[摘 要] 目的：探讨KH型剪切调节蛋白（KHSRP）靶向调控JAK1/STAT3信号轴对食管胃结合部腺癌（AEG）细胞增殖、迁移和侵袭及移植瘤生长与肺转移的影响。方法：收集2017年1月至2018年12月间在淮河医院确诊的64例AEG组织和癌旁组织标本及临床资料，采用免疫组化法观察AEG组织和癌旁组织中KHSRP的表达水平。qPCR法检测AEG细胞OE-19、TE-7、BIC-1、FLO-1、SK-GT-4、BE-3与正常食管上皮细胞Het-1A中KHSRP的表达差异。通过慢病毒载体对KHSRP进行敲减和过表达处理，分别转染OE-19与TE-7细胞、FLO-1与SK-GT-4细胞，实验分为sh-NC组、sh-KHSRP组和Vector组、KHSRP过表达组（KHSRP组）。采用qPCR法检测敲减或过表达效率，CCK-8法、Transwell小室法分别检测敲减或过表达KHSRP对AEG细胞增殖、迁移和侵袭的影响。构建小鼠异种移植瘤和肺转移模型，观察KHSRP对移植瘤体内生长和转移的作用。WB法验证KHSRP靶向JAK/STAT信号通路。细胞拯救实验验证KHSRP是否通过调节JAK1/STAT3信号通路促进AEG细胞的恶性进程。结果：与癌旁组织相比，AEG组织中KHSRP表达水平显著增高（P < 0.05或P < 0.01）。细胞功能实验分析显示，KHSRP过表达在体外均显著促进AEG细胞增殖、迁移和侵袭（P < 0.05或P < 0.01）。动物实验结果显示，KHSRP在裸鼠体内具有促进AEG细胞移植瘤生长与肺转移的作用（P < 0.05或P < 0.01）。在敲减KHSRP后，JAK/STAT信号通路中JAK1、STAT3磷酸化水平均明显降低，过表达KHSRP后情况则均反之（P < 0.05或P < 0.01）。细胞拯救实验显示，KHSRP可以逆转敲减JAK1/STAT3对细胞增殖、迁移和侵袭的抑制作用（P < 0.05或P < 0.01）。结论：KHSRP通过激活JAK1/STAT3信号通路调控AEG细胞转移的恶性进程，KHSRP有望成为AEG临床治疗的潜在靶点。

Objective: To assess the association between the metabolic score for insulin resistance index (METS-IR) and overactive bladder (OAB) in the US population，so as to explore the potential of METS-IR as a predictive tool for OAB risk and to provide insights for early screening and intervention strategies. Methods: Based on the data from the National Health and Nutrition Examination Survey (NHANES) 2005-2018，a cross-sectional design was employed，and multivariate logistic regression models were used to analyze the association between METS-IR and OAB. METS-IR was analyzed both as a continuous variable and categorized into quartiles. To further validate the association between METS-IR and OAB across diverse populations，subgroup analyses were conducted in participants stratified by clinical characteristics. Smooth curve fitting was employed to test the linearity of the METS-IR-OAB relationship. Results: Elevated METS-IR was associated with an increased risk of OAB (P<0.001)，and this positive correlation remained stable when METS-IR was categorized into quartiles (P<0.001). Subgroup analyses revealed that the association between METS-IR and OAB was more pronounced in females，participants younger than 55 years，and non-diabetic individuals (P<0.05). Furthermore，smooth curve fitting confirmed a linear positive correlation between METS-IR and OAB，with this linear relationship observed in both diabetic and non-diabetic groups. Conclusion: This study，based on the NHANES 2005-2018 database，found a linear positive correlation between METS-IR and OAB.

OBJECTIVE: To evaluate the efficacy and safety of Shexiang Tongxin Dropping Pill (STDP) in treating stable angina patients with phlegm-heat and blood-stasis syndrome by exercise duration and metabolic equivalents. METHODS: This multicenter, randomized, double-blind, placebo-controlled clinical trial enrolled stable angina patients with phlegm-heat and blood-stasis syndrome from 22 hospitals. They were randomized 1:1 to STDP (35 mg/pill, 6 pills per day) or placebo for 56 days. The primary outcome was the exercise duration and metabolic equivalents (METs) assessed by the standard Bruce exercise treadmill test after 56 days of treatment. The secondary outcomes included the total angina symptom score, Chinese medicine (CM) symptom scores, Seattle Angina Questionnaire (SAQ) scores, changes in ST-T on electrocardiogram and adverse events (AEs). RESULTS: This trial enrolled 309 patients, including 155 and 154 in the STDP and placebo groups, respectively. STDP significantly prolonged exercise duration with an increase of 51.0 s, compared to a decrease of 12.0 s with placebo (change rate: -11.1% vs. 3.2%, P<0.01). The increase in METs was significantly greater in the STDP group than in the placebo group (change: -0.4 vs. 0.0, change rate: -5.0% vs. 0.0%, P<0.01). The improvement of total angina symptom scores (25.0% vs. 0.0%), CM symptom scores (38.7% vs. 11.8%), reduction of nitroglycerin consumption (100.0% vs. 11.3%), and all domains of SAQ, were significantly greater with STDP than placebo (all P<0.01). The changes in Q-T intervals at 28 and 56 days from baseline were similar between the two groups (both P>0.05). Twenty-five participants (16.3%) with STDP and 16 (10.5%) with placebo experienced AEs (P=0.131), with no serious AEs observed. CONCLUSION STDP could improve exercise tolerance in patients with stable angina and phlegm-heat and blood stasis syndrome, with a favorable safety profile. (Registration No. ChiCTR-IPR-15006020).
Humans ; Double-Blind Method ; Drugs, Chinese Herbal/adverse effects* ; Male ; Female ; Middle Aged ; Angina, Stable/physiopathology* ; Aged ; Syndrome ; Treatment Outcome ; Placebos ; Tablets

Parkinson's disease (PD), a chronic and common neurodegenerative disease, is characterized by the progressive loss of dopaminergic neurons in the dense part of the substantia nigra and abnormal aggregation of alpha-synuclein. Type 2 diabetes mellitus (T2DM) is a metabolic disease characterized by chronic insulin resistance and deficiency in insulin secretion. Extensive evidence has confirmed shared pathogenic mechanisms underlying PD and T2DM, such as oxidative stress caused by insulin resistance, mitochondrial dysfunction, inflammation, and disorders of energy metabolism. Conventional drugs for treating T2DM, such as metformin and glucagon-like peptide-1 receptor agonists, affect nerve repair. Even drugs for treating PD, such as levodopa, can affect insulin secretion. This review summarizes the relationship between PD and T2DM and related therapeutic drugs from the perspective of insulin signaling pathways in the brain.
Humans ; Parkinson Disease/drug therapy* ; Diabetes Mellitus, Type 2/pathology* ; Signal Transduction/physiology* ; Receptor, Insulin/metabolism* ; Animals ; Insulin Resistance/physiology* ; Insulin/metabolism*

Neurodegenerative diseases encompass a diverse array of disorders that have a profoundly detrimental impact on human health, characterized by their intricate and multifaceted pathogenesis. In the recent past, a growing body of scientific research has begun to shed light on the critical involvement of the neuro-immune axis in the onset and advancement of these debilitating conditions. This comprehensive review article delves into the intricate composition of the neuro-immune axis, elucidating the complex mechanisms through which it exerts its influence in the context of neurodegenerative diseases. Furthermore, it explores the potential therapeutic applications of targeting the neuro-immune axis for the management and treatment of these diseases. This extensive examination aims to offer new perspectives and innovative strategies that could pave the way for more effective treatments for neurodegenerative diseases, thereby providing hope for those afflicted by these challenging conditions.
Humans ; Neurodegenerative Diseases/metabolism* ; Animals ; Neuroimmunomodulation/physiology*

OBJECTIVE: To explore the feasibility of incorporating simple bedside indicators into death predictive model for elderly critically ill patients based on interpretability machine learning algorithms, providing a new scheme for clinical disease assessment. METHODS: Elderly critically ill patients aged ≥ 65 years who were hospitalized in the intensive care unit (ICU) of Tacheng People's Hospital of Ili Kazak Autonomous Prefecture from June 2017 to May 2020 were retrospectively selected. Basic parameters including demographic characteristics, basic vital signs and fluid intake and output within 24 hours after admission, as well acute physiology and chronic health evaluation II (APACHE II), Glasgow coma score (GCS) and sequential organ failure assessment (SOFA) were also collected. According to outcomes in hospital, patients were divided into survival group and death group. Four datasets were constructed respectively, namely baseline dataset (B), including age, body temperature, heart rate, pulse oxygen saturation, respiratory rate, mean arterial pressure, urine output volume, infusion volume, and crystal solution volume; B+APACHE II dataset (BA), B+GCS dataset (BG), and B+SOFA dataset (BS). Then three machine learning algorithms, Logistic regression (LR), extreme gradient boosting (XGboost) and gradient boosting decision tree (GBDT) were used to develop the corresponding mortality predictive models within four datasets. The feature importance histogram of each prediction model was drawn by SHapley additive explanation (SHAP) method. The area under curve (AUC), accuracy and F1 score of each model were compared to determine the optimal prediction model and then illuminate the nomogram. RESULTS: A total of 392 patients were collected, including 341 in the survival group and 51 in the death group. There were statistically significant differences in heart rate, pulse oxygen saturation, mean arterial pressure, infusion volume, crystal solution volume, and etiological distribution between the two groups. The top three causes of death were shock, cerebral hemorrhage, and chronic obstructive pulmonary disease. Among the 12 prognostic models trained by three machine learning algorithms, overall performance of prognostic models based on B dataset was behind, whereas the LR model trained by BA dataset achieved the best performance than others with AUC of 0.767 [95% confidence interval (95%CI) was 0.692-0.836], accuracy of 0.875 (95%CI was 0.837-0.903) and F1 score of 0.190. The top 3 variables in this model were crystal solution volume with first 24 hours, heart rate and mean arterial pressure. The nomogram of the model showed that the total score between 150 and 230 were advisable. CONCLUSION The interpretable machine learning model including simple bedside parameters combined with APACHE II score could effectively identify the risk of death in elderly patients with critically illness.
Humans ; Critical Illness ; Machine Learning ; Aged ; Algorithms ; Intensive Care Units ; Retrospective Studies ; APACHE ; Prognosis ; Organ Dysfunction Scores ; Hospital Mortality ; Male ; Female

Biliary tract carcinoma （BTC） is a type of gastrointestinal tumor with a low incidence rate and a strong invasive ability， mainly including intrahepatic cholangiocarcinoma （ICC）， extrahepatic cholangiocarcinoma （ECC）， and gallbladder carcinoma （GC）， often accompanied by local progression or distant metastasis. Surgery is often the preferred treatment method for patients with local resectable tumor； however， there is still a high risk of recurrence after radical surgery. Therefore， multiple treatment modalities are often required for BTC patients， including surgical resection， systemic treatment （such as targeted therapy， chemotherapy， and immunotherapy）， and/or a combination of local treatment methods. With the development of the field of BTC， it is critical for surgical oncologists to understand and master the latest surgical strategies and the best patient selection and management systems. In view of the complexity of treatment and the continuous development of diagnosis and treatment techniques， Annals of Surgical Oncology， an authoritative American journal of cancer surgery， recently published the practical diagnosis and treatment guidelines for hepatobiliary tumors， including hepatocellular carcinoma （HCC）， ICC， ECC， and GC， aiming to provide more evidence-based evidence for the clinical management and decision-making of patients with hepatobiliary tumors. Due to the limitations of length and different emphases， this article mainly introduces the recommendations for the evaluation points and clinical treatment of ECC and GC in the guidelines， so as to provide a reference for clinical practice.

Zuoguiyin， which first recorded in Jingyue Quanshu written by ZHANG Jiebin in the Ming dynasty， was included in the Catalogue of Ancient Famous Classical Formulas（The Second Batch）. This study followed the Principles of Textual Research on Key Information of Ancient Famous Classical Formulas to determine the key information of Zuoguiyin in ancient and modern literature， such as the formula origin， the composition of the formula and the origin of the drugs. It was found that the composition， dosage， preparation and processing methods of Zuoguiyin were basically the same as the original formula. The original dosage of this formula is 41.03 g of Rehmanniae Radix Praeparata（the fresh or dried tuberous roots of Rehmannia glutinosa， processed by wine stewing or wine steaming）， 7.46 g of Dioscoreae Rhizoma（the dried rhizomes of Dioscorea opposita）， 7.46 g of Lycii Fructus（the dried mature fruit of Lycium barbarum）， 3.73 g of Glycyrrhizae Radix et Rhizoma Praeparata cum Melle（the dried roots and rhizomes of Glycyrrhiza uralensis， processed by honey-roasted method）， 5.595 g of Poria（the sclerotium of Poria cocos）， 5.595 g of Corni Fructus（the dried mature fruit pulp of Cornus officinalis）. The method of administration is to add 600 mL of water to all the herbs， decoct to 140 mL and take before meals. The function of Zuoguiyin is to nourish Yin and tonify the kidney， and it is often used in the treatment of lumbar soreness and ejaculation， night sweating， dry mouth and throat， thirst and desire to drink， glossy red tongue， thin and rapid pulse， etc. Since ancient times， Zuoguiyin has been used to treat a variety of internal and gynaecological diseases as well as diseases of the nervous， circulatory and reproductive systems that are predominantly caused by kidney Yin deficiency. However， there is not much research on the modern application and therapeutic mechanism of this formula， and there is no standardized preparation in the market， so the degree of development and utilization is not high， and there is still a lot of room for research.

The article explores the common pathogenesis and transmission mechanism of exogenous febrile diseases.It points out that the invasion of external evils leads to the wei qi resisting evils,the struggle between good and evil,and the stagnation of yang qi,thus showing a series of febrile disease syndromes,and the pathogenesis is characterized by"stagnation-deficiency".The theory of"qi-blood and body-function"is used to summarize the transmission and change patterns of febrile disease syndromes,and the course of febrile diseases is summarized into two stages:qi and blood.The qi phase includes the wei phase,mainly characterized by functional disorders;the blood phase includes the nutrient phase,mainly characterized by substantial damage and accompanied by more severe functional disorders.The pathogenesis of severe exogenous febrile diseases transformation includes excessive heat stimulating blood cir-culation,heat inducing pericardium closure,excessive heat activating wind,the source of generation and transformation being cut off,asthenia cold syndrome of Shaoyin,and collapse of healthy qi,etc.

Pathogenesis and treatment methods of qi-ying fen transformation in warm diseases are explored.It is believed that warm diseases are caused by yang pathogenic factors and are most likely to damage the organs and body fluids.Body fluids,as important components of human body's healthy qi,are usually present in the lungs as lung fluids,in the stomach as stomach fluids,in the intes-tines as intestinal fluids,and in blood vessels as nutrient yin.During the transformation from qi fen syndrome to ying fen syndrome,vis-ceral parenchymal damage acts as its important pathological mechanism and fluid depletion in blood vessels is an important reason for exacerbating qi-ying fen transformation.Excessive fire-toxicity,as an initial factor,promotes qi-ying fen transformation.Fluid deple-tion is the pathological basis for exacerbating qi-ying fen transformation.Clearing heat and protecting fluids,with sweet-flavored and cold-natured drugs to generate fluids,salty-flavored and cold-natured drugs to clear heat,and combination of sweet-flavored and bit-ter-flavored drugs,is an inevitable treatment method for preventing and treating qi-ying fen transformation in warm diseases,and it al-so has important clinical guidance value for internal miscellaneous diseases and acute severe cases.