Humans ; Lung Transplantation/adverse effects* ; Risk Factors

The lysosome is responsible for protein and organelle degradation and homeostasis and the cathepsins play a key role in maintaining protein quality control. Cathepsin D (CTSD), is one such lysosomal protease, which when deficient in humans lead to neurolipofuscinosis (NCL) and is important in removing toxic protein aggregates. Prior studies demonstrated that CTSD germ-line knockout-CtsdKO (CDKO) resulted in accumulation of protein aggregates, decreased proteasomal activities, and postnatal lethality on Day 26 ± 1. Overexpression of wildtype CTSD, but not cathepsin B, L or mutant CTSD, decreased α-synuclein toxicity in worms and mammalian cells. In this study we generated a mouse line expressing human CTSD with a floxed STOP cassette between the ubiquitous CAG promoter and the cDNA. After crossing with Nestin-cre, the STOP cassette is deleted in NESTIN + cells to allow CTSD overexpression-CTSDtg (CDtg). The CDtg mice exhibited normal behavior and similar sensitivity to sub-chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced neurodegeneration. By breeding CDtg mice with CDKO mice, we found that over-expression of CTSD extended the lifespan of the CDKO mice, partially rescued proteasomal deficits and the accumulation of Aβ42 in the CDKO. This new transgenic mouse provides supports for the key role of CTSD in protecting against proteotoxicity and offers a new model to study the role of CTSD enhancement in vivo.

Purinergic P2Y Receptor Antagonists ; Consensus ; Cardiovascular System ; Cardiology ; Asia

The advantages of lymph node dissection through total laparoscopic total gastrectomy (TLTG) seem to be more and more accepted by the academic community. However, reconstruction of digestive tract is challenging and remains a focus of debate and research. Which way is better for esophagojejunostomy, circular stapler or linear stapler,remains to be answered. The authors believe that, under the conditions of existing anastomosis instruments, using of linear stapler for esophagojejunal side-to-side anastomosis may be the most common choice, but it must be used with strict indications, because there are still many problems to be solved. It is believed that with the breakthrough in the development of the circular stapler suitable for esophagojejunostomy in TLTG, the application of circular stapler for digestive tract reconstruction will become the mainstream again in future. Thus, the current routine clinical practice of TLTG should be cautious and the surgical indications should be strictly evaluated.
Humans ; Laparoscopy ; Stomach Neoplasms/pathology* ; Anastomosis, Surgical ; Esophagoplasty ; Gastrectomy ; Retrospective Studies

Objective: To investigate the safety and efficacy of laparoscopic surgery in locally advanced gastric cancer patients with neoadjuvant SOX chemotherapy combined with PD-1 inhibitor immunotherapy. Methods: Between November 2020 and April 2021, patients with locally advanced gastric cancer who were admitted to the Union Hospital of Tongji Medical College of Huazhong University of Science and Technology were prospectively enrolled in this study. Inclusion criteria were: (1) patients who signed the informed consent form voluntarily before participating in the study; (2) age ranging from 18 to 75 years; (3) patients staged preoperatively as cT3-4N+M0 by the TNM staging system; (4) Eastern Collaborative Oncology Group score of 0-1; (5) estimated survival of more than 6 months, with the possibility of performing R0 resection for curative purposes; (6) sufficient organ and bone marrow function within 7 days before enrollment; and (7) complete gastric D2 radical surgery. Exclusion criteria were: (1) history of anti-PD-1 or PD-L1 antibody therapy and chemotherapy; (2) treatment with corticosteroids or other immunosuppre- ssants within 14 days before enrollment; (3) active period of autoimmune disease or interstitial pneumonia; (4) history of other malignant tumors; (5) surgery performed within 28 days before enrollment; and (6) allergy to the drug ingredients of the study. Follow-up was conducted by outpatient and telephone methods. During preoperative SOX chemotherapy combined with PD-1 inhibitor immunotherapy, follow-up was conducted every 3 weeks to understand the occurrence of adverse reactions of the patients; follow-up was conducted once after 1 month of surgical treatment to understand the adverse reactions and survival of patients. Observation indicators were: (1) condition of enrolled patients; (2) reassessment after preoperative therapy and operation received (3) postoperative conditions and pathological results. Evaluation criteria were: (1) tumor staged according to the 8th edition of the American Joint Committee on Cancer (AJCC) TNM staging system; (2) tumor regression grading (TRG) of pathological results were evaluated with reference to AJCC standards; (3) treatment-related adverse reactions were evaluated according to version 5.0 of the Common Terminology Criteria for Adverse Events; (4) tumor response was evaluated by CT before and after treatment with RECIST V1.1 criteria; and (5) Clavien-Dindo complication grading system was used for postoperative complications assessment. Results: A total of 30 eligible patients were included. There were 25 males and 5 females with a median age of 60.5 (35-74) years. The primary tumor was located in the gastroesophageal junction in 12 cases, in the upper stomach in 8, in the middle stomach in 7, and in the lower stomach in 3. The preoperative clinical stage of 30 cases was III. Twenty-one patients experienced adverse reactions during neoadjuvant chemotherapy combined with immunotherapy, including four cases of CTCAE grade 3-4 adverse reactions resulting in bone marrow suppression and thoracic aortic thrombosis. All cases of adverse reactions were alleviated or disappeared after active symptomatic treatment. Among the 30 patients who underwent surgery, the time from chemotherapy combined with immunotherapy to surgery was 28 (23-49) days. All 30 patients underwent laparoscopic radical gastrectomy, of which 20 patients underwent laparoscopic-assisted radical gastric cancer resection; 10 patients underwent total gastrectomy for gastric cancer, combined with splenectomy in 1 case and cholecystectomy in 1 case. The surgery time was (239.9±67.0) min, intraoperative blood loss was 84 (10-400) ml, and the length of the incision was 7 (3-12) cm. The degree of adenocarcinoma was poorly differentiated in 18 cases, moderately differentiated in 12 cases, nerve invasion in 11 cases, and vascular invasion in 6 cases. The number lymph nodes that underwent dissection was 30 (17-58). The first of gas passage, the first postoperative defecation time, the postoperative liquid diet time, and the postoperative hospitalization time of 30 patients was 3 (2-6) d, 3 (2-13) d, 5 (3-12) d, and 10 (7-27) d, respectively. Postoperative complications occurred in 23 of 30 patients, including 7 cases of complications of Clavien-Dindo grade IIIa or above. Six patients improved after treatment and were discharged from hospital, while 1 patient died 27 days after surgery due to granulocyte deficiency, anemia, bilateral lung infection, and respiratory distress syndrome. The remaining 29 patients had no surgery-related morbidity or mortality within 30 days of discharge. Postoperative pathological examination showed TRG grades 0, 1, 2, and 3 in 8, 9, 4, and 9 cases, respectively, and the number of postoperative pathological TNM stages 0, I, II, and III was 8, 7, 8, and 7 cases, respectively. The pCR rate was 25.0% (8/32). Conclusion: Laparoscopic surgery after neoadjuvant SOX chemotherapy combined with PD-1 inhibitor immunotherapy for locally advanced gastric cancer is safe and feasible, with satisfactory short-term efficacy. Early detection and timely treatment of related complications are important.
Male ; Female ; Humans ; Middle Aged ; Aged ; Adolescent ; Young Adult ; Adult ; Stomach Neoplasms/pathology* ; Neoadjuvant Therapy ; Immune Checkpoint Inhibitors ; Gastrectomy/methods* ; Esophagogastric Junction/pathology* ; Laparoscopy ; Immunotherapy ; Postoperative Complications ; Retrospective Studies ; Treatment Outcome

Objective: To clarify the values of autotaxin (ATX) in patients with primary biliary cholangitis (PBC) and PBC-related hepatocellular carcinoma (HCC). Methods: 179 patients with PBC were selected from prospective cohorts of autoimmune liver diseases at the time of first diagnosis of PBC in Department of Hepatology, the Fifth Medical Center of PLA General Hospital, from January 2016 to January 2018, all patients with PBC received UDCA therapy, primary endpoint was event of HCC, the follow-up period was censored at the date of HCC. The relationship between level of ATX and clinical features in patients with PBC and its potential value in predicting disease progression and PBC-related HCC were analyzed. Results: The ATX level in the peripheral blood of patients with PBC was significantly higher than that of alcoholic liver cirrhosis(ALC) (t = 3.278, P = 0.001) and healthy controls(HC) (t = 6.594, P < 0.001), however, when comparing PBC to non-PBC related HCC, no significant difference was found between the groups(t=-0.240, P = 0.811). Consistent with peripheral blood levels, histochemical staining indicated that ATX in the liver of patients with PBC was significantly higher than that of HC (Z=-3.633, P < 0.001) and ALC (Z=-3.283, P < 0.001), and the expression of ATX in PBC with advanced histological stage was significantly higher than PBC with early stage (Z=-2.018, P = 0.034). The baseline ATX level in PBC patients without developing to HCC during follow-up had significant difference to patients with developing to HCC (228.451 ± 124.093 ng/ml vs 301.583 ± 100.512 ng/ml, t = 2.339, P = 0.021). The result in multivariate logistic regression analysis showed that ATX were independent predictors of PBC related HCC(OR 1.245, 95%CI 1.097-1.413). The optimal critical value of peripheral blood ATX level at baseline for predicting HCC was 235.254 ng/ml, with the cut-off value of 0.714 in AUC of the ROC (95% CI was 0.597~ 0.857), sensitivity and specificity were 84.6% and 59.0%, respectively. Conclusion: ATX level was significantly higher in PBC patients over controls, and it's concentration was correlated with UDCA efficacy and fibrosis stage. ATX has potential values in predicting disease progression and PBC-related HCC.

Humans ; Solitary Fibrous Tumors/pathology* ; Osteosarcoma/pathology* ; Fibrosarcoma ; Bone Neoplasms/surgery*

Humans ; Lung Neoplasms/pathology* ; Adenocarcinoma/pathology* ; Papilloma/genetics* ; Receptor, Fibroblast Growth Factor, Type 1/metabolism* ; Gene Amplification ; Carrier Proteins ; Cytoskeletal Proteins

Humans ; Thyroid Cancer, Papillary ; Neck/pathology* ; Lymph Nodes/pathology* ; Thyroid Neoplasms/pathology* ; Lymphoma, T-Cell/pathology*

Objective: To investigate the evolution and clinical significance of HER2 low expression status in HER2 negative patients in primary and recurrent/metastatic breast cancers. Methods: The data and archived sections of 259 breast cancer patients with recurrence/metastasis and HER2-negative primary foci were collected from January 2015 to January 2022 at the Fourth Hospital of Hebei Medical University, and the HER2 status of primary and recurrence/metastasis foci was determined by immunohistochemistry (IHC), among which IHC 2+patients were subject to fluorescence in situ hybridization (FISH). The HER2 status was classified as HER2-0 group; patients with IHC 1+, IHC 2+and no FISH amplification were classified as HER2 low expression group; and patients with IHC 3+, IHC 2+and FISH amplified were classified as HER2-positive group. The changes of HER2 status in patients with HER2 low expression in primary versus recurrent/metastatic breast cancer foci were compared, and their clinicopathologic characteristics and prognosis were analyzed. Results: The overall concordance rate between primary and recurrent/metastatic HER2 status in breast cancer was 60.6% (157/259, κ=0.178). A total of 102 patients (102/259, 39.4%) had inconsistent primary and recurrent/metastatic HER2 status; 37 patients (37/259, 14.3%) had HER2-0 at the primary foci and HER2-low expression at the recurrent/metastatic; and 56 patients (56/259, 21.6%) had HER2-low expression in the primary foci and HER2-0 in the recurrent/metastatic. The recurrent/metastatic foci became low-expressing compared with the recurrent/metastatic foci which remained HER2-0 patients, with longer overall survival time, higher ER and PR positivity, lower Ki-67 positivity index, and lower tumor histological grade; all with statistically significant differences (all P<0.05). In the primary HER2-low group, patients with recurrent/metastatic foci became HER2-0 while those with recurrent/metastatic foci remained low expression; there were no statistically significant differences in clinicopathological features and overall survival time (all P>0.05). Conclusions: Unstable HER2 status in patients with HER2-0 and low expression in primary versus recurrent/metastatic breast cancer foci, and HER2-0 in the primary foci but low HER2 expression status in recurrence/metastasis is associated with favourable prognosis, and testing HER2 status in recurrence/metastasis can provide more treatment options for such patients.
Humans ; Breast Neoplasms/genetics* ; Clinical Relevance ; In Situ Hybridization, Fluorescence ; Female