Long-term outcomes of intraoperative chemotherapy with 5-FU for colorectal cancer patients receiving curative resection (IOCCRC): a randomized, multicenter, prospective, phase III trial.

BACKGROUND: We aimed to compare combined intraoperative chemotherapy and surgical resection with curative surgical resection alone in colorectal cancer patients. METHODS: We performed a multicenter, open-label, randomized, phase III trial. All eligible patients were randomized and assigned to intraoperative chemotherapy and curative surgical resection or curative surgical resection alone (1:1). Survival actualization after long-term follow-up was performed in patients analyzed on an intention-to-treat basis. RESULTS: From January 2011 to January 2016, 696 colorectal cancer patients were enrolled and randomly assigned to intraoperative chemotherapy and radical surgical resection (n=341) or curative surgical resection alone (n=344). Intraoperative chemotherapy with surgical resection showed no significant survival benefit over surgical resection alone in colorectal cancer patients (3-year DFS: 91.1% vs. 90.0%, P=0.328; 3-year OS: 94.4% vs. 95.9%, P=0.756). However, colon cancer patients benefitted from intraoperative chemotherapy, with a relative 4% reduction in liver and peritoneal metastasis (HR=0.336, 95% CI: 0.148-0.759, P=0.015) and a 6.5% improvement in 3-year DFS (HR=0.579, 95% CI: 0.353-0.949, P=0.032). Meanwhile, patients with colon cancer and abnormal pretreatment CEA levels achieved significant survival benefits from intraoperative chemotherapy (DFS: HR=0.464, 95% CI: 0.233-0.921, P=0.029 and OS: (HR=0.476, 95% CI: 0.223-1.017, P=0.049). CONCLUSIONS: Intraoperative chemotherapy showed no significant extra prognostic benefit in total colorectal cancer patients who underwent radical surgical resection; however, in colon cancer patients with abnormal pretreatment serum CEA levels (> 5 ng/ml), intraoperative chemotherapy could improve long-term survival.

Spinal nerve transection-induced upregulation of SAP97 via promoting membrane trafficking of GluA1-containing AMPA receptors in the dorsal horn contributes to the pathogenesis of neuropathic pain.

Emerging evidence has implicated an important role of synapse-associated protein-97 (SAP97)-regulated GluA1-containing AMPARs membrane trafficking in cocaine restate and in contextual episodic memory of schizophrenia. Herein, we investigated the role of SAP97 in neuropathic pain following lumbar 5 spinal nerve transection (SNT) in rats. Our results showed that SNT led to upregulation of SAP97, enhanced the interaction between SAP97 and GluA1, and increased GluA1-containing AMPARs membrane trafficking in the dorsal horn. Microinjection of AAV-EGFP-SAP97 shRNA in lumbar 5 spinal dorsal horn inhibited SAP97 production, decreased SAP97-GluA1 interaction, reduced the membrane trafficking of GluA1-containing AMPARs, and partially attenuated neuropathic pain following SNT. Intrathecal injections of SAP97 siRNA or NASPM, an antagonist of GluA1-containing AMPARs, also partially reversed neuropathic pain on day 7, but not on day 14, after SNT. Spinal overexpression of SAP97 by AAV-EGFP-SAP97 enhanced SAP97-GluA1 interaction, increased the membrane insertion of GluA1-containing AMPARs, and induced abnormal pain in naïve rats. In addition, treatment with SAP97 siRNA or NASPM i.t. injection alleviated SNT-induced allodynia and hyperalgesia and exhibited a longer effect in female rats. Together, our results indicate that the SNT-induced upregulation of SAP97 via promoting GluA1-containing AMPARs membrane trafficking in the dorsal horn contributes to the pathogenesis of neuropathic pain. Targeting spinal SAP97 might be a promising therapeutic strategy to treatment of chronic pain.

Engineered extracellular vesicles efficiently deliver CRISPR-Cas9 ribonucleoprotein (RNP) to inhibit herpes simplex virus1 infection in vitro and in vivo.

Extracellular vesicles (EVs) have recently emerged as a promising delivery platform for CRISPR/Cas9 ribonucleoproteins (RNPs), owing to their ability to minimize off-target effects and immune responses. However, enhancements are required to boost the efficiency and safety of Cas9 RNP enrichment within EVs. In response, we employed the Fc/Spa interaction system, in which the human Fc domain was fused to the intracellular domain of PTGFRN-Δ687 and anchored to the EV membrane. Simultaneously, the B domain of the Spa protein was fused to the C domain of cargos such as Cre or spCas9. Due to the robust interaction between Fc and Spa, this method enriched nearly twice the amount of cargo within the EVs. EVs loaded with spCas9 RNP targeting the HSV1 genome exhibited significant inhibition of viral replication in vitro and in vivo. Moreover, following neuron-targeting peptide RVG modification, the in vivo dosage in neural tissues substantially increased, contributing to the clearance of the HSV1 virus in neural tissues and exhibiting a lower off-target efficiency. These findings establish a robust platform for efficient EV-based SpCas9 delivery, offering potential therapeutic advantages for HSV1 infections and other neurological disorders.

Circulating tumor DNA analysis predicts recurrence and avoids unnecessary adjuvant chemotherapy in I-IV colorectal cancer.

Background: Circulating tumor DNA (ctDNA) has emerged as a biomarker that can define the risk of recurrence after curative-intent surgery for patients with colorectal cancer (CRC). However, beyond the predictive power of postoperative ctDNA detection, the efficacy and potential limitations of ctDNA detection urgently need to be fully elucidated in a large cohort of CRC. Objectives: To define potentially cured CRC patients through ctDNA monitoring following surgery. Design: A prospective, multicenter, observational study. Methods: We enrolled 309 patients with stages I-IV CRC who underwent definitive surgery. Tumor tissues were sequenced by a custom-designed next-generation sequencing panel to identify somatic mutations. Plasma was analyzed using a ctDNA-based molecular residual disease (MRD) assay which integrated tumor-genotype-informed and tumor-genotype-naïve ctDNA analysis. The turnaround time of the assay was 10-14 days. Results: Postoperative ctDNA was detected in 5.4%, 13.8%, 15%, and 30% of patients with stage I, II, III, and IV disease, respectively, and in 17.5% of all longitudinal samples. Patients with positive postsurgery MRD had a higher recurrence rate than those with negative postsurgery MRD [hazard ratio (HR), 13.17; p < 0.0001], producing a sensitivity of 64.6%, a specificity of 94.8%, a positive predictive value (PPV) of 75.6%, and a negative predictive value (NPV) of 91.5%. Furthermore, patients with positive longitudinal MRD also had a significantly higher recurrence rate (HR, 14.44; p < 0.0001), with increased sensitivity (75.0%), specificity (94.9%), PPV (79.6%), and NPV (93.4%). Subgroup analyses revealed that adjuvant therapy did not confer superior survival for patients with undetectable or detectable MRD. In addition, MRD detection was less effective in identifying lung-only and peritoneal metastases. Conclusion: Postoperative ctDNA status is a strong predictor of recurrence independent of stage and microsatellite instability status. Longitudinal undetectable MRD could be used to define the potentially cured population in CRC patients undergoing curative-intent surgery.

Computational profiling and prognostic modeling based on lysosome-related genes in colorectal cancer.

Background: Despite significant advances over the past decade, patients diagnosed with advanced colorectal cancer (CRC) continue to face unfavorable prognoses. Recent studies have underscored the pivotal role of lysosomes in tumor development and progression. This led us to postulate and develop a novel lysosomal-centric model for predicting CRC risk and therapeutic response. Methods: CRC tissue samples were sourced from the TCGA database, while lysosome-associated genes were collated from the GSEA database. Differentially expressed lysosome-related genes (DE-LRGs) were discerned by contrasting tumor samples with normal tissue. Based on the expression profile of DE-LRGs, patients were stratified into two distinct clusters. Survival disparities between the clusters were delineated using Kaplan-Meier estimators. For tumor microenvironment assessment, we employed ESTIMATE and ssGSEA. Functional pathway enrichment was ascertained using both GSVA and GSEA. Subsequent uni- and multi-variate Cox regression analyses pinpointed risk-associated DE-LRGs. Leveraging these genes, we constructed a novel risk prediction model and derived risk scores. The model's prognostic capability was externally validated using dataset GSE39084. The mutational landscape across risk categories was evaluated using the Maftools algorithm. The potential efficacy of targeted and immunotherapeutic interventions for each patient cohort was gauged using pRRophetic, CYT, and IMvigor210. Results: We identified 46 DE-LRGs. Tumor Immune MicroEnvironment (TIME) assessment revealed that cluster 2 patients exhibited elevated ESTIMATE, Immunocore, and stromal scores, yet diminished tumor purity relative to cluster 1. Notable differences in immune cell infiltration patterns were observed between clusters, and distinct pathway enrichments were evident. Cluster 2 manifested a pronounced expression of immune checkpoint-related genes. Four DE-LRGs (ATP6V0A4, GLA, IDUA, and SLC11A1) were deemed critical for risk association, leading to the formulation of our novel risk model. The model exhibited commendable predictive accuracy, which was corroborated in an external validation cohort. A palpable survival advantage was observed in high-TMB, low-risk subgroups. Moreover, the low-risk cohort displayed heightened sensitivity to both targeted and immunotherapeutic agents. Conclusion: Our findings underscore the potential of lysosome-associated genes as robust prognostic and therapeutic response markers in CRC patients.

Neurotransmitter receptor-related gene signature as potential prognostic and therapeutic biomarkers in colorectal cancer.

Background: Colorectal cancer is one of the most common malignant tumors worldwide. A various of neurotransmitter receptors have been found to be expressed in tumor cells, and the activation of these receptors may promote tumor growth and metastasis. This study aimed to construct a novel neurotransmitter receptor-related genes signature to predict the survival, immune microenvironment, and treatment response of colorectal cancer patients. Methods: RNA-seq and clinical data of colorectal cancer from The Cancer Genome Atlas database and Gene Expression Omnibus were downloaded. Neurotransmitter receptor-related gene were collected from publicly available data sources. The Weighted Gene Coexpression Network Analysis (WGCNA), Least Absolute Shrinkage and Selection Operator (LASSO) logistic regression, Support Vector Machine-Recursive Feature Elimination (SVM-RFE), and Random Forest (RF) algorithms were employed to construct the Neurotransmitter receptor-related gene prognostic signature. Further analyses, functional enrichment, CIBERSORTx, The Tumor Immune Single Cell Center (TISCH), survival analysis, and CellMiner, were performed to analyze immune status and treatment responses. Quantitative real-time polymerase chain reaction (qRT-PCR) assays were carried out to confirm the expression levels of prognostic genes. Results: By combining machine learning algorithm and WGCNA, we identified CHRNA3, GABRD, GRIK3, and GRIK5 as Neurotransmitter receptor-related prognostic genes signature. Functional enrichment analyses showed that these genes were enriched with cellular metabolic-related pathways, such as organic acid, inorganic acid, and lipid metabolism. CIBERSORTx and Single cell analysis showed that the high expression of genes were positively correlated with immunosuppressive cells infiltration, and the genes were mainly expressed in cancer-associated fibroblasts and endothelial cells. A nomogram was further built to predict overall survival (OS). The expression of CHRNA3, GABRD, GRIK3, and GRIK5 in cancer cells significantly impacted their response to chemotherapy. Conclusion: A neurotransmitter receptor-related prognostic gene signature was developed and validated in the current study, giving novel sights of neurotransmitter in predicting the prognostic and improving the treatment of CRC.

A novel TOX3-WDR5-ABCG2 signaling axis regulates the progression of colorectal cancer by accelerating stem-like traits and chemoresistance.

The eradication of cancer stem cells (CSCs) with drug resistance confers the probability of local tumor control after chemotherapy or targeted therapy. As the main drug resistance marker, ABCG2 is also critical for colorectal cancer (CRC) evolution, in particular cancer stem-like traits expansion. Hitherto, the knowledge about the expression regulation of ABCG2, in particular its upstream transcriptional regulatory mechanisms, remains limited in cancer, including CRC. Here, ABCG2 was found to be markedly up-regulated in CRC CSCs (cCSCs) expansion and chemo-resistant CRC tissues and closely associated with CRC recurrence. Mechanistically, TOX3 was identified as a specific transcriptional factor to drive ABCG2 expression and subsequent cCSCs expansion and chemoresistance by binding to -261 to -141 segments of the ABCG2 promoter region. Moreover, we found that TOX3 recruited WDR5 to promote tri-methylation of H3K4 at the ABCG2 promoter in cCSCs, which further confers stem-like traits and chemoresistance to CRC by co-regulating the transcription of ABCG2. In line with this observation, TOX3, WDR5, and ABCG2 showed abnormal activation in chemo-resistant tumor tissues of in situ CRC mouse model and clinical investigation further demonstrated the comprehensive assessment of TOX3, WDR5, and ABCG2 could be a more efficient strategy for survival prediction of CRC patients with recurrence or metastasis. Thus, our study found that TOX3-WDR5/ABCG2 signaling axis plays a critical role in regulating CRC stem-like traits and chemoresistance, and a combination of chemotherapy with WDR5 inhibitors may induce synthetic lethality in ABCG2-deregulated tumors.

Modelo de atención farmacéutica en medicina de precision en China / Pharmaceutical care model in precision medicine in China

Pharmacy service is to provide individualized pharmaceutical care for patients, which should follow the current evidence-based pharmacy, and constantly verify the evidence and then produce new evidence. In pharmaceutical care, differences are often found in the efficacy and adverse reactions of drugs among individuals, even within individuals, which are closely related to patient's genetics, liver and kidney functions, disease states, and drug interactions. Back in the 1980s, therapeutic drug monitoring (TDM) has been applied to routinely monitor the blood drug concentration of patients taking antiepileptic drugs or immunosuppressants after transplantation to provide individualized dosage recommendations and accumulate a large amount of pharmacokinetic (PK)/pharmacodynamic (PD) data. As individualized pharmaceutical care proceeds, the concept of precision medicine was introduced into pharmacy services in combination with evidence-based pharmacy, PK/PD theories and big data to further promote the TDM technology and drugs, and carry out pharmacogenomics analysis. The TDM and pharmacogenomics have been applied gradually to the fields of antimicrobial, antitumor and antipsychotic drugs and immunosuppressants. Based on the concept of precision pharmacy, we adpoted approaches including PK/PD, quantitative pharmacology, population pharmacokinetics, and big data machine learning to provide more personalized pharmacy services, which is mainly for special patients, such as critical patients, patients with interaction risk of multiple drugs, patients with liver and renal insufficiency, pregnant women, children and elderly patients. As the service pattern of precision pharmacy has been constructed and constantly improved, better evidence in clinical practice will be produced to provide patients with better precision pharmacy service. (AU)

El servicio de farmacia se encarga de prestar atención farmacéutica personalizada a los pacientes. Los servicios de farmacia deben utilizar aquellas prácticas con mayor nivel de evidencia, y realizar una continua validación de dicha evidencia antes de elaborar nuevas prácticas. En la terapia farmacológica, se observan diferencias inter e intra individuales respecto a los efectos terapéuticos y a las reacciones adversas de los medicamentos, lo que está estrechamente relacionado con las variaciones genéticas, la función hepática y renal, el estado de la enfermedad y la interacción entre medicamentos. Desde la década de los 80 del siglo pasado, se utiliza la monitorización terapéutica de fármacos (MTF) de forma rutinaria para controlar las concentraciones sanguíneas de fármacos antiepilépticos o de inmunosupresores postrasplante y elaborar recomendaciones de dosis personalizadas y recoger una gran cantidad de datos farmacocinéticos (PC)/farmacodinámicos (PD). Con el desarrollo de la atención farmacéutica personalizada, el concepto de medicina de precisión se introduce en la atención farmacéutica, combinando la farmacia basada en evidencias, los enfoques PC/PD y los macrodatos (big data), promover técnicas de MTF en medicamentos, y la realización de análisis farmacogenómicos. La MTF y la farmacogenómica se están aplicando de forma gradual en el tratamiento con antimicrobianos, antitumorales, antipsicóticos e inmunosupresores. Sobre la base del concepto de farmacia de precisión, utilizamos métodos de PC/PD, farmacología cuantitativa, farmacocinética poblacional y aprendizaje automático con big data para ofrecer una atención farmacéutica más personalizada, principalmente a pacientes con necesidades especiales, como los pacientes en estado crítico, con riesgo de interacciones farmacológicas múltiples, pacientes con insuficiencia hepática y renal, mujeres embarazadas, niños y ancianos... (AU)

Neuralized1-Mediated CPEB3 Ubiquitination in the Spinal Dorsal Horn Contributes to the Pathogenesis of Neuropathic Pain in Rats.

Compelling evidence has shown that Neuralized1 (Neurl1) facilitates hippocampal-dependent memory storage by modulating cytoplasmic polyadenylation element-binding protein 3 (CPEB3)-dependent protein synthesis. In the current study, we investigated the role of Neurl1 in the pathogenesis of neuropathic pain and the underlying mechanisms. The neuropathic pain was evaluated by lumbar 5 spinal nerve ligation (SNL) in rats. Immunofluorescence staining, Western blotting, qRT-PCR, and coimmunoprecipitation (Co-IP) were performed to investigate the underlying mechanisms. Our results showed that SNL led to an increase of Neurl1 in the spinal dorsal horn. Spinal microinjection of AAV-EGFP-Neurl1 shRNA alleviated mechanical allodynia; decreased the level of CPEB3 ubiquitination; inhibited the production of GluA1, GluA2, and PSD95; and reduced GluA1-containing AMPA receptors in the membrane of the dorsal horn following SNL. Knockdown of spinal CPEB3 decreased the production of GluA1, GluA2, and PSD95 in the dorsal horn and attenuated abnormal pain after SNL. Overexpression of Neurl1 in the dorsal horn resulted in pain-related hypersensitivity in naïve rats; raised the level of CPEB3 ubiquitination; increased the production of GluA1, GluA2, and PSD95; and augmented GluA1-containing AMPA receptors in the membrane in the dorsal horn. Moreover, spinal Neurl1 overexpression-induced mechanical allodynia in naïve rats was partially reversed by repeated intrathecal injections of CPEB3 siRNA. Collectively, our results suggest that SNL-induced upregulation of Neurl1 through CPEB3 ubiquitination-dependent production of GluA1, GluA2, and PSD95 in the dorsal horn contributes to the pathogenesis of neuropathic pain in rats. Targeting spinal Neurl1 might be a promising therapeutic strategy for the treatment of neuropathic pain.

Pharmaceutical care model in precision medicine in China. / [Artículo traducido] Modelo de atención farmacéutica en medicina de precisión en China.

Pharmacy service is to provide individualized pharmaceutical care for patients, which should follow the current evidence-based pharmacy, and constantly verify the evidence and then produce new evidence. In pharmaceutical care, differences are often found in the efficacy and adverse reactions of drugs among individuals, even within individuals, which are closely related to patients' genetics, liver and kidney functions, disease states, and drug interactions. Back in the 1980s, therapeutic drug monitoring (TDM) has been applied to routinely monitor the blood drug concentration of patients taking antiepileptic drugs or immunosuppressants after transplantation to provide individualized dosage recommendations and accumulate a large amount of pharmacokinetic (PK)/pharmacodynamic (PD) data. As individualized pharmaceutical care proceeds, the concept of precision medicine was introduced into pharmacy services in combination with evidence-based pharmacy, PK/PD theories, and big data to further promote the TDM technology and drugs, and carry out pharmacogenomics analysis. The TDM and pharmacogenomics have been applied gradually to the fields of antimicrobial, antitumor, and antipsychotic drugs and immunosuppressants. Based on the concept of precision pharmacy, we adopted approaches including PK/PD, quantitative pharmacology, population pharmacokinetics, and big data machine learning to provide more personalized pharmacy services, which is mainly for special patients, such as critical patients, patients with interaction risk of multiple drugs, patients with liver and renal insufficiency, pregnant women, children, and elderly patients. As the service pattern of precision pharmacy has been constructed and constantly improved, better evidence in clinical practice will be produced to provide patients with better precision pharmacy service.

Upregulation of lysine-specific demethylase 6B aggravates inflammatory pain through H3K27me3 demethylation-dependent production of TNF-α in the dorsal root ganglia and spinal dorsal horn in rats.

AIMS: Lysine-specific demethylase 6B (KDM6B) serves as a key mediator of gene transcription. It regulates expression of proinflammatory cytokines and chemokines in variety of diseases. Herein, the role and the underlying mechanisms of KDM6B in inflammatory pain were studied. METHODS: The inflammatory pain was conducted by intraplantar injection of complete Freund's adjuvant (CFA) in rats. Immunofluorescence, Western blotting, qRT-PCR, and chromatin immunoprecipitation (ChIP)-PCR were performed to investigate the underlying mechanisms. RESULTS: CFA injection led to upregulation of KDM6B and decrease in the level of H3K27me3 in the dorsal root ganglia (DRG) and spinal dorsal horn. The mechanical allodynia and thermal hyperalgesia following CFA were alleviated by the treatment of intrathecal injection of GSK-J4, and by microinjection of AAV-EGFP-KDM6B shRNA in the sciatic nerve or in lumbar 5 dorsal horn. The increased production of tumor necrosis factor-α (TNF-α) following CFA in the DRGs and dorsal horn was inhibited by these treatments. ChIP-PCR showed that CFA-induced increased binding of nuclear factor κB with TNF-α promoter was repressed by the treatment of microinjection of AAV-EGFP-KDM6B shRNA. CONCLUSIONS: These results suggest that upregulated KDM6B via facilitating TNF-α expression in the DRG and spinal dorsal horn aggravates inflammatory pain.

Pharmaceutical care model in precision medicine in China.

Pharmacy service is to provide individualized pharmaceutical care for patients, which should follow the current evidence-based pharmacy, and constantly verify the evidence and then produce new evidence. In pharmaceutical care, differences are often found in the efficacy and adverse reactions of drugs among individuals, even within individuals, which are closely related to patient's genetics, liver and kidney functions, disease states, and drug interactions. Back in the 1980s, therapeutic drug monitoring (TDM) has been applied to routinely monitor the blood drug concentration of patients taking antiepileptic drugs or immunosuppressants after transplantation to provide individualized dosage recommendations and accumulate a large amount of pharmacokinetic (PK)/pharmacodynamic (PD) data. As individualized pharmaceutical care proceeds, the concept of precision medicine was introduced into pharmacy services in combination with evidence-based pharmacy, PK/PD theories and big data to further promote the TDM technology and drugs, and carry out pharmacogenomics analysis. The TDM and pharmacogenomics have been applied gradually to the fields of antimicrobial, antitumor and antipsychotic drugs and immunosuppressants. Based on the concept of precision pharmacy, we adpoted approaches including PK/PD, quantitative pharmacology, population pharmacokinetics, and big data machine learning to provide more personalized pharmacy services, which is mainly for special patients, such as critical patients, patients with interaction risk of multiple drugs, patients with liver and renal insufficiency, pregnant women, children and elderly patients. As the service pattern of precision pharmacy has been constructed and constantly improved, better evidence in clinical practice will be produced to provide patients with better precision pharmacy service.

Prognostic and predictive value of Immunoscore and its correlation with ctDNA in stage II colorectal cancer.

This study aimed to validate the prognostic value of Immunoscore (IS) in stage II colorectal cancer (CRC), and explore the roles of IS and circulating tumor DNA (ctDNA) in the adjuvant treatment for early-stage CRC. Resected tumor samples from stage II CRC patients were collected from the Sun Yat-sen University Cancer Center. The densities of CD3+ and CD8+ lymphocytes were quantified and converted to IS and classified into Low, Intermediate (Int), and High groups according to predefined cutoffs. A total of 113 patients were included in the study. Patients with IS-High, Int, and Low were 43 (38%), 62 (55%), and 8 (7%), respectively. Patients with IS-High had an excellent clinical outcome, with none recurring during a median follow-up of 3 years, including 15 (35%) clinical high-risk patients. The 3-year disease-free survival (DFS) was 100% for IS-High, 76% for IS-Int, and 47% for IS-Low (P < .001). In the multivariate Cox analysis, IS was the only significant parameter associated with DFS. IS-Int and IS-Low patients with adjuvant chemotherapy had improved DFS compared to those who did not receive adjuvant chemotherapy (HR = 0.3; 95% CI 0.1-0.92; P = .026). Among the 49 patients with postoperative ctDNA data, IS-High patients had the lowest ctDNA positivity rate, suggesting that they were most eligible for chemotherapy-free treatment. IS had a strong prognostic value in Chinese patients with stage II CRC and demonstrates its clinical utility. IS and ctDNA will jointly optimize the adjuvant treatment strategies for early-stage CRC.

Multidimensional fatigue in Chinese patients with newly diagnosed meningiomas: Prevalence, severity and associated factors.

OBJECTIVE: The purpose of this study was to explore the prevalence, severity, and factors associated with multidimensional fatigue in Chinese patients with newly diagnosed meningiomas. METHODS: This cross-sectional study included 120 Chinese meningioma patients. Data were collected before surgery, including demographic, clinical, psychological, and sleep characteristics, as well as fatigue scores based on completion of the Multidimensional Fatigue Inventory (MFI-20). Mann-Whitney U tests, Kruskal-Wallis H tests, Spearman correlation and multiple linear regression were used to analyze the data. RESULTS: The results showed there was a high prevalence of severe fatigue for each dimension: general fatigue (33.3%), physical fatigue (27.5%), reduced activity (28.3%), reduced motivation (12.5%), mental fatigue (11.7%), and total fatigue (23.3%). Headache and anxiety were found to be associated with general fatigue. Depression was related with physical fatigue. The Karnofsky Performance Status (KPS) score and depression were associated with reduced activity. Depression and the Epworth Sleepiness Scale (ESS) score were correlated with reduced motivation, while the KPS score and anxiety were associated with mental fatigue. Importantly, comorbidity, the KPS score, headache, depression, sleep disturbances, and the ESS score remained strong correlates of total fatigue. CONCLUSIONS: Our findings indicate that newly diagnosed meningioma patients are affected by multidimensional fatigue. For patients with risk factors of fatigue, targeted interventions are advised to decrease fatigue and improve HRQoL.

Neoadjuvant Chemotherapy With CAPOX Versus Chemoradiation for Locally Advanced Rectal Cancer With Uninvolved Mesorectal Fascia (CONVERT): Initial Results of a Phase III Trial.

OBJECTIVE: To compare neoadjuvant chemotherapy (nCT) with CAPOX alone versus neoadjuvant chemoradiotherapy (nCRT) with capecitabine in locally advanced rectal cancer (LARC) with uninvolved mesorectal fascia (MRF). BACKGROUND DATA: nCRT is associated with higher surgical complications, worse long-term functional outcomes, and questionable survival benefits. Comparatively, nCT alone seems a promising alternative treatment in lower-risk LARC patients with uninvolved MRF. METHODS: Patients between June 2014 and October 2020 with LARC within 12 cm from the anal verge and uninvolved MRF were randomly assigned to nCT group with 4 cycles of CAPOX (Oxaliplatin 130 mg/m2 IV day 1 and Capecitabine 1000 mg/m2 twice daily for 14 d. Repeat every 3 wk) or nCRT group with Capecitabine 825 mg/m² twice daily administered orally and concurrently with radiation therapy (50 Gy/25 fractions) for 5 days per week. The primary end point is local-regional recurrence-free survival. Here we reported the results of secondary end points: histopathologic response, surgical events, and toxicity. RESULTS: Of the 663 initially enrolled patients, 589 received the allocated treatment (nCT, n=300; nCRT, n=289). Pathologic complete response rate was 11.0% (95% CI, 7.8-15.3%) in the nCT arm and 13.8% (95% CI, 10.1-18.5%) in the nCRT arm ( P =0.33). The downstaging (ypStage 0 to 1) rate was 40.8% (95% CI, 35.1-46.7%) in the nCT arm and 45.6% (95% CI, 39.7-51.7%) in the nCRT arm ( P =0.27). nCT was associated with lower perioperative distant metastases rate (0.7% vs. 3.1%, P =0.03) and preventive ileostomy rate (52.2% vs. 63.6%, P =0.008) compared with nCRT. Four patients in the nCT arm received salvage nCRT because of local disease progression after nCT. Two patients in the nCT arm and 5 in the nCRT arm achieved complete clinical response and were treated with a nonsurgical approach. Similar results were observed in subgroup analysis. CONCLUSIONS: nCT achieved similar pCR and downstaging rates with lower incidence of perioperative distant metastasis and preventive ileostomy compared with nCRT. CAPOX could be an effective alternative to neoadjuvant therapy in LARC with uninvolved MRF. Long-term follow-up is needed to confirm these results.

Rituximab for connective tissue disease-associated interstitial lung disease: A systematic review and meta-analysis.

OBJECTIVE: To assess the efficacy of rituximab (RTX) on lung function and the prevalence of adverse events (AEs) in connective tissue disease-associated interstitial lung disease (CTD-ILD) by meta-analysis. METHODS: EMBASE, Web of Science, PubMed and ClinicalKey were searched up to July 16, 2021. The lung function (forced vital capacity, FVC% predicted, and diffusing capacity of the lung for carbon monoxide, DLCO% predicted) and prevalence of AEs of RTX in CTD-ILD were analyzed by meta-analysis, and 95% confidence interval (CI) was calculated. Subgroup analyses and meta-regression were used to explore the heterogeneity. RESULTS: We identified 29 studies, including 827 CTD-ILD patients with a median age of 53.05 years. In observational studies, FVC% (mean difference - 1.24, 95% CI [-2.35, -0.12]; P = .030) and DLCO% (-7.71, [-11.79, -3.63]; P = .014) of CTD-ILD decreased significantly after RTX treatment. In randomized controlled trials, FVC% of CTD-ILD decreased after RTX treatment (-5.24, [-9.94, - 0.54]; P = .029), but the difference of DLCO% was not significant (1.15, [-4.33, 6.63]; P = .681). The prevalence of AEs, all-cause mortality and infections was 29.7% (95% CI [0.17, 0.42]), 11.6% (95% CI [0.08, 0.16]) and 20.9% (95% CI [0.15, 0.27]), respectively. CONCLUSIONS: RTX was associated with AEs such as decreased pulmonary function, all-cause mortality, and infections in CTD-ILD. Adverse reactions during and after RTX treatment should be carefully monitored. Further prospective studies are needed to compare RTX with other immunosuppressants, antifibrotic drugs or placebos, which can provide therapeutic approaches for CTD-ILD.

Acetyl-CoA Carboxylase (ACC) Inhibitor, CP640186, Effectively Inhibited Dengue Virus (DENV) Infection via Regulating ACC Phosphorylation.

Dengue fever is the most common mosquito-borne viral disease and is caused by the dengue virus (DENV). There is still a lack of efficient drugs against DENV infection, so it is urgent to develop new inhibitors for future clinical use. Our previous research indicated the role of VEGFR2/AMPK in regulating cellular metabolism during DENV infection, while acetyl-CoA carboxylase (ACC) is located downstream of AMPK and plays a crucial role in mediating cellular lipid synthesis; therefore, we speculated that an ACC inhibitor could serve as an antiviral agent against DENV. Luckily, we found that CP640186, a reported noncompetitive ACC inhibitor, significantly inhibited DENV proliferation, and CP640186 clearly reduced DENV2 proliferation at an early stage with an EC50 of 0.50 µM. A mechanism study indicated that CP640186 inhibited ACC activation and destroyed the cellular lipid environment for viral proliferation. In the DENV2 infection mice model, oral CP640186 administration (10 mg/kg/day) significantly improved the mice survival rate after DENV2 infection. In summary, our research suggests that lipid synthesis plays an important role during DENV2 proliferation and indicates that CP640186 is a promising drug candidate against DNEV2 in the future.

Impact of defecation dysfunction on quality of life in mid-low rectal cancer patients following sphincter-sparing surgery.

Objectives: A large proportion of mid-low rectal cancer patients develop low anterior resection syndrome (LARS) after Sphincter-sparing surgery. This study aimed to investigate the effect of low anterior resection syndrome (LARS) on quality of life (QoL) in Chinese rectal cancer patients following sphincter-sparing surgery. Methods: This was a comparative cross-sectional study. Between Jan 2019 to Jun 2020, 146 mid-low rectal cancer patients following sphincter-sparing surgery were enrolled. The low anterior resection syndrome (LARS) score was used to assess bowel dysfunction. According to the LARS score, patients were divided into three levels, no LARS (n â€‹= â€‹34), minor LARS (n â€‹= â€‹60), and major LARS (n â€‹= â€‹52). The Functional Assessment of Cancer Therapy-Colorectal (FACT-C) was used to assess the QoL of the patients. Results: The major LARS group had a significantly shorter level of tumor from the dentate line than the no LARS group. The total FACT-C score of 146 patients was 98.45 â€‹± â€‹17.83. The total FACT-C score and the score of each dimension (physical, emotional, functional dimensions, and colorectal cancer subscale) were significantly different between the minor LARS and major LARS groups, as well as between the no LARS and major LARS groups. Subgroups analyses of the FACT-C score stratified by each item in the LARS scales showed that except for flatus incontinence, patients with different frequencies of other symptoms (bowel frequency, liquid stool incontinence, liquid stool incontinence, stool clustering, urgent bowel movement) had a significantly different total score of FACT (all P â€‹< â€‹0.01). Conclusions: The LARS had a significant impact on the QoL in Chinese mid-low rectal cancer patients following sphincter-sparing surgery, especially in patients with major LARS.

PKCß Inhibition Promotes TXNIP Degradation to Ameliorate Pancreatic ß-Cell Dysfunction.

INTRODUCTION: Pancreatic ß-cell dysfunction is largely regulated by TXNIP accumulation, we have previously disclosed the role of PKA in TXNIP degradation during ß-cell dysfunction. However, whether other kinases (PKCs) still regulate TXNIP is unclear, which is beneficial to alleviate ß-cell dysfunction. METHODS: Thapsigargin (ER stress inducer) was used to induce ß-cell dysfunction. PKC's inhibitors were screened by Western blotting indicated by TXNIP. Also RT-qPCR and Co-immunoprecipitation were applied for evaluating the ß-cell improvement ability of PKC's inhibitors, and the insulin secretion ability was evaluated by glucose-stimulated insulin secretion assay. RESULTS: PKC's pan-inhibitor, Ro31-8220, decreased ß-cell apoptosis and improved insulin secretion under ER stress or high glucose (HG) conditions. Further studies showed that Ro31-8220 reduced ER stress or HG-induced TXNIP levels. On the other side, PKCß activation or overexpression could reverse the effect of Ro31-8220 on TXNIP. Also, PKCß selective inhibitor, ruboxistaurin, induced TXNIP degradation as significantly as Ro31-8220 did. CONCLUSION: This study reveals the regulating mechanism of PKCß inhibitor on TXNIP degradation to improve ß-cell dysfunction. These data indicated PKCß inhibitor is a promising agent for ameliorating ß-cell dysfunction through TXNIP.

Real-world safety of ulinastatin: a post-marketing surveillance of 11,252 patients in China.

BACKGROUND: The safety assessment of ulinastatin can guide clinical practice. The present study aimed to investigate the real-world safety of ulinastatin in China. METHODS: This multicenter study retrospectively analyzed the post-marketing surveillance data of consecutive patients treated with ulinastatin between August 2014 and June 2017 in the general wards and the intensive care units (ICU) of nine hospitals in China. Adverse drug reactions/adverse drug events (ADRs/ADEs) were collected and evaluated in a post-marketing database. RESULTS: A total of 11,252 consecutive patients were included in the study: 7009 ICU patients and 4243 general ward patients. Eleven patients with ADRs/ADEs were observed, including nine ICU patients and two general ward patients. The clinical manifestations were liver dysfunction (n = 5 ICU cases, n = 1 general case), thrombocytopenia (n = 2 ICU cases, n = 1 general case), leukopenia (n = 1 ICU case), and rash (n = 1 ICU case). During the study period, the drug ADR/ADE rate of ulinastatin injection was 0.98‰ (11/11,252 × 1000‰). Among the 11,252 valid patients, only 327 received ulinastatin in accordance with the drug specifications. After excluding unreasonable drug use, the calculated ADR rate was 3.06‰ (1/327 × 1000‰) (95% confidence interval: 0.0‰-17.1‰). In ICU and general ward patients, the use of other drugs combined with ulinastatin was associated with the occurrence of ADRs/ADEs (100% with ADRs/ADEs vs. 0% in controls, P < 0.001). CONCLUSIONS: The incidence of ADRs/ADEs of ulinastatin is < 5‰. The ADRs/ADEs involved limited organs, mainly the skin, gastrointestinal tract, and blood. In most cases, the ADRs/ADEs gradually alleviated or recovered after drug withdrawal. The inappropriate/off-label use of ulinastatin should be the focus of surveillance.