Case report: Immunotherapy in rare high TMB pancreatic acinar carcinoma.

This case report details a patient with Pancreatic Acinar Cell Carcinoma (PACC), a rare malignancy with distinctive biological and imaging features. In the absence of standardized treatment protocols for PACC, we embarked on a diagnostic journey that led to the adoption of an innovative therapeutic regimen in our institution. A 45-year-old female patient presented with a pancreatic mass, which was histologically confirmed as PACC following a biopsy. Subsequent genomic profiling revealed a high tumor mutational burden (21.4/Mb), prompting the initiation of combined immunotherapy and targeted therapy. Notably, the patient experienced a unique adverse reaction to the immunotherapy-recurrent subcutaneous soft tissue nodules, particularly in the gluteal and lower limb regions, accompanied by pain, yet resolving spontaneously. Following six cycles of the dual therapy, radiological evaluations indicated a decrease in tumor size, leading to a successful surgical excision. Over a 20-month post-surgical follow-up, the patient showed no signs of disease recurrence. This narrative adds to the existing knowledge on PACC and highlights the potential efficacy of immunotherapy in managing this challenging condition, emphasizing the importance of close monitoring for any adverse reactions.

Low pulse pressure and high serum complement C1q are risk factors for hemodialysis headache: A case-control study.

BACKGROUND AND OBJECTIVE: Hemodialysis headache (HDH) is a common complication of dialysis that negatively affects the patient's quality of life. The etiology and triggering factors of HDH are not fully understood. This study aims to assess the prevalence and characteristics of HDH among patients undergoing hemodialysis across multiple centers in China. Furthermore, we conducted a case-control study at one hospital to identify risk factors associated with HDH. METHODS: The study consisted of two phases including a cross-sectional observational study and a case-control study. Participants underwent neurological examinations and interviews. Demographic and medical information were collected from both medical records and patient files. Serum creatinine, uric acid, urea, estimated glomerular filtration rate (eGFR), plasma osmolarity, glucose, C1q, and a variety of electrolytes including potassium, sodium, chloride, calcium, magnesium, and phosphorus were measured before and after dialysis. Blood pressure variables including systolic blood pressure, diastolic blood pressure, pulse pressure (PP), and heart rate were monitored hourly. Serum levels of inflammatory factors, including tumor necrosis factor α (TNF-α), interleukin (IL)-1ß, IL-4, IL-6, and IL-10 were quantified using a double-antibody sandwich enzyme-linked immunosorbent assay (ELISA). RESULTS: The prevalence of HDH was 37.7% (183/485). HDH was characterized by a bilateral tightening headache of moderate intensity and duration of <2 h, occurring in different locations. The case-control study included 50 patients with HDH and 84 control patients, pre-dialysis PP was found to be lower in the HDH group than in the control group (mean ± standard deviation 51.5 ± 18.2 vs. 67.9 ± 14.9, p = 0.027). Furthermore, the pre-dialysis serum complement C1q level was significantly higher for the HDH group than the control group (median and interquartile range 201.5 [179.0-231.5] vs. 189.0 [168.9-209.0], p = 0.021). Pre-dialysis PP was associated with 5.1% decreased odds of HDH (odds ratio [OR] = 0.96; 95% confidence interval [CI], 0.93-0.99, p = 0.026), body weight was associated with a 5.4% decreased risk of HDH (OR = 0.95; 95% CI, 0.91-0.99, p = 0.013), and pre-dialysis C1q levels increased the odds of HDH by 1.9% (OR = 1.02; 95% CI, 1.01-1.03, p = 0.005). CONCLUSION: Low PP, low body weight, and high blood complement C1q may be potential risk factors associated with HDH.

Biotransformation of zearalenone to non-estrogenic compounds with two novel recombinant lactonases from Gliocladium.

BACKGROUND: The mycotoxin zearalenone (ZEA) produced by toxigenic fungi is widely present in cereals and its downstream products. The danger of ZEA linked to various human health issues has attracted increasing attention. Thus, powerful ZEA-degrading or detoxifying strategies are urgently needed. Biology-based detoxification methods are specific, efficient, and environmentally friendly and do not lead to negative effects during cereal decontamination. Among these, ZEA detoxification using degrading enzymes was documented to be a promising strategy in broad research. Here, two efficient ZEA-degrading lactonases from the genus Gliocladium, ZHDR52 and ZHDP83, were identified for the first time. This work studied the degradation capacity and properties of ZEA using purified recombinant ZHDR52 and ZHDP83. RESULTS: According to the ZEA degradation study, transformed Escherichia coli BL21(DE3) PLySs cells harboring the zhdr52 or zhdp83 gene could transform 20 µg/mL ZEA within 2 h and degrade > 90% of ZEA toxic derivatives, α/ß-zearalanol and α/ß-zearalenol, within 6 h. Biochemical analysis demonstrated that the optimal pH was 9.0 for ZHDR52 and ZHDP83, and the optimum temperature was 45 °C. The purified recombinant ZHDR52 and ZHDP83 retained > 90% activity over a wide range of pH values and temperatures (pH 7.0-10.0 and 35-50 °C). In addition, the specific activities of purified ZHDR52 and ZHDP83 against ZEA were 196.11 and 229.64 U/mg, respectively. The results of these two novel lactonases suggested that, compared with ZHD101, these two novel lactonases transformed ZEA into different products. The slight position variations in E126 and H242 in ZDHR52/ZEA and ZHDP83/ZEA obtained via structural modelling may explain the difference in degradation products. Moreover, the MCF-7 cell proliferation assay indicated that the products of ZEA degradation using ZHDR52 and ZHDP83 did not exhibit estrogenic activity. CONCLUSIONS: ZHDR52 and ZHDP83 are alkali ZEA-degrading enzymes that can efficiently and irreversibly degrade ZEA into non-estrogenic products, indicating that they are potential candidates for commercial application. This study identified two excellent lactonases for industrial ZEA detoxification.

Enterohemorrhagic Escherichia coli effector EspF triggers oxidative DNA lesions in intestinal epithelial cells.

Attaching/effacing (A/E) pathogens induce DNA damage and colorectal cancer by injecting effector proteins into host cells via the type III secretion system (T3SS). EspF is one of the T3SS-dependent effector proteins exclusive to A/E pathogens, which include enterohemorrhagic Escherichia coli. The role of EspF in the induction of double-strand breaks (DSBs) and the phosphorylation of the repair protein SMC1 has been demonstrated previously. However, the process of damage accumulation and DSB formation has remained enigmatic, and the damage response is not well understood. Here, we first showed a compensatory increase in the mismatch repair proteins MutS homolog 2 (MSH2) and MSH6, as well as poly(ADP-ribose) polymerase 1, followed by a dramatic decrease, threatening cell survival in the presence of EspF. Flow cytometry revealed that EspF arrested the cell cycle at the G2/M phase to facilitate DNA repair. Subsequently, 8-oxoguanine (8-oxoG) lesions, a marker of oxidative damage, were assayed by ELISA and immunofluorescence, which revealed the accumulation of 8-oxoG from the cytosol to the nucleus. Furthermore, the status of single-stranded DNA (ssDNA) and DSBs was confirmed. We observed that EspF accelerated the course of DNA lesions, including 8-oxoG and unrepaired ssDNA, which were converted into DSBs; this was accompanied by the phosphorylation of replication protein A 32 in repair-defective cells. Collectively, these findings reveal that EspF triggers various types of oxidative DNA lesions with impairment of the DNA damage response and may result in genomic instability and cell death, offering novel insight into the tumorigenic potential of EspF.IMPORTANCEOxidative DNA lesions play causative roles in colitis-associated colon cancer. Accumulating evidence shows strong links between attaching/effacing (A/E) pathogens and colorectal cancer (CRC). EspF is one of many effector proteins exclusive to A/E pathogens with defined roles in the induction of oxidative stress, double-strand breaks (DSBs), and repair dysregulation. Here, we found that EspF promotes reactive oxygen species generation and 8-oxoguanine (8-oxoG) lesions when the repair system is activated, contributing to sustained cell survival. However, infected cells exposed to EspF presented 8-oxoG, which results in DSBs and ssDNA accumulation when the cell cycle is arrested at the G2/M phase and the repair system is defective or saturated by DNA lesions. In addition, we found that EspF could intensify the accumulation of nuclear DNA lesions through oxidative and replication stress. Overall, our work highlights the involvement of EspF in DNA lesions and DNA damage response, providing a novel avenue by which A/E pathogens may contribute to CRC.

Risk Factors and Predictive Nomogram for Carbapenem-Resistant Klebsiella pneumoniae in Children in a Grade 3 First-Class General Hospital in Central China.

Background: This study determined risk factors for Carbapenem-resistant Klebsiella pneumoniae (CRKP)in children admitted to a grade 3 first-class general hospital and developed an individualized line graph predictive model. Methods: The clinical data of 185 children infected with Klebsiella pneumoniae from January 2015 to December 2019 were analyzed retrospectively. Patients were grouped according to carbapenem resistance: CRKP group (50 cases) and CSKP (carbapenem-sensitive Klebsiella pneumoniae) group (135 cases). Risk factors for CRKP in children were screened by logistic regression analysis. The predictive model was established using R software and validated using the Bootstrap method. Results: Age (odds ratio [OR]=0.104, 95% confidence interval [CI]: 0.026-0.408), intensive care unit admission (OR =2.829, 95% CI: 1.138-7.030), mechanical ventilation (OR =7.510, 95% CI: 3.140-17.961), surgery history (OR =5.005, 95% CI: 1.507-16.618) and glucocorticoid (OR =0.235, 95% CI: 0.099-0.557) were independent risk factors for CRKP in children (P < 0.05), The total risk score of each factor was 362.5, and the risk rate was 0.1-0.9. In receiver-operating characteristic curve analysis, the area under the curve of CRKP predicted by the total risk score was 0.872 (95% CI=0.844-0.901; P < 0.001). The correction curve indicated that the consistency between the observed value and the predicted value was good. Discussion and Conclusion: This study successfully established a model based on the risk factors, with high accuracy and good predictive value for CRKP in children. Hospitals should take necessary preventive measures against the risk factors for drug-resistant bacteria, such as optimizing the configuration of ICU space, timely isolation of infected children, and adequate disinfection of ICU equipment. Which may reduce CRKP infection rate.

Cancer immunotherapy efficacy and machine learning.

INTRODUCTION: Immunotherapy is one of the major breakthroughs in the treatment of cancer, and it has become a powerful clinical strategy, however, not all patients respond to immune checkpoint blockade and other immunotherapy strategies. Applying machine learning (ML) techniques to predict the efficacy of cancer immunotherapy is useful for clinical decision-making. AREAS COVERED: Applying ML including deep learning (DL) in radiomics, pathomics, tumor microenvironment (TME) and immune-related genes analysis to predict immunotherapy efficacy. The studies in this review were searched from PubMed and ClinicalTrials.gov (January 2023). EXPERT OPINION: An increasing number of studies indicate that ML has been applied to various aspects of oncology research, with the potential to provide more effective individualized immunotherapy strategies and enhance treatment decisions. With advances in ML technology, more efficient methods of predicting the efficacy of immunotherapy may become available in the future.

Study of Low-Velocity Impact Behavior of Hybrid Fiber-Reinforced Metal Laminates.

In this paper, the low-velocity impact behavior and damage modes of carbon/glass-hybrid fiber-reinforced magnesium alloy laminates (FMLs-H) and pure carbon-fiber-reinforced magnesium alloy laminates (FMLs-C) are investigated using experimental, theoretical modeling, and numerical simulation methods. Low-velocity impact tests were conducted at incident energies of 20 J, 40 J, and 60 J using a drop-weight impact tester, and the load-displacement curves and energy-time curves of the FMLs were recorded and plotted. The results showed that compared with FMLs-C, the stiffness of FMLs-H was slightly reduced, but the peak load and energy absorption were both greatly improved. Finally, a finite element model based on the Abaqus-VUMAT subroutine was developed to simulate the experimental results, and the damage modes of the metal layer, fiber layer, and interlayer were observed and analyzed. The experimental results are in good agreement with the finite element analysis results. The damage mechanisms of two kinds of FMLs under low-velocity impacts are discussed, providing a reference for the design and application of laminates.

Use of 18F-FDG PET/MRI as an Initial Staging Procedure for Nasopharyngeal Carcinoma.

BACKGROUND: Compared with the conventional work-up (CWU) including computed tomography (CT) of the chest and abdomen, MRI of the head and neck, and skeletal scintigraphy, positron emission tomography (PET)/MRI might improve diagnostic accuracy, shorten the work-up time, and reduce false-positive (FP) findings in patients with nasopharyngeal carcinoma (NPC). However, evidence of cost-effectiveness is needed for the adoption of PET/MRI for the initial staging in NPC. PURPOSE: To evaluate the cost-effectiveness and clinical value of PET/MRI as an initial staging procedure for NPC. STUDY TYPE: Retrospective cohort cost effectiveness study. SUBJECTS: Three hundred forty-three patients with a median age of 51 (13-81) years underwent PET/MRI before treatment (the PET/MRI group) and the remaining 677 patients with a median age of 55 (15-95) years only underwent CWU (the CWU group). There were 80 (23.3%) females and 193 (28.5%) females in the PET/MRI and CWU groups, respectively. FIELD STRENGTH/SEQUENCE: 3-T integrated PET/MRI system, diffusion-weighted echo-planar imaging (b = 0 and 1000 s/mm2 ) and [18F] fluorodeoxyglucose PET. ASSESSMENT: The primary end point was the FP rate. Costs were determined as issued in 2021 by the Medical Insurance Administration Bureau of Zhejiang, China. STATISTICAL TESTS: Incremental cost effectiveness ratio (ICER) measured cost of using PET/MRI per percent of patients who avoided a FP. A P-value <0.05 was considered statistically significant. RESULTS: For the whole group, the de novo metastatic disease rate was 5.2% (53/1020). A total of 187 patients with FP results were observed. Significantly more patients with FP results were observed in the CWU group compared to the PET/MRI group (25.6% vs. 4.1%). The ICER was $54 for each percent of patients avoiding a FP finding. DATA CONCLUSION: Compared with CWU, PET/MRI may reduce the FP risk. Furthermore, PET/MRI may be cost-effective as an initial staging procedure for NPC. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: Stage 6.

Study on the Influence of Steel Fiber Distribution on the Mechanical Properties of Perfobond Leiste (PBL) Shear Connectors.

In order to study the influence of steel fibers on the mechanical properties of Perfobond Leiste (PBL) shear connectors and improve the utilization of steel fibers in this structure, four push-out test specimens and eight finite element numerical models were produced to study PBL-type shear connector specimens with different steel fiber blending amounts and blending forms. The results show that in this structure, when the blending amount of steel fiber was 0.5% to 1.5%, the ultimate bearing capacity of the specimen improved linearly, and the steel fiber helped to give full play to the performance of the PBL shear connector. The steel fibers distributed in the Z-direction have a significant impact on the mechanical properties of the PBL shear connector, and the steel fibers distributed in this direction have a significant effect on increasing the ultimate bearing capacity of the specimen. Steel fibers distributed in the Y-direction can greatly improve the plasticity of concrete. In addition, the effective action area of steel fibers is the triangular area from the bottom of the PBL shear connector to the two tops of the concrete.

GW4869 Can Inhibit Epithelial-Mesenchymal Transition and Extracellular HSP90α in Gefitinib-Sensitive NSCLC Cells.

Objective: GW4869 is an exosomal inhibitor. It is necessary to delay the occurrence of gefitinib resistance during non-small-cell lung cancer (NSCLC) treatment. This study aimed to investigate the anti-tumor effects of GW4869 on epithelial-mesenchymal transition (EMT) and expression of extracellular heat shock protein 90α (eHSP90α) that contributes to acquired resisitance. Our study provides a new sight into the treatment of EGFR-mutated NSCLC. Materials and Methods: We performed western blotting to detect levels of EMT and eHSP90α. Wound healing and transwell assays were performed to evaluate the behavioral dynamics of EMT. A nude mouse model of HCC827 was established in vivo. Results: GW4869 inhibited the expression of eHSP90α, EMT, invasion and migration abilities of HCC827 and PC9. GW4869 enhanced sensitivity to gefitinib in BALB/c nude mice bearing tumors of HCC827. Conclusion: These studies suggest that GW4869 can inhibit EMT and extracellular HSP90α, providing new strategies for enhancing gefitinib sensitivity in NSCLC.

Erratum: SNHG3 promotes migration, invasion, and epithelial-mesenchymal transition of breast cancer cells through the miR-186-5p/ZEB1 axis.

[This corrects the article on p. 585 in vol. 13, PMID: 33594311.].

Comparison of clinicopathological characteristics and survival outcomes between gallbladder mucinous adenocarcinoma and gallbladder adenocarcinoma: A propensity score-matched study.

BACKGROUND: Gallbladder mucinous adenocarcinoma (GBMAC) is a rare subtype of gallbladder adenocarcinoma (GBAC), with limited knowledge of its survival outcomes from small case series and single-center retrospective analysis. AIM: To compare the clinicopathological characteristics of GBMAC with typical GBAC and its prognostic factors to gain insights into this field. METHODS: This study was conducted using data from the Surveillance, Epidemiology, and End Results database, including cases of GBMAC and typical GBAC diagnosed from 2010 to 2017. The Pearson chi-square test or Fisher exact test was used to examine the differences in clinicopathological features between these two cohorts. In addition, propensity score matching (PSM) analysis was performed to balance the selection biases. Univariate and multivariate Cox hazards regression analyses were performed to determine independent prognostic factors for cancer-specific survival (CSS) and overall survival (OS). The Kaplan-Meier curves and log-rank tests were used to assess the OS and CSS of GBMAC and typical GBAC patients. RESULTS: The clinicopathological and demographic characteristics of GBMAC were different from typical GBAC. They included a larger proportion of patients with unmarried status, advanced American Joint Committee on Cancer (AJCC) stage, higher T stage, higher N1 stage rate and lower N0 and N2 stage rates (P < 0.05). Multivariate analyses demonstrated that surgery [OS: Hazard ratio (HR) = 2.27, P = 0.0037; CSS: HR = 2.05, P = 0.0151], chemotherapy (OS: HR = 6.41, P < 0.001; CSS: HR = 5.24, P < 0.001) and advanced AJCC stage (OS: Stage IV: HR = 28.99, P = 0.0046; CSS: Stage III: HR = 12.31, P = 0.015; stage IV: HR = 32.69, P = 0.0015) were independent prognostic indicators for OS and CSS of GBMAC patients. Furthermore, after PSM analysis, there was no significant difference between GBMAC and matched typical GBAC patients regarding OS (P = 0.82) and CSS (P = 0.69). CONCLUSION: The biological behaviors of GBMAC are aggressive and significantly different from that of typical GBAC. However, they show similar survival prognoses. Surgery, chemotherapy, and lower AJCC stage were associated with better survival outcomes. Further research is needed in the future to verify these results.

Rational design of a ratiometric fluorescent aptasensor for patulin in traditional Chinese medicine through the studies of the interaction mechanism between its DNA aptamer and the target molecule.

Patulin (PAT) is a kind of mycotoxin which must be monitored for the sake of quality and safety in traditional Chinese medicine (TCM) owing to its harm to human health. On this account, a rationally designed ratiometric fluorescent aptasensor was developed based on the studies of the interaction mechanism between PAT and its aptamer (PAT-APT). First, CD spectroscopy, molecular docking, and molecular dynamic simulation were applied to investigate the details on how PAT-APT binds with its target molecule. The results indicated that the structure of PAT-APT changed to a certain extent and was stabilized after binding with PAT. C-11, C-37 and C-38 were the key sites for the recognition and interaction between PAT-APT and its target. Second, based on these results, a ratiometric aptasensor was designed using fluorescence resonance energy transfer (FRET) and synchronous fluorescence spectroscopy. A complementary sequence (cDNA) to the aptamer with an appropriate length and hybridization position was obtained through rational design and optimization. Both PAT-APT and cDNA were labeled using a pair of fluorophores, which could generate FRET when the two single-stranded oligonucleotides hybridized. The accurate detection of PAT could be realized according to the change ratio of the fluorescence intensity at the corresponding wavelengths of the two fluorophores before and after the assay. The aptasensor achieved an ultralow limit of detection of 0.16 nM, perfect selectivity, and satisfactory practicability in complex TCM samples. To our knowledge, this is the first aptasensor for PAT designed through the interaction mechanism between its aptamer and the target molecule. Moreover, the assay for PAT is cost-effective, does not need complicated pretreatment and only takes less than an hour. In summary, this study makes a contribution to the safety control of TCM and provides a thinking mode from mechanism to rational design to conquer the problem of sensitive aptasensing of one component in a complex system.

Mets-IR as a predictor of cardiovascular events in the middle-aged and elderly population and mediator role of blood lipids.

Background: Cardiovascular disease (CVD) is a global health concern, with a significant impact on morbidity and mortality rates. Using fasting glucose, fasting triglycerides, body mass index (BMI), and high-density lipoprotein cholesterol (HDL-C), the metabolic score of insulin resistance (Mets-IR), a novel index created by Mexican researchers to assess insulin sensitivity, is a more precise way to measure insulin sensitivity. This study aimes to explore the association between Mets-IR and CVD, as well as investigate the potential mediating role of of low-density lipoprotein cholesterol (LDL-C). Methods: The study's data came from the 2011 and 2018 China Health and Retirement Longitudinal Studies (CHARLS). We used three logistic regression models to account for the potential effects of ten factors on cardiovascular disease/stroke/heart disease. Moreover, We performed mediation analyses to evaluate the role of LDL-C in the association between Mets-IR and incident CVD. Results: This study comprised 4,540 participants, of whom 494 (10.88%) were found to develop disease (CVD). Each interquartile range (IQR) increased in Mets-IR raised the risk of developing CVD by 38% (OR=1.38; 95% CI, 1.21-1.56) and there was a linear dose-response relationship between Mets-IR and the risk of new-onset cardiovascular disease, stroke, and heart disease (P overall<0.05, P non-linear>0.05). Approximately 5% (indirect effect/total effect) of the significant association of Mets-IR with stroke was mediated by LDL-C, respectively. With the addition of Mets-IR to the base model, the continuous net reclassification improvement and integrated discrimination improvement for predicting cardiovascular disease increased by 0.175 (P <0.001) and 0.006 (P <0.001), respectively. Conclusion: ets-IR is associated with an increased risk of cardiovascular disease/stroke/cardiac issues, with LDL-C mediating these relationships. Improving insulin sensitivity and lipid regulation may be essential and effective preventive measures for cardiovascular events.

Experimental and Numerical Investigation of the Tensile and Failure Response of Multiple-Hole-Fiber-Reinforced Magnesium Alloy Laminates under Various Temperature Environments.

In this paper, the tensile mechanical behavior and progressive damage morphology of glass-fiber-reinforced magnesium alloy laminate for different numbers of holes in a temperature range of 25-180 °C were investigated. In addition, based on extensive tensile tests, the tensile mechanical behavior and microscopic damage morphology of porous-glass-fiber-reinforced magnesium alloy laminates at different temperatures were observed by finite element simulation and scanning electron microscopy (SEM). Finally, the numerical simulation and experimental results were in good accordance with the prediction of mechanical properties and fracture damage patterns of the laminates, the average difference between the residual strength values of the specimens at ambient temperature was 5.57%, and the stress-strain curves were in good agreement. The experimental and finite element analysis results showed that the damaged area of the bonded layer tended to expand with the increase in the number of holes, which has a lesser effect on the ultimate tensile strength. As the temperature increased, the specimens changed from obvious fiber breakage (pull-out) and the resin matrix damage mode to matrix softening damage and interfacial delamination fracture damage. As the testing temperature of the specimens increased from 25 °C to 180 °C, the tensile strength of the specimens decreased by an average of 51.59%, while the tensile strength of the specimens showed a nonlinear decreasing trend. The damage mechanism of porous-glass-fiber-reinforced magnesium alloy laminates at different temperatures is discussed in this paper, which can provide a reference for engineering applications and design.

Recent advances in targeted therapy for pancreatic adenocarcinoma.

Pancreatic adenocarcinoma (PDAC) is a fatal disease with a 5-year survival rate of 8% and a median survival of 6 mo. In PDAC, several mutations in the genes are involved, with Kirsten rat sarcoma oncogene (90%), cyclin-dependent kinase inhibitor 2A (90%), and tumor suppressor 53 (75%-90%) being the most common. Mothers against decapentaplegic homolog 4 represents 50%. In addition, the self-preserving cancer stem cells, dense tumor microenvironment (fibrous accounting for 90% of the tumor volume), and suppressive and relatively depleted immune niche of PDAC are also constitutive and relevant elements of PDAC. Molecular targeted therapy is widely utilized and effective in several solid tumors. In PDAC, targeted therapy has been extensively evaluated; however, survival improvement of this aggressive disease using a targeted strategy has been minimal. There is currently only one United States Food and Drug Administration-approved targeted therapy for PDAC - erlotinib, but the absolute benefit of erlotinib in combination with gemcitabine is also minimal (2 wk). In this review, we summarize current targeted therapies and clinical trials targeting dysregulated signaling pathways and components of the PDAC oncogenic process, analyze possible reasons for the lack of positive results in clinical trials, and suggest ways to improve them. We also discuss emerging trends in targeted therapies for PDAC: combining targeted inhibitors of multiple pathways. The PubMed database and National Center for Biotechnology Information clinical trial website (www.clinicaltrials.gov) were queried to identify completed and published (PubMed) and ongoing (clinicaltrials.gov) clinical trials (from 2003-2022) using the keywords pancreatic cancer and targeted therapy. The PubMed database was also queried to search for information about the pathogenesis and molecular pathways of pancreatic cancer using the keywords pancreatic cancer and molecular pathways.

2-Deoxyglucose alleviates migraine-related behaviors by modulating microglial inflammatory factors in experimental model of migraine.

Background: Targeting metabolic pathways has emerged as a new migraine treatment strategy as researchers realize the critical role metabolism plays in migraine. Activated inflammatory cells undergo metabolic reprogramming and rely on glycolysis to function. The objective of this study was to investigate the glycolysis changes in the experimental model of migraine and the effect of glycolysis inhibitor 2-Deoxy-D-glucose (2-DG) in the pathophysiology of migraine. Methods: We used a rat model of migraine that triggered migraine attacks by applying inflammatory soup (IS) to the dura and examined changes in glycolysis. 2-DG was used to inhibit glycolysis, and the effects of 2-DG on mechanical ectopic pain, microglial cell activation, calcitonin gene-related peptides (CGRP), c-Fos, and inflammatory factors induced by inflammatory soup were observed. LPS stimulated BV2 cells to establish a model in vitro to observe the effects of 2-DG on brain-derived neurotrophic factor (BDNF) after microglia activation. Results: In the experimental model of migraine, key enzymes involved in glycolysis such as phosphofructokinase platelet (PFKP), hexokinase (HK2), hypoxia inducible factor-1α (HIF-1α), lactate dehydrogenase (LDH) and pyruvate kinase (PKM2) were expressed in the medullary dorsal horn. While the expression of electronic respiratory transport chain complex IV (COXIV) decreased. There were no significant changes in glucose 6-phosphate dehydrogenase (G6PD), a key enzyme in the pentose phosphate pathway. The glycolysis inhibitor 2-DG alleviated migraine-like symptoms in an experimental model of migraine, reduced the release of proinflammatory cytokines caused by microglia activation, and decreased the expression of CGRP and c-Fos. Further experiments in vitro demonstrated that glycolysis inhibition can reduce the release of Iba-1/proBDNF/BDNF and inhibit the activation of microglia. Conclusion: The migraine rat model showed enhanced glycolysis. This study suggests that glycolytic inhibitor 2-DG is an effective strategy for alleviating migraine-like symptoms. Glycolysis inhibition may be a new target for migraine treatment.

Burden of Common Neurologic Diseases in Asian Countries, 1990-2019: An Analysis for the Global Burden of Disease Study 2019.

BACKGROUND AND OBJECTIVES: Based on the Global Burden of Diseases, Injuries, and Risk Factors (GBD) study, neurologic disorders are a major cause of morbidity and mortality worldwide. However, there has been no comprehensive assessment of neurologic disorders in Asia. Data from the GBD 1990-2019 study were investigated to provide new details for neurologic disorders in Asia. METHODS: The burden of common neurologic disorders in Asia was calculated for 1990 and 2019 as incidence, prevalence, deaths, and disability-adjusted life-years (DALYs). Thirteen common neurologic disorders were analyzed. Data are presented as totals and by sex, age, year, location, risk factors, and sociodemographic index (SDI) and shown as counts and rates. RESULTS: In 2019, the most burdensome neurologic disorders in Asia for the absolute number of DALYs were stroke (98.8 million, 95% uncertainty interval [UI] 91.0-107.0), migraine (24.6 million, 95% UI 3.4-56.4), and Alzheimer disease (AD) and other dementias (13.5 million, 95% UI 5.9-29.8). From 1990 to 2019, the absolute number of DALYs and deaths caused by combined neurologic disorders (deaths by 60.7% and DALYs by 17.6%) increased, but the age-standardized rates (deaths by 34.1% and DALYs by 36.3%) decreased. The burden of neurologic disorders peaked among individuals aged 65-74 years and was higher among male than among female individuals; moreover, this burden varied considerably across Asian subregions and countries. Risk-attributable DALYs accounted for 86.9%, 28.5%, and 11.1% of DALYs for stroke, AD and other dementias, and multiple sclerosis, respectively. SDI was associated with both stroke and communicable neurological disorders. In terms of crude rate, the higher the SDI value, the higher the prevalence of stroke, and the lower all metrics of communicable neurological disorders. DISCUSSION: Neurologic disorders were the leading cause of DALYs and the second leading cause of deaths in Asia in 2019, and the burden may likely increase with the growth and aging of the Asian population. Urgent measures are needed for prevention, treatment, rehabilitation, and support services for common neurologic disorders regionally and nationally.

Stable Plating and Stripping of Lithium Metal Anodes through Space Confinement and Stress Regulation.

Lithium metal anodes suffer from enormous mechanical stress derived from volume changes during electrochemical plating and stripping. The utilization of derived stress has the potential for the dendrite-free deposition and electrochemical reversibility of lithium metal. Here, we investigated the plating and stripping process of lithium metal held within a cellular three-dimensional graphene skeleton decorated with homogeneous Ag nanoparticles. Owing to appropriate reduction-splitting and electrostatic interaction of nitrogen dopants, the cellular skeletons show micron-level pores and superior elastic property. As lithium hosts, the cellular skeletons can physically confine the metal deposition and provide continuous volume-derived stress between Li and collectors, thus meliorating the stress-regulated Li morphology and improving the reversibility of Li metal anodes. Consequently, the symmetrical batteries exhibit a stable cycling performance with a span life of more than 1900 h. Full batteries (NCM811 as cathodes) achieve a reversible capacity of 181 mA h g-1 at 0.5 C and a stable cycling performance of 300 cycles with a capacity retention of 83.5%. The meliorative behavior of lithium metal within the cellular skeletons suggests the advantage of a stress-regulating strategy, which could also be meaningful for other conversion electrodes with volume fluctuation.

Assessment of bone lesions with 18 F-FDG PET/MRI in patients with nasopharyngeal carcinoma.

PURPOSE: The purpose of this study is to evaluate the role of 18 fluorodeoxyglucose ( 18 F) PET/MRI ( 18 F-FDG PET/MRI) for detecting bone metastasis in nasopharyngeal carcinoma (NPC). PATIENTS AND METHODS: Between May 2017 and May 2021, 58 histologically proven NPC patients who underwent both 18 F-FDG PET/MRI and 99m Tc-MDP planar bone scintigraphy (PBS) for tumor staging were included. With the exception of the head, the skeletal system was classified into four groups: the spine, the pelvis, the thorax and the appendix. RESULTS: Nine (15.5 %) of 58 patients were confirmed to have bone metastasis. There was no statistical difference between PET/MRI and PBS in patient-based analysis ( P = 0.125). One patient with a super scan was confirmed to have extensive and diffuse bone metastases and excluded for lesion-based analysis. Of the 57 patients, all 48 true metastatic lesions were positive in PET/MRI whereas only 24 true metastatic lesions were positive in PBS (spine: 8, thorax: 0, pelvis: 11 and appendix: 5). PET/MRI was observed to be more sensitive than PBS in lesion-based analysis (sensitivity 100.0% versus 50.0 %; P < 0.001). CONCLUSIONS: Compared with PBS for tumor staging of NPC, PET/MRI was observed to be more sensitive in the lesion-based analysis of bone metastasis.