How to achieve sustainable distribution in the fast fashion industry? An electric vehicle solution under the "vehicle-battery separation" mode.

Exploring sustainable urban distribution based on electric vehicles is crucial given the rise in global greenhouse gas emissions, especially for fast fashion industries with extremely high distribution frequencies. However, most studies have overlooked the impact of deep discharge on the distribution route scheme, and few studies fit the characteristics of the fast fashion industry. As a result, this study presents a novel electric vehicle routing problem considering deep discharge model (EVRP-DD) for distribution route optimization, which fully considers deep discharge under the emerging mode of vehicle-battery separation. The characteristics of fashion consumers and products were also integrated into the model, such as consumer satisfaction and 3D loading constraints. To solve this complex programming problem, a sophisticated hybrid ant colony optimization (HACO) algorithm was designed by combining the advantages of ACO and A-star algorithms. Using real-life data, the experimental results verify the effectiveness and superiority of the proposed solution. EVRP-DD achieved reduced driving distance, total distribution cost, and deep discharge distance. HACO can enhance the computation speed and reduce the total distribution cost compared with the two conventional algorithms. The proposed solution showed excellent flexibility and could effectively adjust the optimal route scheme according to the ever-changing external environment. Thus, it can be concluded that this solution is a powerful tool for enterprises to achieve sustainable distribution. This study has realized theoretical innovation in sustainable distribution under the new mode of vehicle-battery separation, and its successful application in the fast fashion industry reflects its valuable application value.

Construction of a lung adenocarcinoma prognostic model based on N6-methyl-adenosine-related long noncoding RNA and screening of potential drugs based on this model.

Lung adenocarcinoma (LUAD) has a high mortality rate. N6-methyl-adenosine (m6A)-related long noncoding RNA (lncRNA) is associated with tumor prognosis. Our objective was to construct an m6A-related lncRNA prognostic model and screen potential drugs for the treatment of LUAD. The LUAD sequencing data were randomly divided into Train and Test cohorts. In the Train group, the LASSO Cox regression was used to construct the m6A-related lncRNA prognostic model. The LUAD tumor immune dysfunction and exclusion model was used to evaluate immunotherapy efficacy in LUAD. The 'pRRophetic' package was utilized to screen potential drugs for the treatment of LUAD. Eleven m6A-related lncRNAs were identified by LASSO Cox regression and were used to construct the risk model to calculate sample risk scores. Patients were divided into high- and low-risk groups based on their median risk scores. The LUAD data of The Cancer Genome Atlas database showed that the overall survival (OS) of the high-risk group was significantly lower than that of the low-risk group in both cohorts. Multivariate Cox regression analysis showed that this risk model could serve as an independent prognostic factor of LUAD, and receiver operating characteristic curves suggested that m6A-related lncRNA prognostic signature has a good ability in predicting OS. Finally, nine potential drugs for LUAD treatment were screened based on this prognostic model. The prognostic model constructed based on the m6A-related lncRNAs facilitated prognosis prediction in LUAD patients. The screened therapeutic agents have potential application values and provide a reference for the clinical treatment of LUAD.

Selective poly adenylation predicts the efficacy of immunotherapy in patients with lung adenocarcinoma by multiple omics research.

The aim of this study was to find the application value of selective polyadenylation in immune cell infiltration, biological transcription function and risk assessment of survival and prognosis in lung adenocarcinoma (LUAD). The processed original mRNA expression data of LUAD were downloaded, and the expression profiles of 594 patient samples were collected. The (APA) events in TCGA-NA-SEQ data were evaluated by polyadenylation site use Index (PDUI) values, and the invasion of stromal cells and immune cells and tumor purity were calculated to group and select the differential genes. Lasso regression and stratified analysis were used to examine the role of risk scores in predicting patient outcomes. The study also used the GDSC database to predict the chemotherapeutic sensitivity of each tumor sample and used a regression method to obtain an IC50 estimate for each specific chemotherapeutic drug treatment. Then CIBERSORT algorithm was used to conduct Spearman correlation analysis, immune regulatory factor analysis and TIDE immune system function analysis for gene expression level and immune cell content. Finally, the Kaplan-Meier curve was used to analyze the correlation between stromal score and the immune score of LUAD. In this study, APA's LUAD risk score prognostic model was constructed. KM survival analysis showed that immune score affected the prognosis of LUAD patients ( P = 0.027) but the matrix score was not statistically significant ( P = 0.1). We extracted 108 genes with APA events from 827 different genes and based on PUDI clustering and heat map, the survival rate of patients in the four groups was significantly different ( P = 0.05). Multiple omics studies showed that risk score was significantly positively correlated with Macrophages M0, T cells Follicular helper, B cells naive and NK cells resting. It is significantly negatively correlated with dendritic cells resting, mast cells resting, monocyte, T cells CD4 memory resting and B cells memory. We further explored the relationship between the expression of immunosuppressor genes and risk score and found that ADORA2A, BTLA, CD160, CD244, CD274, CD96, CSF1R and CTLA4 genes were highly correlated with the risk score. Selective poly adenylation plays an important role in the development and progression of LUAD, immune invasion, tumor cell invasion and metastasis and biological transcription, and affects the survival and prognosis of LUAD patients.

Comparative proteomic study reveals 17ß-HSD13 as a pathogenic protein in nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is characterized by a massive accumulation of lipid droplets (LDs). The aim of this study was to determine the function of 17ß-hydroxysteroid dehydrogenase-13 (17ß-HSD13), one of our newly identified LD-associated proteins in human subjects with normal liver histology and simple steatosis, in NAFLD development. LDs were isolated from 21 human liver biopsies, including 9 cases with normal liver histology (group 1) and 12 cases with simple steatosis (group 2). A complete set of LD-associated proteins from three liver samples of group 1 or group 2 were determined by 2D LC-MS/MS. By comparing the LD-associated protein profiles between subjects with or without NAFLD, 54 up-regulated and 35 down-regulated LD-associated proteins were found in NAFLD patients. Among them, 17ß-HSD13 represents a previously unidentified LD-associated protein with a significant up-regulation in NAFLD. Because the 17ß-HSD family plays an important role in lipid metabolism, 17ß-HSD13 was selected for validating the proteomic findings and exploring its role in the pathogenesis of NAFLD. Increased hepatic 17ß-HSD13 and its LD surface location were confirmed in db/db (diabetic) and high-fat diet-fed mice. Adenovirus-mediated hepatic overexpression of human 17ß-HSD13 induced a fatty liver phenotype in C57BL/6 mice, with a significant increase in mature sterol regulatory element-binding protein 1 and fatty acid synthase levels. The present study reports an extensive set of human liver LD proteins and an array of proteins differentially expressed in human NAFLD. We also identified 17ß-HSD13 as a pathogenic protein in the development of NAFLD.

Mir-449a, a potential diagnostic biomarker for WNT group of medulloblastoma.

Medulloblastoma (MB) is the most common malignant brain tumor in childhood. The 5 year disease-free survival rate is rather low. There is a consensus that MB can be divided into at least four clinically, transcriptionally, and genetically distinct molecular variants, being designated as wingless (WNT), sonic hedgehog (SHH), Group 3 and Group 4. It poses a great challenge to the design of therapeutic strategy for MB patients. Intensive clinical intervention, including high dose radiotherapy, is commonly used in treatment of high risk MB, most of which are considered to be Group 3 patients. But such intensive therapy should be avoided to protect neurologic function of patients in the lower risk WNT group. In present study, MB subgroup assignment in formalin-fixed paraffin embedded (FFPE) specimens from 45 Chinese patients were performed by Nanostring platform using 22 well-known signature genes. Based on comparative expression profiles of miRNA real-time PCR microarray in MB cells with and without treatment of demethylation reagent, as well as MSP assay, miR-449a was demonstrated to be significantly silenced by aberrant DNA methylation in tumor cells. Real-time PCR showed that expression level of miR-449a in WNT group was significantly different from other subgroups, although it was down-regulated in most of the MB samples. In conclusion, current study demonstrates for the first time the feasibility of using the Nanostring assay for subgrouping of MBs in Chinese patients. In addition, MiR-449a, a candidate tumor suppressor regulated by hypermethylation, is a novel potential diagnostic marker for WNT group of MBs.

[The clinical pathological characteristics and follow-up of 4 cases of immune-mediated necrotizing myopathy].

OBJECTIVE: To characterize the clinical, electrophysiology and neuropathological features of 4 cases with immune-mediated necrotizing myopathy (IMNM). METHODS: We retrospectively analyzed the clinical, electrophysiology, neuropathological characteristics of 4 IMNM patients with muscular and skin biopsy in our department during 4 years (from January 2011 to January 2014). RESULTS: Among these 4 patients, 2 were men and 2 were women (aged 37 to 58 years) with disease duration ranging from 1 month to 60 months. Two patients were with acute onset and 2 with chronic onset. All 4 patients had proximal muscle weakness with three patients with cervical flexor muscle weakness and one with respiratory muscles weakness and noninvasive ventilator assisted respiration. One patient had interstitial lung disease. The anti-signal recognition particle antibodies were strong positive in all 4 patients. Muscle biopsy showed group necrotizing and regenerating fibers in one patient and few scattered necrotizing and regenerating fibers in the other 3 patients. Both muscle fiber hypertrophy and muscle fiber atrophy together with proliferation of connective tissue on endomysium could be viewed in all 4 patients. However, very few inflammatory cells were detectable in patients. One patient was treated with corticosteroids and the other three were treated with combination of corticosteroids and immunosuppressant drugs. CONCLUSIONS: IMNM is characterized by heterogeneity at disease onset, severity and iInvolvement of muscles with, however, similary pathological changes including the presence of numerous necrotic and regenerating fibers with little or none inflammation. Corticosteroid and/or immunosuppressant is effective for patients.

[The clinical electrophysiology and pathological characteristics of 15 cases of vasculitic neuropathy].

OBJECTIVE: To summarize the clinical features, electrophysiology and neuropathological characteristics of peripheral nerves in patients with vasculitic neuropathy. METHODS: We retrospectively analyzed the clinical, electrophysiology and neuropathological characteristics of 15 patients with vasculitic neuropathy who underwent electrophysiology and sural nerve biopsy in our department from January 2009 to June 2013. RESULTS: There were 8 males and 7 females, aged from 38 to 82 years old, with a peripheral neuropathy course ranged from 0.5 month to 60 months. In the total of 15 patients, 3 patients were diagnosed as nonsystemic vasculitic neuropathy, while the other 12 patients were diagnosed as systemic vasculitis neuropathy (SVN) including 5 cases of primary systemic vasculitis and 7 cases of secondary systemic vasculitis. In patients diagnosed as primary systemic vasculitis, there were 2 cases of Churg-Strass syndrome (CSS) and 3 cases of ANCA associated vasculitis. In patients diagnosed as secondary systemic vasculitis, there were 1 case of systemic lupus erythematosus (SLE), 2 cases of sicca syndrome (SS), 3 cases of rheumatoid arthritis (RA), 1 case of Behcet' s disease associated with thyroid papillary carcinoma, 1 case of hepatitis B and 1 case of RA-associated SS. For the pathological features of vasculitic neuropathy, type 1 lesion was found in 4 patients, type 2 lesion in 2 patients, and type 3 lesion in 9 patients. Axon degeneration was observed in 8 patients, while 7 patients manifested as axon degeneration associated with demyelination and local thickening of the perineurium was found in 2 patients. CONCLUSION: Multiple mononeuropathy and asymmetric polyneuropathy are the common clinical presentations of vasculitic neuropathy. Electrodiagnostic testing almost always reveals the evidence of a predominantly axonal and sensorimotor process with associated demyelination presented in some cases. Sural nerve biopsy shows changes indicative of an axonopathy.

[Clinico-electrophysiological and pathological characteristics of neuropathy in Sjögren's syndrome: a report of 5 cases].

OBJECTIVE: To summarize the clinical features, electrophysiological and neuropathological characteristics of peripheral nerves in patients with primary Sjögren's syndrome (SS). METHODS: We retrospectively analyzed the clinical, electrophysiological and neuropathological characteristics of 5 female SS patients with neuropathy complications undergoing electrophysiology and sural nerve biopsy at our department from January 2011 to June 2013. RESULTS: They had an age range of 20-75 years. The course of peripheral neuropathy ranged 0.5-60 months and the whole course 12-240 months. pSS-associated neuropathy included multiple mononeuropathy (n = 1), symmetrical axonal sensorimotor polyneuropathy (n = 1) and sensory ganglioneuronopathy (n = 3). All biopsies showed varying degrees of myelinated fiber loss. Three biopsies had axonal degeneration associated with demyelination. However, there was no formation of onion bulb regeneration or plexus. Necrotizing vasculitis was diagnosed in 2 cases. CONCLUSION: The manifestations of peripheral nerve n pSS include multiple mononeuropathy, axonal symmetric sensorimotor polyneuropathy and sensory gangioneuronopathy. Sural biopsy shows typical necrotizing vasculitis in some cases and myelinated fiber loss and axonal degeneration in others. The pathogenic mechanisms of neurological involvement in pSS remain unknown. However, vasculitis, ischemic and immunological insults resulting in sensory gangioneuronopathy have been described.

An anatomical, histopathological, and molecular biological function study of the fascias posterior to the interperitoneal colon and its associated mesocolon: their relevance to colonic surgery.

The study aim was to explore the anatomy, histopathology, and molecular biological function of the fascias posterior to the interperitoneal colon and its mesocolon to provide information for improving complete mesocolic excision. To accomplish this aim, we performed intraoperative observations in 60 interperitoneal colon-cancer patients accepted for complete mesocolic excision and conducted local anatomy observations for five embalmed cadavers. An additional two embalmed child cadaver specimens were studied with large slices and paraffin sections. Ten of the 60 patients were examined with a lymph node tracer technique in vivo, while fresh specimens from these patients were assessed by histopathological examination and transwell cell migration assays in vitro. The anatomical and histopathological findings showed that the fascias posterior to the interperitoneal colon and its associated mesocolon were composed of two independent layers: the visceral and parietal fascias. These two fascias were primarily composed of collagen fibers, with the parietal fascia containing a small amount of muscle fiber. The in vivo test showed that the visceral fascia surrounded the colon and its associated mesocolon, including vessels and lymphatics, and that it had no lymphatic flow through it into the rear tissues. Moreover, the in vitro assays showed the visceral fascia was able to block tumor cell migration. Although many surgical scholars have known of the existence of fascia tissue posterior to the intraperitoneal colon, the detailed structure has been ignored and been unclear. As shown by our findings, the visceral and parietal fascias are truly formed structures that have not been previously reported. A thorough understanding of fascial structures and the function of the visceral fascia barrier in blocking tumor cells will facilitate surgeons when performing high-quality complete mesocolic excision procedures.

[Mutation of isocitrate dehydrogenase gene in Chinese patients with glioma].

OBJECTIVE: To investigate mutation status of isocitrate dehydrogenase (IDH) 1 and IDH2 genes in Chinese patients with gliomas in correlation with clinicopathological characteristics. METHODS: Formalin-fixed and paraffin-embedded (FFPE) tissue samples of 234 gliomas were collected including the matched blood samples in 30 patients. DNA was extracted, followed by PCR-Sanger sequencing to detect IDH1 and IDH2 gene mutations. Immunohistochemistry was performed using mutation-specific antibody recognizing IDH1R132H mutation. Immunostains for p53 and epidermal growth factor receptor (EGFR) were also performed. Oligodendroglial tumors with IDH mutation were double stained with IDH1R132H and GFAP by immunofluorescence to investigate the location of IDH1R132H expression. RESULTS: (1) By IDH1 heterozygous somatic mutation analysis, Arg132His (c: G395A) was found in 31.6% (74 of 234) of the cases. IDH mutations were more frequent in oligoastrocytomas (9/13), anaplastic oligoastrocytomas (7/11), oligodendrogliomas(18/26, 69.2%), anaplastic oligodendrogliomas (8/10), and less frequent in diffuse astrocytomas (17/47, 36.2%), anaplastic astrocytomas (5/18), and glioblastomas (10/69, 14.5%). The mutation rate inversely correlated with the tumor grade in a linear fashion in astrocytic tumors (P = 0.007). Primary glioblastomas were characterized by a lower frequency of mutations than secondary glioblastomas (5/55 vs. 5/14, P = 0.036); IDH mutation was not detected in pilocytic astrocytoma and ependymoma. No IDH2 mutation was identified in this study cohort. (2) Immunohistochemistry of IDH1R132H demonstrated a strong cytoplasmic staining in 80 cases, which was highly correlated with IDH mutation status (P = 0.001). IDH1R132H was highly specific to tumor cells. (3) p53 immunostain was significantly correlated the IDH mutation in diffuse astrocytoma, anaplastic astrocytoma and secondary glioblastomas (P = 0.007, 0.026, 0.038 respectively). (4) No correlation between EGFR and IDH mutation was found. CONCLUSIONS: High prevalence of IDH heterozygous somatic mutation occurs in the earlier stage of gliomas, which can be detected by mutation-specific antibody IDH1R132H. Furthermore, evaluation of p53 and EGFR expression combined with IDH mutation analysis may significantly aid in the diagnosis and differential diagnoses of gliomas in Chinese patients.

Purpose Orientation and Its Protective Effect on Self-Esteem Among Chinese Depressive Patients: A Comparative Study.

Purpose: Although previous studies have confirmed that purpose in life may negatively predict depressive symptoms, focusing on the intensity of purpose without focusing on content may ignore significant individual differences. This study explores differences in purpose orientations between depressive patients and healthy population to examine the relationship between the purpose content and self-esteem, one of the symptoms of depression. In addition, the moderating role of purpose orientations in the relationship between depression and self-esteem was analyzed to verify the protective effect of purpose orientation on self-esteem. Patients and Methods: The study utilized the questionnaire approach. The Purpose Orientation Scale (Self and Forced Rating) and the Rosenberg Self-Esteem Scale were administered to the participants. The study recruited 73 depressive patients using convenience sampling. Moreover, using random sampling, 146 participants matched based on depressive patients' demographics were selected as a healthy population in a 1:2 ratio. Results: The results showed that: 1) depressive patients valued all four types of purpose orientations to a lesser extent compared to healthy population, both depressive patients and healthy population valued family well-being and personal growth to a greater extent than personal well-being and social promotion. 2) Depressive patients reported lower self-esteem than healthy people. 3) All four types of Purpose orientations positively correlated with self-esteem in depressive patients, while only personal well-being positively correlated with self-esteem in healthy population. Family well-being and social promotion moderated the predictive effect of depression on self-esteem. Conclusion: The above results imply that prosocial purpose orientations may attenuate the harmful effects of depression on self-esteem. Additionally, intervention focusing on enhancing depressive patients' purpose in life (especially prosocial purpose) could be helpful.

Multiple Omics Analysis of the Role of RBM10 Gene Instability in Immune Regulation and Drug Sensitivity in Patients with Lung Adenocarcinoma (LUAD).

OBJECTIVE: The RNA-binding protein RBM10 can regulate apoptosis during the proliferation and migration of pancreatic cancer, endometrial cancer, and osteosarcoma cells; however, the molecular mechanism underlying lung adenocarcinoma is rarely reported. Recent studies have detected multiple truncated and missense mutations in RBM10 in lung adenocarcinoma, but the role of RBM10 in lung adenocarcinoma is unclear. This study mainly explored the immune regulation mechanism of RBM10 in the development of lung adenocarcinoma and its influence on sensitivity to targeted therapy drugs. METHODS: The transcriptome data of CGAP were used to analyze the RNA-seq data of lung adenocarcinoma patients from different subgroups by using the CIBERSORT algorithm to infer the relative proportion of various immune infiltrating cells, and Spearman correlation analysis was performed to determine the gene expression and immune cell content. In addition, this study utilized drug trial data from the GDSC database. The IC50 estimates for each specific targeted therapy were obtained by using a regression method, and the regression and prediction accuracy were tested via ten cross-validations with the GDSC training set. An immunohistochemical test was performed on the samples of 20 patients with lung adenocarcinoma in the subcomponent analysis of immune cells, and the protein expression of RBM10 in lung adenocarcinoma tissues was verified by cellular immunofluorescence assays. Nucleic acids were extracted at low temperatures, and qRT-PCR was used to verify the expression levels of the mRNA of RBM10 in lung adenocarcinoma tissues and normal tissues (p < 0.05). RESULTS: After screening and inclusion using a machine language, the results showed that RBM10 was significantly highly expressed in the lung adenocarcinoma tissues. The related signaling pathways were mainly concentrated in ncRNA processing, rRNA metabolic processes, ribosome biogenesis, and the regulation of translation. The qRT-PCR for 20 lung adenocarcinoma tissues showed that the expression of RBM10 in these tissues was significantly different from that in normal tissues (p = 0.0255). Immunohistochemistry analysis and cell immunofluorescence staining also confirmed that RBM10 was involved in the immune regulation of lung adenocarcinoma tissues, and the number of immune cell aggregations was significantly higher than that of the control group. RBM10 regulates B cell memory-CIBERSORT (p = 0.042) and B cell memory-CIBERSOTRT-abs (p = 0.027), cancer-associated fibroblast-EPIC (p = 0.001), cancer-associated fibroblast- MCPCounter (p = 0.0037), etc. The risk score was significantly associated with the sensitivity of patients to lapatinib (p = 0.049), nilotinib (p = 0.015), pazopanib (p = 0.001), and sorafenib (p = 0.048). CONCLUSIONS: RBM10 can inhibit the proliferation and invasion of lung adenocarcinoma cells through negative regulation and promote the apoptosis of lung adenocarcinoma cells through immunomodulatory mechanisms. The expression level of RBM10 affects the efficacy of targeted drug therapy and the survival prognosis of lung adenocarcinoma patients, which has a certain guiding significance for the clinical treatment of these patients.

Comparison study of clinicopathological features of cellular schwannoma between retroperitoneum and other sites.

Background: Cellular schwannoma (CS) is a relatively rare neural tumor with few reports. This study aimed to compare the clinicopathological characteristics of CS in the retroperitoneum and other sites by analyzing the hematoxylin-eosin (HE) staining and immunohistochemical (IHC) staining results, to provide some help for pathological diagnosis. Methods: A total of 79 CS cases from the Department of Pathology, Peking University International Hospital were collected, and the diagnosis was based on the 5th WHO classification of soft tissue tumors. The staining results of HE and IHC were judged and analyzed according to the instructions. The t-tests, Chi-square test and Fisher's exact probability test were used for statistical analysis. Results: Compared with other sites, the volume of retroperitoneal CS tumors were larger (t=4.265, P=0.001) and more likely to recur (χ2=4.223, P=0.04). Nerve sheath structures were rare around the tumors (χ2=60.096, P=0.000). Immunohistochemically, there was a difference in the expression of glial fibrillary acidic protein (GFAP), Cytokeratin (CK), and myelin basic protein (MBP) between the two groups (χ2=54.290, P=0.000; χ2=4.879, P=0.027; χ2=31.792, P=0.000). But there was no difference in expression between the two groups in the other indexes. Conclusions: It founded that Retroperitoneal CS was often positive for GFAP and CK, suggesting it originated from unmyelinated Schwann cells. CS in other sites, the expression of GFAP and CK was often negative, indicating they derived from myelinated Schwann cells. The expression of MBP in the peripheral nerve sheath structure of CS can be used to determine whether the tumor originates from myelinated or unmyelinated Schwann cells. These findings may provide a reference for revealing pathogenesis, diagnosis and evaluating prognosis of CS.

MicroRNAs in Pulmonary Hypertension, from Pathogenesis to Diagnosis and Treatment.

Pulmonary hypertension (PH) is a fatal and untreatable disease, ultimately leading to right heart failure and eventually death. microRNAs are small, non-coding endogenous RNA molecules that can regulate gene expression and influence various biological processes. Changes in microRNA expression levels contribute to various cardiovascular disorders, and microRNAs have been shown to play a critical role in PH pathogenesis. In recent years, numerous studies have explored the role of microRNAs in PH, focusing on the expression profiles of microRNAs and their signaling pathways in pulmonary artery smooth muscle cells (PASMCs) or pulmonary artery endothelial cells (PAECs), PH models, and PH patients. Moreover, certain microRNAs, such as miR-150 and miR-26a, have been identified as good candidates of diagnosis biomarkers for PH. However, there are still several challenges for microRNAs as biomarkers, including difficulty in normalization, specificity in PH, and a lack of longitudinal and big sample-sized studies. Furthermore, microRNA target drugs are potential therapeutic agents for PH treatment, which have been demonstrated in PH models and in humans. Nonetheless, synthetic microRNA mimics or antagonists are susceptible to several common defects, such as low drug efficacy, inefficient drug delivery, potential toxicity and especially, off-target effects. Therefore, finding clinically safe and effective microRNA drugs remains a great challenge, and further breakthrough is urgently needed.

Immunomodulatory Factor TIM3 of Cytolytic Active Genes Affected the Survival and Prognosis of Lung Adenocarcinoma Patients by Multi-Omics Analysis.

[Objective] Using multi-omics research methods to explore cytolytic activity-related genes through the immunoregulatory factors HAVCR2 (TIM3) affecting the survival and prognosis of lung adenocarcinoma. [Methods] We combined Cox single factor regression and lasso regression feature selection algorithm to screen out the key genes of cytolytic activity in lung adenocarcinoma, and applied multi-omics research to explore the clinical predictive value of the model, including onset risk, independent prognosis, clinical relevance, signal transduction pathways, drug sensitivity, and the correlation of immune regulatory factors, etc. TCGA data are used as the experimental group, and GEO data is used as the external data control group to verify the stability of the model. The survival curve was generated by the Kaplan-Meier method and compared by log-rank, and the Cox proportional hazard model was used for multivariate analysis. In this study, 10 fresh tissue samples of lung adenocarcinoma were collected for cellular immunohistochemical experiments to analyze the expression of immunoregulatory factors in cancer tissues, and the key immunoregulatory factors were verified and screened out. [Results] A total of 450 genes related to cytolytic activity were differentially expressed, of which 273 genes were up-regulated and 177 genes were down-regulated. A total of 91 key genes related to cytolytic activity related to the prognosis of lung adenocarcinoma were screened through Cox single factor regression. The ROC curve results showed that the AUC values of 1, 3, and 5 years in the training set and test set were all greater than 0.7, indicating that the model has a valid verification. The level of risk score is significantly related to the sensitivity of patients to AKT inhibitor VIII, Lenalidomide, and Tipifarnib. In addition, our study also found that receptor and MHC genes related to immunomodulatory, and chemokines, including HAVCR2, are more highly expressed in the low-risk group. [Conclusions] HAVCR2 (TIM3) immunoregulatory factors affect the expression of key genes that affect cytolytic activity in lung adenocarcinoma cells, and to some extent indirectly affect the survival and prognosis of patients with lung adenocarcinoma.

Crystal-storing histiocytosis in the stomach: A case report and review of the literature.

Crystal-storing histiocytosis (CSH) is a rare disorder characterized by the accumulation of non-neoplastic histiocytes that contain intracytoplasmic crystallized immunoglobulins. Although CSH can occur in various organs, gastric CSH is very rare. Therefore, diagnosing gastric CSH remains a challenge. Here, we present the case of a 69-year-old man with localized gastric CSH who presented with positive fecal occult blood for 2 days. Gastroscopy showed that there was a piece of irregular whitish focus in the big bend of the gastric antrum, which was soft and elastic. Histologically, the biopsied gastric mucosa showed chronic inflammation, mild activity with erosion, and numerous eosinophilic mononuclear cells containing fibrillary crystalloid inclusions in the lamina propria. Immunohistochemically, these crystal-containing cells were positive for CD68/PGM1 and Igk, which revealed that the cells were histiocytes harboring kappa light chain-restricted immunoglobulin crystals. Electron microscopic examination showed numerous high-electron-density particles in the cytoplasm of cells, with crystal structures of different sizes and shapes. This case highlights how immunohistochemistry can help with differential diagnosis and classification.

Methylation-mediated silencing of PTPRD induces pulmonary hypertension by promoting pulmonary arterial smooth muscle cell migration via the PDGFRB/PLCγ1 axis.

OBJECTIVE: Pulmonary hypertension is a lethal disease characterized by pulmonary vascular remodeling and is mediated by abnormal proliferation and migration of pulmonary arterial smooth muscle cells (PASMCs). Platelet-derived growth factor BB (PDGF-BB) is the most potent mitogen for PASMCs and is involved in vascular remodeling in pulmonary hypertension development. Therefore, the objective of our study is to identify novel mechanisms underlying vascular remodeling in pulmonary hypertension. METHODS: We explored the effects and mechanisms of PTPRD downregulation in PASMCs and PTPRD knockdown rats in pulmonary hypertension induced by hypoxia. RESULTS: We demonstrated that PTPRD is dramatically downregulated in PDGF-BB-treated PASMCs, pulmonary arteries from pulmonary hypertension rats, and blood and pulmonary arteries from lung specimens of patients with hypoxic pulmonary arterial hypertension (HPAH) and idiopathic PAH (iPAH). Subsequently, we found that PTPRD was downregulated by promoter methylation via DNMT1. Moreover, we found that PTPRD knockdown altered cell morphology and migration in PASMCs via modulating focal adhesion and cell cytoskeleton. We have demonstrated that the increase in cell migration is mediated by the PDGFRB/PLCγ1 pathway. Furthermore, under hypoxic condition, we observed significant pulmonary arterial remodeling and exacerbation of pulmonary hypertension in heterozygous PTPRD knock-out rats compared with the wild-type group. We also demonstrated that HET group treated with chronic hypoxia have higher expression and activity of PLCγ1 in the pulmonary arteries compared with wild-type group. CONCLUSION: We propose that PTPRD likely plays an important role in the process of pulmonary vascular remodeling and development of pulmonary hypertension in vivo .

Multiple organ infection and the pathogenesis of SARS.

After >8,000 infections and >700 deaths worldwide, the pathogenesis of the new infectious disease, severe acute respiratory syndrome (SARS), remains poorly understood. We investigated 18 autopsies of patients who had suspected SARS; 8 cases were confirmed as SARS. We evaluated white blood cells from 22 confirmed SARS patients at various stages of the disease. T lymphocyte counts in 65 confirmed and 35 misdiagnosed SARS cases also were analyzed retrospectively. SARS viral particles and genomic sequence were detected in a large number of circulating lymphocytes, monocytes, and lymphoid tissues, as well as in the epithelial cells of the respiratory tract, the mucosa of the intestine, the epithelium of the renal distal tubules, the neurons of the brain, and macrophages in different organs. SARS virus seemed to be capable of infecting multiple cell types in several organs; immune cells and pulmonary epithelium were identified as the main sites of injury. A comprehensive theory of pathogenesis is proposed for SARS with immune and lung damage as key features.

[Insulin protects the loss of colonic interstitial cells of Cajal and acetylcholine in patients with type 2 diabetes mellitus].

OBJECTIVE: A deficiency of interstitial cells of Cajal (ICC) and neuronal nitric oxide synthase (nNOS) in the gastrointestinal muscle layer have been shown in both diabetic animal models and patients with diabetes mellitus (DM), but little is known about the alteration of colonic acetylcholine (Ach) expression in patients with DM, and it is remain unclear whether those changes are related to different treatments. This study examined whether the ICC density, or the expression of Ach containing nerves in the colon, was altered in patients with type 2 DM, and whether those changes were protected by insulin treatment. METHODS: Paraffin embedded colonic specimens that have been fixed in 10% formalin were collected from 81 patients with colon cancer who underwent colectomy (non-DM as controls, M/F = 17/12; DM with insulin treatment, M/F = 12/12; DM with oral medication treatment, M/F = 19/9). Serial sections were stained with antibodies to c-kit and Ach using immunohistochemical method.Meanwhile, mast cells were stained with toluidine blue. The ICC number was calculated by subtraction of the number of mast cells from the number of c-kit positive cells. The number of ICC and the expression of Ach were compared among the controls and DM patients with different treatment. RESULTS: C-kit positive cells, which located within the inner muscle layer and muscular plexus mainly, were expressed in control group and they were much more regular and less vacuolization than that of controls. The density of both intramuscular-ICC (ICC-IM) and myenteric ICC (ICC-MY) were much lower in patients with DM than that in the controls. Furthermore, ICC density in DM patients who underwent insulin treatment was higher than that in patients with oral medical therapy (control vs insulin vs oral medication group: ICC-MY, 60.12 vs 23.95 vs 16.49, P = 0.000; ICC-IM, 41.79 vs 33.18 vs 25.88, P = 0.000). In addition, the alteration of Ach expression in colonic enteric nerves was similar as the pattern of ICC (control vs insulin vs oral medication group: 147.50 vs 103.82 vs 86.38, P = 0.000). There was no influence of gender and age to the alteration of ICC and Ach. CONCLUSIONS: The colonic ICC and Ach in DM patients is irregular, and the distribution is loose, with lots of vacuolization. The density of clonic ICC-IM and ICC-MY were lower in DM patients than that in controls accompanied with downregulation of enteric nerves Ach expression. These alterations could be protected by insulin treatment.

Recovery of High Interference Memory in Spite of Lingering Cognitive Deficits in a Longitudinal Pilot Study of Hospitalized Depressed Patients.

BACKGROUND: Major depressive disorder has deleterious impacts on mood, cognition, and many functions of daily life. Even after remission of mood symptoms, patients frequently report persistent cognitive deficits. By contrast, the neurogenic theory of depression posits that recovery from depression is dependent upon a restoration of neurogenesis. The present study was designed to test this prediction by assessing performance in MDD in-patients on a broad battery of cognitive tasks including the Mnemonic Similarity Task, a high interference memory test that is a putative correlate of neurogenesis. We predicted that remitted patients should exhibit recovery of function on this task, even though they may show residual deficits on other cognitive tasks. METHODS: 18 hospitalized patients diagnosed with MDD and 22 healthy control participants matched for age, sex, and education completed a battery of mood and cognitive tests at two time points. Patients completed their baseline assessments when first admitted to hospital and repeated the same assessments upon remission, typically 4-5 weeks later and just prior to their release from hospital. Control participants were tested at baseline and 4-5 weeks later on the same assessment battery, which included the BDI-II, BAI, Cohen's PSS, Mnemonic Similarity Task, and several sub-tests adapted from the CANTAB. RESULTS: At baseline, MDD patients were impaired relative to controls on the MST and many other cognitive tasks. Upon remission, patients' MST scores did not differ from those of healthy controls, although patients were still impaired on Pattern Recognition Memory, Spatial Recognition Memory, Delayed Matching to Sample and Paired Associates Learning relative to healthy control participants. CONCLUSION: The lingering memory deficits observed in remitted patients with MDD observed here are broadly consistent with findings in the literature. Importantly, however, remitted patients showed recovery of cognitive function on the Mnemonic Similarity Task. This is the first study that we are aware of to report recovery of function on a high interference, putatively neurogenesis-dependent memory test in a longitudinal sample of hospitalized MDD patients from admission to remission. Our findings are consistent with the neurogenic theory of depression, which posits that a restoration of neurogenesis is linked to recovery from depression.