Fatty Acid Binding Protein-4 Silencing Inhibits Ferroptosis to Alleviate Lipopolysaccharide-induced Injury of Renal Tubular Epithelial Cells by Blocking Janus Kinase 2/Signal Transducer and Activator of Transcription 3 Signaling.

Sepsis-induced kidney injury (SAKI) has been frequently established as a prevailing complication of sepsis which is linked to unfavorable outcomes. Fatty acid-binding protein-4 (FABP4) has been proposed as a possible target for the treatment of SAKI. In the current work, we aimed to explore the role and underlying mechanism of FABP4 in lipopolysaccharide (LPS)-induced human renal tubular epithelial cell damage. In LPS-induced human kidney 2 (HK2) cells, FABP4 expression was tested by the reverse transcription-quantitative polymerase chain reaction and Western blot. Cell counting kit-8 method assayed cell viability. Inflammatory levels were detected using the enzyme-linked immunosorbent assay. Immunofluorescence staining measured the nuclear translocation of nuclear factor kappa B p65. Thiobarbituric acid-reactive substances assay and C11 BODIPY 581/591 probe were used to estimate the level of cellular lipid peroxidation. Fe2+ content was examined by the kit. In addition, the expression of proteins related to inflammation-, ferroptosis- and Janus kinase 2 (JAK2)/signal transducer, and activator of transcription 3 (STAT3) signaling was detected by the Western blot analysis. The results revealed that FABP4 was significantly upregulated in LPS-treated HK2 cells, the knockdown of which elevated the viability, whereas alleviated the inflammation and ferroptosis in HK2 cells challenged with LPS. In addition, down-regulation of FABP4 inactivated JAK2/STAT3 signaling. JAK2/STAT3 stimulator (colivelin) and ferroptosis activator (Erastin) partially restored the effects of FABP4 interference on LPS-triggered inflammation and ferroptosis in HK2 cells. Together, FABP4 knockdown inhibited ferroptosis to alleviate LPS-induced injury of renal tubular epithelial cells through suppressing JAK2/STAT3 signaling.

Efficacy and safety of guselkumab in patients with active psoriatic arthritis who had inadequate efficacy and/or intolerance to one prior tumor necrosis factor inhibitor: study protocol for SOLSTICE, a phase 3B, multicenter, randomized, double-blind, placebo-controlled study.

BACKGROUND: Tumor necrosis factor inhibitors (TNFi) are frequently chosen as the first biologic for patients with psoriatic arthritis (PsA). Given that many patients with PsA are TNFi inadequate responders (TNF-IR; either inadequate efficacy or intolerance), treatments utilizing alternative mechanisms of action are needed. In phase 3 studies, the fully human interleukin (IL)-23p19 subunit-inhibitor, guselkumab, was efficacious in patients with active PsA, including TNFi-IR. Efficacy was generally consistent between TNFi-naïve and TNFi-experienced cohorts; however, in the latter, higher response rates have been observed with the Q4W dosing regimen relative to the Q8W dosing regimen for some endpoints, suggesting the need to evaluate whether more frequent dosing may provide an incremental clinical benefit for TNFi-IR patients. METHODS: The phase 3b SOLSTICE study will assess guselkumab efficacy and safety in TNFi-IR PsA patients. Eligibility criteria include a PsA diagnosis for ≥ 6 months; active disease (≥ 3 swollen, ≥ 3 tender joints, C-reactive protein ≥ 0.3 mg/dL); and inadequate efficacy with, and/or intolerance to, one prior TNFi. Participants will be randomized 1:1:1 to guselkumab Q4W or Q8W or placebo→guselkumab Q4W (at Week 24). The primary endpoint is the proportion of patients achieving ≥ 20% improvement in the American College of Rheumatology criteria (ACR20) at Week 24. Major secondary endpoints include ACR50, ACR70; an Investigator's Global Assessment (IGA) of psoriasis score of 0/1 plus ≥ 2-grade reduction and ≥ 90% improvement in Psoriasis Area and Severity Index (both among patients with ≥ 3% body surface area affected by psoriasis and baseline IGA ≥ 2); minimal/very low disease activity; and changes from baseline in Health Assessment Questionnaire-Disability Index, the 36-item Short-Form Health Survey Physical Component Summary, and Functional Assessment of Chronic Illness Therapy-Fatigue scores. The target sample size (N = 450) is estimated to provide > 90% power in detecting differences between each guselkumab group and the placebo group for the primary endpoint assuming a 2-sided α = 0.05. Cochran-Mantel-Haenszel testing and analyses of covariance will be used to compare efficacy for binary and continuous endpoints, respectively. DISCUSSION: Findings from the phase 3b SOLSTICE study, the design of which was informed by results from previously conducted phase 3 studies, is expected to provide important efficacy and safety information on guselkumab therapy in TNFi-IR patients with PsA. TRIAL REGISTRATION: This trial was registered at ClinicalTrials.gov, NCT04936308, on 23 June 2021.

Successful management of postpartum venous thrombosis following splenectomy for traumatic splenic rupture: a case report.

Traumatic splenic rupture is rare in pregnant women; and multiple venous thromboses of the portal vein system, inferior vena cava and ovarian vein after caesarean section and splenectomy for splenic rupture has not been previously reported. This case report describes a case of multiple venous thromboses after caesarean section and splenectomy for traumatic splenic rupture in late pregnancy. A 34-year-old G3P1 female presented with abdominal trauma at 33+1 weeks of gestation. After diagnosis of splenic rupture, she underwent an emergency caesarean section and splenectomy. Multiple venous thromboses developed during the recovery period. The patient eventually recovered after anticoagulation therapy with low-molecular-weight heparin and warfarin. These findings suggest that in patients that have had a caesarean section and a splenectomy, which together might further increase the risk of venous thrombosis, any abdominal pain should be thoroughly investigated and thrombosis should be ruled out, including the possibility of multiple venous thromboses. Anticoagulant therapy could be extended after the surgery.

18F-FDG PET/CT findings in nevoid basal cell carcinoma syndrome: a systematic review and a new case report.

BACKGROUND: To demonstrate and analyze the 18F-FDG positron emission tomography/computed tomography (PET/CT) findings in this rare nevoid basal cell carcinoma syndrome (NBCCS). CASE PRESENTATION: A 71-year-old woman with the left invasive breast cancer was treated with hormone therapy for six months and underwent the 18F-FDG PET/CT examination for efficacy evaluation. 18F-FDG PET/CT revealed the improvement after treatment and other unexpected findings, including multiple nodules on the skin with 18F-FDG uptake, bone expansion of cystic lesions in the bilateral ribs, ectopic calcifications and dilated right ureter. She had no known family history. Then, the patient underwent surgical excision of the all skin nodules and the postoperative pathology were multiple basal cell carcinomas. Finally, the comprehensive diagnosis of NBCCS was made. The patient was still in follow-up. Additionally, we have summarized the reported cases (n = 3) with 18F-FDG PET/CT from the literature. CONCLUSIONS: It is important to recognize this syndrome on 18F-FDG PET/CT because of different diagnoses and therapeutic consequences.

Application of dual chemotherapeutic drug delivery system based on metal-organic framework platform in enhancing tumor regression for breast cancer research.

The nanomedicine system based on dual drug delivery systems (DDDs) can significantly enhance the efficacy of tumor treatment. Herein, a metal-organic framework, Zeolite imidazole salt frames 8 (ZIF-8), was successfully utilized as a carrier to load the dual chemotherapeutic drugs doxorubicin (DOX) and camptothecin (CPT), named DOX/CPT@ZIF-8 (denoted as DCZ), and their inhibitory effects on 4T1 breast cancer cells were evaluated. The study experimentally demonstrated the synergistic effects of the dual chemotherapeutic drugs within the ZIF-8 carrier and showed that the ZIF-8 nano-carrier loaded with the dual drugs exhibited stronger cytotoxicity and inhibitory effects on 4T1 breast cancer cells compared to single-drug treatment. The use of a ZIF-8-based dual chemotherapeutic drug carrier system highlighted its potential advantages in suppressing 4T1 breast cancer cells.

Development and Characterization of a Novel Carbon-11 Labeled Positron Emission Tomography Radiotracer for Neuroimaging of Sirtuin 1 with Benzoxazine-Based Compounds.

Introduction: Sirtuins (SIRTs) comprise a group of histone deacetylase enzymes crucial for regulating metabolic pathways and contributing significantly to various disease mechanisms. Sirtuin 1 (SIRT1), among the seven known mammalian homologs, is extensively investigated and understood, playing a key role in neurodegenerative disorders and cancer. This study focuses on potential as a therapeutic target for conditions such as Parkinson's disease (PD), Huntington's disease (HD), and Alzheimer's disease (AD). Methods: Utilizing positron emission tomography (PET) as a noninvasive molecular imaging modality, we aimed to expedite the validation of a promising sirtuin 1 inhibitor for clinical trials. However, the absence of a validated sirtuin 1 PET radiotracer impedes clinical translation. We present the development of [11C]1, and 11C-labeled benzoxazine-based derivative, as a lead imaging probe. The radiosynthesis of [11C]1 resulted in a radiochemical yield of 31 ± 4%. Results: Baseline studies demonstrated that [11C]1 exhibited excellent blood-brain barrier (BBB) penetration capability, with uniform accumulation throughout various brain regions. Self-blocking studies revealed that introducing an unlabeled compound 1, effectively blocking sirtuin 1, led to a substantial reduction in whole-brain uptake, emphasizing the in vivo specificity of [11C]1 for sirtuin 1. Discussion: The development of [11C]1 provides a valuable tool for noninvasive imaging investigations in rodent models with aberrant sirtuin 1 expression. This novel radiotracer holds promise for advancing our understanding of sirtuin 1's role in disease mechanisms and may facilitate the validation of sirtuin 1 inhibitors in clinical trials.

Humanistic Health Management and Cancer: Associations of Psychology, Nutrition, and Exercise with Cancer Progression and Pathogenesis.

The incidence rate of cancer is increasing year by year due to the aging of the population, unhealthy living, and eating habits. At present, surgery and medication are still the main treatments for cancer, without paying attention to the impact of individual differences in health management on cancer. However, increasing evidence suggests that individual psychological status, dietary habits, and exercise frequency are closely related to the risk and prognosis of cancer. The reminder to humanity is that the medical concept of the unified treatment plan is insufficient in cancer treatment, and a personalized treatment plan may become a breakthrough point. On this basis, the concept of "Humanistic Health Management" (HHM) is proposed. This concept is a healthcare plan that focuses on self-health management, providing an accurate and comprehensive evaluation of individual lifestyle habits, psychology, and health status, and developing personalized and targeted comprehensive cancer prevention and treatment plans. This review will provide a detailed explanation of the relationship between psychological status, dietary, and exercise habits, and the regulatory mechanisms of cancer. Intended to emphasize the importance of HHM concept in cancer prevention and better prognostic efficacy, providing new ideas for the new generation of cancer treatment.

Quercetin inhibits necroptosis in cardiomyocytes after ischemia-reperfusion via DNA-PKcs-SIRT5-orchestrated mitochondrial quality control.

We investigated the mechanism by which quercetin preserves mitochondrial quality control (MQC) in cardiomyocytes subjected to ischemia-reperfusion stress. An enzyme-linked immunosorbent assay was employed in the in vivo experiments to assess myocardial injury markers, measure the transcript levels of SIRT5/DNAPK-cs/MLKL during various time intervals of ischemia-reperfusion, and observe structural changes in cardiomyocytes using transmission electron microscopy. In in vitro investigations, adenovirus transfection was employed to establish a gene-modified model of DNA-PKcs, and primary cardiomyocytes were obtained from a mouse model with modified SIRT5 gene. Reverse transcription polymerase chain reaction, laser confocal microscopy, immunofluorescence localization, JC-1 fluorescence assay, Seahorse energy analysis, and various other assays were applied to corroborate the regulatory influence of quercetin on the MQC network in cardiomyocytes after ischemia-reperfusion. In vitro experiments demonstrated that ischemia-reperfusion injury caused changes in the structure of the myocardium. It was seen that quercetin had a beneficial effect on the myocardial tissue, providing protection. As the ischemia-reperfusion process continued, the levels of DNA-PKcs/SIRT5/MLKL transcripts were also found to change. In vitro investigations revealed that quercetin mitigated cardiomyocyte injury caused by mitochondrial oxidative stress through DNA-PKcs, and regulated mitophagy and mitochondrial kinetics to sustain optimal mitochondrial energy metabolism levels. Quercetin, through SIRT5 desuccinylation, modulated the stability of DNA-PKcs, and together they regulated the "mitophagy-unfolded protein response." This preserved the integrity of mitochondrial membrane and genome, mitochondrial dynamics, and mitochondrial energy metabolism. Quercetin may operate synergistically to oversee the regulation of mitophagy and the unfolded protein response through DNA-PKcs-SIRT5 interaction.

Phosphorylation of AGO2 by TBK1 Promotes the Formation of Oncogenic miRISC in NSCLC.

Non-small-cell lung cancer (NSCLC) is a highly lethal tumor that often develops resistance to targeted therapy. It is shown that Tank-binding kinase 1 (TBK1) phosphorylates AGO2 at S417 (pS417-AGO2), which promotes NSCLC progression by increasing the formation of microRNA-induced silencing complex (miRISC). High levels of pS417-AGO2 in clinical NSCLC specimens are positively associated with poor prognosis. Interestingly, the treatment with EGFR inhibitor Gefitinib can significantly induce pS417-AGO2, thereby increasing the formation and activity of oncogenic miRISC, which may contribute to NSCLC resistance to Gefitinib. Based on these, two therapeutic strategies is developed. One is jointly to antagonize multiple oncogenic miRNAs highly expressed in NSCLC and use TBK1 inhibitor Amlexanox reducing the formation of oncogenic miRISC. Another approach is to combine Gefitinib with Amlexanox to inhibit the progression of Gefitinib-resistant NSCLC. This findings reveal a novel mechanism of oncogenic miRISC regulation by TBK1-mediated pS417-AGO2 and suggest potential therapeutic approaches for NSCLC.

Gut microbiome as a treatment in colorectal cancer.

BACKGROUND: The gut microbiome plays a role in the development and progression of colorectal cancer (CRC). AIM AND OBJECTIVE: This review focuses on whether the gut microbiome is involved in the development and regulation of the host immune system. METHODS: The gut microbiome can influence the production and activity of immune cells and molecules that help to maintain the integrity of the intestinal barrier and prevent inflammation. Gut microbiota modulates the anti-cancer immune response. The gut microbiota can influence the function of immune cells, like T cells, that recognize and eliminate cancer cells. Gut microbiota can affect various aspects of cancer progression and the efficacy of various anti-cancer treatments. RESULTS: Gut microbiota provide promise as a potential biomarker to identify the effect of immunotherapy and as a target for modulation to improve the efficacy of immunotherapy in CRC treatment. CONCLUSION: The potential synergistic effect between the gut microbiome and anti-cancer treatment modalities provides an interest in developing strategies to modulate the gut microbiome to improve the efficacy of anti-cancer treatment.

This review focuses on the gut microbiome in the development and regulation of the host immune system. Gut microbiota provides potential biomarkers to identify the effect of immunotherapy and as a target for modulation of immunotherapy in the treatment of CRC. This provides potential synergistic effects between the gut microbiome and anti-cancer treatment modalities.

N4-acetylcytidine modifies primary microRNAs for processing in cancer cells.

N4 acetylcytidine (ac4C) modification mainly occurs on tRNA, rRNA, and mRNA, playing an important role in the expression of genetic information. However, it is still unclear whether microRNAs have undergone ac4C modification and their potential physiological and pathological functions. In this study, we identified that NAT10/THUMPD1 acetylates primary microRNAs (pri-miRNAs) with ac4C modification. Knockdown of NAT10 suppresses and augments the expression levels of mature miRNAs and pri-miRNAs, respectively. Molecular mechanism studies found that pri-miRNA ac4C promotes the processing of pri-miRNA into precursor miRNA (pre-miRNA) by enhancing the interaction of pri-miRNA and DGCR8, thereby increasing the biogenesis of mature miRNA. Knockdown of NAT10 attenuates the oncogenic characters of lung cancer cells by regulating miRNA production in cancers. Moreover, NAT10 is highly expressed in various clinical cancers and negatively correlated with poor prognosis. Thus, our results reveal that NAT10 plays a crucial role in cancer initiation and progression by modulating pri-miRNA ac4C to affect miRNA production, which would provide an attractive therapeutic strategy for cancers.

Value of 18F-FDG PET/CT in breast cancer with second primary malignancies.

PURPOSE: To investigate the value of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) in breast cancer (BC) with second primary malignancies (SPMs). MATERIALS AND METHODS: 149 BC patients (149/1419, 10.5 %) ultimately diagnosed with SPMs were included in the study. The following data were evaluated: age, location, the treatment of the first BC, the interval between the first BC and SPMs, the maximum diameter of SPMs, the maximum standardized uptake value (SUVmax) of SPMs, and SPMs metastases. The overall survival (OS) and progression-free survival (PFS) of follow-up patients were analyzed. The diagnostic efficiency of 18F-FDG PET/CT for SPMs and consistency with the pathological findings were calculated. RESULTS: The most common SPMs of BC was lung cancer (81/149, 54.4 %), particularly early-stage lung adenocarcinoma. There were the shorter maximum diameter of SPMs, the lower SUVmax of SPMs, and the fewer SPMs metastases in the lung cancer group than non-lung cancer group (P<0.001). The OS and PFS of the follow-up patients in the lung cancer group were longer than non-lung cancer group (P<0.001). The SPMs metastases was independent prognostic indicator of OS. The pathological grouping and the SPMs metastases were independent prognostic indicators of PFS. 18F-FDG PET/CT efficacy in diagnosing SPMs in BC patients was high. Compared with the pathological findings, the consistency was good (P = 0.010). CONCLUSION: Applying 18F-FDG PET/CT in BC patients might be helpful in detecting SPMs and partially predicting patient prognosis, in addition to its primary function in the diagnosis and staging of BC.

Nuclear translocation of cleaved PCDH9 impairs gastric cancer metastasis by downregulating CDH2 expression.

Loss of Protocadherin 9 (PCDH9) is associated with the metastasis and the prognosis of gastric cancer patients, while the molecular mechanism of PCDH9-impaired gastric cancer metastasis remains unclear. Here we show that PCDH9 is cleaved in gastric cancer cells. Intracellular domain of PCDH9 translocates into nucleus, where it interacts with DNA methyltransferase 1 (DNMT1) and increases DNMT1 activity. Activated DNMT1 downregulates cadherin 2 (CDH2) expression by increasing DNA methylation at its promoter, thereby dampening the migration and in vivo metastasis of gastric cancer cells. In addition, the levels of nuclear PCDH9 correlate with CDH2 expression, lymph node metastasis, and the prognosis of gastric cancer patients. Our finding demonstrates a unique mechanism of nuclear PCDH9-impaired gastric cancer metastasis by promoting DNA methylation of CDH2 promoter.

A novel molecular subtyping based on multi-omics analysis for prognosis predicting in colorectal melanoma: A 16-year prospective multicentric study.

Colorectal melanoma (CRM) is a rare malignant tumor with severe complications, and there is currently a lack of systematic research. We conducted a study that combined proteomics and mutation data of CRM from a cohort of three centers over a 16-years period (2005-2021). The patients were divided into a training set consisting of two centers and a testing set comprising the other center. Unsupervised clustering was conducted on the training set to form two molecular subtypes for clinical characterization and functional analysis. The testing set was used to validate the survival differences between the two subtypes. The comprehensive analysis identified two subtypes of CRM: immune exhausted C1 cluster and DNA repair C2 cluster. The former subtype exhibited characteristics of metabolic disturbance, immune suppression, and poor prognosis, along with APC mutations. A machine learning algorithm named Support Vector Machine (SVM) was applied to predict the classification of CRM patients based on protein expression in the external testing cohort. Two subtypes of primary CRM with clinical and proteomic characteristics provides a reference for subsequent diagnosis and treatments.

Advances in artificial intelligence for the diagnosis and treatment of ovarian cancer (Review).

Artificial intelligence (AI) has emerged as a crucial technique for extracting high­throughput information from various sources, including medical images, pathological images, and genomics, transcriptomics, proteomics and metabolomics data. AI has been widely used in the field of diagnosis, for the differentiation of benign and malignant ovarian cancer (OC), and for prognostic assessment, with favorable results. Notably, AI­based radiomics has proven to be a non­invasive, convenient and economical approach, making it an essential asset in a gynecological setting. The present study reviews the application of AI in the diagnosis, differentiation and prognostic assessment of OC. It is suggested that AI­based multi­omics studies have the potential to improve the diagnostic and prognostic predictive ability in patients with OC, thereby facilitating the realization of precision medicine.

Association of elastic power in mechanical ventilation with the severity of acute respiratory distress syndrome: a retrospective study.

BACKGROUND: Mechanical power (MP) is the total energy released into the entire respiratory system per minute which mainly comprises three components: elastic static power, Elastic dynamic power and resistive power. However, the energy to overcome resistance to the gas flow is not the key factor in causing lung injury, but the elastic power (EP) which generates the baseline stretch of the lung fibers and overcomes respiratory system elastance may be closely related to the ARDS severity. Thus, this study aimed to investigate whether EP is superior to other ventilator variables for predicting the severity of lung injury in ARDS patients. METHODS: We retrieved patient data from the Medical Information Mart for Intensive Care III (MIMIC-III) database. The retrieved data involved adults (≥ 18 years) diagnosed with ARDS and subjected to invasive mechanical ventilation for ≥ 48 h. We employed univariate and multivariate logistic regression analyses to investigate the correlation between EP and development of moderate-severe ARDS. Furthermore, we utilized restricted cubic spline models to assess whether there is a linear association between EP and incidence of moderate-severe ARDS. In addition, we employed a stratified linear regression model and likelihood ratio test in subgroups to identify potential modifications and interactions. RESULTS: Moderate-severe ARDS occurred in 73.4% (296/403) of the patients analyzed. EP and MP were significantly associated with moderate-severe ARDS (odds ratio [OR] 1.21, 95% confidence interval [CI] 1.15-1.28, p < 0.001; and OR 1.15, 95%CI 1.11-1.20, p < 0.001; respectively), but EP showed a higher area-under-curve (95%CI 0.72-0.82, p < 0.001) than plateau pressure, driving pressure, and static lung compliance in predicting ARDS severity. The optimal cutoff value for EP was 14.6 J/min with a sensitivity of 75% and specificity of 66%. Quartile analysis revealed that the relationship between EP and ARDS severity remained robust and reliable in subgroup analysis. CONCLUSION: EP is a good ventilator variable associated with ARDS severity and can be used for grading ARDS severity. Close monitoring of EP is advised in patients undergoing mechanical ventilation. Additional experimental trials are needed to investigate whether adjusting ventilator variables according to EP can yield significant improvements in clinical outcomes.

PTEN-mediated dephosphorylation of 53BP1 confers cellular resistance to DNA damage in cancer cells.

Homologous recombination (HR) repair for DNA double-strand breaks (DSBs) is critical for maintaining genome stability and conferring the resistance of tumor cells to chemotherapy. Nuclear PTEN which contains both phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and protein phosphatase plays a key role in HR repair, but the underlying mechanism remains largely elusive. We find that SUMOylated PTEN promotes HR repair but represses nonhomologous end joining (NHEJ) repair by directly dephosphorylating TP53-binding protein 1 (53BP1). During DNA damage responses (DDR), tumor suppressor ARF (p14ARF) was phosphorylated and then interacted efficiently with PTEN, thus promoting PTEN SUMOylation as an atypical SUMO E3 ligase. Interestingly, SUMOylated PTEN was subsequently recruited to the chromatin at DSB sites. This was because SUMO1 that was conjugated to PTEN was recognized and bound by the SUMO-interacting motif (SIM) of breast cancer type 1 susceptibility protein (BRCA1), which has been located to the core of 53BP1 foci on chromatin during S/G2 stage. Furthermore, these chromatin-loaded PTEN directly and specifically dephosphorylated phosphothreonine-543 (pT543) of 53BP1, resulting in the dissociation of the 53BP1 complex, which facilitated DNA end resection and ongoing HR repair. SUMOylation-site-mutated PTENK254R mice also showed decreased DNA damage repair in vivo. Blocking the PTEN SUMOylation pathway with either a SUMOylation inhibitor or a p14ARF(2-13) peptide sensitized tumor cells to chemotherapy. Our study therefore provides a new mechanistic understanding of PTEN in HR repair and clinical intervention of chemoresistant tumors.

Outcomes of preoperative chemotherapy for colorectal cancer with peritoneal metastasis underwent cytoreductive surgery.

BACKGROUND: This study aims to assess and compare the extent to which preoperative chemotherapy prior to CRS improves survival in patients diagnosed with CRCPM. METHODS: We included 251 patients from 2012 to 2019 in our center. Inverse probability of treatment weighting (IPTW) analysis was used to minimize the selection bias. Survival analysis was performed to compare the survival outcomes. Multivariate Cox regression analysis was conducted to identify prognostic factors. RESULT: The baseline characteristics were well balanced using IPTW (standardized mean difference < 0.1). Preoperative chemotherapy cannot significantly improve overall survival (HR, 1.03; 95% CI 0.71-1.49; P = 0.88). In subgroup analysis, we found that intestinal obstruction after preoperative chemotherapy significantly reduced survival (HR, 2.25; 95% CI 1.01-5.03; P = 0.048), while in the upfront surgery group, intestinal obstruction had no impact on prognosis. CONCLUSION: For CRCPM patients treated with CRS, preoperative chemotherapy does not seem to prolong overall survival. Furthermore, the emergence of intestinal obstruction after chemotherapy may compromise the effectiveness of treatment, resulting in a worse prognosis. This finding has important clinical implications for treatment decisions.

Long-Term Safety of Guselkumab in Patients with Psoriatic Disease: An Integrated Analysis of Eleven Phase II/III Clinical Studies in Psoriasis and Psoriatic Arthritis.

INTRODUCTION: The benefit/risk profiles of biologics can be affected by comorbidities, certain demographic characteristics, and concomitant medications; therefore, it is important to evaluate the long-term safety profiles of biologics across broad patient populations. Guselkumab was well tolerated and efficacious across individual pivotal clinical studies in adults with moderate-to-severe psoriasis and/or active psoriatic arthritis (PsA). OBJECTIVES: The objective of the current analysis was to evaluate guselkumab safety in a large population of patients with psoriatic disease by pooling adverse event (AE) data from 11 phase II/III studies (seven in psoriasis; four in PsA). METHODS: Guselkumab was generally administered as 100 mg subcutaneous injections at Week 0, Week 4, then every 8 weeks (Q8W) in psoriasis studies and at Week 0, Week 4, then every 4 weeks (Q4W) or Q8W in PsA studies. Safety data were summarized for the placebo-controlled period (Weeks 0-16 in psoriasis; Weeks 0-24 in PsA) and through the end of the reporting period (up to 5 years in psoriasis; up to 2 years in PsA). Using the integrated data, incidence rates of key AEs were determined post hoc, adjusted for duration of follow-up, and reported per 100 patient-years (PYs). AE rates were also determined in subgroups of patients defined by sex, age, body mass index (BMI), and prior biologic use. RESULTS: During the placebo-controlled period, 1061 patients received placebo (395 PYs) and 2257 received guselkumab (856 PYs). Through the end of the reporting period, 4399 guselkumab-treated patients contributed 10,787 PYs of follow-up. During the placebo-controlled period, in the guselkumab and placebo groups, respectively, rates of AEs were 281 versus 272/100 PYs, and infections were 76.0 versus 72.2/100 PYs. Rates of serious AEs (5.6 vs. 7.8/100 PYs), AEs leading to discontinuation (4.9 vs. 6.6/100 PYs), serious infections (1.0 vs. 2.3/100 PYs), malignancy (0.59 vs. 0.25 patients/100 PYs), and major adverse cardiovascular events (MACE; 0.35 vs. 0.25/100 PYs) were low and comparable between guselkumab and placebo. Among guselkumab-treated patients, safety event rates through the end of the reporting period were numerically lower than or comparable with rates observed during the placebo-controlled period: AEs, 164/100 PYs; infections, 61.2/100 PYs; serious AEs, 5.4/100 PYs; AEs leading to discontinuation, 1.8/100 PYs; serious infections, 1.0/100 PYs; malignancy, 0.6/100 PYs; and MACE, 0.3/100 PYs. No AEs of Crohn's disease, ulcerative colitis, or active tuberculosis were reported among guselkumab-treated patients. In the psoriasis studies, no opportunistic infections were reported among guselkumab-treated patients. Three AEs of opportunistic infections were reported in guselkumab-treated patients with PsA (0.14/100 PYs; all after Week 52 in DISCOVER-2). AE rates were largely consistent across subgroups of guselkumab-treated patients defined by sex, age, BMI, and prior biologic use. CONCLUSIONS: In this analysis of 4399 guselkumab-treated patients with psoriatic disease followed for 10,787 PYs, guselkumab had a favorable AE profile. AE rates were similar between guselkumab- and placebo-treated patients and were consistent throughout long-term guselkumab treatment and across broad subgroups of patients with psoriatic disease. CLINICAL TRIALS REGISTRATIONS: Clinicaltrials.gov identifiers: NCT01483599, NCT02207231, NCT02207244, NCT02203032, NCT02905331, NCT03090100, NCT02325219, NCT02319759, NCT03162796, NCT03158285, and NCT03796858.

USP7 reduces the level of nuclear DICER, impairing DNA damage response and promoting cancer progression.

Endoribonuclease DICER is an RNase III enzyme that mainly processes microRNAs in the cytoplasm but also participates in nuclear functions such as chromatin remodelling, epigenetic modification and DNA damage repair. The expression of nuclear DICER is low in most human cancers, suggesting a tight regulation mechanism that is not well understood. Here, we found that ubiquitin carboxyl-terminal hydrolase 7 (USP7), a deubiquitinase, bounded to DICER and reduced its nuclear protein level by promoting its ubiquitination and degradation through MDM2, a newly identified E3 ubiquitin-protein ligase for DICER. This USP7-MDM2-DICER axis impaired histone γ-H2AX signalling and the recruitment of DNA damage response (DDR) factors, possibly by influencing the processing of small DDR noncoding RNAs. We also showed that this negative regulation of DICER by USP7 via MDM2 was relevant to human tumours using cellular and clinical data. Our findings revealed a new way to understand the role of DICER in malignant tumour development and may offer new insights into the diagnosis, treatment and prognosis of cancers.