Pancreatic ductal adenocarcinoma(PDAC)is one of the leading causes of cancer-related mortality worldwide,but current clinical methods lack effective screening and treatment options.Despite the widespread use of gemcitabine as a first-line chemotherapeutic agent in the treatment of PDAC over the past decade,its efficacy is limited by the development of drug resistance,which significantly shortens patient survival.This review systematically elucidates the critical role of the tumor microenvironment in the development of gemcitabine resistance of PDAC cells,highlighting the contributions of the extracellular matrix barrier,hypoxia-induced adaptive changes in cancer cells,and the formation of an immunosuppressive microenvironment as key factors in gemcitabine resistance.Additionally,we also introduce novel strategies for reversing chemoresistance,including advanced drug delivery systems,and provide a comprehensive overview of the current opportunities and challenges.

ObjectiveTo investigate whether there exists gender differences in mechanical pain hypersensitivity induced by the subcutaneous injection of macrophage colony-stimulating factor （M-CSF） in normal mice and to explore the preliminary mechanism. MethodsThirty 10-week-old C57BL/6J mice were randomly divided into three groups， (n = 10 mice/group, half male and half female). The albumin control group （BSA， 0.3 μg）， low dose M-CSF group （L M-CSF， 0.075 μg） and high dose M-CSF group （H M-CSF， 0.3 μg） received 50 μL BSA or M-CSF injected subcutaneously into the left medial thigh once daily for 3 consecutive days. Before and after drug administration， von-Frey mechanical sensitivity test was used to detect the mechanical paw withdrawal threshold （PWT） in each group. Immunofluorescence was performed to examine the expression changes of Ionized calcium-binding adaptor molecule 1 (Iba1) in skin， calcitonin gene-related peptide （CGRP） and phosphorylated ERK1/2 （p-ERK） in L5-L6 DRG and lumbar spinal dorsal horn. ResultsIn female mice， only high dose of M-CSF caused mechanical allodynia， whereas in male mice both doses produced marked allodynia. Mechanically， high-dose M-CSF induced massive aggregation of subcutaneous macrophages （marked by Iba1） in male and female mice， but more dramatic dependence in female mice. Similar gender differences were also found in the increase of p-ERK and CGRP expression in dorsal root ganglion （DRGs）. Notably， CGRP expression was especially elevated in the fibers of DRG in male mice. Correspondingly， the expressions of p-ERK and CGRP⁺ terminals in the superficial spinal dorsal horn of male mice were significantly higher than those of female mice after M-CSF treatment. ConclusionSubcutaneous injection of M-CSF triggers sexual dimorphism in mechanical pain hypersensitivity, which is related with differential changes in peripheral macrophage expansion and sensitization of the nociceptive pathway.

Objective: To explore the application and efficacy of paclitaxel liposome in the treatment of advanced breast cancer among Chinese population in the real world. Methods: The clinical characteristics of patients with advanced breast cancer who received paclitaxel liposome as salvage treatment from January 1, 2016 to August 31, 2019 in 11 hospitals were collected and retrospectively analyzed. The primary outcome was progression free survival (PFS), and the secondary outcome included objective response rate (ORR) and safety. The survival curve was drawn by Kaplan-Meier analysis and the Cox regression model were used for the multivariate analysis. Results: Among 647 patients with advanced breast cancer who received paclitaxel liposome, the first-line treatment accounted for 43.3% (280/647), the second-line treatment accounted for 27.7% (179/647), and the third-line and above treatment accounted for 29.1% (188/647). The median dose of first-line and second-line treatment was 260 mg per cycle, and 240 mg in third line and above treatment. The median period of paclitaxel liposome alone and combined chemotherapy or targeted therapy is 4 cycles and 6 cycles, respectively. In the whole group, 167 patients (25.8%) were treated with paclitaxel liposome combined with capecitabine±trastuzumab (TX±H), 123 patients (19.0%) were treated with paclitaxel liposome alone (T), and 119 patients (18.4%) were treated with paclitaxel liposome combined with platinum ± trastuzumab (TP±H), 108 patients (16.7%) were treated with paclitaxel liposome combined with trastuzumab ± pertuzumab (TH±P). The median PFS of first-line and second-line patients (5.5 and 5.5 months, respectively) were longer than that of patients treated with third line and above (4.9 months, P<0.05); The ORR of the first line, second line, third line and above patients were 46.7%, 36.8% and 28.2%, respectively. Multivariate analysis showed that event-free survival (EFS) and the number of treatment lines were independent prognostic factors for PFS. The common adverse events were myelosuppression, gastrointestinal reactions, hand foot syndrome and abnormal liver function. Conclusion: Paclitaxel liposomes is widely used and has promising efficacy in multi-subtype advanced breast cancer.
Humans ; Female ; Breast Neoplasms/chemically induced* ; Paclitaxel/adverse effects* ; Liposomes/therapeutic use* ; Retrospective Studies ; Treatment Outcome ; Trastuzumab/therapeutic use* ; Capecitabine/therapeutic use* ; Antineoplastic Combined Chemotherapy Protocols/adverse effects*

Objective: The investigate the effects and mechanism of exosomes derived from human umbilical vein endothelial cells (HUVECs) on wound healing in diabetes rabbits. Methods: The experimental research methods were used. The primary vascular endothelial cells (VECs) and human skin fibroblasts (HSFs) were extracted from skin tissue around ulcer by surgical excision of two patients with diabetic ulcer (the male aged 49 years and the female aged 58 years) admitted to Xiangya Third Hospital of Central South University in June 2019. The cells were successfully identified through morphological observation and flow cytometry. The HUVEC exosomes were extracted by ultracentrifugation and identified successfully by morphological observation, particle size detection, and Western blotting detection. Twenty female 3-month-old New Zealand rabbits were taken to create one type 2 diabetic full-thickness skin defect wound respectively on both sides of the back. The wounds were divided into exosomes group and phosphate buffer solution (PBS) group and treated accordingly, with 20 wounds in each group, the time of complete tissue coverage of wound was recorded. On PID 14, hematoxylin-eosin staining or Masson staining was performed to observe angiogenesis or collagen fiber hyperplasia (n=20). The VECs and HSFs were co-cultured with HUVEC exosomes for 24 h to observe the uptake of HUVEC exosomes by the two kinds of cells. The VECs and HSFs were divided to exosome group treated with HUVEC exosomes and PBS group treated with PBS to detect the cell proliferation on 4 d of culture with cell count kit 8, to detect and calculate the cell migration rate at 24 and 48 h after scratch by scratch test, to detect the cell migration number at 24 h of culture with Transwell test, and to detect the mRNA expressions of nuclear factor-erythroid 2-related factor 2 (NRF2) and transcription activating factor 3 (ATF3) by real time fluorescence quantitative reverse transcription polymerase chain reaction. Besides, the number of vascular branches and vascular length were observed in the tube forming experiment after 12 h of culture of VECs (n=3). The VECs and HSFs were taken and divided into PBS group and exosome group treated as before, and NRF2 interference group, ATF3 interference group, and no-load interference group with corresponding gene interference. The proliferation and migration of the two kinds of cells, and angiogenesis of VECs were detected as before (n=3). Data were statistically analyzed with analysis of variance for repeated measurement, one-way analysis of variance, independent sample t test, and least significant difference test. Results: The time of complete tissue coverage of wound in exosome group was (17.9±1.9) d, which was significantly shorter than (25.2±2.3) d in PBS group (t=4.54, P<0.05). On PID14, the vascular density of wound in PBS group was significantly lower than that in exosome group (t=10.12, P<0.01), and the collagen fiber hyperplasia was less than that in exosome group. After 24 h of culture, HUVEC exosomes were successfully absorbed by VECs and HSFs. The proliferative activity of HSFs and VECs in exosome group was significantly higher than that in PBS group after 4 d of culture (with t values of 54.73 and 7.05, respectively, P<0.01). At 24 and 48 h after scratch, the migration rates of HSFs (with t values of 3.42 and 11.87, respectively, P<0.05 or P<0.01) and VECs (with t values of 21.42 and 5.49, respectively, P<0.05 or P<0.01) in exosome group were significantly higher than those in PBS group. After 24 h of culture, the migration numbers of VECs and HSFs in exosome group were significantly higher than those in PBS group (with t values of 12.31 and 16.78, respectively, P<0.01). After 12 h of culture, the mRNA expressions of NRF2 in HSFs and VECs in exosome group were significantly higher than those in PBS group (with t values of 7.52 and 5.78, respectively, P<0.05 or P<0.01), and the mRNA expressions of ATF3 were significantly lower than those in PBS group (with t values of 13.44 and 8.99, respectively, P<0.01). After 12 h of culture, the number of vascular branches of VECs in exosome group was significantly more than that in PBS group (t=17.60, P<0.01), and the vascular length was significantly longer than that in PBS group (t=77.30, P<0.01). After 4 d of culture, the proliferation activity of HSFs and VECs in NRF2 interference group was significantly lower than that in PBS group and exosome group (P<0.05 or P<0.01); the proliferation activity of HSFs and VECs in ATF3 interference group was significantly higher than that in PBS group (P<0.05 or P<0.01) and significantly lower than that in exosome group (P<0.05 or P<0.01). At 24 and 48 h after scratch, the migration rates of HSFs and VECs in ATF3 interference group were significantly higher than those in PBS group (P<0.05 or P<0.01) and significantly lower than those in exosome group (P<0.05 or P<0.01). At 24 and 48 h after scratch, the migration rates of HSFs and VECs in NRF2 interference group were significantly lower than those in PBS group and exosome group (P<0.05 or P<0.01). After 24 h of culture, the migration numbers of VECs and HSFs in ATF3 interference group were significantly more than those in PBS group (P<0.05) and significantly less than those in exosome group (P<0.05 or P<0.01); the migration numbers of VECs and HSFs in NRF2 interference group were significantly less than those in PBS group and exosome group (P<0.01). After 12 h of culture, the vascular length and number of branches of VECs in NRF2 interference group were significantly decreased compared with those in PBS group and exosome group (P<0.01); the vascular length and number of branches of VECs in ATF3 interference group were significantly increased compared with those in PBS group (P<0.01) and were significantly decreased compared with those in exosome group (P<0.01). Conclusions: HUVEC exosomes can promote the wound healing of diabetic rabbits by promoting the proliferation and migration of VECs and HSFs, and NRF2 and ATF3 are obviously affected by exosomes in this process, which are the possible targets of exosome action.
Animals ; Female ; Humans ; Male ; Rabbits ; Collagen/metabolism* ; Diabetes Mellitus ; Exosomes/metabolism* ; Human Umbilical Vein Endothelial Cells ; Hyperplasia/metabolism* ; NF-E2-Related Factor 2/metabolism* ; RNA, Messenger/metabolism* ; Ulcer ; Wound Healing ; Middle Aged

ObjectiveTo explore whether acrolein can induce ferroptosis in vitro and in vivo. MethodsHT22 cells were treated with acrolein and then incubated with ferroptosis inhibitor ferrostatin-1 （Fer-1） and deferoxamine （DFO）. MTT assay was used to detect the cell survival rate. Dihydroethidium （DHE） and FerroOrange probes were used to detect the contents of free radicals and ferrous ions in cells. A transmission electron microscope observed the structure of mitochondria in standard and acrolein groups. Western blot was used to detect the levels of ferroptosis-related proteins GPX4， COX-2， and FTH1 in vitro. In vivo， male C57BL/6 mice were given 3 mg/kg acrolein every day at the age of 7-8 weeks for 1， 2， and 4 weeks， and the levels of ferroptosis-related proteins GPX4， COX-2， and FTH1 in the hippocampus was detected by western blot. ResultsAcrolein significantly reduced the survival rate of HT22 cells and induced mitochondrial shrinkage， and decreased the number of cristae. Meanwhile， acrolein could remarkably increase intracellular free radical and ferrous ions. In addition， acrolein promoted the increase in the expression of Cyclooxygenase-2 （COX-2） and Ferritin Heavy Chain 1 （FTH1） at the cellular level and decreased the expression of Glutathione peroxidase 4 （GPX4）. At the animal level， acrolein promoted the increase of COX-2 expression and decreased the expressions of GPX4 and FTH1. ConclusionAcrolein induced neuronal ferroptosis in vitro and in vivo， suggesting ferroptosis inhibitors could attenuate acrolein-associated diseases in CNS， such as Alzheimer's disease.

BACKGROUND: The ongoing new coronavirus pneumonia (Corona Virus Disease 2019, COVID-19) outbreak is spreading in China, but it has not yet reached its peak. Five million people emigrated from Wuhan before lockdown, potentially representing a source of virus infection. Determining case distribution and its correlation with population emigration from Wuhan in the early stage of the epidemic is of great importance for early warning and for the prevention of future outbreaks. METHODS: The official case report on the COVID-19 epidemic was collected as of January 30, 2020. Time and location information on COVID-19 cases was extracted and analyzed using ArcGIS and WinBUGS software. Data on population migration from Wuhan city and Hubei province were extracted from Baidu Qianxi, and their correlation with the number of cases was analyzed. RESULTS: The COVID-19 confirmed and death cases in Hubei province accounted for 59.91% (5806/9692) and 95.77% (204/213) of the total cases in China, respectively. Hot spot provinces included Sichuan and Yunnan, which are adjacent to Hubei. The time risk of Hubei province on the following day was 1.960 times that on the previous day. The number of cases in some cities was relatively low, but the time risk appeared to be continuously rising. The correlation coefficient between the provincial number of cases and emigration from Wuhan was up to 0.943. The lockdown of 17 cities in Hubei province and the implementation of nationwide control measures efficiently prevented an exponential growth in the number of cases. CONCLUSIONS The population that emigrated from Wuhan was the main infection source in other cities and provinces. Some cities with a low number of cases showed a rapid increase in case load. Owing to the upcoming Spring Festival return wave, understanding the risk trends in different regions is crucial to ensure preparedness at both the individual and organization levels and to prevent new outbreaks.
Betacoronavirus ; China ; epidemiology ; Coronavirus Infections ; epidemiology ; Emigration and Immigration ; Epidemics ; Humans ; Pandemics ; Pneumonia, Viral ; epidemiology

Betacoronavirus ; Coronavirus Infections ; epidemiology ; transmission ; Disease Outbreaks ; Humans ; Pandemics ; Pneumonia, Viral ; epidemiology ; transmission ; Severe Acute Respiratory Syndrome ; epidemiology

This study aimed to explore the main active ingredients and potential targets of Solanum nigrum(SN), so as to reveal the potential molecular mechanism of SN in the treatment of hepatocellular carcinoma(HCC) based on network pharmacology and molecular docking. First,the main active ingredients and predictive targets of SN were collected in the traditional Chinese medicine systems pharmacology database and analysis platform(TCMSP). Then,the targets relating to HCC were collected through retrieval of integrated bio-pharmacological network database for traditional Korean medicine(PharmDB-K), oncogenomic database of hepatocellular carcinoma(OncoDB.hcc). The common targets of disease-drug component were selected through intersection between predictive targets and disease targets. Next, based on the String platform, protein-protein interaction network(PPI) model of the potential anti-HCC targets was constructed using the software Cytoscape 3.7.1. ClueGO and CluePedia APP in Cytoscape were used to analyze the gene function of SN in the treatment of HCC, and construct the main active ingredients-potential targets-signal pathways topology network of SN. Finally,DISCOVERY STUDIO software was applied in verifying the molecular docking between the key active ingredient and potential protein target. The results showed that there were 4 main active ingredients of SN, involving 22 potential targets relating to HCC and 7 signal pathways relating to potential anti-HCC targets of SN. Network analysis showed that SN may play a therapeutic role in HCC by acting on key targets, such as EGFR, TP53, MYC, CCND1 and CTNNB1. Molecular docking results showed that quercetin and EGFR could bind stably and interact through amino acid residues LEU718, LYS745 and GLN791. This study revealed the potential active ingredients and the possible molecular mechanism of SN for treatment of HCC, providing scientific basis for follow-up exploration of the molecular mechanism of SN against HCC.
Carcinoma, Hepatocellular/drug therapy* ; Drugs, Chinese Herbal/pharmacology* ; Humans ; Liver Neoplasms/drug therapy* ; Molecular Docking Simulation ; Solanum nigrum/chemistry*

【Objective】 To summarize the CT and MRI imaging features of gallbladder neuroendocrine tumor.【Methods】 CT and MRI data of 10 patients with gallbladder neuroendocrine tumors proven by surgical pathology between January 2010 and May 2018 were retrospectively analyzed. Among them，6 patients underwent CT examination，3 underwent MRI examination，and 1 patient underwent both CT and MRI examinations. The size，morphologic features and contrast enhancement pattern of gallbladder tumors，and the presence of liver metastasis，bile duct and perihepatic metastasis，lymph node metastasis，and the presence of gallbladder stone were assessed.【Results】Among these 10 cases of gallbladder neuroendocrine tumor，the largest dimension of tumors ranged from 39 mm to 120 mm. The tumors manifest? ed as a mass protruding into the lumen with a broad base adhering to the wall of the gallbladder. In 7 patients who had undergone CT examination，the tumors manifested as an irregular mass with soft tissue density on CT. In 4 patients who had undergone MRI，the tumors showed homogeneous iso-intense signal on T1-weightedimaging，heterogenous hyper-intense signal on T2- weighted imaging，and limited diffusion on diffusion- weighted imaging. All tumors in 10 patients showed moderate，heterogeneous and persistent enhancement. Eight patients had liver metastasis，among whom 7 had metastases in liver segments 4 and 5，and 1 had multiple metastases in other liver segments. Six patients had bile duct invasion and 3 had hilar fat invasion. Seven patients had lymph node metastasis. One patient had gallstone.【Conclusion】Gallbladder neuroendocrine tumor has certain characteristic CT and MRI findings，such as a large mass in gallbladder，which tends to invade adjacent liver parenchyma，and extend along gallbladder neck and gallbladder ducts，accompanied with hepatic portal and retroperitoneal lymph node metastasis，and hilar fat invasion.

OBJECTIVETo explore the anatomic features of mesoesophagus in combined thoracoscopic and laparoscopic esophagectomy with three-fields lymphadenectomy.

METHODSClinical data of 67 patients undergoing thoracoscopic and laparoscopic esophagectomy with three-fields lymphadenectomy from July 2011 to September 2012 were analyzed retrospectively. All the patients underwent three-fields lymphadenectomy. Proper surgical planes were selected according to anatomy of mesoesophagus. Thoracoscopic surgical space was bounded on azygotic vein and divided into upper and low esophageal triangle. Pancreas was the key anatomical mark for laparoscopic gastric dissection, and peripancreatic space was the natural laparoscopic surgical plane. Prevertebral fascia was bottom surface of neck dissection and carotid sheath was the boundary of two sides.

RESULTSThe median operative time was 251.6 min (range, 220 to 320 min). The median operative blood loss was 105.6 ml (range, 40 to 320 ml). The median number of lymph nodes dissected was 29.1 (range, 13 to 46, totally 1949). There was no perioperative death. Sixty-six patients were followed up with a mean follow-up time of 8.2 months (range, 2 to 14 months). Postoperative complications included reflux esophagitis in 10 and anastomotic stenosis in 3 cases.

CONCLUSIONIt is safe and more radical for minimally invasive esophagectomy that overall concept of minimally invasive anatomy of mesoesophagus is applied to identify the anatomic plane and landmark during operation.

Aged ; Esophageal Neoplasms ; pathology ; surgery ; Esophagectomy ; Esophagus ; anatomy & histology ; pathology ; Female ; Humans ; Lymph Node Excision ; Male ; Middle Aged ; Retrospective Studies