Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder worldwide, causing dementia and affecting millions of individuals. One prominent characteristic in the brains of AD patients is glucose hypometabolism. In the context of galactose metabolism, intracellular glucose levels are heightened. Galactose mutarotase (GALM) plays a crucial role in maintaining normal galactose metabolism by catalyzing the conversion of β-D-galactose into α-D-galactose (α-D-G). The latter is then converted into glucose-6-phosphate, improving glucose metabolism levels. However, the involvement of GALM in AD progression is still unclear. In the present study, we found that the expression of GALM was significantly increased in AD patients and model mice. Genetic knockdown of GALM using adeno-associated virus did not change the expression of amyloid precursor protein (APP) and APP-cleaving enzymes including a disintegrin and metalloprotease 10 (ADAM10), β-site APP-cleaving enzyme 1 (BACE1), and presenilin-1 (PS1). Interestingly, genetic overexpression of GALM reduced APP and Aβ deposition by increasing the maturation of ADAM10, although it did not alter the expression of BACE1 and PS1. Further electrophysiological and behavioral experiments showed that GALM overexpression significantly ameliorated the deficits in hippocampal CA1 long-term potentiation (LTP) and spatial learning and memory in AD model mice. Importantly, direct α-D-G (20 mg/kg, i.p.) also inhibited Aβ deposition by increasing the maturation of ADAM10, thereby improving hippocampal CA1 LTP and spatial learning and memory in AD model mice. Taken together, our results indicate that GALM shifts APP processing towards α-cleavage, preventing Aβ generation by increasing the level of mature ADAM10. These findings indicate that GALM may be a potential therapeutic target for AD, and α-D-G has the potential to be used as a dietary supplement for the prevention and treatment of AD.
Animals ; ADAM10 Protein/metabolism* ; Alzheimer Disease/pathology* ; Amyloid Precursor Protein Secretases/metabolism* ; Disease Models, Animal ; Humans ; Mice ; Amyloid beta-Peptides/metabolism* ; Male ; Mice, Transgenic ; Membrane Proteins/metabolism* ; Cognitive Dysfunction/pathology* ; Mice, Inbred C57BL ; Amyloid beta-Protein Precursor/metabolism* ; Female ; Hippocampus/metabolism* ; Long-Term Potentiation/physiology*

Objective:To explore the clinical features, histopathological morphology, and differential diagnosis of lymphoepithelioma-like carcinoma with abnormal expression of follicular dendritic cell markers.Methods:From 2020 to 2021, 4 cases of lymphoepithelioma-like carcinoma with abnormal expression of follicular dendritic cell markers diagnosed in Fujian Cancer Hospital (2 cases) and the Second Affiliated Hospital of Fujian Medical University (2 cases) were collected. Different ancillary procedures such as HE, special stains, immunohistochemistry, and in situ hybridization techniques were used to assess the histopathological features and immunophenotypes. The clinical data were collected and literature was reviewed.Results:All 4 cases of lymphoepithelioma-like carcinoma with abnormal expression of follicular dendritic cell markers were male. They were 32, 45, 67 and 39 years old, respectively. The main clinical manifestations were bloody phlegm, abdominal pain, fatigue and anorexia. The clinical stages at diagnosis were stage Ⅳ (3 cases) and stage Ⅱ (1 case). Cases 2 and 3 had two pathological examinations at different sites, with a total of six pathological examinations. The histomorphology showed singly scattered or nests of tumor cells in a background of abundant small lymphocytes. The tumor cells were enlarged and pleomorphic, some appeared polygonal with inconspicuous cell borders, and they were arranged in a syncytial pattern. There were megakaryocytes, multinucleated tumor cells, and a few spindle-shaped cells seen. Atypical mitosis was commonly noted. By immunohistochemistry, the tumor cells were positive for CKpan(5/6), CK8/18(4/4), CAM5.2(2/5), CK-H(0/4), CK-L(3/4), EMA(4/5), CK5/6(3/6), p63(1/6), p40(1/6), E-cadherin (4/6), SSTR2(6/6), PD-L1(5/5), LCA(0/6), vimentin(5/6), CD2 (6/6), CD23(6/6), CD35(5/6), CXCL-13(4/5) and D2-40(1/5). The Ki-67 proliferative index was 60%-95%. In situ hybridization for EBER were all positive (6/6). Special stain for reticulin showed positive staining surrounding nests of tumor cells.Conclusions:The expression of follicular dendritic cell markers in lymphoepithelioma-like carcinoma is very rare, which may be related to EBV infection. Occasionally, it can overlap with follicular dendritic cell sarcoma by morphology and immunophenotype, which can lead to misdiagnosis. Only by combining clinical information, morphological characteristics and immunophenotype can an appropriate diagnosis be made.

Purpose To investigate the expression of chromogranin A(CgA)in gastroenteropancreatic neuroendo-crine neoplasms(GEP-NENs)and its relationship with clinicopathological features.Methods The clinicopathological data of GEP-NENs diagnosed in the Department of Pathology,Beijing Chao-yang Hospital,Capital Medical University from May 2011 to December 2024 were retrospectively analyzed.Immunohistochemical staining was applied to evaluate the expression of CgA,and the patients were divided into CgA(+)group and CgA(-)group.Differences in clinico-pathological features between the 2 groups were compared.Results The age of 229 patients ranged from 21 to 89 years,with an average age of 54.4 years.The most common primary site was the rectum(56.8％,130/229),fol-lowed by the stomach(16.6％,38/229),pancreas(14.4％,33/229),small intestine(6.1％,14/229),and colon(6.1％,14/229).There were 206 cases of single lesion and 23 cases of multiple lesions(number of tumors ≥2).There were 153 cases of G1(66.8％),29 cases of G2(12.7％),7 cases of G3(3.1％),and 40 cases of neuroendocrine carcinoma(NEC,17.5％).The positive rates of CgA in G1,G2,G3,and NEC groups were 37.2％,75.8％,71.4％,and 65.0％,respectively,with statistically significant differences(P＜0.001).The positive rates of CgA in T1,T2,T3,and T4 were 37.2％,83.3％,75.9％,and 57.7％,respectively,with statistically significant differences(P＜0.001).There were significant differences in age,vascular invasion,lymph node metasta-sis,and number of tumors between CgA(+)group and CgA(-)group(P＜0.001),but there was no significant difference in sex,tumor location,Syn,and CD56 expression between the two groups(P=0.595,P=0.098,P=0.173,P=0.557).Conclusion Immunohistochemical antibody CgA is a useful marker for GEP-NENs.CgA positiv-ity may be a poor prognostic factor for GEP-NENs patients.

Purpose To investigate the independent risk factors for early papillary gastric adenocarcinoma(EP-GA)and construct a diagnostic nomogram.Methods A retrospective analysis was performed on the clinicopathologi-cal characteristics of 325 cases of early differentiated gastric adenocarcinoma.Taking EPGA as the case group and early well-moderately differentiated tubular gastric adenocarcinoma(ETGA)as the control group,the independent risk fac-tors for the occurrence of EPGA were identified through univariate and multivariate analyses,and a nomogram was con-structed.The diagnostic performance of the nomogram was evaluated using the receiver operating characteristic(ROC)curves,Hosmer-Lemeshow goodness-of-fit tests,and calibration curves.Results Among the 325 cases of early differ-entiated gastric adenocarcinoma,there were 121 cases of EPGA and 204 cases of ETGA.Univariate analysis showed that elevated appearance(56.3％),ulcer formation(11.5％),tumor maximum diameter of 2.15(1.60,3.00)cm,moderately-differentiated(55.2％),submucosal invasion(21.9％),lymphovascular invasion(10.4％),high ex-pression of MUC5AC(75.0％),microsatellite instability-high(15.6％),and wild-type expression of p53(59.4％)were significantly associated with an increased risk of EPGA.Multivariate analysis revealed that gross appearance,ul-cer formation,tumor maximum diameter,and the expression of MUC5AC was independent risk factors for EPGA.A di-agnostic nomogram was constructed,and the area under the ROC curve(AUC)was calculated.In the training and val-idation cohorts,the AUC values were 0.847(95％CI=0.799-0.896)and 0.830(95％CI=0.733-0.927),re-spectively.The Hosmer-Lemeshow goodness-of-fit tests showed that x2=13.498,P=0.096,and x2=7.138,P=0.415,respectively.Conclusion The nomogram,based on independent risk factors,exhibits good accuracy for diag-nosing EPGA and can help pathologists in achieving rapid and precise EPGA diagnosis.

Purpose To investigate the expression of chromogranin A(CgA)in gastroenteropancreatic neuroendo-crine neoplasms(GEP-NENs)and its relationship with clinicopathological features.Methods The clinicopathological data of GEP-NENs diagnosed in the Department of Pathology,Beijing Chao-yang Hospital,Capital Medical University from May 2011 to December 2024 were retrospectively analyzed.Immunohistochemical staining was applied to evaluate the expression of CgA,and the patients were divided into CgA(+)group and CgA(-)group.Differences in clinico-pathological features between the 2 groups were compared.Results The age of 229 patients ranged from 21 to 89 years,with an average age of 54.4 years.The most common primary site was the rectum(56.8％,130/229),fol-lowed by the stomach(16.6％,38/229),pancreas(14.4％,33/229),small intestine(6.1％,14/229),and colon(6.1％,14/229).There were 206 cases of single lesion and 23 cases of multiple lesions(number of tumors ≥2).There were 153 cases of G1(66.8％),29 cases of G2(12.7％),7 cases of G3(3.1％),and 40 cases of neuroendocrine carcinoma(NEC,17.5％).The positive rates of CgA in G1,G2,G3,and NEC groups were 37.2％,75.8％,71.4％,and 65.0％,respectively,with statistically significant differences(P＜0.001).The positive rates of CgA in T1,T2,T3,and T4 were 37.2％,83.3％,75.9％,and 57.7％,respectively,with statistically significant differences(P＜0.001).There were significant differences in age,vascular invasion,lymph node metasta-sis,and number of tumors between CgA(+)group and CgA(-)group(P＜0.001),but there was no significant difference in sex,tumor location,Syn,and CD56 expression between the two groups(P=0.595,P=0.098,P=0.173,P=0.557).Conclusion Immunohistochemical antibody CgA is a useful marker for GEP-NENs.CgA positiv-ity may be a poor prognostic factor for GEP-NENs patients.

Purpose To investigate the independent risk factors for early papillary gastric adenocarcinoma(EP-GA)and construct a diagnostic nomogram.Methods A retrospective analysis was performed on the clinicopathologi-cal characteristics of 325 cases of early differentiated gastric adenocarcinoma.Taking EPGA as the case group and early well-moderately differentiated tubular gastric adenocarcinoma(ETGA)as the control group,the independent risk fac-tors for the occurrence of EPGA were identified through univariate and multivariate analyses,and a nomogram was con-structed.The diagnostic performance of the nomogram was evaluated using the receiver operating characteristic(ROC)curves,Hosmer-Lemeshow goodness-of-fit tests,and calibration curves.Results Among the 325 cases of early differ-entiated gastric adenocarcinoma,there were 121 cases of EPGA and 204 cases of ETGA.Univariate analysis showed that elevated appearance(56.3％),ulcer formation(11.5％),tumor maximum diameter of 2.15(1.60,3.00)cm,moderately-differentiated(55.2％),submucosal invasion(21.9％),lymphovascular invasion(10.4％),high ex-pression of MUC5AC(75.0％),microsatellite instability-high(15.6％),and wild-type expression of p53(59.4％)were significantly associated with an increased risk of EPGA.Multivariate analysis revealed that gross appearance,ul-cer formation,tumor maximum diameter,and the expression of MUC5AC was independent risk factors for EPGA.A di-agnostic nomogram was constructed,and the area under the ROC curve(AUC)was calculated.In the training and val-idation cohorts,the AUC values were 0.847(95％CI=0.799-0.896)and 0.830(95％CI=0.733-0.927),re-spectively.The Hosmer-Lemeshow goodness-of-fit tests showed that x2=13.498,P=0.096,and x2=7.138,P=0.415,respectively.Conclusion The nomogram,based on independent risk factors,exhibits good accuracy for diag-nosing EPGA and can help pathologists in achieving rapid and precise EPGA diagnosis.

Objective:To explore the clinical features, histopathological morphology, and differential diagnosis of lymphoepithelioma-like carcinoma with abnormal expression of follicular dendritic cell markers.Methods:From 2020 to 2021, 4 cases of lymphoepithelioma-like carcinoma with abnormal expression of follicular dendritic cell markers diagnosed in Fujian Cancer Hospital (2 cases) and the Second Affiliated Hospital of Fujian Medical University (2 cases) were collected. Different ancillary procedures such as HE, special stains, immunohistochemistry, and in situ hybridization techniques were used to assess the histopathological features and immunophenotypes. The clinical data were collected and literature was reviewed.Results:All 4 cases of lymphoepithelioma-like carcinoma with abnormal expression of follicular dendritic cell markers were male. They were 32, 45, 67 and 39 years old, respectively. The main clinical manifestations were bloody phlegm, abdominal pain, fatigue and anorexia. The clinical stages at diagnosis were stage Ⅳ (3 cases) and stage Ⅱ (1 case). Cases 2 and 3 had two pathological examinations at different sites, with a total of six pathological examinations. The histomorphology showed singly scattered or nests of tumor cells in a background of abundant small lymphocytes. The tumor cells were enlarged and pleomorphic, some appeared polygonal with inconspicuous cell borders, and they were arranged in a syncytial pattern. There were megakaryocytes, multinucleated tumor cells, and a few spindle-shaped cells seen. Atypical mitosis was commonly noted. By immunohistochemistry, the tumor cells were positive for CKpan(5/6), CK8/18(4/4), CAM5.2(2/5), CK-H(0/4), CK-L(3/4), EMA(4/5), CK5/6(3/6), p63(1/6), p40(1/6), E-cadherin (4/6), SSTR2(6/6), PD-L1(5/5), LCA(0/6), vimentin(5/6), CD2 (6/6), CD23(6/6), CD35(5/6), CXCL-13(4/5) and D2-40(1/5). The Ki-67 proliferative index was 60%-95%. In situ hybridization for EBER were all positive (6/6). Special stain for reticulin showed positive staining surrounding nests of tumor cells.Conclusions:The expression of follicular dendritic cell markers in lymphoepithelioma-like carcinoma is very rare, which may be related to EBV infection. Occasionally, it can overlap with follicular dendritic cell sarcoma by morphology and immunophenotype, which can lead to misdiagnosis. Only by combining clinical information, morphological characteristics and immunophenotype can an appropriate diagnosis be made.

OBJECTIVE To investigate the current status of quality management of cold chain medicines in direct-to-patient(DTP)pharmacies and propose measures for pre-emptive risk management,providing references for the quality risk management of cold chain medicines.METHODS Based on the requirements of national regulations,a survey was conducted on the quality management of cold chain medicines in DTP pharmacies of J Province from November 2023 to February 2024,focusing on the receipt,storage,distribution,and delivery processes,using questionnaires,telephone interviews,and on-site visits.Common quality management issues in the operation of cold chain medicines were identified,and the causes of these issues were analyzed to propose feasible pre-emptive risk management measures.RESULTS&CONCLUSIONS A total of 122 DTP pharmacies participated in the questionnaire survey,and personnel from 30 DTP pharmacies participated in on-site and telephone interviews.Typical problems were identified in some DTP pharmacies,including insufficient personnel allocation or training,incomplete or inadequate implementation of quality system documentation,inadequate provision or management of cold chain facilities and equipment,and non-compliant storage and distribution of cold chain medicines.These issues posed certain risks to the quality management of cold chain medicines.It is recommended that DTP pharmacies strengthen personnel allocation and training,improve quality system documentation,enhance the provision and management of facilities and equipment,standardize storage and transportation operations,and strengthen supervision and assessment as pre-emptive measures.In addition,all sectors of society should also collaborate in governance from the perspective of ensuring the safety of cold chain drug storage and transportation,in order to mitigate the risk of quality and safety issues during the distribution of cold chain drugs and guarantee the safe and effective use of medications for patients.

Objective Triple-negative breast cancer(TNBC)poses a significant challenge for treatment efficacy.CD8+T cells,which are pivotal immune cells,can be effectively analyzed for differential gene expression across diverse cell populations owing to rapid advancements in sequencing technology.By leveraging these genes,our objective was to develop a prognostic model that accurately predicts the prognosis of patients with TNBC and their responsiveness to immunotherapy. Methods Sample information and clinical data of TNBC were sourced from The Cancer Genome Atlas and METABRIC databases.In the initial stage,we identified 67 differentially expressed genes associated with immune response in CD8+T cells.Subsequently,we narrowed our focus to three key genes,namely CXCL13,GBP2,and GZMB,which were used to construct a prognostic model.The accuracy of the model was assessed using the validation set data and receiver operating characteristic(ROC)curves.Furthermore,we employed various methods,including Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway,immune infiltration,and correlation analyses with CD274(PD-L1)to explore the model's predictive efficacy in immunotherapeutic responses.Additionally,we investigated the potential underlying biological pathways that contribute to divergent treatment responses. Results We successfully developed a model capable of predicting the prognosis of patients with TNBC.The areas under the curve(AUC)values for the 1-,3-,and 5-year survival predictions were 0.618,0.652,and 0.826,respectively.Employing this risk model,we stratified the samples into high-and low-risk groups.Through KEGG enrichment analysis,we observed that the high-risk group predominantly exhibited enrichment in metabolism-related pathways such as drug and chlorophyll metabolism,whereas the low-risk group demonstrated significant enrichment in cytokine pathways.Furthermore,immune landscape analysis revealed noteworthy variations between(PD-L1)expression and risk scores, Conclusion Our study demonstrates the potential of CXCL13,GBP2,and GZMB as prognostic indicators of clinical outcomes and immunotherapy responses in patients with TNBC.These findings provide valuable insights and novel avenues for developing immunotherapeutic approaches targeting TNBC.

Objective:To investigate the efficacy and safety of chemotherapy combined with inetetamab and pyrotinib (triplet therapy group), and capecitabine combined with pyrotinib (doublet therapy group) in second-line treatment for HER2-positive metastatic breast cancer patients who have failed on trastuzumab.Methods:A retrospective analysis was conducted on 30 HER2-positive metastatic breast cancer patients who underwent second-line treatment with a regimen of chemotherapy plus inetetamab and pyrotinib at Fujian Provincial Tumor Hospital between Jan. 1, 2020 and Dec. 31, 2023, and on 28 HER2-positive metastatic breast cancer patients treated with capecitabine plus pyrotinib during the same period. The study analyzed the differences in ORR (objective response rate), CBR (clinical benefit rate), PFS (progression free survival), and OS (overall survival) between the two groups and documented any adverse reactions observed during treatment.Results:The three-drug group exhibited a higher ORR rate than the two-drug group (60.0% vs. 39.2%, P>0.05), and a higher CBR rate (83.3% vs. 57.1%, P<0.05). Univariate analysis and multivariate Logistic regression analysis showed that group (three drug group compared to two drug group) was the only independent prognostic factor affecting median PFS in patients ( P<0.05). The median PFS of the three drug group was higher than that of the two drug group (19 months vs. 11 months, P<0.05), but by the end of follow-up, neither group had reached the median OS ( P>0.05) .The three-drug group and the two-drug group demonstrated 1-year OS rates of 85% and 85%, 2-year OS rates of 74% and 63%, and 3-year OS rates of 56% and 52%, respectively. The most frequent hematological toxicities in the three-drug group were leukopenia, neutropenia, and anemia, with diarrhea being the most common non-hematological toxicity. No significant differences were observed in adverse reaction profiles between the two groups ( P>0.05) . Conclusion:In the second-line treatment of HER2 positive metastatic breast cancer, chemotherapy + inetetamab + pyrotinib significantly prolonged the median PFS and increased the CBR compared with the current domestic standard capecitabine + pyrotinib regimen, and did not increase the incidence of adverse reactions, demonstrating higher efficacy and safety.