bluuebunny/crossref_metadata_2025 huggingface dataset:
Loss of SATB2 and CDX2 Expression is Associated with DNA Mismatch Repair Protein Deficiency and BRAF Mutation in Colorectal Cancer
Authors: Li Jiezhen , Zeng Qiang , Huang Haijian , Qin Xiaoying , Chen Lingfeng
Published: October 2021

The relationship between the expression of the SATB2, CDX2, and p53 proteins and common molecular changes in colorectal cancer (CRC) has rarely been studied. Recent literature suggests that the loss of SATB2 and CDX2 expression is more frequently observed in cases of colon cancer with DNA mismatch repair (MMR) protein deficiency and BRAF mutation. We collected 1180 cases of CRC and explored the association between the expression of SATB2, CDX2, and p53 and clinicopathological characteristics and molecular alterations of CRC using whole-slide immunohistochemistry. Our results showed that negative expression of SATB2 and CDX2 was more common in MMR-protein-deficient CRC than in MMR-protein-proficient CRC (15.8% vs. 6.0%, P = 0.001; 14.5% vs. 4.0%, P = 0.000, respectively). Negative expression of SATB2 and CDX2 was more common in BRAF-mutant CRC than in BRAF wild-type CRC (17.2% vs. 6.1%, P = 0.003; 13.8% vs. 4. 2%; P = 0.004, respectively). There was no relationship between SATB2 and/or CDX2 negative expression and KRAS, NRAS, and PIK3CA mutations. The expression of p53 was not associated with MMR protein status or BRAF, KRAS, NRAS and PIK3CA mutations. In addition, the lack of expression of SATB2, CDX2, and p53 was associated with poor histopathological features of CRC. In conclusion, the lack of SATB2 and CDX2 expression in CRC was associated with MMR protein deficiency and BRAF mutation, but not with KRAS, NRAS and PIK3CA mutation. The expression of p53 protein was not related to the common molecular changes of CRC.
Tumor Budding-Derived CCL5 Recruits Fibroblasts to Promote Colorectal Cancer Progression Through CCR5-SLC25A24 Signaling
Authors: Gao Ling-Fang , Zhong Yan , Long Ting , Wang Xia , Zhu Jia-Xian , Wang Xiao-Yan , Hu Zhi-Yan , Li Zuguo
Published: October 2021

Background: Tumor buddings have been included in the routine diagnosis of colorectal cancer (CRC) and considered to be a tumor prognostic factor independent of TNM staging. This study aimed at identifying the contribution of tumor budding-derived C-C chemokine ligand 5 (CCL5) to tumor microenvironment (TME) through fibroblasts. Methods: Co-cultivation recruitment assays and human cytokine array were used to detect the main cytokine derived from CRC tumor buddings to recruit fibroblasts. siRNA transfection and inhibitor treatment were applied to investigate the effective receptor of CCL5 on fibroblasts. Transcriptome sequencing was performed to explore the mechanism inside fibroblasts when stimulated by CCL5. Stimulation with CCL5 in vitro, orthotopic xenograft mouse model and clinical specimens were designed to clarify the contribution of CCL5 to angiogenesis and collagen synthesis.Results: H&E and immunochemistry staining confirmed that CRC with tumor buddings in the invasive front was accompanied by more fibroblasts compared with CRC without tumor buddings. Further vitro study indicated that CCL5 derived from tumor buddings could recruit fibroblasts through CCR5 receptor on fibroblasts and positively regulate solute carrier family 25 member 24 (SLC25A24) expression in fibroblasts, which could activate pAkt-pmTOR signaling. Moreover, CCL5 can increase the number of α-SMA+CD90+FAP- fibroblasts to promote tumor angiogenesis through enhancing the expression of VEGFA and making fibroblasts transdifferentiate into vascular endothelial cells. Meanwhile, CCL5 also can promote collagen synthesis through fibroblasts, thus contributing to tumor progression.Conclusions: In the invasive front of CRC, tumor-budding-derived CCL5 can recruit fibroblasts through CCR5-SLC25A24 signaling, further promoting angiogenesis and collagen synthesis through fibroblasts, eventually creating a tumor-promoting microenvironment.
Study on the Correlation Between B Vitamins and Breast Cancer
Authors: Xie Siqi , Tan Mingjian , Li Hongwan , Li Lv , Zhang Hengyu , Wang Qing , Li Sijia , Yang Jiali , Xie Gaoling , Chen Pengyan , Liu Dequan , Guo Rong , Tang Shicong
Published: October 2021

Background: The relationship between serum vitamin levels and breast cancer remains controversial. In this study, we compared the serum vitamin expression levels of healthy people, benign breast patients, and breast cancer patients, and evaluated the relationship between B vitamin levels and breast cancer risk.Methods: The study used liquid chromatography-tandem mass spectrometry to determine the serum vitamin levels of 520 people who attended Yunnan Cancer Hospital from September 2020 to December 2020. After screening by exclusion criteria, 38 patients with benign breast diseases, 87 patients with breast cancer and 91 healthy controls were finally included. The kruskal-wallis H test was used to compare the differences in serum vitamin levels of subjects. Χ² test was used to evaluate the relationship between B vitamin level and age, BIM, TNM staging, Ki-67, Her-2,surgery and chemotherapy, and other baseline characteristics.And through binary logistic regression analysis, calculating odds ratio and 95% confidence interval (CI) to evaluate the relationship between B vitamins and breast cancer risk.Conclusion: The levels of VitB1 and VitB5 in the serum of breast cancer patients and patients with benign breast diseases were higher than those in the healthy control group, while the expression levels of VitB3 in breast cancer patients were lower than those in the healthy control group and the breast benign disease groups. The level of VitB1 was positively correlated with breast cancer risk. The VitB3 level was negatively correlated with breast cancer risk.The VitB5 level is not significantly related to the risk of breast cancer.
Insuline use could increase the risk of obstructive sleep apnea in type 2 diabetes mellitus
Authors: Martorina Wagner , Tavares Almir
Published: October 2021

Background Obstructive sleep apnea (OSA) is a common disorder, that can increase cardiovascular risk in patients with type 2 diabetes mellitus (T2DM). Little is known about specific risk factors for OSA in patients with T2DM. Objective Identify variables associated with an increased risk of OSA in T2DM. Setting T2DM outpatient clinic. Measurements Sleep-T2DM relevant variables were stratified according to STOP-Bang questionnaire scores, in order to recognize OSA risk associations. Results Insulin use was directly related to a higher risk of OSA in T2DM outpatients: RP 1,86; IC 1,315 – 2,649; p< 0,001 Limitation Cross-sectional study, OSA diagnosed by non-objective measures. Conclusions In T2DM, the use of insulin increased the chances of belonging to a group of patients with a higher risk of OSA. The cost-benefit of treatment with insulin should be compared with other options, in patients already with T2DM with an increased risk for OSA.Primary founding sourceNone
The influence of different glucose tolerance on QTc interval: a population-based study
Authors: Lin Ning , Zhang Hongmei , Li Xiaoyong , Niu Yixin , Gu Hongxia , Lu Shuai , Yang Zhen , Qin Li , Su Qing
Published: October 2021

Background
Corrected QT (QTc) interval has been reported to be associated with type 2 diabetes. This study aimed to explore the relationship between different glucose tolerance and QTc interval among middle-aged and older Chinese individuals.
Methods
We conducted a cross-sectional analysis that included 9898 subjects (3194 men and 6704 women) in a Chinese population. Glucose tolerance was studied during OGTT. Insulin, blood pressure, HbA1c, serum lipids, hepatic transaminases and waist-to-hip ratio were assessed.The QTc interval was derived from ECG recordings, and the subjects were stratified based on different glucose tolerance.
Results
QTc interval levels were increased significantly in the subjects with abnormal glucose metabolism compared with the normal glucose regulation group. Multiple regression analyses QTc interval was significantly associated with fasting plasma glucose, 2-h OGTT plasma glucose and HbA1c. The odds ratios of prolonged QTc was 1.396 for IFG/IGT (95% CI: 0.126-1.730), 1.342 for type 2 diabetes (95% CI: 0.142-1.577) after all the potential confounders were adjusted.
Conclusions
IGR and diabetes are associated with prolonged QTc interval among middle-aged and older Chinese individuals. Abnormal glucose regulation can be used to monitor QTc interval in the population.
Globulin and Albumin To Globulin Ratio Precisely Diagnose Periprosthetic Joint Infection and Determine The Timing of Second-Stage Reimplantation
Authors: Shang Guangqian , Fei Zhixuan , Xu Hao , Wang Yingzhen , Xiang Shuai
Published: October 2021

Background
Periprosthetic joint infection (PJI) is one of the most challenging complication of total joint arthroplasty (TJI). An early and accurate diagnosis of PJI is associated with better treatment outcomes. However, whether the platelet-related markers and globulin-related markers can be used to assist the diagnosis of PJI remains elusive.
Methods
206 patients underwent revision hip or knee arthroplasty in our institution were divided into two groups: 79 patients in PJI group and 127 patients in aseptic failure group. The levels of erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), platelet-related markers including platelet count (PLT), mean platelet volume (MPV), plateletcrit (PCT) and PLT to MPV raito (PMR) and globulin-related markers, such as globulin, albumin to globulin ratio (AGR), and PLT to AGR ratio were compared. The diagnostic value was measured using area under the curve (AUC) after constructing receiver operating characteristic (ROC) curves. The potential of each marker for determining the timing of second-staged reimplantation was also evaluated.
Results
Significantly increased levels of ESR, CRP, PLT, PCT, PMR, GLB, and PLT to AGR ratio were identified in PJI group, while decreased levels of MPV and AGR were also found. The diagnostic values of all platelet-related markers and GLB were considered as fair, and good diagnostic values of AGR and PLT to AGR ratio were found, which were comparable to those of ESR and CRP. The levels of GLB and AGR can also be used to predict negative culture result and the timing of second-stage reimplantation.
Conclusions
Globulin and albumin to globulin ratio were found to have good diagnostic values for PJI, and they can precisely predict the culture results and persistent infection.
Don’t Forget That Chorea!
Authors: Kolhe Lokesh Krishnaji , Tham Yumin Audrey
Published: October 2021

Background: Hemichorea-hemiballismus is a spectrum of involuntary, continuous non-patterned movement involving one side of the body. Possible causes of hemichorea-hemiballismus include haemorrhagic or ischemic stroke, neoplasm, systemic lupus erythematosus, NHH (non-ketotic hyperglycaemic hemichorea), Wilson’s disease, and thyrotoxicosis. Amongst the metabolic causes, chorea associated with NHH is noteworthy and is mainly reported in elderly Asian women. The pathophysiology of this syndrome remains controversial. It is likely that a combination of hyperglycaemia induced basal ganglia metabolic derangement and failure of cerebral blood flow autoregulation contribute to the syndrome.Case presentation: A 45-year-old Malay gentleman presented to our Emergency Department with right upper and lower limb weakness associated with hemichorea for 3-4 days. His initial blood glucose level was 22 mg/dl with normal serum ketone and bicarbonate levels. CT brain showed a hyperdensity in the left caudate nucleus and globus pallidus region. Subsequent brain MRI revealed an asymmetric T1 hyperintensity of the left putamen. This specific finding was compatible with hyperglycaemia-induced hemichorea-hemiballismus syndrome. The hemiballismus/hemichorea improved rapidly within the next day. Conclusions: This unusual clinical presentation is often accompanied by severe hyperglycaemia. Appropriate blood glycaemic control is important because it is reversible with correction of hyperglycaemia. Thus, prompt recognition and treatment is essential to avoid adverse outcomes.
Blood Compatibility of Widely used Central Venous Catheters; an Experimental Study
Authors: Thorarinsdottir Hulda , Kander Thomas , Johansson Dorota , Nilsson Bo , Klarin Bengt , Sanchez Javier
Published: October 2021

Background: An inserted central venous catheter (CVC) is considered foreign material by the inert host defence systems and induce inflammation and thrombus formation. The objective of this study was to evaluate blood compatibility of six commonly used CVCs.Methods: Three coated and three uncoated CVC materials were tested in a modified Chandler loop model. Each catheter material circulated in blood from ten different healthy volunteers for 1 hour. Blood cell counts and measurements of the inert host defence systems were performed on blood samples from the loop.Results: All the tested catheters demonstrated impact on blood cells, contact coagulation, the complement system, or inflammatory markers, although the impact varied significantly.Conclusions: Of the catheters we evaluated, the most unfavourable blood compatibility profile was found for the polyurethane CVC coated with chlorohexidine and silver sulfadiazine. The greatest variation in blood compatibility between test runs was noted for the silicone dialysis catheter. Poor blood compatibility should be taken seriously but given the experimental design of the current study the clinical significance remains to be evaluated.
Coagulation/Fibrinolysis and Circulating Tumor Cells in Patients With Advanced Breast Cancer.
Authors: Dirix Luc , Oeyen Steffi , Buys Andy , Liégois Vincent , Prové Annemie , De Mooter Tom Van , Laere Steven Van , Vermeulen Peter B.
Published: October 2021

Purpose: To evaluate the quantitative relationship between circulating tumor cells (CTCs) and standard coagulation tests in both a discovery and a validation cohort of patients with advanced breast cancer.Methods: In a retrospective (n=77) and a prospective (n=92) study of patients with progressive advanced breast cancer, CTC count, platelet number, fibrinogen level, D-dimers, prothrombin time (PTT), and activated partial thromboplastin time (aPTT) were measured. The association between these coagulation studies and CTC count was analyzed. The impact of these measurements on overall survival (OS) was assessed.Results: In both cohorts results were strikingly similar; absolute CTC count was significantly related to D-dimer level and inversely with platelet count. In the prospective cohort, quantification of tumor derived extracellular vesicles (tdEVs) was related with CTC count, and with coagulation abnormalities (low platelet count and increased D-dimers). tdEVs did not add to CTC count in predicting changes in platelets or D-dimers. In multivariate analysis only CTC ≥ 5 CTC /7.5mL, ER status, HER2 status and lines of chemotherapy were associated with OS. In patients with terminally metastatic breast cancer (MBC), very high CTC counts are prevalent.Conclusion: A significant relationship exists between increasing CTC number and increased D-dimers and decreased platelet counts, supporting the role of CTCs as a direct contributor of intravascular coagulation activation.In patients with advanced and progressive breast cancer, abnormalities in routine coagulation tests is the rule. In patients with terminally advanced breast cancer a “leukemic” phase with high CTC count is prevalent.
Effects of Iron Oxide Nanoparticles as T2-MRI Contrast Agents on Reproductive System in Male Mice
Authors: Yang Heyu , Wang Hui , Wen Chenghao , Bai Shun , Wei Pengfei , Xu Bo , Xu Yunjun , Liang Chaozhao , Zhang Yunjiao , Zhang Guilong , Wen Huiqin , Zhang Li
Published: October 2021

Iron oxide nanoparticles (IONPs)-based contrast agents are widely used for T2-weighted magnetic resonance imaging (MRI) in clinical diagnosis, highlighting the necessity and importance to evaluate their potential systematic toxicities. Although a few previous studies have documented the toxicity concerns of IONPs to major organs, limited data are available on the potential reproductive toxicity caused by IONPs, especially when administrated via intravenous injection to mimic clinical use of MRI contrast agents. Our study aimed to determine whether exposure to IONPs would affect male reproductive system and cause other related health concerns in ICR mice. The mice were intravenously injected with different concentrations IONPs once followed by routine toxicity tests of major organs and a series of reproductive function-related analyses at different time points. As a result, most of the contrast agents were captured by reticuloendothelial system (RES) organs such as liver and spleen, while IONPs have not presented adverse effects on the normal function of these major organs. In contrast, although IONPs were not able to enter testis through the blood testicular barrier (BTB), and they have not impaired the normal testicular structure or altered the serum sex hormones levels, IONPs exposure could damage Sertoli cells in BTB at a relative high concentration. Moreover, IONPs administration led to a short-term reduction in the quantity and quality of sperms in a dose-dependent manner, which might be attributed to the increase of oxidative stress in epididymis. However, the semen parameters have gradually returned to the normal range within 14 days after the initial injection of IONPs. Collectively, these results demonstrated that IONPs could cause reversible damage to the reproductive system of male mice without affecting the main organs, providing new guidance for the clinical application of IONPs as T2-MRI contrast agents.
Evidence of Autism Spectrum Disorder Caused By A Mutation In ATRX Gene
Authors: López-Garrido María-Pilar , Carrascosa-Romero María-Carmen , Montero-Hernández Minerva , Ruiz-Almansa Jesús , Sánchez-Sánchez Francisco
Published: October 2021

Background: ATRX gene mutations are commonly associated with alpha-thalassaemia mental retardation syndrome (ATRX syndrome). This X-linked disorder is characterized by intellectual disability to a higher or lesser degree, in which alpha-thalassaemia feature is not always present. Here, we report the first case of a Spanish child with a missense ATRX mutation (Thr1621Met) and an Autism Spectrum Disorder (ASD) diagnosis. Except for intellectual disability, no typical signs of ATRX syndrome were found in the patient. Methods: A 23-month-old male patient was clinically evaluated at the Department of Paediatrics of the “Complejo Hospitalario Universitario de Albacete”, Spain. The baby was diagnosed with ASD according to the established criteria by the American Psychiatric Association (DMS-5). To determine the genetic cause of the pathology, an exome sequencing of a targeted gene panel of 215 genes associated to autism, intellectual disability, and/or seizure was carried out on an Ion Proton (Life Technologies) platform. The mutation was confirmed in the baby and analysed in the rest of the members of the family by PCR-terminator cycle sequencing.Results: Thr1621Met ATRX hemizygous mutation was identified in the ASD patient. Proband´s mother was identified as an asymptomatic heterozygous carrier and the mutation was not found in the father neither the sister. Thr1621Met change is predicted to have a pathogenic effect and it has been previously associated with ATRX syndrome in only one German family with phenotypic variability. Limitations: Given the limited number of families with ATRX mutations and, concretely, with Thr1621Met, it is very difficult to establish a genotype-phenotype relationship. Also, we cannot rule out the existence of other genetic, epigenetic and/or environmental factors that may modulate the phenotype of the patient. Furthermore, a functional analysis of Thr1621Met would be necessary to clarify the molecular mechanism by which this mutation causes ASD. Conclusions: Results suggest one common altered molecular pathway in both, ATRX syndrome and ASD pathologies that opens new research lines in ASD aetiology. Furthermore, the results confirm the extent phenotypic variability associated with ATRX mutations and focus the attention on an exhaustive clinical examination to achieve the most accurate diagnosis.
Primary Hemangioblastoma of Kidney with Molecular Analyses by Next Generation Sequencing: A Case Report and Review of the Literature
Authors: Wang Xintong , Haines George K , Houldsworth Jane , Si Qiusheng
Published: October 2021

Background: Hemangioblastoma is an indolent mesenchymal tumor most frequently occurring in the central nervous system (CNS), but can also arise extraneuraxially, as part of von Hippel-Lindau (VHL) disease or in sporadic cases. Extraneuraxial hemangioblastomas (EH) occur outside the central nervous system. It includes tumors arising from the nervous paraneuraxial structures and visceral organs. Sporadic hemangioblastoma of the kidney, a rare subset of EH, is an under-recognized renal neoplasm. There have been only 25 cases described to date in the English language literature. We report herein one additional case in a patient without VHL disease.Case presentation: A 61 year old male presenting with gross hematuria was found to have a 3.5 cm renal mass at the lateral mid to lower pole of the left kidney on computed tomography urogram. Patient underwent a partial nephrectomy for the mass. The pathological examination showed a well-circumscribed non-encapsulated tumor composed of sheets of large polygonal cells traversed by a rich vascular network. The tumor cells showed clear to eosinophilic cytoplasm and overall bland nuclei. The diagnosis of hemangioblastoma was confirmed by positive immunostaining for alpha-inhibin, S100, neuron-specific enolase, PAX8, and negative staining for epithelial membrane antigen, HMB-45, and Melan-A. VHL gene mutation was not detected in this tumor. The diagnosis of sporadic renal hemangioblastoma was made.Conclusion: Sporadic renal hemangioblastoma (RH) is a rare subset of EH. We report herein one such case in a patient without clinical or molecular evidence of VHL disease. We reviewed the literature to better understand the clinical, radiological and pathologic features of this neoplasm. From our review cases and the present case, we have found that the majority of RHs showed a positive immunostaining for PAX8, which supports the idea that the immunoprofiles of EH can vary depending on sites of origin. Diagnosis of renal hemangioblastoma is challenging because of its rarity and overlapping microscopic and immunophenotypic features with renal cell tumor, especially with clear cell renal cell carcinoma. However, accurate diagnosis is necessary, since RH is clinically benign and correct recognition of this pathological entity is important to avoid unnecessary over treatment.
Is Childhood Mortality Higher in Urban Poor Than in Rural India?
Authors: Das Ujjwal , Chakrabortty Druheen
Published: October 2021

The present paper examines the childhood mortality differential among urban poor and rural India using data from two rounds of National Family Health Survey Conducted in 2005-06 and 2015-16. Concentration index (CI), and cox regression were applied to address the research problem. Furthermore predicted probability was used to identify the potential predictors of infant and child mortality after adjusting the predictor variables. The findings suggest a decreasing trend in in infant mortality and child mortality both urban poor and rural India during this period. The economic inequalities respect to child mortality is higher in urban poor than in rural India. Hazard regression suggested that higher risk of child mortality in urban areas, due to poverty, low female literacy, low coverage antenatal care and safe delivery in the community. Even after controlling the possible bio-demographic variables, the study reveals that percentage declined mortality in rural areas higher than the urban poor but inequality is more widened in urban poor in India. The health program should be initiatives a major role to reducing infant and child mortality rates for both urban poor and rural India.
Preliminary Fluid Geochemical Survey in Tete Province and Prospective Development of Geothermics in Mozambique
Authors: Procesi Monia , Marini L. , Cinti D. , Sciarra A. , Basile P. , Mazzoni T. , Zarlenga F.
Published: October 2021

An evaluation of the feasible development of geothermal energy in Mozambique is proposed based on some thermal springs geochemical characterization in the Tete region. Chemical and isotopic data suggest that the springs have a meteoric origin and do not show connection with any active magmatic system. The proposed circulation model suggests high depths infiltration of meteoric waters along faults and fractures in a system characterised by discrete permeability and reservoir temperature between 90 and 120°C. These results, jointly with low salinity fluids and corrosive components absence suggest that the geothermal system may be conveniently exploited for direct and indirect uses.
LOCOM: A logistic regression model for testing differential
abundance in compositional microbiome data with false discovery rate control
Authors: Hu Yingtian , Satten Glen , Hu Yijuan
Published: October 2021

Motivation: Compositional analysis is based on the premise that a relatively small proportion of taxa are differentially abundant", while the ratios of the relative abundances of the remaining taxa remain unchanged. Most existing methods of compositional analysis such as ANCOM or ANCOM-BC use log-transformed data, but log-transformation of data with pervasive zero counts is problematic, and these methods cannot always control the false discovery
rate (FDR). Further, high-throughput microbiome data such as 16S amplicon or metagenomic sequencing are subject to experimental biases that are introduced in every step of the experimental workflow. McLaren, Willis and Callahan [1] have recently proposed a model for how these biases affect relative abundance data.

Methods: Motivated by [1], we show that the (log) odds ratios in a logistic regression comparing counts in two taxa are invariant to experimental biases. With this motivation, we propose LOCOM, a robust logistic regression approach to compositional analysis, that does not require pseudocounts. We use a Firth bias-corrected estimating function to account for sparse data. Inference is based on permutation to account for overdispersion and small sample sizes. Traits can be either binary or continuous, and adjustment for continuous and/or discrete confounding covariates is supported.

Results: Our simulations indicate that LOCOM always preserved FDR and had much improved sensitivity over existing methods. In contrast, ANCOM often had inflated FDR; ANCOM-BC largely controlled FDR but still had modest inflation occasionally; ALDEx2
generally had low sensitivity. LOCOM and ANCOM were robust to experimental biases in every situation, while ANCOM-BC and ALDEx2 had elevated FDR when biases at causal and non-causal taxa were differentially distributed. The flexibility of our method for a variety of microbiome studies is illustrated by the analysis of data from two microbiome studies.

Availability and implementation: Our R package LOCOM is available on GitHub at https://github.com/yijuanhu/LOCOM in formats appropriate for Macintosh or Windows.
Identification of Key Pathways and Targets of Kai Xin San in The Treatment of Alzheimer's Disease Based On a Network Pharmacology Approach and Experimental Validation
Authors: Yang Rong , Wang Kan , Li Tuo , Liao Mianmian , Kong Mingwang
Published: October 2021

Background: Alzheimer's disease (AD) is the commonest neurodegenerative disease characterized with a progressive loss of cognitive functions and memory decline. Kai Xin San (KXS), a traditional Chinese herbal classic prescription, has been used to ameliorate cognitive dysfunction for thousands of years. However, its specific pharmacological molecular mechanisms have not been fully clarified.Methods: The ingredients of KXS and their corresponding targets were firstly screened from ETCM database. AD-related target proteins were obtained from Malacards database and DisGeNet database. Venn diagram was used to intersect the common targets between KXS and AD. Then, key ingredients and key targets were identified from compound-target-disease network and protein-protein interaction (PPI) network analysis respectively. Moreover, the binding affinity between the key ingredients and targets were verified by molecular docking. KEGG enrichment analysis further predicted the potential key signaling pathway involved in the treatment of KXS on AD, and the predicted signaling pathway was validated via experimental approach.Results: A total of 38 ingredients and 469 corresponding targets were screened, and 264 target proteins associated with AD were obtained. Compound-target-disease network and PPI identified the key active ingredients and targets, which correlate with the treatment of KXS on AD. Molecular docking revealed a good binding affinity between key ingredients and targets. KEGG pathway analysis suggested the potential effect of KXS in treatment of AD via Aβ-GSK3β-Tau pathway. Aβ1-42-injected induced a decline in spatial learning and memory and upregulated the expression of GSK3β and CDK5 along with the downregulated PP1 and PP2 expression. However, KXS significantly improve the cognitive deficits induced by Aβ1-42, decrease the GSK3β and CDK5 levels and increase the expression of PP1 and PP2.Conclusions: Our research elucidated that KXS exerted neuroprotective effects through regulating the Aβ-GSK3β-Tau signaling pathway, which provided a novel insight into the therapeutic mechanism of KXS in treatment of AD.
Loss of Stat3 in Osteoblasts Impaired the Bone Remodeling in Inflammatory Microenvironment
Authors: Feng Jingyi , Huang Zijing , Chan Laiting , Lu Jiarui , Feng Xin , Lei Lizhen , Huang Zhuwei , Lin Lichieh , Yao Yichen , Zhang Xiaolei
Published: October 2021

Introduction: Oral diseases including periodontitis, periapical periodontitis, and peri-implantitis are characterized by inflammation and loss of alveolar bone. Signal transducer and activator of transcription 3 (Stat3) involved in bone formation and maintenance. This study aimed to investigate the effect of Stat3 on the osteoblast-mediated bone remodeling in the inflammatory lesion.Methods: The conditional knockout of Stat3 in osteoblasts (Stat3 CKO) was generated via the Cre-loxP recombination system using Osterix-Cre (Osx-Cre) transgenic mice. The lipopolysaccharide (LPS)-induced calvarial bone inflammatory lesions were harvested at day 3, 7 and 14 for micro-CT scanning, histological staining, quantitative real-time PCR (qRT-PCR) and western blot to assess the bone remodeling. Osteoblasts were harvested from Stat3 CKO and wildtype mice and were cultured in vitro. In response to LPS-stimulation, the cells were subjected to alizarin red staining, qRT-PCR and western blot to examine the formation of calcium deposit, the expression of osteogenic markers (i.e. Runx2, OPN, COL1A1) and osteoclast-related markers (i.e. RANKL, OPG). The EdU and transwell assays were performed to assess the proliferation and migration of the cells.Results: Compared with the wildtype control, a decrease of bone mass and an increase of osteolysis were found in the inflammatory lesions on Stat3 CKO mice. More osteoclastic-like cells, as well as an increased expression of RANKL, were observed in the lesions on Stat3 CKO mice. Both mRNA and protein expressions of Stat3 and osteogenic markers in the lesions was significantly decreased on Stat3 CKO mice. After co-cultured with osteogenic medium, the Stat3-deficient osteoblasts were found with a significant decrease of calcium deposits and the expression of osteogenic markers, and with a significant increased expression of RANKL, when compared with the control osteoblasts. The impaired ossification of Stat3-deficient osteoblasts was even more pronounced with the presence of LPS in vitro. According to the EdU and transwell assays, the most decrease of cell proliferation and migration was found in Stat3-deficient osteoblasts in response to LPS. Conclusions: Loss of Stat3 in osteoblasts impaired bone regeneration in inflammatory microenvironment, which might be resulted from the effect of Stat3 on the ossification, activation of osteoclast activationic signals, proliferation and migration of osteoblasts.
Selected Aspects of a Cold Forging Process for Hollow Balls
Authors: Samolyk Grzegorz , Winiarski Grzegorz
Published: October 2021

This paper presents the results of a study investigating a cold forging process for producing hollow balls with different wall thicknesses. The study was performed by FEM numerical modelling, which made it possible to obtain a wide spectrum of results. For the analysis of FEM results obtained for problematic cases (shape defects in forged balls), novel hypotheses for results interpretation are proposed. The FEM numerical model and hypotheses are then verified via experimental testing, and selected theoretical results are compared with experimental findings. Finally, obtained results are discussed (e.g. the effect of billet dimensions on forging conditions, wall thickness and hole size), a method for FEM results interpretation is presented, and design-related solutions ensuring the production of defect-free hollow balls are proposed.
Upregulation of MMPs in Metastatic Cascade of Breast Cancer To Brain
Authors: Farahani Mohammad Kamalabadi , Atashi Amir , Bitaraf Fateme Sadat , Karimi Roqaye , Eslami Mohammad Masoud
Published: October 2021

Background

Brain metastasis is a lethal complication in triple negative breast cancer (TNBC) patients. Many factors including tumor cell molecular characteristics and biological environment are the main determinant in the brain metastasis process. Matrix metalloproteinases (MMPs) play a key role in extracellular matrix degradation, implicated in numerous aspects of metastasis processes of breast cancer.
Methods

After development of syngenic animal model of TNBC, primary breast cancer cells named 4T1T were isolated from tumor mass. Highly metastatic tumor cells named 4T1B were isolated and expanded from brain metastasis lesions of cancerous mice. Quantitative real-time polymerase chain reaction and gelatinase zymography were performed to analyze the expression of MMPs in transcriptomic and proteomic level in 4T1T and 4T1B.
Results

Our data revealed that, expression of MMPs was significantly upregulated in brain metastatic tumor cells. In transcriptomic level, MMP-2 and MMP-9 genes expression were up-regulated 4 and 3.4 folds in 4T1B, respectively. Zymographic analysis could be detect MMPs activity only in 4T1B.
Conclusion

These findings provided important insights regarding the gross alteration of MMPs expression in brain metastatic cascade of TNBC for the first time. Analysis of molecular properties of brain metastatic tumor cells can be used for understanding of molecular and genetic aspects of brain metastasis and also designing a targeted therapeutic strategies in combat with brain metastasis of TNBC.
Treatment of Severe Kyphotic Deformity Secondary to Ankylosing Spondylitis by Staged Osteotomy in Lateral Decubitus Position: A Retrospective Study
Authors: Zhong Rui , Hu Zhengjun , Zhao Deng , Wang Fei , Huang Huaqiang , Jiang Dengxu , Zhang Zhong , Yijian Liang
Published: October 2021

Background: Patients are often complicated with severe kyphotic deformity (Cobb>100 °) in the advanced stage of ankylosing spondylitis (AS). Corrective osteotomy based on prone position seems to be the only effective treatment. Sometimes, it is difficult to place AS patients with severe kyphosis in a prone position even with a specially prepared folding bed.Methods: 23 patients who underwent staged osteotomy in lateral position from October 2015 to June 2017 were analyzed. All but one patient underwent a single-level Ponte osteotomy in the first stage surgery; pedicle subtraction osteotomy was then carried out in the second stage surgery. The average follow-up was 30.8±4.6 months. The global kyphosis (GK), thoracic kyphosis (TK), lumbar lordosis (LL), the sagittal vertical axis (SVA), the osteotomized vertebra intervertebral angle (OVI), Chin-brow vertical angle (CBVA), the Oswestry Disability Index (ODI) score and the Scoliosis Research Society-22 Patient Questionnaire (SRS-22), were compared pre-and post-operation.Results：All kyphosis parameters were significantly improved (all P< 0.05). The GK was corrected from 115.0± 13.4 ° to 46.5 ± 9.0 ° postoperatively, with a mean correction of 68.5 °. The SVA was improved from 21.2 ± 5.1 cm to 5.1 ± 1.8 cm postoperatively. The CBVA was corrected from 64.1±23.2 ° to 5.7±10.6 ° postoperatively; The OVI was corrected from 9.0±2.7 ° to -20.1±5.6 ° postoperatively. There were significant improvements in the ODI and SRS-22 (all P< 0.05). 4 mild complications were observed perioperatively.Conclusion：Satisfactory correction is safely achieved by staged osteotomy in lateral decubitus position in AS patients with severe kyphosis, which can not only correct the sagittal imbalance of the spine with acceptable complications but also facilitate the placement of intraoperative position.
A Missing Piece of the Puzzle in Pulmonary Fibrosis: Anoikis Resistance Promotes Fibroblast Activation
Authors: Yin Juan , Wang Jing , Zhang Xinxin , Liao Yan , Luo Wei , Wang Sha , Ding Jiawei , Huang Jie , Chen Mengling , Wang Wei , Fang Shencun , Chao Jie
Published: October 2021

Background Pulmonary fibrosis initiates a pneumonic cascade that leads to the dysfunction of fibroblasts characterized by excess proliferation. Anoikis is a physiological process that ensures tissue development and homeostasis. Whether disruption of anoikis is involved in pulmonary fibrosis remains unclear. Results Here, we investigated the mechanism by which silica induces fibroblast activation via anoikis resistance in the subsequent fibrosis. Anoikis of lung fibroblasts, alveolar epithelial cells and endothelial cells during the process of fibrosis was detected by CCK-8, western blot, cell count and flow cytometry (FCM) assays. While the three cell types showed similar increases in cell proliferation, the expression of NTRK2, a marker of anoikis resistance, was upregulated specifically in fibroblasts, indicating the unique proliferative mechanism of fibroblasts in pulmonary fibrosis, which may be related to anoikis resistance. Furthermore, the CRISPR/Cas9 system was used to investigate the molecular mechanism of anoikis resistance; the SiO2-induced inflammatory response activated the MAPK/PI3K signaling pathway in lung fibroblasts and then induced the protein expression of ZC3H4, which specifically mediated anoikis resistance, followed by pulmonary fibrosis. Conclusion The current study revealed a specific pattern of fibroblast proliferation, and targeting anoikis resistance may inhibit the pathological process of pulmonary fibrosis. This result provides a new approach for treating pulmonary fibrosis and new insights for the potential application of ZC3H4 in the development of novel therapeutic strategies for mitigating pulmonary fibrosis.
Identification of Novel Prognostic Factors Focusing on Clinical Outcomes in Patients With Non-small Cell Lung Cancers After Stereotactic Body Radiotherapy
Authors: Sato Hikari , Ito Fumiki , Hasegawa Kazuki , Saga Ryo , Hosokawa Yoichiro , Tanaka Mitsuki , Aoki Masahiko
Published: October 2021

BackgroundStereotactic body radiotherapy (SBRT) has extensively attracted attention as an effective treatment for patients with early-stage non-small cell lung cancers (NSCLCs). However, the factors affecting prognosis after SBRT have not been fully elucidated. The purpose of this study was to investigate the prognostic factors associated with overall survival (OS) and local control (LC) after SBRT.MethodsFrom March, 2003 to March, 2020, 497 patients with primary or oligo-metastatic lung cancer who underwent SBRT treatment were retrospectively reviewed. Univariate analysis was performed against various factors related to patient and tumor characteristics using Kaplan–Meier method. Furthermore, the factors with a statistically significant differences identified via univariate analysis were put in a stratified Cox proportional hazard regression analysis.ResultsThe median follow-up period for all patients was 26.17 months (range, 0.36–194.37), and the 5-year OS and LC rates were 66.3% and 86.0%, respectively. Multivariate analysis showed that surfactant protein-D (SP-D), tumor CT values (TCTV) and iodine density values (IDV) were independent prognostic factors for OS, and histology, TCTV, and IDV were for LC. Although histology was not selected as a prognostic factor related to OS, it was indicated that squamous cell carcinoma patients were associated with the SP-D high group compared to the SP-D normal group. In addition, TCTV was correlated to water density values (WDV) which tended to decrease with increasing IDV.ConclusionThis study suggested that SP-D and TCTV are new candidate prognostic factors after SBRT. There is possibility that combining SP-D and histology, and TCTV and IDV might be improved the accuracy of prognostic prediction.
Neural circuitry for maternal oxytocin release induced by infant cries
Authors: Froemke Robert , Valtcheva Silvana , Issa Habon , Martin Kathleen , Jung Kanghoon , Kwon Hyung-Bae
Published: October 2021

Oxytocin is a neuropeptide important for maternal physiology and childcare, including parturition and milk ejection during nursing1-8. Suckling triggers oxytocin release, but other sensory cues- specifically infant cries- can elevate oxytocin levels in new human mothers9-11 indicating that cries can activate hypothalamic oxytocin neurons. Here we describe a neural circuit routing auditory information about infant vocalizations to mouse oxytocin neurons. We performed in vivo electrophysiological recordings and photometry from identified oxytocin neurons in awake maternal mice presented with pup calls. We found that oxytocin neurons responded to pup vocalizations, but not pure tones, via input from the posterior intralaminar thalamus, and repetitive thalamic stimulation induced lasting disinhibition of oxytocin neurons. This circuit gates central oxytocin release and maternal behavior in response to calls, providing a mechanism for the integration of sensory cues from the offspring in maternal endocrine networks to ensure modulation of brain state for successful parenting.
Postoperative Changes After Phacoemulsification with Posterior Intraocular Lens Implantation Combined with Goniosynechialysis in Patients with Different Axial Lengths
Authors: Xia Jiali , Hu Fei , Fan Liqi , Yu Ling , Ye Jian
Published: October 2021

Background: With the aging of the global population, the incidence of primary angle-closure glaucoma (PACG) or primary angle closure (PAC) with concomitant cataracts has been increasing. We aimed to compare the corneal higher-order aberrations, refractive error and ocular biological parameters changes after phacoemulsification with posterior intraocular lens implantation combined with goniosynechialysis (Phaco-IOL-GSL) was performed in PACG or PAC patients with concomitant cataracts and different axial lengths. Methods: 83 eyes of 69 patients in cataracts with PACG or PAC were divided into two groups according to the axial length (AL): the short (AL ≤ 22.5 mm) and normal axial group (22.5 < AL ≤ 24.5 mm). The intraocular pressure (IOP) and best-corrected visual acuity (BCVA) were measured before surgery and 1-day, 1-week, 1-month, 3-month, 6-month, 12-month after surgery. The corneal higher-order aberrations, antiglaucoma medications, visual fields, refractive diopter and other ocular biological parameters were measured before surgery and at the last follow-up. The difference between the two groups was assessed after surgery. Results: Compared with the baseline, the BCVA significantly improved, while IOP was decreased in both groups (P < 0.01). Both anterior and total cornea HOAs and Z (3,-3) were increased in both groups (P < 0.05 and P < 0.05, respectively) and the larger increments in Z (3,-3) were found in normal axial group. The anterior chamber depth (ACD) and the AL were increased in both groups after Phaco-IOL-GSL ( P< 0.01 and P < 0.01, respectively); however, no difference was found between two groups (P = 0.191, P = 0.066). The refractive outcomes were significantly different in both groups (P = 0.029), and a slight shift towards hyperopia was observed in normal axial group (P = 0.002). Correlation analysis found that refractive error was positively correlated with increments in ACD (r = 0.373, P = 0.001) and decrements in AL (r = 0.331, P = 0.002). Conclusions: Phaco-IOL-GSL is an effective surgery for cataract patients with PACG or PAC. After surgery, anterior and total cornea Z (3, -3) varied with different AL at one-year follow-up. The refractive errors such as hyperopic shifts increased when the ACD was increased, and AL was decreased after surgery, especially in patients with normal axial lengths.
The Impact of Age in Acute Type A Aortic Dissection: a Retrospective Study
Authors: Wang Junxia , Xue Yunxing , Zhu Xiyu , Chong Hoshun , Chen Zhong , Zhou Qing , Qu Jason Zhensheng , Wang Dongjin
Published: October 2021

Background: Acute type A aortic dissection (aTAAD) is a lethal disease and age is an important risk factor for outcomes. This retrospective study was to analyze the impact of age stratification in aTAAD, and to provide clues for surgeons when they make choices of therapy strategies. Methods: From January 2011 to December 2019, 1092 aTAAD patients from Nanjing Drum Tower Hospital received surgical therapy. Patients were divided into 7 groups according to every ten-year interval (20s-80s). The differences between the groups were analyzed in terms of the baseline preoperative conditions, surgical methods and postoperative outcomes of patients of different age groups. During a median follow-up term of 17 months, the survival rates were compared among 7 groups through Kaplan-Meier analysis.Results: The median age was 52.0 years old in whole cohort. The multiple comorbidities were more common in old age groups (60s, 70s, 80s), while the 20s group patients had the highest proportion of Marfan syndrome (28.1%). Preoperative hypotension was highest in 80s (16.7%, P=0.038). Young age groups (20s-60s) had a higher rate of root replacement and total arch replacement, which led to a longer duration of operation and hypothermic circulation arrest. The overall mortality was 14.1%, the tendency of mortality was increased with age except 20s group (33.3% in 80s, P=0.016). The postoperative morbidity of gastrointestinal bleeding and bowel ischemia were 16.7% and 11.1% in 80s group. Conclusions: Age is a major impact factor for aTAAD surgery. Old patients presented more comorbidities before surgery, the mortality and complications rate were significantly higher even with less invasive and conservative surgical therapy. But the favorable long term survival indicated that the simple or less extensive arch repair is the preferred surgery for patients over 70 years old.