The GFPT2-O-GlcNAcylation-YBX1 axis promotes IL-18 secretion to regulate the tumor immune microenvironment in pancreatic cancer.

The immunosuppressive microenvironment caused by several intrinsic and extrinsic mechanism has brought great challenges to the immunotherapy of pancreatic cancer. We identified GFPT2, the key enzyme in hexosamine biosynthesis pathway (HBP), as an immune-related prognostic gene in pancreatic cancer using transcriptome sequencing and further confirmed that GFPT2 promoted macrophage M2 polarization and malignant phenotype of pancreatic cancer. HBP is a glucose metabolism pathway leading to the generation of uridine diphosphate N-acetylglucosamine (UDP-GlcNAc), which is further utilized for protein O-GlcNAcylation. We confirmed GFPT2-mediated O-GlcNAcylation played an important role in regulating immune microenvironment. Through cellular proteomics, we identified IL-18 as a key downstream of GFPT2 in regulating the immune microenvironment. Through CO-IP and protein mass spectrum, we confirmed that YBX1 was O-GlcNAcylated and nuclear translocated by GFPT2-mediated O-GlcNAcylation. Then, YBX1 functioned as a transcription factor to promote IL-18 transcription. Our study elucidated the relationship between the metabolic pathway of HBP in cancer cells and the immune microenvironment, which might provide some insights into the combination therapy of HBP vulnerability and immunotherapy in pancreatic cancer.

Incidence of chemotherapy-related cardiac dysfunction in cancer patients.

BACKGROUND: Cancer patients are increasingly affected by chemotherapy-related cardiac dysfunction. The reported incidence of this condition vary significantly across different studies. HYPOTHESIS: A better comprehensive understanding of chemotherapy-related cardiac dysfunction incidence in cancer patients is imperative. Therefore, we performed a meta-analysis to establish the overall incidence of chemotherapy-related cardiac dysfunction in cancer patients. METHODS: We searched articles in PubMed and EMBASE from database inception to May 1, 2023. Studies that reported the incidence of chemotherapy-related cardiac dysfunction in cancer patients were included. RESULTS: A total of 53 studies involving 35 651 individuals were finally included in the meta-analysis. The overall pooled incidence of chemotherapy-related cardiac dysfunction in cancer patients was 63.21 per 1000 person-years (95% CI: 57.28-69.14). The chemotherapy-related cardiac dysfunction incidence increased steeply within half a year of cancer chemotherapy. Also, the trend of chemotherapy-related cardiac dysfunction incidence appeared to have plateaued after a longer duration of follow-up. In addition, chemotherapy-related cardiac dysfunction incidence rates are significantly higher among patients with age ≥50 years versus patients with age <50 years (99.96 vs. 34.48 per 1000 person-years). The incidence rate of cardiac dysfunction was higher among breast cancer patients (72.97 per 1000 person-years), leukemia patients (65.21 per 1000 person-years), and lymphoma patients (55.43 per 1000 person-years). CONCLUSION: Our meta-analysis unveiled a definitive overall incidence rate of chemotherapy-related cardiac dysfunction in cancer patients. In addition, it was found that the risk of developing this condition escalates within the initial 6 months postchemotherapy, subsequently tapering off to become statistically insignificant after a duration of 6 years.

Hydrogen alleviates impaired lung epithelial barrier in acute respiratory distress syndrome via inhibiting Drp1-mediated mitochondrial fission through the Trx1 pathway.

Acute respiratory distress syndrome (ARDS) is an acute and severe clinical complication lacking effective therapeutic interventions. The disruption of the lung epithelial barrier plays a crucial role in ARDS pathogenesis. Recent studies have proposed the involvement of abnormal mitochondrial dynamics mediated by dynamin-related protein 1 (Drp1) in the mechanism of impaired epithelial barrier in ARDS. Hydrogen is an anti-oxidative stress molecule that regulates mitochondrial function via multiple signaling pathways. Our previous study confirmed that hydrogen modulated oxidative stress and attenuated acute pulmonary edema in ARDS by upregulating thioredoxin 1 (Trx1) expression, but the exact mechanism remains unclear. This study aimed to investigate the effects of hydrogen on mitochondrial dynamics both in vivo and in vitro. Our study revealed that hydrogen inhibited lipopolysaccharide (LPS)-induced phosphorylation of Drp1 (at Ser616), suppressed Drp1-mediated mitochondrial fission, alleviated epithelial tight junction damage and cell apoptosis, and improved the integrity of the epithelial barrier. This process was associated with the upregulation of Trx1 in lung epithelial tissues of ARDS mice by hydrogen. In addition, hydrogen treatment reduced the production of reactive oxygen species in LPS-induced airway epithelial cells (AECs) and increased the mitochondrial membrane potential, indicating that the mitochondrial dysfunction was restored. Then, the expression of tight junction proteins occludin and zonula occludens 1 was upregulated, and apoptosis in AECs was alleviated. Remarkably, the protective effects of hydrogen on the mitochondrial and epithelial barrier were eliminated after applying the Trx1 inhibitor PX-12. The results showed that hydrogen significantly inhibited the cell apoptosis and the disruption of epithelial tight junctions, maintaining the integrity of the epithelial barrier in mice of ARDS. This might be related to the inhibition of Drp1-mediated mitochondrial fission through the Trx1 pathway. The findings of this study provided a new theoretical basis for the application of hydrogen in the clinical treatment of ARDS.

Hydrogen ameliorates endotoxin-induced acute lung injury through AMPK-mediated bidirectional regulation of Caspase3.

Septic lung injury is characterized by uncontrollable inflammatory infiltrations and acute onset bilateral hypoxemia. Evidence has emerged of the beneficial effect of hydrogen in acute lung injury (ALI), but the underlying mechanism is unclear. In this research, the recovery action of hydrogen on lipopolysaccharide (LPS)-induced ALI in mice and A549 cells was investigated. The 7-day survival rate and body weight of mice were measured after intraperitoneal injection of LPS. Lung function was determined by a whole body plethysmography (WBP) system using the indicators respiratory rate and enhanced pause. Hematoxylin and eosin (HE) staining confirmed the signs of pulmonary edema and inflammatory ooze. Reverse transcription-polymerase chain reaction (RT-PCR) quantification was used to detect the expression of inflammatory factors. Western blotting analysis evaluated the expression levels of involved proteins in the AMP-activated protein kinase (AMPK) pathway. The experimental results confirmed that hydrogen provided an essential solution to the dissipative effects of LPS on survival rate, weight loss and lung function. The LPS-stimulated inflammatory factors, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß) were also suppressed by hydrogen in A549 cells. Western blot analysis showed that hydrogen significantly upregulated the levels of phosphorylated AMPK (p-AMPK) and lowered the LPS-induced increased expression of dynamin-related protein 1 (Drp1) and Caspase3. These findings prove that hydrogen attenuated LPS-treated ALI by activating the AMPK pathway, supporting the feasibility of hydrogen treatment for sepsis.

Maintaining moderate versus lower PEEP after cardiac surgery: a propensity-scored matched analysis.

BACKGROUND: Setting positive end-expiratory pressure (PEEP) at around 5 cm H2O in the early postoperative period seems a common practice for most patients. It remains unclear if the routine application of higher levels of PEEP confers any meaningful clinical benefit for cardiac surgical patients. The aim of this study was to compare moderate versus conventional lower PEEP on patient-centered outcomes in the intensive care unit (ICU). METHODS: This is a single-center retrospective study involving patients receiving cardiac surgery from June 2022 to May 2023. Propensity-score matching (PSM) was used to balance the baseline differences. Primary outcomes were the duration of mechanical ventilation and ICU length of stay. Secondary outcomes included PaO2/FiO2 ratio at 24 h and the need for prone positioning during ICU stay. RESULTS: A total of 334 patients were included in the study, 102 (31%) of them received moderate PEEP (≥ 7 cm H2O) for the major time in the early postoperative period (12 h). After PSM, 79 pairs of patients were matched with balanced baseline data. The results showed that there was marginal difference in the distribution of mechanical ventilation duration (p = 0.05) and the Moderate PEEP group had a higher extubation rate at the day of T-piece trial (65 [82.3%] vs 52 [65.8%], p = 0.029). Applying moderate PEEP was also associated with better oxygenation. No differences were found regarding ICU length of stay and patients requiring prone positioning between groups. CONCLUSION: In selective cardiac surgical patients, using moderate PEEP compared with conventional lower PEEP in the early postoperative period correlated to better oxygenation, which may have potential for earlier liberation of mechanical ventilation.

SIMPLIFIED IMMUNE-DYSREGULATION INDEX: A NOVEL MARKER PREDICTS 28-DAY MORTALITY OF INTENSIVE CARE PATIENTS WITH SEPSIS.

ABSTRACT: Background: Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. There is currently no simple immune-imbalance-driven indicator for patients with sepsis. Methods: This study was conducted in Peking Union Medical College Hospital. Patients with sepsis were identified according to Sepsis 3.0 after reviewing patient data from May 2018 through October 2022. Least absolute shrinkage and selection operator logistic regression was used for features selection. Receiver operating characteristic curves for 28-day mortality were used to compare the predictive performance of level of interleukin 6 (IL-6) and lymphocyte count (LY#) with that of the combined ratio, namely, the IL-6/LY# ratio. A Cox hazard model was also used to test the predictive performance of IL-6/LY# versus several other measurements. The dynamic trend of IL-6/LY# based on day 1 IL-6/LY# level was analyzed. Results: The mortality rate was 24.5% (220/898) in the study cohort. The LY#, IL-6 level, blood platelet count, Sequential Organ Failure Assessment score, Acute Physiology and Chronic Health Evaluation II score, heart rate, age and Fi o2 level were identified as key factors for predicting 28-day mortality. IL-6/LY# was identified as a core indicator according to Least absolute shrinkage and selection operator logistic regression analysis. IL-6/LY# was significantly higher in nonsurvivors than in survivors (348 [154.6-1371.7] vs. 42.3 [15.4-117.1]). IL-6/LY# yielded a higher area under the curve (0.852 [95% CI = 0.820-0.879]) than the level of IL-6 (0.776 [95% CI = 0.738-0.809]) and LY# (0.719 [95% CI = 0.677-0.755]) separately. Survival analysis of mortality risk versus the IL-6/LY# ratio suggested that IL-6/LY# was significantly more predictive of patient risk than the Sequential Organ Failure Assessment score or the other factors ( P = 1.5 × 10 -33 ). In trend analysis, as the trend of D1-D3-D7 IL-6/LY# decreases, the morality rate is lower than increase or fluctuate group (42.1% vs. 58.3%, 37.9% vs. 43.8%, 37.5% vs. 38.5% in high, moderate, and low D1 IL-6/LY# group separately). Conclusion: IL-6/LY# examined on first day in intensive care unit can be used as an immune-imbalance alert to identify sepsis patients with higher risk of 28-day mortality. Decreasing trend of IL-6/LY# suggests a lower 28-day mortality rate of sepsis patients.

Factors influencing DVT formation in sepsis.

INTRODUCTION: Sepsis is a global public health burden. Deep vein thrombosis (DVT) is the third most common cause of death from cardiovascular disease after heart attacks and strokes. We designed this experiment to investigate the factors influencing DVT formation in patients with sepsis. METHODS: In this survey, 918 septic patients admitted to Peking Union Medical College Hospital, who underwent DVT screening were enrolled. The data were collected from June 8, 2013 to October 12, 2022. The differences between septic patients with and without DVT were studied from following aspects: basic information, comorbidities, inflammatory cytokines, albumin, source of infection, sequential organ failure assessment (SOFA) score, coagulation and prognosis. MAIN RESULTS: In this study, the prevalence of DVT in patients with sepsis was 0.23. Elderly patients with sepsis were prone to DVT (p value < 0.001). In terms of comorbidities, septic patients with hypertension and atrial fibrillation were prone to DVT (p value 0.045 and 0.048). Inflammatory cytokines, such as procalcitonin (PCT), C-reactive protein (CRP), interleukin (IL)-6, IL-8, IL-10, tumor necrosis factor (TNF)-α, had no significant correlation with DVT in patients with sepsis (p value 0.364, 0.882, 0.912, 0.789, 0.245, and 0.780). Levels of serum albumin correlated with DVT in patients with sepsis (p value 0.003). The SOFA total score had no relationship with DVT formation (p value 0.254). Coagulation and respiration function were negatively correlated with DVT (p value 0.018). Liver function was positively correlated with DVT (p value 0.020). Patients in the DVT group had longer duration of mechanical ventilation and longer intensive care unit (ICU) stays (p value < 0.001 and 0.006). There was no significant difference in survival in septic patients with and without DVT (p value 0.868). CONCLUSIONS: The SOFA total score had no relationship with DVT formation. The function of each organ had different effects on DVT formation. Better coagulation and respiration function, easier DVT formation. Poorer liver function, easier DVT formation. DVT was associated with longer duration of mechanical ventilation and longer ICU stays.

Prediction of mechanical ventilation outcome by early abdominal-visceral-blood-flow-and-function score in critically ill patients after cardiopulmonary bypass in the ICU: A prospective observational study.

Background: Abdominal organs are important organs that sense and respond to ischemia and hypoxia, but there are few evaluation methods.We use ultrasonography to evaluate abdominal organ function and blood flow in patients with mechanical ventilation (MV) after cardiopulmonary bypass and to obtain a semiquantitative score for abdominal organ function and blood flow. Methods: Patients with cardiopulmonary bypass in the Critical Care Department of Peking Union Medical College Hospital in China from March to July 2021 were enrolled in this prospective observational study. The correlation of the abdominal-visceral-blood-flow-and-function score (AVBFS) with the duration of MV, number of days spent in the intensive care unit (ICU), acute physiology and chronic health evaluation II (APACHE-II), sequential organ failure assessment (SOFA), lactate, epinephrine, and norepinephrine use was analyzed, and the results were used to assess the predictive value of the receiver operating characteristic curve (ROC) regression analysis score for the duration of MV. Results: Of the 92 patients who underwent cardiopulmonary bypass, 41 were finally included. The AVBFS were significantly correlated with the duration of MV, number of days spent in the ICU, APACHE-II score, SOFA score, and norepinephrine use time. The AVBFS in a group of patients using ventilators ≥36 h were significantly higher than those obtained for a group of patients using ventilators <36 h (P <0.05). The evaluation results for the AVBFS at 0-12 h after ICU admission were as follows: area under the ROC curve (AUC)=0.876 (95% confidence interval [CI]: 0.767 to 0.984), cut-off value=2.5, specificity=0.842, and sensitivity=0.773. Conclusions: Abdominal visceral organ function and blood perfusion can be used to evaluate gastrointestinal function. It is related to early and late extubation after cardiac surgery.

Efficacy and Safety of Nerve Block for Postoperative Analgesia in Patients Undergoing Breast Cosmetic Surgery: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

BACKGROUND: To evaluate the postoperative analgesic efficacy and safety of nerve block (NB) in patients undergoing breast surgery for cosmetic purposes. METHODS: PubMed, Web of Science, Embase and Cochrane Libraries were searched from inception to September 2022, to identify all eligible randomized controlled trials (RCTs). Continuous data are presented as mean difference (MD) with 95% confidence intervals (CI), whereas dichotomous data are provided as odds ratios (OR) with 95% CI. This meta-analysis was performed in RevMan 5.4. RESULTS: A total of 10 RCTs with 565 patients were meta-analyzed. Compared to the control group, the pain score of the NB group was significantly lower at postoperative 2, 3-4, 6-8, 12-16 and 24 h. Opioid consumption in the first postoperative 24 h was significantly lower in the NB group (MD = - 9.02, 95% CI - 14.29 to - 3.75, P < 0.05), I2 = 95%). In addition, the NB group showed a prolonged time to first postoperative analgesic requirement (MD = 43.15, 95% CI 4.74-81.56, P < 0.05, I2 = 96%), decreased incidence of additional postoperative analgesia (OR 0.14, 95% CI 0.07-0.28, P < 0.05, I2 = 0%) and reduced incidence of postoperative nausea or vomiting (OR 0.33; 95% CI 0.22-0.48; P < 0.05; I2 = 0%). There was no significant difference in operation duration between the two groups. CONCLUSIONS: Nerve block is an effective and safe option for postoperative analgesia after breast cosmetic surgery. LEVEL OF EVIDENCE II: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Correlation between carcinoembryonic antigen (CEA) expression and EGFR mutations in non-small-cell lung cancer: a meta-analysis.

OBJECTIVES: The purpose of this meta-analysis was to investigate the relationship between serum carcinoembryonic antigen (CEA) expression and epidermal growth factor receptor (EGFR) mutation status in non-small cell lung cancer (NSCLC). METHODS: Databases such as PubMed, Cochrane, EMBASE and Google Scholar were systematically searched to identify studies assessing the association of serum CEA expression with EGFR mutations. Across 19 studies, 4168 patients were included between CEA expression and EGFR mutations odds ratio (OR) conjoint analysis of correlations. RESULTS: Compared with CEA-negative NSCLC, CEA-positive tumors had an increased EGFR mutation rate (OR = 1.85, 95% confidence interval: 1.48-2.32, P < 0.00001). This association was observed in both stage IIIB/IV patients (OR = 1.60, 95% CI: 1.18-2.15, P = 0.002) and stage I-IIIA (OR = 1.67, 95% CI: 1.01-2.77, P = 0.05) patients. In addition, CEA expression was associated with exon 19 (OR = 1.97, 95% CI: 1.25-3.11, P = 0.003) and exon 21 (OR = 1.51, 95% CI: 1.07-2.12, P = 0.02) EGFR mutations. In ADC pathological type had also showed the correlation (OR = 1.84, 95% CI: 1.31-2.57, P = 0.0004). CONCLUSIONS: This meta-analysis indicated that serum CEA expression was associated with EGFR mutations in NSCLC patients. The results of this study suggest that CEA level may play a predictive role in the EGFR mutation status of NSCLC patients. Detecting serum CEA expression levels can give a good suggestion to those patients who are confused about whether to undergo EGFR mutation tests. Moreover, it may help better plan of the follow-up treatment.

Direct degradation and stabilization of proteins: New horizons in treatment of nonalcoholic steatohepatitis.

Nonalcoholic fatty liver disease (NAFLD) is featured with excessive hepatic lipid accumulation and its global prevalence is soaring. Nonalcoholic steatohepatitis (NASH), the severe systemic inflammatory subtype of NAFLD, is tightly associated with metabolic comorbidities, and the hepatocytes manifest severe inflammation and ballooning. Currently the therapeutic options for treating NASH are limited. Potent small molecules specifically intervene with the signaling pathways that promote pathogenesis of NASH. Nevertheless they have obvious adverse effects and show long-term ineffectiveness in clinical trials. It poses the fundamental question to efficiently and safely inhibit the pathogenic processes. Targeted protein degradation (TPD) belongs to the direct degradation strategies and is a burgeoning strategy. It utilizes the small molecules to bind to the target proteins and recruit the endogenous proteasome, lysosome and autophagosome-mediated degradation machineries. They effectively and specifically degrade the target proteins. It has exhibited promising therapeutic effects in treatment of cancer, neurodegenerative diseases and other diseases in a catalytic manner at low doses. We critically discuss the principles of multiple direct degradation strategies, especially PROTAC and ATTEC. We extensively analyze their emerging application in degradation of excessive pathogenic proteins and lipid droplets, which promote the progression of NASH. Moreover, we discuss the opposite strategy that utilizes the small molecules to recruit deubiquinases to stabilize the NASH/MASH-suppressing proteins. Their advantages, limitations, as well as the solutions to address the limitations have been analyzed. In summary, the innovative direct degradation strategies provide new insights into design of next-generation therapeutics to combat NASH with optimal safety paradigm and efficiency.

Quantitative electroencephalography predicts postoperative delirium in cardiac surgical patients after cardiopulmonary bypass: a prospective observational study.

Objective: Despite its frequency and associated negative effect, delirium remains poorly recognized in postoperative patients after ICU admission, especially among those who have undergone cardiac surgery with cardiopulmonary bypass. Postoperative delirium is triggered by a wide variety of acute medical conditions associated with impaired neuronal network connectivity. The lack of objective biomarkers primarily hinders the early detection of delirium. Seeking early biomarkers for tracking POD could potentially assist in predicting the onset of delirium and assessing the severity of delirium and response to interventions. Methods: QEEGs were taken from 46 sedated postoperative patients, with 24 of them having undergone cardiac surgery. The assessment of delirium was performed twice daily using the Confusion Assessment Method for the ICU (CAM-ICU) to screen for postoperative delirium (POD). QEEG data were interpreted clinically by neurophysiologists and processed by open-source EEGLAB to identify features in patients who had or did not have POD after cardiac or non-cardiac surgery. Results: The incidence of delirium in patients after undergoing cardiac surgery was nine times greater than in those after non-cardiac surgeries (41.7% vs. 4.5%; p = 0.0046). Patients with delirium experienced longer use of mechanical ventilation (118 h (78,323) compared to 20 h (18,23); p < 0.0001) and an extended ICU length of stay (7 days (6, 20) vs. 2 days (2, 4); p < 0.0001). The depth of anesthesia, as measured by RASS scores (p = 0.3114) and spectral entropy (p = 0.1504), showed no significant difference. However, notable differences were observed between delirious and non-delirious patients in terms of the amplitude-integrated EEG (aEEG) upper limit, the relative power of the delta band, and spectral edge frequency 95 (SEF95) (p = 0.0464, p = 0.0417, p = 0.0337, respectively). Conclusion: In a homogenous population of sedated postoperative patients, robust qEEG parameters strongly correlate with delirium and could serve as valuable biomarkers for early detection of delirium and assist in clinical decision-making.

Follicle-stimulating hormone orchestrates glucose-stimulated insulin secretion of pancreatic islets.

Follicle-stimulating hormone (FSH) is involved in mammalian reproduction via binding to FSH receptor (FSHR). However, several studies have found that FSH and FSHR play important roles in extragonadal tissue. Here, we identified the expression of FSHR in human and mouse pancreatic islet ß-cells. Blocking FSH signaling by Fshr knock-out led to impaired glucose tolerance owing to decreased insulin secretion, while high FSH levels caused insufficient insulin secretion as well. In vitro, we found that FSH orchestrated glucose-stimulated insulin secretion (GSIS) in a bell curve manner. Mechanistically, FSH primarily activates Gαs via FSHR, promoting the cAMP/protein kinase A (PKA) and calcium pathways to stimulate GSIS, whereas high FSH levels could activate Gαi to inhibit the cAMP/PKA pathway and the amplified effect on GSIS. Our results reveal the role of FSH in regulating pancreatic islet insulin secretion and provide avenues for future clinical investigation and therapeutic strategies for postmenopausal diabetes.

Whole-process respiratory management strategies based on electrical impedance tomography in a pregnant woman with diffuse alveolar hemorrhage induced by systemic lupus erythematosus under veno-venous extracorporeal membrane oxygenation.

Electrical impedance tomography (EIT) as a bedside, noninvasive, radiation-free technology, could quantify alveolar collapse and over-distension and provide real-time ventilation images of lungs. Clinical studies have shown potential benefit in reducing lung injury by EIT to guide mechanical ventilation setting in acute respiratory distress syndrome (ARDS). The respiratory management of ARDS with venous-venous extracorporeal membrane oxygenation (VV ECMO) remains a challenge for ICU doctors. Moreover, EIT has gained great interests in the respiratory management in VV ECMO therapy. Here, EIT was used for respiratory management in the presented case of a 36-year-old gravida with systemic lupus erythematosus, who developed severe hypoxia caused by diffuse alveolar hemorrhage. Although the patient received mechanical ventilation, VV ECMO was further used for the refractory respiratory failure. EIT was applied to titrate positive end-expiratory pressure (PEEP), guide prone position and early mobilization, dynamic evaluating lung development during ECMO therapy. She was successfully rescued after comprehensive therapy. In summary, an EIT-guided whole-process respiratory management strategy that included PEEP titration, prone position, early mobilization, and dynamic lung ventilation monitoring was proposed. This case demonstrated that EIT-guided whole-process respiratory management strategy was feasible in the respiratory failure patient with VV ECMO therapy.

Deubiquitinating PABPC1 by USP10 upregulates CLK2 translation to promote tumor progression in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is extremely malignant with limited treatment options. Deubiquitinases (DUBs), which cleave ubiquitin on substrates, can regulate tumor progression and are appealing therapeutic targets, but there are few related studies in PDAC. In our study, we screened the expression levels and prognostic value of USP family members based on published databases and selected USP10 as the potential interventional target in PDAC. IHC staining of the PDAC microarray revealed that USP10 expression was an adverse clinical feature of PDAC. USP10 promoted tumor growth both in vivo and in vitro in PDAC. Co-IP experiments revealed that USP10 directly interacts with PABPC1. Deubiquitination assays revealed that USP10 decreased the K27/29-linked ubiquitination level of the RRM2 domain of PABPC1. Deubiquitinated PABPC1 was able to couple more CLK2 mRNA and eIF4G1, which increased the translation efficiency. Replacing PABPC1 with a mutant that could not be ubiquitinated impaired USP10 knock-down-mediated tumor suppression in PDAC. Targeting USP10 significantly delayed the growth of cell-derived xenograft and patient-derived xenograft tumors. Collectively, our study first identified USP10 as the DUB of PABPC1 and provided a rationale for potential therapeutic options for PDAC with high USP10 expression.

Expert Consensus on Acute Respiratory Failure in Critically Ill Cancer Patients (2023).

Objective This consensus aims to provide evidence-based recommendations on common questions in the diagnosis and treatment of acute respiratory failure (ARF) for critically ill cancer patients.Methods We developed six clinical questions using the PICO (Population, Intervention, Comparison, and Outcome) principle in diagnosis and treatment for critical ill cancer patients with ARF. Based on literature searching and meta-analyses, recommendations were devised. The GRADE (Grading of Recommendation Assessment, Development and Evaluation) method was applied to each question to reach consensus in the expert panel. Results The panel makes strong recommendations in favor of (1) metagenomic next-generation sequencing (mNGS) tests may aid clinicians in rapid diagnosis in critically ill cancer patients suspected of pulmonary infections; (2) extracorporeal membrane oxygenation (ECMO) therapy should not be used as a routine rescue therapy for acute respiratory distress syndrome in critically ill cancer patients but may benefit highly selected patients after multi-disciplinary consultations; (3) cancer patients who have received immune checkpoint inhibitor therapy have an increased incidence of pneumonitis compared with standard chemotherapy; (4) critically ill cancer patients who are on invasive mechanical ventilation and estimated to be extubated after 14 days may benefit from early tracheotomy; and (5) high-flow nasal oxygen and noninvasive ventilation therapy can be used as a first-line oxygen strategy for critically ill cancer patients with ARFs. A weak recommendation is: (6) for critically ill cancer patients with ARF caused by tumor compression, urgent chemotherapy may be considered as a rescue therapy only in patients determined to be potentially sensitive to the anticancer therapy after multidisciplinary consultations. Conclusions The recommendations based on the available evidence can guide diagnosis and treatment in critically ill cancer patients with acute respiratory failure and improve outcomes.

Expression of aldose reductase in mouse endometrial epithelial cells and its role in sperm capacitation.

The survival, motility and capacitation of sperm in the female reproductive tract are important prerequisites for fertilization. The uterus is the main location for sperm capacitation. One of the most important physiological functions of the endometrial epithelium is to create a suitable uterine environment under the regulation of ovarian hormones, to ensure sperm capacitation. The composition of uterine fluid directly affects sperm capacitation. Fructose is an important component of semen that supports sperm viability and motility. Aldose reductase, a rate-limiting enzyme in the polyol pathway, metabolizes sorbitol and fructose, thereby supplying cells with necessary energy for functional activities. Existing studies have reported the presence aldose reductase in the endometrium, leading us to hypothesize that its expression in endometrial epithelium might promote sperm capacitation by maintaining the uterine environment. Yet, the mechanism of regulation has not been clarified. In this study, we investigated the expression of aldose reductase in mouse endometrial epithelium and its potential role in sperm capacitation. We initially investigated the periodic characteristics of glucose, fructose and sorbitol in uterine fluid. We then studied the temporal and spatial characteristics of aldose reductase in the endometrial epithelium. Next, we examined the effect of aldose reductase on glucose, fructose and sorbitol in uterine fluid. Finally, we explored the effect of aldose reductase on sperm capacitation and fertilization. The results showed that glucose and fructose content in uterine fluid and the expression of aldose reductase fluctuated periodically during physiological periods. Inhibition of aldose reductase in the endometrial epithelium interfered with sperm capacitation and fertilization by reducing the fructose levels in the uterine fluid. To conclude, the aldose reductase-mediated polyol pathway in endometrial epithelial cells is essential to maintain an appropriate fructose environment in the uterine fluid for sperm capacitation and fertilization.

New application of saline contrast-enhanced electrical impedance tomography method for right ventriculography besides lung perfusion: detection of right-to-left intracardiac shunt.

AIM: Saline contrast-enhanced electrical impedance tomography (EIT) has been used to identify the respiratory failure etiologies through assessment of regional lung perfusion at the bedside. In this study, we introduce a novel approach to detect right-to-left intracardiac shunt based on the center of heart (CoH) parameter determined from the early phase of impedance-time curve after saline bolus injection. METHODS AND RESULT: The timepoints when the saline bolus enters the heart (T0) and the lung regions (T1) are identified at first. A moving time window from T0 to T1 is then generated with steps of 0.5 s and the slope of the impedance-time curve in each pixel within the window calculated. CoH is calculated as the geometric center of pixel slope values in the right-to-left image direction. To illustrate how this method works in practice, we calculated the CoH values at T0 to T1 in 10 control hypoxic patients with no right-to-left shunt. In addition, we examined two critically ill patients with right-to-left intracardiac shunt. one was postcardiac surgery patient who had a residual atrial septal defect by color doppler of transesophageal echocardiograph. The other patient had a congenital heart disease of ventricular septal defect by color doppler of trans-thoracic echocardiography. A large difference in CoH between T0 to T1 was observed in the two patients with intracardiac shunt than in the control patients (11.06 ± 3.17% vs. 1.99 ± 1.43%, P = 0.030). CONCLUSION: saline bolus EIT for lung perfusion might be used as ventriculography to identify the right-to-left intracardiac shunt at the bedside.

Inhibition of epithelial-to-mesenchymal transition augments antitumor efficacy of nanotherapeutics in pancreatic ductal adenocarcinoma.

Intrinsic drug resistance mechanisms of tumor cells often reduce intracellular drug concentration to suboptimal levels. Epithelial-to-mesenchymal transition (EMT) is a pivotal process in tumor progression and metastasis that confers an aggressive phenotype as well as resistance to chemotherapeutics. Therefore, it is imperative to develop novel strategies and identify new targets to improve the overall efficacy of cancer treatment. We developed SN38 (active metabolite of irinotecan)-assembled glycol chitosan nanoparticles (cSN38) for the treatment of pancreatic ductal adenocarcinoma (PDAC). Furthermore, cSN38 and the TGF-ß1 inhibitor LY364947 formed composite nanoparticles upon self-assembly (cSN38 + LY), which obviated the poor aqueous solubility of LY364947 and enhanced drug sensitivity. The therapeutic efficacy of cSN38 + LY nanotherapeutics was studied in vitro and in vivo using suitable models. The cSN38 nanoparticles exhibited an antitumor effect that was significantly attenuated by TGF-ß-induced EMT. The cellular uptake of SN38 was impeded during EMT, which affected the therapeutic efficacy. The combination of LY364947 and cSN38 markedly enhanced the cellular uptake of SN38, increased cytotoxic effects, and inhibited EMT in PDAC cells in vitro. Furthermore, cSN38 + LY significantly inhibited PDAC xenograft growth in vivo. The cSN38 + LY nanoparticles increased the therapeutic efficacy of cSN38 via repressing the EMT of PDAC cells. Our findings provide a rationale for designing nanoscale therapeutics to combat PDAC.

Enhanced Visible-Photocatalytic Activities in Strong Acids and Strong Alkalis of Flexible Iron-SrTiO3 Nanofibrous Membranes.

Traditional SrTiO3 (STO) materials have high brittleness and poor deformation resistance. In this work, macroscopically flexible iron-doped SrTiO3 (SFTO) nanofibrous membranes were prepared by electrospinning and calcination, which can be easily isolated and can maintain integrity to recycle as photocatalysts. Moreover, the SFTO nanofibrous membranes showed enhanced photocatalytic performance under strong acids (pH = 2) and strong alkalis (pH = 12). The SFTO nanofibrous membranes increased the catalytic rate of Congo red (CR) dye by about 10 times in visible light. The mechanism of photocatalytic activity enhancement was discussed by the combined effects of hydroxyl radicals and superoxide radicals. The successful preparation of SFTO nanofibrous membranes has offered a simple and economical approach to photocatalysis as well as environmental remediation.