Heteromeric amino acid transporters (HATs), formed by the assembly of solute carrier 3(SLC3) and solute carrier 7(SLC7) family members, play essential roles in amino acid transmembrane transport, cellular nutrient sensing, and redox homeostasis. Dysregulation of multiple HATs members has been closely associated with tumor metabolic reprogramming, ferroptosis resistance, and inherited amino acid metabolic disorders, making them important targets for drug development. However, the high conservation of substrate-binding pockets, the limited druggability of zwitterionic compounds, and safety concerns arising from their broad expression in normal tissues have collectively hindered the clinical translation of HATs-targeted therapeutics. Recent advances in cryo-electron microscopy (Cryo-EM) have enabled the determination of high-resolution structures of multiple HATs, providing a critical foundation for understanding their molecular mechanisms and for guiding targeted interventions. These structural studies have systematically revealed the molecular basis of selective substrate recognition and ion coupling among different family members and have identified non-conserved structural features that may serve as potential opportunities for subtype-selective targeting. In this review, we systematically summarize recent advances in the structural biology of HATs, with a particular emphasis on their assembly mechanisms, substrate recognition modes, and conformational transitions. Furthermore, we highlight recent progress in structure-based drug design (SBDD), including strategies to enhance ligand affinity by exploiting non-conserved hydrophobic side pockets, as well as approaches to block the transport cycle by disrupting the secondary structures of transmembrane helices TM3 and TM10. Collectively, these insights provide an important structural framework and new perspectives for the development of highly selective inhibitors for HATs and related therapeutic strategies.

Pancreatic cancer is a extremely high malignant digestive cancer, which usually occurred in the elderly. The cases and the portion of the elder patients in all pancreatic cancer patients are gradually increasing, resulted from the aging population in China. However, the management of the elder pancreatic cancer patients is challenging due to the multiple comorbidity, the poor tolerance to treatment and lack of social support. Meanwhile, these patients could be neglected by physician and relatives easily. More detailed physical, psychological and social support evaluations ought to be done before treatment in the elderly. The clinical care should be individualized based on the evaluations and tumor stage, in order to improve the prognosis and quality of life.

Pancreatic cancer is a extremely high malignant digestive cancer, which usually occurred in the elderly. The cases and the portion of the elder patients in all pancreatic cancer patients are gradually increasing, resulted from the aging population in China. However, the management of the elder pancreatic cancer patients is challenging due to the multiple comorbidity, the poor tolerance to treatment and lack of social support. Meanwhile, these patients could be neglected by physician and relatives easily. More detailed physical, psychological and social support evaluations ought to be done before treatment in the elderly. The clinical care should be individualized based on the evaluations and tumor stage, in order to improve the prognosis and quality of life.

Since the utilization of anthracyclines in cancer therapy, severe cardiotoxicity has become a major obstacle. The major challenge in treating cancer patients with anthracyclines is minimizing cardiotoxicity without compromising antitumor efficacy. Herein, histone deacetylase SIRT6 expression was reduced in plasma of patients treated with anthracyclines-based chemotherapy regimens. Furthermore, overexpression of SIRT6 alleviated doxorubicin-induced cytotoxicity in cardiomyocytes, and potentiated cytotoxicity of doxorubicin in multiple cancer cell lines. Moreover, SIRT6 overexpression ameliorated doxorubicin-induced cardiotoxicity and potentiated antitumor efficacy of doxorubicin in mice, suggesting that SIRT6 overexpression could be an adjunctive therapeutic strategy during doxorubicin treatment. Mechanistically, doxorubicin-impaired mitochondria led to decreased mitochondrial respiration and ATP production. And SIRT6 enhanced mitochondrial biogenesis and mitophagy by deacetylating and inhibiting Sgk1. Thus, SIRT6 overexpression coordinated metabolic remodeling from glycolysis to mitochondrial respiration during doxorubicin treatment, which was more conducive to cardiomyocyte metabolism, thus protecting cardiomyocytes but not cancer cells against doxorubicin-induced energy deficiency. In addition, ellagic acid, a natural compound that activates SIRT6, alleviated doxorubicin-induced cardiotoxicity and enhanced doxorubicin-mediated tumor regression in tumor-bearing mice. These findings provide a preclinical rationale for preventing cardiotoxicity by activating SIRT6 in cancer patients undergoing chemotherapy, but also advancing the understanding of the crucial role of SIRT6 in mitochondrial homeostasis.

Although primary vesical calculi is an ancient disease, the mechanism of calculi formation remains unclear. In this study, we established a novel primary vesical calculi model with d,l-choline tartrate in mice. Compared with commonly used melamine and ethylene glycol models, our model was the only approach that induced vesical calculi without causing kidney injury. Previous studies suggest that proteins in the daily diet are the main contributors to the prevention of vesical calculi, yet the effect of fat is overlooked. To assay the relationship of dietary fat with the formation of primary vesical calculi, d,l-choline tartrate-treated mice were fed a high-fat, low-fat, or normal-fat diet. Genetic changes in the mouse bladder were detected with transcriptome analysis. A high-fat diet remarkably reduced the morbidity of primary vesical calculi. Higher fatty acid levels in serum and urine were observed in the high-fat diet group, and more intact epithelia in bladder were observed in the same group compared with the normal- and low-fat diet groups, suggesting the protective effect of fatty acids on bladder epithelia to maintain its normal histological structure. Transcriptome analysis revealed that the macrophage differentiation-related gene C-X-C motif chemokine ligand 14 (Cxcl14) was upregulated in the bladders of high-fat diet-fed mice compared with those of normal- or low-fat diet-fed mice, which was consistent with histological observations. The expression of CXCL14 significantly increased in the bladder in the high-fat diet group. CXCL14 enhanced the recruitment of macrophages to the crystal nucleus and induced the transformation of M2 macrophages, which led to phagocytosis of budding crystals and prevented accumulation of calculi. In human bladder epithelia (HCV-29) cells, high fatty acid supplementation significantly increased the expression of CXCL14. Dietary fat is essential for the maintenance of physiological functions of the bladder and for the prevention of primary vesical calculi, which provides new ideas for the reduction of morbidity of primary vesical calculi.

Objective:To investigate the risk factors for tumor recurrence after radical resection of stage Ⅱ-Ⅲ colon cancer, and application value of a nomogram prediction model.Methods:The retrospective case-control study was conducted. The clinicopathological data of 228 patients with stage Ⅱ-Ⅲ colon cancer who underwent radical resection in the First Affiliated Hospital of Xi′an Jiaotong University from January 2013 to June 2016 were collected. There were 118 males and 110 females, aged from 25 to 87 years, with a median age of 62 years. All patients underwent open or laparoscopic-assisted radical resection of colon cancer. Observation indicators: (1) postoperative tumor recurrence; (2) risk factors analysis for tumor recurrence after radical resection of stage Ⅱ-Ⅲ colon cancer; (3) development and evaluation of a nomogram prediction model for tumor recurrence after radical resection of stage Ⅱ-Ⅲ colon cancer. Follow-up using outpatient examination and telephone interview was performed to detect postoperative 3-year tumor recurrence up to June 2019. Measurement data with skewed distribution were represented as M (range). Count data were described as absolute numbers, and comparison between groups was analyzed using the Pearson chi-square test or Fisher exact probability. Multivariate analysis was performed using Logistic stepwise regression analysis. The independent risk factors were included into R 3.6.1 software to construct a nomogram prediction model. The receiver operating characteristic curve (ROC) was drawed, and the area under curve (AUC) was used to evaluate discrimination of the nomogram prediction model. The calibration chart with R software was used to evaluate consistency of the nomogram prediction model. Results:(1)Postoperative tumor recurrence: 53 of 228 patients had postoperative tumor recurrence including 19 cases with locoregional recurrence and 34 cases with distant metastasis. Of the 34 patients with distant metastasis, there were 14 cases with liver metastasis, 7 cases with lung metastasis, 4 cases with brain metastasis, and 9 cases with multiple metastasis or isolated metastasis in other sites. The time to recurrence was 12 months (range, 6-19 months). (2) Risk factors analysis for tumor recurrence after radical resection of stage Ⅱ-Ⅲ colon cancer:results of univariate analysis showed that bowel obstruction, preoperative carcinoembryonic antigen (CEA) level, ascites, vascular invasion were related factors for tumor recurrence after radical resection of stage Ⅱ-Ⅲ colon cancer ( χ2=4.463, 13.622, 10.914, 5.911, P<0.05). Pathological N stage was also a related factor for tumor recurrence after radical resection of stage Ⅱ-Ⅲ colon cancer ( P<0.05). Results of multivariate analysis showed that preoperative CEA level >5 μg/L, ascites, vascular invasion and pathological N stage as stage N1 or N2 were independent risk factors for tumor recurrence after radical resection of stage Ⅱ-Ⅲ colon cancer ( odds ratio=3.129, 3.071, 7.634, 3.439, 15.467, 95% confidence interval as 1.328-7.373, 1.047-9.007, 1.103-52.824, 1.422-8.319, 3.498-68.397, P<0.05). (3) Development and evaluation of a nomogram prediction model for tumor recurrence after radical resection of stage Ⅱ-Ⅲ colon cancer: based on preoperative CEA level, ascites, vascular invasion and pathological N stage of multivariate analysis, a nomogram prediction model for tumor recurrence after radical resection of stage Ⅱ-Ⅲ colon cancer was developed using R 3.6.1 software. The nomogram score was 41.7 for preoperative CEA level >5 μg/L, 41.0 for ascites, 74.2 for vascular invasion, 45.1 and 100.0 for pathological N stage as stage N1 and N2, respectively. The total of different scores for risk factors corresponded to the probability of postoperative recurrence. The ROC of nomogram for recurrence after radical resection of stage Ⅱ-Ⅲ colon cancer was drawed,with the AUC of 0.805(95% confidence interval as 0.737-0.873, P<0.05). The calibration chart showed a good consistency between the probability of recurrence after radical resection of stage Ⅱ-Ⅲ colon cancer predicted by nomogram and the actual probability of postoperative recurrence. Conclusions:Preoperative CEA level >5 μg/L, ascites, vascular invasion and pathological N stage as stage N1 or N2 are independent risk factors for tumor recurrence after radical resection of stage Ⅱ-Ⅲ colon cancer. The nomogram prediction model contributes to prediction of the recurrent risks after radical resection of stage Ⅱ-Ⅲ colon cancer.

BACKGROUNDGastric neuroendocrine carcinomas (g-NECs) are rare tumors that have aggressive biological behaviors and poor prognosis, but the prognostic factors of postoperative patients with g-NEC are still unclear. Our aim was to study and explore the clinical characteristics and prognostic factors of patients with g-NEC treated with radical surgery.

METHODSThe clinical data of 43 g-NEC patients who underwent surgery from January 2002 to January 2011 at the Zhongshan Hospital of Fudan University were analyzed. Follow-up was conducted by telephone, mail, or returning visit survey.

RESULTSThe sizes of the 43 neuroendocrine carcinomas (G3) were 1.5 cm × 1.5 cm × 0.5 cm to 7 cm × 8 cm × 1.5 cm. Eight NECs were localized, and 35 had lymph node involvement, of which 1 also had hepatic metastasis. At the end of the follow-up, the follow-up rate was 97.7% (42/43), and the median follow-up time was 22.2 months. The median overall survival of g-NEC patients was 36.5 months, and the 1-, 3-, and 5-year overall survival rates were 86.0%, 51.6%, and 36.7%, respectively. Sex (P < 0.05) and lymph node involvement (P < 0.05) were prognostic factors of postoperative g-NEC patients, among which sex was an independent prognostic factor (P < 0.05), as a survival advantage of female patients over male was observed.

CONCLUSIONSMost of the g-NECs were diagnosed at an advanced stage. The prognosis of g-NECs was related with sex and lymph node involvement, of which sex was an independent prognostic factor, with female patients having a survival advantage.

Aged ; Aged, 80 and over ; Carcinoma, Neuroendocrine ; surgery ; Female ; Humans ; Male ; Middle Aged ; Prognosis ; Stomach Neoplasms ; surgery ; Survival Analysis

Objective To investigate the diagnosis and treatment of anaplastic carcinoma of the pancreas.Methods The clinical data of 10 patients with anaplastic carcinoma of the pancreas who were admitted to the Zhongshan Hospital from January 1999 to June 2010 were retrospectively analyzed.Computed tomography was carried out preoperatively and surgical plan was designed according to the site of tumors.Chemoradiotherapy was applied postoperatively.Patients were followed up till March 2012 by phone call and out-patient examination.The clinical and imaging features,pathological characteristics,treatment and follow-up data were analyzed.The clinical and pathological features were analyzed by descriptive statistics.The continuous data were described as (x) ± s,and categorical data were presented by frequency and precentage.Results The tumors located at the head of the pancreas were observed in 5 patients,tumor located at the neck of the pancreas in 1 patient,and tumors located at the body and tail of the pancreas in 4 patients.Two patients underwent pancreaticoduodenectomy (PD),2 underwent PD + extended lymph node dissection,1 underwent PD + portal vein reconstruction,1 underwent pancreatectomy,4 underwent resection of body and tail of pancreas and splenectomy.The size of the tumors ranged from 2.0 cm × 2.0 cm × 2.0 cm to 14.0 cm × 12.0 cm × 9.0 cm.Duodenal and biliary invasion was observed in 4 patients,superior mesenteric vein-portal vein invasion in 1 patient,splenic artery invasion in 1 patient.Neural invasion was observed in 8 patients,including 4 patients with lymph node metastasis.The results of immunohistochemical staining showed that 10 patients were with positive expression of cytokeratin 7,and 1 patient was with positive expression of vimentin.Nine patients were followed up,2 patients did not receive postoperative chemoradiotherapy,6 received chemotherapy with Gemicitabine and 1 received interventional treatment.The survival time of the 9 patients ranged from 8 to 20 months,and the median survival time was 12 months.Eight patients died of tumor recurrence and metastasis.Conclusions Pancreatic anaplastic carcinoma is a distinct rare variant of pancreatic ductal adenocarcinoma.Pancreatic anaplastic carcinoma has high malignancy,definite diagnosis depends on pathological examination,and the surgical plan should be made according to the result of imaging examination.Conventional radiotherapy and chemotherapy are ineffective for the treatment of this disease.