the full-length dystrophin protein at a level that was ~6.12% of that in the healthy control samples. Off-target analysis revealed no abnormal editing at the ten sites predicted to be the most likely off-target sites. The excision of multiple duplications by the CRISPR/Cas9 system restored the expression of full-length dystrophin. This study provides proof of evidence for future genome-editing therapy in patients with DMD caused by multiple duplication mutations.

SKI knockdown suppresses apoptosis and extracellular matrix degradation of nucleus pulposus cells via inhibition of the Wnt/ß-catenin pathway and ameliorates disc degeneration.

This study aimed to determine the effects of SKI on interleukin (IL)-1ß-induced apoptosis of nucleus pulposus (NP) cells, intervertebral disc degeneration (IDD), and the Wnt signaling pathway. NP tissue specimens of different Pfirrmann grades (II-V) were collected from patients with different grades of IDD. Real-time polymerase chain reaction and western blotting were used to compare SKI mRNA and protein expression in NP tissues from patients. Using the IL-1ß-induced IDD model, NP cells were infected with lentivirus-coated si-SKI to downregulate the expression of SKI and treated with LiCl to evaluate the involvement of the Wnt/ß-catenin signaling pathway. Western blotting, immunofluorescence, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining were used to detect NP cell apoptosis, extracellular matrix (ECM) metabolism, and related protein expression changes in the Wnt/ß-catenin signaling pathway. To investigate the role of SKI in vivo, a rat IDD model was established by needle puncture of the intervertebral disc. Rats were injected with lentivirus-coated si-SKI and evaluated by magnetic resonance imaging (MRI), and hematoxylin and eosin (HE) and safranin O staining. SKI expression positively correlated with the severity of human IDD. In the IL-1ß-induced NP cell degeneration model, SKI expression increased significantly and reached a peak at 24 h. SKI knockdown protected against IL-1ß-induced NP cell apoptosis and ECM degradation. LiCl treatment reversed the protective effects of si-SKI on NP cells. Furthermore, lentivirus-coated si-SKI injection partially reversed the NP tissue damage in the IDD model in vivo. SKI knockdown reduced NP cell apoptosis and ECM degradation by inhibiting the Wnt/ß-catenin signaling pathway, ultimately protecting against IDD. Therefore, SKI may be an effective target for IDD treatment.

Intermolecular interactions, photocatalysis and THz-TDS interrelationships for lanthanide phosphine oxide complexes based on {PW12}.

A series of rare earth complexes containing (α-PW12O40)3- and PO ligand are synthesized by water bath in 70 °C, [Ln(OPPh3)4(H2O)3](PW12O40)·4CH3CN (Ln = La, Pr, Nd, Sm, Gd, Tb, Ho 1-7) (OPPh3 = Triphenylphosphine oxide, {PW12} = phosphotungstic acid). The precise structures are confirmed by X-ray single crystal diffraction and the result shows all complexes are isostructural. Complexes 1-7 are fully characterized by PXRD, FT-IR, TGA, UV diffuse reflectance spectra and terahertz time-domain spectroscopy (THz-TDS). Complex 3 exhibits the highest photocatalytic degradation efficiency for methylene blue (MB) in this series of complexes. The experimental results showed that the photodegradation efficiency can remain constant at the level of 95% after five consecutive cycles. The photocatalytic reaction kinetics and mechanism of complexes were investigated. Additionally, complexes also exhibit photocatalytic hydrogen evolution activity. THz-TDS was used to characterize the complexes and its raw materials, the characteristic peaks of OPPh3 (broad peak at 1.20 THz) and phosphotungstic acid (sharp peaks at 0.23, 0.32 THz) were obtained.