Optogenetic Stimulation of the Cardiac Vagus Nerve to Promote Heart Regenerative Repair after Myocardial Infarction.

Background: It had been shown that selective cardiac vagal activation holds great potential for heart regeneration. Optogenetics has clinical translation potential as a novel means of modulating targeted neurons. This study aimed to investigate whether cardiac vagal activation via optogenetics could improve heart regenerative repair after myocardial infarction (MI) and to identify the underlying mechanism. Methods: We used an adeno-associated virus (AAV) as the vector to deliver ChR2, a light-sensitive protein, to the left nodose ganglion (LNG). To assess the effects of the cardiac vagus nerve on cardiomyocyte (CM) proliferation and myocardial regeneration in vivo, the light-emitting diode illumination (470 nm) was applied for optogenetic stimulation to perform the gain-of-function experiment and the vagotomy was used as a loss-of-function assay. Finally, sequencing data and molecular biology experiments were analyzed to determine the possible mechanisms by which the cardiac vagus nerve affects myocardial regenerative repair after MI. Results: Absence of cardiac surface vagus nerve after MI was more common in adult hearts with low proliferative capacity, causing a poor prognosis. Gain- and loss-of-function experiments further demonstrated that optogenetic stimulation of the cardiac vagus nerve positively regulated cardiomyocyte (CM) proliferation and myocardial regeneration in vivo. More importantly, optogenetic stimulation attenuated ventricular remodeling and improved cardiac function after MI. Further analysis of sequencing results and flow cytometry revealed that cardiac vagal stimulation activated the IL-10/STAT3 pathway and promoted the polarization of cardiac macrophages to the M2 type, resulting in beneficial cardiac regenerative repair after MI. Conclusions: Targeting the cardiac vagus nerve by optogenetic stimulation induced macrophage M2 polarization by activating the IL-10/STAT3 signaling pathway, which obviously optimized the regenerative microenvironment and then improved cardiac function after MI.

Neoadjuvant chemotherapy plus concurrent chemoradiotherapy versus concurrent chemoradiotherapy alone in elderly patients with stage III-IVa nasopharyngeal carcinoma: A real-world study based on medical comorbidities.

PURPOSE: To evaluate the outcomes and toxicities of adding neoadjuvant chemotherapy (NAC) to concurrent chemoradiotherapy (CCRT) in elderly (≥65 years) patients with locoregionally advanced nasopharyngeal carcinoma (LANPC, stage III-IVa). METHODS AND MATERIALS: Using an NPC-specific database, 245 elderly patients with stage III-IVa NPC, receiving CCRT +/- NAC, and an Adult Co-morbidity Evaluation 27 (ACE-27) score <2 were included. Recursive partitioning analysis (RPA) based on TNM stage and Epstein-Barr virus (EBV) DNA were applied for risk stratification. The primary end point was disease-free survival (DFS). RESULTS: Two risk groups were generated by the RPA model. In the high-risk group (EBV DNA < 4000 copy/ml with stage IVa & EBV DNA ≥4000 copy/ml with stage III-IVa), patients treated with NAC plus CCRT achieved improved 5-year DFS rates compared to those who received CCRT alone (56.9% vs. 29.4%; p = 0.003). But we failed to observe the survival benefit of additional NAC in the low-risk group (EBV DNA <4000 copy/ml with stage III). The most common severe acute toxic effects were leucopenia (46.8% vs. 24.4%) and neutropenia (43.7% vs. 20.2%) in the NAC plus CCRT group versus CCRT group with statistically significant differences. CONCLUSIONS: The addition of NAC to CCRT was associated with better DFS for the high-risk group of elderly LANPC patients with ACE-27 score <2. However, the survival benefit of additional NAC was not observed in low-risk patients.

Pancreatic Cancer: An Exocrine Tumor with Endocrine Characteristics.

OBJECTIVE: To examine the characteristics of pancreatic cancer patients with long-term survival. BACKGROUND: Although pancreatic cancer is a highly lethal malignancy, a minority of patients experience long-term survival. The characteristics of these patients remain largely unidentified. METHODS: An indolent subgroup was established using carbohydrate antigen 19-9 (CA19-9), which is the best-validated biomarker for pancreatic cancer. Of 1558 patients, 13.9% were included in the CA19-9-normal (≤ 37 U/mL) subgroup. RESULTS: A normal A19-9 level was an independent variable for overall survival (median survival, 18.1 vs. 9.7 months, hazard ratio = 0.53, P < 0.001). The 5-year survival of patients with stage IV CA19-9-normal cancer was higher than that of patients with stage I-IV CA19-9-high cancer (22.4% vs. 6.8%, P = 0.034). The CA19-9-normal subgroup exhibited reduced levels of circulating glucose (P < 0.001) and increased expression of insulin (P < 0.001) compared with the CA19-9-high subgroup. Glucose was a substrate for CA19-9 biosynthesis through the hexosamine biosynthesis pathway. In addition, in pancreatic cancer animal models of diabetes, glucose control decreased CA19-9 levels and improved overall survival. In a clinical trial (NCT05306028) of patients before undergoing major anticancer treatments, glucose control decreased CA19-9 levels in 90.9% of the patients. CONCLUSIONS: CA19-9-normal pancreatic cancer is a strikingly indolent subgroup with low glucose and high insulin. Glucose control is a promising therapeutic strategy for pancreatic cancer.

CapMatch: Semi-Supervised Contrastive Transformer Capsule With Feature-Based Knowledge Distillation for Human Activity Recognition.

This article proposes a semi-supervised contrastive capsule transformer method with feature-based knowledge distillation (KD) that simplifies the existing semisupervised learning (SSL) techniques for wearable human activity recognition (HAR), called CapMatch. CapMatch gracefully hybridizes supervised learning and unsupervised learning to extract rich representations from input data. In unsupervised learning, CapMatch leverages the pseudolabeling, contrastive learning (CL), and feature-based KD techniques to construct similarity learning on lower and higher level semantic information extracted from two augmentation versions of the data", weak" and "timecut", to recognize the relationships among the obtained features of classes in the unlabeled data. CapMatch combines the outputs of the weak-and timecut-augmented models to form pseudolabeling and thus CL. Meanwhile, CapMatch uses the feature-based KD to transfer knowledge from the intermediate layers of the weak-augmented model to those of the timecut-augmented model. To effectively capture both local and global patterns of HAR data, we design a capsule transformer network consisting of four capsule-based transformer blocks and one routing layer. Experimental results show that compared with a number of state-of-the-art semi-supervised and supervised algorithms, the proposed CapMatch achieves decent performance on three commonly used HAR datasets, namely, HAPT, WISDM, and UCI_HAR. With only 10% of data labeled, CapMatch achieves F1 values of higher than 85.00% on these datasets, outperforming 14 semi-supervised algorithms. When the proportion of labeled data reaches 30%, CapMatch obtains F1 values of no lower than 88.00% on the datasets above, which is better than several classical supervised algorithms, e.g., decision tree and k -nearest neighbor (KNN).

Incremental Benefit of Lipid Lowering in a Large Chinese Population Aged 75 Years and Older With Established Atherosclerotic Cardiovascular Disease.

OBJECTIVE: To explore the optimal low-density lipoprotein cholesterol (LDL-C) level in patients aged 75 years and older with established atherosclerotic cardiovascular disease (ASCVD). PATIENTS AND METHODS: We conducted a retrospective multicenter cohort study of veterans aged 75 years and older with ASCVD who were regularly hospitalized or medically examined in 15 medical institutions in southern China from January 1, 2006, to December 31, 2013. Follow-up continued through October 1, 2021. The time-weighted average (TWA) LDL-C level represented the average LDL-C level during follow-up. Participants were divided into TWA LDL-C groups of 55.0 mg/dL or lower, 55.1 to 70.0 mg/dL, 70.1 to 85.0 mg/dL, 85.1 to 100.0 mg/dL, and greater than 100.0 mg/dL. The subgroup with LDL-C levels lower than 55.0 mg/dL was further subdivided into groups with LDL-C levels from 40.1 to 55.0 mg/dL and 40.0 mg/dL or less. The association of TWA LDL-C levels with outcomes was evaluated with Cox proportional hazards models. RESULTS: Overall, 6387 patients aged 75 years or older with ASCVD were included (mean age, 79.4 years). In total, 4267 major adverse cardiovascular events, 1518 stroke events, and 515 myocardial infarction events occurred during a mean follow-up of 12.7 years. Generally, lower TWA LDL-C level was associated with a lower risk of cardiovascular events but was not associated with a higher risk of adverse events in elderly individuals with ASCVD, with the lowest cardiovascular risk observed for LDL-C levels of less than 55.0 mg/dL. After multivariable adjustment, the risk of a major adverse cardiovascular event was 1.30 (95% CI, 1.26 to 1.34; P<.001) for a per SD increment in TWA LDL-C level. Compared with TWA LDL-C levels of 40.1 to 55.0 mg/dL, TWA LDL-C levels of 40.0 mg/dL or less were associated with an increased risk of hemorrhagic stroke (hazard ratio, 3.71; 95% CI, 1.89 to 7.26). CONCLUSION: Low-density lipoprotein cholesterol levels from 40.1 to 55.0 mg/dL exhibited the maximum cardiovascular benefit in patients aged 75 years and older who had ASCVD. Lowering LDL-C levels to 40.0 mg/dL or less might increase the risk of hemorrhagic stroke.

C2orf48 promotes the progression of nasopharyngeal carcinoma by regulating high mobility group AT-hook 2.

Recurrence and metastasis are the major factors affecting the survival of nasopharyngeal carcinoma (NPC), and the mechanism remains unclear. Long non-coding RNA chromosome 2 open reading frame 48 (C2orf48) has been shown to influence the prognosis of many cancers. However, C2orf48's function in NPC has not been clarified. In this investigation, C2orf48 expression in NPC was measured by quantitative real-time PCR (qRT-PCR) at the cellular and tissue levels, and the association between C2orf48 expression and the prognosis of patients with NPC was examined. Additionally, the effects of C2orf48 and high mobility group AT-hook 2 (HMGA2) upon NPC proliferation, migration, and invasion were examined employing the MTT assay, colony formation assay, and transwell assay, respectively. Furthermore, the association between C2orf48 and HMGA2 in NPC was investigated. Our research demonstrated that C2orf48 was overexpressed in NPC tissues and cell lines, and compared to patients with lower levels of C2orf48 expression, those with higher levels had poorer 5-year overall survival and progression-free survival. Functionally, C2orf48 overexpression accelerated NPC cells proliferation, migration, and invasion. Besides, the tandem mass tag (TMT) quantitative proteomic analysis indicated that HMGA2 may be a target of C2orf48. Moreover, upregulation of C2orf48 could increase HMGA2 expression, and HMGA2 silencing could counteract the proliferation, migration, and invasion changes induced by C2orf48 in NPC cells. These results reveal that overexpression of C2orf48 can promote NPC cells proliferation, migration, and invasion via regulating the expression of HMGA2 and C2orf48 may be a potentially important prognostic marker for NPC.

Cumulative remnant cholesterol predicts cardiovascular outcomes in elderly patients with atherosclerotic cardiovascular disease.

AIMS: Remnant cholesterol (RC) reportedly mediates residual cardiovascular risk in atherosclerotic cardiovascular diseases (ASCVD). However, few studies have characterized long-term cumulative RC exposure among elderly people. The study aimed to evaluate the association between cumulative exposure to RC and incident major adverse cardiovascular events (MACE) by analysing a cohort of elderly patients with ASCVD. METHODS AND RESULTS: This retrospective multicentre cohort study enrolled ASCVD participants aged ≥75 years with baseline visits occurring from 2006 to 2012 followed by four in-person visits. Cumulative RC was estimated as the area under the curve using measurements from the first to fourth visits by using 9-year data. The time-weighted average (TWA) RC was expressed as cumulative exposure to RC averaged by years. All outcomes were follow-up from the fourth visit to the year 2021. Outcomes included a composite of MACE (stroke, unstable angina pectoris, myocardial infarction, and cardiac death). We included 4,680 participants (73.1% male, mean age 79.3 ± 2.5 years). The median follow-up duration was 6.1 years (interquartile range: 3.4-6.6 years). In the multivariable model adjusted for traditional cardiovascular risk factors, low-density lipoprotein cholesterol level, and most recent RC level, the hazard ratios for MACE that compared the high and low tertiles of the RC variables were 1.30 [95% confidence interval (CI), 1.16-1.44] for cumulative RC and 1.36 (95% CI, 1.23-1.52) for TWA RC. Consistent significant associations were observed among most propensity score analyses. CONCLUSIONS: Long-term cumulative RC was independently associated with incident MACE in elderly participants with ASCVD, suggesting that achieving and maintaining optimal RC levels later in life may still improve cardiovascular outcomes.

This retrospective multicentre cohort study, enrolling 4680 participants aged ≥75 years with pre-existing atherosclerotic cardiovascular diseases (ASCVD), found that greater cumulative exposure to remnant cholesterol (RC) across a 9-year span was independently associated with an increased incidence of cardiovascular events, suggesting that cumulative RC may be a powerful predictor of cardiovascular outcomes in patients with ASCVD.

The screening, identification, design and clinical application of tumor-specific neoantigens for TCR-T cells.

Recent advances in neoantigen research have accelerated the development of tumor immunotherapies, including adoptive cell therapies (ACTs), cancer vaccines and antibody-based therapies, particularly for solid tumors. With the development of next-generation sequencing and bioinformatics technology, the rapid identification and prediction of tumor-specific antigens (TSAs) has become possible. Compared with tumor-associated antigens (TAAs), highly immunogenic TSAs provide new targets for personalized tumor immunotherapy and can be used as prospective indicators for predicting tumor patient survival, prognosis, and immune checkpoint blockade response. Here, the identification and characterization of neoantigens and the clinical application of neoantigen-based TCR-T immunotherapy strategies are summarized, and the current status, inherent challenges, and clinical translational potential of these strategies are discussed.

Racism, self-rated general health status, and health-related quality of life among Black and Asian Americans.

Race is a consequential sociocultural cue in healthcare contexts. Racism is associated with health disparities. Extant research shows significant health inequities between white and Black people. However, little is known about health gaps between or among other racial groups. This study investigated how Blacks and Asian Americans perceive and experience racism in healthcare settings and in general daily life situations, and how these factors relate to their self-rated general health status and health-related quality of life. Findings from an online survey suggest strong similarities and subtle differences between the two racial groups and within the Asian subgroups.

Comparative study of optical coherence tomograph and histological images of eustachian tube nasopharyngeal region and adjacent structures in vivo and ex-vivo miniature pigs.

OBJECTIVES: Optical Coherence Tomograph (OCT) imaging technology can be used to examine, in vivo, the human ET. At present, it is impossible to achieve the OCT scanning vivo and ex vivo in the same individual human body, or study the consistency between OCT images and histological images of the eustachian tube nasopharyngeal region and adjacent structures. The aim of this study was to determine the consistency between OCT images and histological sections in vivo and ex vivo in miniature pigs. METHODS: OCT imaging was performed on five adult miniature pigs in vivo and ex vivo. The images of the eustachian tube OCT (ET-OCT), nasopharynx OCT (NP-OCT) and histological cross sections were further studied. RESULTS: All five miniature pigs achieved the OCT scan successfully, acquiring ET-OCT and NP-OCT images in vivo and ex vivo on both sides. The acquired ET OCT images closely matched the histological images, revealing details of the cartilage, submucosa, glands, and mucosa. The lower segment of the ET wall mucosa had an abundance of glands and submucosal tissues, with more low-signal areas appearing in the ex vivo images. The NP-OCT images of the nasopharynx matched the details of the mucosa and submucosal tissues. The ex-vivo OCT images showed thicker mucosa and more scattered slightly lower signal areas compared to the vivo OCT images. CONCLUSIONS: ET-OCT images and NP-OCT images matched the histological structure of eustachian tube nasopharyngeal region structures in miniature pigs both in vivo and ex vivo. OCT images may be sensitive to changes in edema and ischemia status. There is a great potential for morphological assessment of inflammation, edema, injure, mucus gland status.

Matrix Metalloproteinase-7 Associated with Congestive Heart Failure in Peritoneal Dialysis Patients: A Prospective Cohort Study.

Background: Matrix metalloproteinase-7 (MMP7) is markedly expressed in patients with chronic kidney disease; its expression in dialysate and role in patients undergoing peritoneal dialysis (PD) have not been well established. Methods: Participants undergoing PD from June 1st, 2015, to June 30th, 2020, were involved and were followed up every 3 months for the first year and every 6 months thereafter until death, PD withdrawal, or the end of the study. Data at each follow-up point were collected and analyzed for the association with congestive heart failure (CHF), PD withdrawal, and combined endpoint. Results: A total of 283 participants were included in this study. During a median follow-up of 21 months, 20 (7%) participants died, 93 (33%) withdrew from PD, and 105 (37%) developed CHF. A significantly increased level of serum and dialysate MMP7 was observed at baseline. Dialysate MMP7 presented a good linearity with serum MMP7. Baseline serum and dialysate MMP7 levels were associated with CHF in multivariable Cox proportional hazards regression models. After categorization, participants with high baseline MMP7 levels had a higher incidence of CHF (42%), and the hazard ratios (95% confidence intervals) were 1.595 (1.023-2.488). Interestingly, participants with higher serum MMP7 levels were trended to use dialysate with higher glucose concentration. However, the ultrafiltration volumes were not significantly increased. Higher MMP7 levels were also positively associated with PD withdrawal and combined endpoint. Conclusions: The expression of MMP7 in serum and dialysate was markedly increased and was tightly associated with the risk of CHF in PD patients. This finding suggests that the measurement of MMP7 may inform strategies for managing CHF at an earlier stage.

EGFR is a potential therapeutic target for highly glycosylated and aggressive pancreatic neuroendocrine neoplasms.

pNENs are relative indolent tumors with heterogeneous clinical presentation at diagnosis. It is important to establish aggressive subgroups of pNENs and identify potential therapeutic targets. Patients with pNEN (322 cases) were included to examine the association between glycosylation biomarkers and clinical/pathological traits. The molecular and metabolic features stratified by glycosylation status were assessed by RNA-seq/whole exome sequencing and immunohistochemistry. A considerable proportion of patients had elevated glycosylation biomarkers (carbohydrate antigen [CA] 19-9, 11.9%; CA125, 7.5%; carcinoembryonic antigen [CEA], 12.8%). CA19-9 (hazard ratio [HR] = 2.26, P = .019), CA125 (HR = 3.79, P = .004) and CEA (HR = 3.16, P = .002) were each independent prognostic variables for overall survival. High glycosylation group, defined as pNENs with elevated level of circulating CA19-9, CA125 or CEA, accounted for 23.4% of all pNENs. High glycosylation (HR = 3.14, P = .001) was an independent prognostic variable for overall survival and correlated with G3 grade (P < .001), poor differentiation (P = .001), perineural invasion (P = .004) and distant metastasis (P < .001). Epidermal growth factor receptor (EGFR) was enriched in high glycosylation pNENs using RNA-seq. EGFR was expressed in 21.2% of pNENs using immunohistochemistry and associated with poor overall survival (P = .020). A clinical trial focusing on EGFR expressed pNENs was initiated (NCT05316480). Thus, pNEN with aberrant glycosylation correlates with a dismal outcome and suggests potential therapeutic target of EGFR.

Glutamine deprivation induces ferroptosis in pancreatic cancer cells.

Ferroptosis is a type of programmed cell death closely related to amino acid metabolism. Pancreatic cancer cells have a strong dependence on glutamine, which serves as a carbon and nitrogen substrate to sustain rapid growth. Glutamine also aids in self-protection mechanisms. However, the effect of glutamine on ferroptosis in pancreatic cancer remains largely unknown. Here, we aim to explore the association between ferroptosis and glutamine deprivation in pancreatic cancer. The growth of pancreatic cancer cells in culture media with or without glutamine is evaluated using Cell Counting Kit-8. Reactive oxygen species (ROS) are measured by 2',7'-dichlorodihydrofluorescein diacetate staining. Ferroptosis is assessed by BODIPY-C11 dye using confocal microscopy and flow cytometry. Amino acid concentrations are measured using ultrahigh-performance liquid chromatography-tandem mass spectrometry. Isotope-labelled metabolic flux analysis is performed to track the metabolic flow of glutamine. Additionally, RNA sequencing is performed to analyse the genetic alterations. Glutamine deprivation inhibits pancreatic cancer growth and induces ferroptosis both in vitro and in vivo. Additionally, glutamine decreases ROS formation via glutathione production in pancreatic cancer cells. Interestingly, glutamine inhibitors (diazooxonorleucine and azaserine) promotes ROS formation and ferroptosis in pancreatic cancer cells. Furthermore, ferrostatin, a ferroptosis inhibitor, rescues ferroptosis in pancreatic cancer cells. Glutamine deprivation leads to changes in molecular pathways, including cytokine-cytokine receptor interaction pathways ( CCL5, CCR4, LTA, CXCR4, IL-6R, and IL-7R). Thus, exogenous glutamine is required for the detoxification of ROS in pancreatic cancer cells, thereby preventing ferroptosis.

Association of long-term time in target range for systolic blood pressure with cardiovascular risk in the elderly: a Chinese veteran cohort study.

AIMS: Short-term blood pressure (BP) time in target range (TTR) independently predicts cardiovascular (CV) outcomes in adults. However, there are limited data regarding long-term TTR for BP among elderly participants. We aimed to determine whether future CV risk varies for those who can maintain a long-term systolic BP (SBP) target range by assessing TTR in elderly individuals with hypertension. METHODS AND RESULTS: The Chinese veteran cohort study included 943 elderly participants with hypertension aged over 75 years. The primary outcome was the first occurrence of CV events during annual visits. Time in target range was estimated over 15 years of follow-up using linear interpolation. The target range was defined as 120-140 mmHg according to guidelines. The association between SBP TTR and CV outcomes was estimated using multivariable Cox proportional hazards models. During the 15 year follow-up, the probability of CV events gradually decreased with increasing TTR for SBP. After multivariable adjustment for traditional CV risk factors and mean BP, comparing the highest vs. lowest quartiles of TTR for SBP, the hazard ratios (HRs) [95% confidence intervals (CIs)] were 0.424 (0.289-0.624) for the primary outcome. For each 1 SD increase in TTR, the risk of the primary outcome decreased by 25.4% (HR: 0.746; 95% CI: 0.666-0.834). Consistent findings were observed in sensitivity analyses. CONCLUSION: Greater long-term TTR for SBP was associated with a decreased risk of CV events in elderly individuals independent of mean BP, suggesting that SBP TTR might serve as a modifiable risk factor for future CV health in elderly patients with hypertension. LAY SUMMARY: This ongoing Chinese veteran cohort study adds to the understanding of the relationship between higher long-term systolic blood pressure (SBP) time in target range (TTR) and cardiovascular benefits among elderly individuals with hypertension.

Higher long-term systolic blood pressure (SBP) time in target range (TTR) is associated with a significantly decreased risk of cardiovascular events independent of mean SBP, suggesting that TTR might serve as an essential measure for monitoring BP status. It might be helpful for lowering the risk of cardiovascular events when the time in SBP target range is maintained after antihypertensive therapy.

Nasopharyngeal necrosis contributes to overall survival in nasopharyngeal carcinoma without distant metastasis: a comprehensive nomogram model.

OBJECTIVES: This study focused on developing and validating a nomogram to predict the overall survival (OS) of patients with nasopharyngeal carcinoma (NPC) without distant metastasis based on their clinical characteristics, serum biomarkers, and presence of nasopharyngeal (NP) necrosis. METHODS: This study included 9298 patients with NPC. Patients from January 2009 to December 2014 were randomly categorized into the training cohort and validation cohort A. Validation cohort B, whose data were collected from January 2015 to December 2017, was also included. OS was the primary endpoint of this study. Cox regression analysis was used to detect independent risk variables. Decision curve analysis, calibration curve, time-dependent receiver operating characteristic (ROC) curve, and concordance index (C-index) were used to evaluate the performance of the nomogram model. RESULTS: A total of 267 patients developed NP necrosis after the first routine radiotherapy. After radiotherapy, patients with NP necrosis had significantly lower OS than other patients in all three cohorts (p < 0.001). Eleven factors, including NP necrosis, were involved in the nomogram, which had favorable discrimination and calibration with a C-index of 0.768 in the training cohort, 0.749 in validation cohort A, and 0.739 in validation cohort B. The nomogram exhibited a significantly larger area under the ROC curve for predicting OS than the TNM stage and Epstein-Barr virus (EBV) DNA (p < 0.001). CONCLUSION: Compared with the TNM system and EBV DNA, we established a nomogram model with an accurate prognostic prediction for patients with NPC, which might help with patient management in NPC. KEY POINTS: • This study included 9298 patients with NPC, and 11 factors were involved in the final model. • The nomogram had a significantly higher C-index and area under the ROC curve than the TNM stage and EBV DNA. • We established the first nomogram model for NPC involving the occurrence of NP necrosis, which was valuable for providing individual counseling and clinical assessments.

Glutamine is a substrate for glycosylation and CA19-9 biosynthesis through hexosamine biosynthetic pathway in pancreatic cancer.

BACKGROUND: Carbohydrate antigen 19-9 (CA19-9) is the most widely used biomarker for pancreatic cancer. Since CA19-9 closely correlates with patient outcome and tumor stage in pancreatic cancer, the deciphering of CA19-9 biosynthesis provides a potential clue for treatment. METHODS: Concentration of amino acids was detected by ultrahigh-performance liquid chromatography tandem mass spectrometry. Metabolic flux of glutamine was examined by isotope tracing untargeted metabolomics. Label-free quantitative N-glycosylation proteomics was used to examine N-glycosylation alterations. RESULTS: Among all amino acids, glutamine was higher in CA19-9-high pancreatic cancers (> 37 U/mL, 66 cases) than in CA19-9-normal clinical specimens (≤ 37 U/mL, 37 cases). The glutamine concentration in clinical specimens was positively correlated with liver metastasis or lymphovascular invasion. Glutamine blockade using diazooxonorleucine suppressed pancreatic cancer growth and intraperitoneal and lymphatic metastasis. Glutamine promotes O-GlcNAcylation, protein glycosylation, and CA19-9 biosynthesis through the hexosamine biosynthetic pathway. UDP-N-acetylglucosamine (UDP-GlcNAc) levels correlated with the glutamine influx through hexosamine biosynthetic pathway and supported CA19-9 biosynthesis. CONCLUSIONS: Glutamine is a substrate for CA19-9 biosynthesis in pancreatic cancer. Glutamine blockade may be a potential therapeutic strategy for pancreatic cancer.

Hyperglycemia predicts adverse prognosis in advanced pancreatic cancer patients.

BACKGROUND: Diabetes mellitus is a prevalent comorbidity in pancreatic cancer. Previous studies have mainly concentrated on the association between diabetes and pancreatic cancer outcomes. However, research on the impact of hyperglycemia on the prognosis of patients with advanced pancreatic cancer is limited. METHODS: Information on patients with advanced pancreatic cancer was collected from a prospectively maintained database, and the patients were divided into the hyperglycemia group (fasting blood glucose ≥7.0 mmol/L) and the normoglycemia group (fasting blood glucose < 7.0 mmol/L). Patients with preexisting diabetes were not included in these groups. The associations between hyperglycemia and clinical variables or prognosis were analyzed. RESULTS: Among 697 patients with advanced pancreatic cancer and no prior history of diabetes, 25.3% were diagnosed with hyperglycemia. Patients older than 65 years had a higher risk of developing hyperglycemia (P = 0.044). Patients with hyperglycemia had a worse prognosis than those with normoglycemia (median survival, 7.5 vs. 8.8 months, P < 0.001). Hyperglycemia was associated with increased mortality (hazard ratio = 1.38; P = 0.003). CONCLUSIONS: Hyperglycemia predicts worse overall survival in patients with advanced pancreatic cancer.

Reactive oxygen species-induced long intergenic noncoding RNA p21 accelerates abdominal aortic aneurysm formation by promoting secretary smooth muscle cell phenotypes.

Whether long noncoding RNAs participate in the formation of abdominal aortic aneurysms (AAAs) through the regulation of SMC phenotypic switching is unknown. lincRNA-p21 induced by reactive oxygen species (ROS) is likely functionally associated with SMC phenotypic switching. We thus investigated the role of lincRNA-p21 in SMC phenotypic switching-associated AAA formation and its underlying mechanisms. An analysis of human and mouse abdominal aortic samples revealed that the lincRNA-p21 levels were significantly higher in AAA tissue. Stimulation with hydrogen peroxide upregulated the expression of lincRNA-p21 in a dose-dependent manner and converted SMCs from a contractile phenotype to a synthetic, proteolytic, and proinflammatory phenotype in vitro. Moreover, lincRNA-p21 promoted fracture of elastic fibres, reconstruction of the vascular wall, and AAA formation in vivo by modulating SMC phenotypic switching in two mouse models of AAA induced by angiotensin II or porcine pancreatic elastase (PPE) perfusion. Using a bioinformatics prediction method and luciferase reporter gene assays, we further proved that lincRNA-p21 sponged miR-204-5p to release the transcriptional activity of Mekk3 and promoted the NF-κB pathway and thereby played a role in the SMC phenotypic switch and AAA formation. The ROS levels were positively correlated with the lincRNA-p21 levels in human and mouse AAA tissues. The knockdown of lincRNA-p21 in a PPE-induced mouse AAA model increased the miR-204-5p levels and reduced the expression of Mekk3, whereas lincRNA-p21 overexpression had the opposite effect. Collectively, the results indicated that ROS-induced lincRNA-p21 sponges miR-204-5p to accelerate synthetic and proinflammatory SMC phenotypes through the Mekk3/NF-κB pathway in AAA formation. Thus, lincRNA-p21 may have therapeutic potential for AAA formation.

Safety and efficacy of liraglutide on reducing visceral and ectopic fat in adults with or without type 2 diabetes mellitus: A systematic review and meta-analysis.

AIM: To assess the efficacy and safety of liraglutide to reduce visceral and ectopic fat in adults with or without type 2 diabetes mellitus (T2DM). METHODS: Four databases were searched up to 6 May 2022 for randomized clinical trials assessing the effect of liraglutide on visceral and ectopic fat. The mean and standard deviation of the values of visceral fat, ectopic fat and body mass index were calculated. Subgroup analyses were performed based on the type of disease (T2DM or non-T2DM), duration of intervention, dosage of liraglutide and whether life interventions were added to liraglutide therapy. We extracted and integrated the safety assessments reported in each article. RESULTS: Sixteen randomized clinical trials with, in total, 845 participants were included in the meta-analysis. Liraglutide could significantly decrease visceral fat [standard mean difference (SMD) = -0.72, 95% confidence interval (CI; -1.12, -0.33)], liver fat [SMD = -0.78, 95% CI (-1.24, -0.32)] and body mass index [weighted mean difference = -1.44, 95% CI (-1.95, -0.92)] in adult patients with or without T2DM when compared with the control group. However, reduction of epicardial fat by liraglutide [SMD = -0.74, 95% CI (-1.82, 0.34)] was not statistically significant. Subgroup analysis revealed that an adequate dosage (≥1.8 mg/day) and appropriate duration of treatment (ranging from 16 to 40 weeks) were the decisive factors for liraglutide to reduce visceral fat effectively. Mild gastrointestinal reactions were the main adverse event of liraglutide. CONCLUSIONS: Liraglutide significantly and safely reduces visceral and ectopic liver fat irrespective of T2DM status, and reduces visceral fat provided adequate dosage and duration of therapy are ensured.

Radioimmunotherapy as a pathogen-agnostic treatment method for opportunistic mucormycosis infections.

Invasive fungal infections (IFIs) such as mucormycosis are causing devastating morbidity and mortality in immunocompromised patients as anti-fungal agents do not work in the setting of a suppressed immune system. The coronavirus disease 2019 (COVID-19) pandemic has created a novel landscape for IFIs in post-pandemic patients, resulting from severe immune suppression caused by COVID-19 infection, comorbidities (diabetes, obesity) and immunosuppressive treatments such as steroids. The antigen-antibody interaction has been employed in radioimmunotherapy (RIT) to deliver lethal doses of ionizing radiation emitted by radionuclides to targeted cells and has demonstrated efficacy in several cancers. One of the advantages of RIT is its independence of the immune status of a host, which is crucial for immunosuppressed post-COVID-19 patients. In the present work we targeted the fungal pan-antigens 1,3-beta-glucan and melanin pigment, which are present in the majority of pathogenic fungi, with RIT, thus making such targeting pathogen-agnostic. We demonstrated in experimental murine mucormycosis in immunocompetent and immunocompromised mice that lutetium-177 (177Lu)-labelled antibodies to these two antigens effectively decreased the fungal burden in major organs, including the brain. These results are encouraging because they show the effectiveness of pathogen-agnostic RIT in significantly decreasing fungal burden in vivo, while they can also potentially be applied to treat the broad range of invasive fungal infections that express the pan-antigens 1,3-beta-glucan or melanin.