[Analysis of Clinical Characteristics and Laboratory Indicators in Patients with Solid Malignant Tumor-Associated Venous Thromboembolism].

OBJECTIVE: To analyze the clinical features and laboratory indicators in patients with solid malignant tumor-associated venous thromboembolism (Ta-VTE), and to study the risk factors for Ta-VTE. METHODS: The hospitalized patients with VTE in Guizhou Provincial People's Hospital from January to December 2020 were enrolled, and they were divided into Ta-VTE group and pure VTE group based on the presence or absence of solid malignant tumor. The differences in clinical data and laboratory indicators between the two groups were analyzed, and the indicators with significant differences were included in logistic regression model to analyze the risk factors of Ta-VTE. RESULTS: A total of 288 patients with VTE were included in this study, including 64 cases in Ta-VTE group and 224 cases in pure VTE group, respectively. There were significant differences in the following indexes between the two groups, including the hospitalization time (14.20±15.29 d vs 10.05±6.90 d, t=3.112, P =0.002), pain (35.94% vs 65.18%, χ2=17.554, P =0.000), recent surgery (75.00% vs 37.50%, χ2=28.196, P =0.000), D-dimer [2.8 (0.92, 7.55) µg/ml vs 5.69 (2.25, 13.91) µg/ml, Z=-2.710, P =0.007], PLR[198.59 (139.54, 312.16) vs 149.76 (114.08, 233.66), Z=-2.924, P =0.003] and TBIL[10.90 (7.63, 15.68) µmol/L vs 12.90 (9.33, 18.28) µmol/L, Z=-2.066, P =0.039]. There was no significant difference in the other indicators (P >0.05). The result of multivariate logistic regression analysis showed that elevated PLR (OR =1.003, 95%CI : 1.000-1.006, P =0.027), recent surgery (OR =4.312, 95%CI : 2.093-8.885, P =0.000) and prolonged hospitalization (OR =1.037, 95%CI : 1.002-1.074, P =0.038）were independent risk factors for Ta-VTE. However, pain (OR =0.274, 95%CI : 0.133-0.564, P =0.000) was a protective factor. CONCLUSION: Elevated PLR level, recent surgery and prolonged hospital stay are independent risk factors for Ta-VTE patients, and rational use of these indicators is helpful for the clinical diagnosis and treatment of Ta-VTE patients.

Molecular classification of human papillomavirus-positive cervical cancers based on immune signature enrichment.

Background: Human papillomavirus-positive (HPV+) cervical cancers are highly heterogeneous in clinical and molecular characteristics. Thus, an investigation into their heterogeneous immunological profiles is meaningful in providing both biological and clinical insights into this disease. Methods: Based on the enrichment of 29 immune signatures, we discovered immune subtypes of HPV+ cervical cancers by hierarchical clustering. To explore whether this subtyping method is reproducible, we analyzed three bulk and one single cell transcriptomic datasets. We also compared clinical and molecular characteristics between the immune subtypes. Results: Clustering analysis identified two immune subtypes of HPV+ cervical cancers: Immunity-H and Immunity-L, consistent in the four datasets. In comparisons with Immunity-L, Immunity-H displayed stronger immunity, more stromal contents, lower tumor purity, proliferation potential, intratumor heterogeneity and stemness, higher tumor mutation burden, more neoantigens, lower levels of copy number alterations, lower DNA repair activity, as well as better overall survival prognosis. Certain genes, such as MUC17, PCLO, and GOLGB1, showed significantly higher mutation rates in Immunity-L than in Immunity-H. 16 proteins were significantly upregulated in Immunity-H vs. Immunity-L, including Caspase-7, PREX1, Lck, C-Raf, PI3K-p85, Syk, 14-3-3_epsilon, STAT5-α, GATA3, Src_pY416, NDRG1_pT346, Notch1, PDK1_pS241, Bim, NF-kB-p65_pS536, and p53. Pathway analysis identified numerous immune-related pathways more highly enriched in Immunity-H vs. Immunity-L, including cytokine-cytokine receptor interaction, natural killer cell-mediated cytotoxicity, antigen processing and presentation, T/B cell receptor signaling, chemokine signaling, supporting the stronger antitumor immunity in Immunity-H vs. Immunity-L. Conclusion: HPV+ cervical cancers are divided into two subgroups based on their immune signatures' enrichment. Both subgroups have markedly different tumor immunity, progression phenotypes, genomic features, and clinical outcomes. Our data offer novel perception in the tumor biology as well as clinical implications for HPV+ cervical cancer.

The Clinical Observation on PONV with the Intervention of Thumbtack Needles Combined with Chinese Medicine Ironing Therapy.

Objective: This study aimed to analyze the clinical efficacy of the intervention of thumbtack needles (applicable to subcutaneous embedding) combined with Chinese medicine ironing therapy on postoperation nausea and vomiting (PONV). Methods: 106 patients who scheduled elective surgery were enrolled and randomized into control group and experimental group, with 53 cases in each group. The control group received modern medication, while the experimental group was given thumbtack needles combined with Chinese medicine ironing therapy based on the control group. The PONV score, incidence rate, gastrointestinal hormone level, Functional Living Index-Emesis (FLIE), and General Comfort Questionnaire (GCQ) of the two groups were compared. Results: After treatment, the incidence of PONV and GCQ in the experimental group was observed to be remarkably lower than that in the control group (P < 0.05), while the levels of gastrointestinal hormones and the level in the FLIE of the experimental group were comparatively higher than those in the control group (P < 0.05). Conclusion: Thumbtack needles combined with Chinese medicine ironing therapy can be utilized to reduce the incidence of PONV, to improve the level of gastrointestinal hormones, and to improve the comfort and quality of patients' lives.

Inferring Users' Social Roles with a Multi-Level Graph Neural Network Model.

Users of social networks have a variety of social statuses and roles. For example, the users of Weibo include celebrities, government officials, and social organizations. At the same time, these users may be senior managers, middle managers, or workers in companies. Previous studies on this topic have mainly focused on using the categorical, textual and topological data of a social network to predict users' social statuses and roles. However, this cannot fully reflect the overall characteristics of users' social statuses and roles in a social network. In this paper, we consider what social network structures reflect users' social statuses and roles since social networks are designed to connect people. Taking an Enron email dataset as an example, we analyzed a preprocessing mechanism used for social network datasets that can extract users' dynamic behavior features. We further designed a novel social network representation learning algorithm in order to infer users' social statuses and roles in social networks through the use of an attention and gate mechanism on users' neighbors. The extensive experimental results gained from four publicly available datasets indicate that our solution achieves an average accuracy improvement of 2% compared with GraphSAGE-Mean, which is the best applicable inductive representation learning method.

CsIL-11, a teleost interleukin-11, is involved in promoting phagocytosis and antibacterial immune defense.

Interleukin (IL)-11 is a multifunctional cytokine belonging to the IL-6 family, which plays essential roles in immune response. However, much less is known about the immunological functions of IL-11 in teleost. In this study, we investigated the immune properties of a teleost IL-11 homologue (CsIL-11) from tongue sole Cynoglossus semilaevis. CsIL-11 possesses four conserved α-helices and conserved CsIL-11 receptor binding residues L86 and R187, and shares 23.3%-80.1% identities with other IL-11 homologues. CsIL-11 expression was constitutive in tissues, with most abundant in blood and least abundant in spleen, and upregulated by bacterial challenge in blood, spleen, and head kidney. Recombinant CsIL-11 (rCsIL-11) in the native form of monomer, could bind to peripheral blood leukocytes (PBLs) membrane and enhance the activation and phagocytosis of PBLs. When administered in vivo, rCsIL-11 could markedly promote the host to defend against microbial infection. Overall, our findings show that CsIL-11 plays a pivotal role in regulating PBLs phagocytosis and antibacterial immunity.

[Osteogenic Capacity and Mettl14 and Notch1 Expression of Adipose-Derived Stem Cells from Osteoporotic Rats].

OBJECTIVE: To investigate the differences in the osteogenic capacity of osteoporotic adipose-derived stem cells (OP-ASCs) and normal control adipose-derived stem cells (Ctrl-ASCs), and to examine the expression levels of RNA methyltransferase like 14 (Mettl14) and the Notch signaling molecule 1 (Notch1). METHODS: The osteoporosis (OP) model of SD rats was established with ovariectomy (OVX). Micro-CT, HE staining and Masson staining were performed to identify the successful establishment of the OP model, OP-ASCs and Ctrl-ASCs were isolated and cultured adherently. Then, the three-way differentiation capacity of the adipose-derived stem cells (ASCs) was determined through alizarin red staining, alcian blue staining and oil red O staining and flow cytometry was conducted to examine the surface antigens CD29, CD44, CD90, CD31, CD34, and CD45. Alizarin red staining and comparison of the mRNA and protein expression of Run-related transcription factor 2 (Runx2) were done to explore the differences in osteogenic potential of OP-ASCs and Ctrl-ASCs. Real-time PCR and Western blot were performed to explore the expression differences of Mettl14 and Notch1 at mRNA and protein levels between OP-ASCs and Ctrl-ASCs. RESULTS: Micro-CT, HE and Masson staining results showed that the number of trabecular bone decreased and the spacing increased in the tibias of the osteoporosis group (OP group) compared with those of the control group (Ctrl group), indicating that the OP model was established successfully. Three-way differentiation and flow cytometry results confirmed the successful isolation and culture of ASCs. After osteogenic induction, alizarin red staining showed that OP-ASCs had fewer number and more scattered distribution of mineralized nodules than Ctrl-ASCs did. The expression of Runx2 in OP-ASCs was lower than that in Ctrl-ASCs ( P<0.05). Mettl14 as well as Notch1 showed lower expression in OP-ASCs than they did in Ctrl-ASCs ( P<0.05). CONCLUSION: The osteogenic capacity of OP-ASCs was lower compared with that of Ctrl-ASCs, Mettl14 expression of OP-ASCs was decreased compared with that of Ctrl-ASCs, and the Notch signaling pathway was inhibited in OP-ASCs. The study helps build the foundation for further investigation in the specific mechanisms of Mettl14 and Notch1 during osteogenic differentiation of OP-ASCs.

The Predictive Significance of the Advanced Lung Cancer Inflammation Index (ALI) in Patients with Melanoma Treated with Immunotherapy as Second-Line Therapy.

PURPOSE: The advanced lung cancer inflammation index (ALI) is a useful tool to predict the clinical outcome in several malignancies. The ALI not only contains indices related to inflammation but also the body mass index (BMI), which was reported to correlate with the sarcopenic status. However, to date, its predictive significance in metastatic melanoma patients treated with second-line immunotherapy has not been evaluated. METHODS: We retrospectively analyzed data from patients who were diagnosed with metastatic melanoma and treated with immunotherapy as second-line therapy between 2016 and 2019. Weight, height, neutrophil, lymphocyte and serum albumin were collected at baseline prior to receiving immunotherapy. The BMI was calculated by dividing the weight by height squared. The neutrophil-to-lymphocyte ratio (NLR) was calculated by dividing the absolute neutrophil count by the absolute lymphocyte count. The ALI was defined as follows: ALI=BMI×serum albumin/NLR. The receiver operator curve (ROC) was used to determine the best cutoff value for ALI in predicting disease control (consisting of complete response, partial response and stable disease). The aim of this study was to investigate whether the ALI is a predictive indicator for progression-free survival in melanoma patients. RESULTS: Forty-three patients were included in this retrospective cohort study. By ROC, ALI>50.98 before immunotherapy was predictive of disease control. Baseline continuous variables, such as BMI, NLR, C-reactive protein and C-reactive protein-to-albumin ratio, had significantly worse scores in patients of the low-ALI group (n=24) than high-ALI group (n=19). The median progression-free survival was significantly worse in the patients with ALI<50.98 than the patients with ALI>50.98 (2.60 months vs 11.17 months, P = 0.023, hazard ratio: 2.241, 95% confidence interval: 1.167-5.097). CONCLUSION: The advanced lung cancer inflammation index (ALI) >50.98 before immunotherapy is a strong predictor for disease control. The ALI also provides great predictive value for metastatic melanoma patients treated with immunotherapy as second-line therapy.

[Retracted] p53 suppresses stress­induced cellular senescence via regulation of autophagy under the deprivation of serum.

Following the publication of this article, an interested reader drew to the Editor's attention that certain GAPDH control bands were strikingly similar, comparing between two different figures in the paper. Two GAPDH bands in Fig. 1D appeared to be duplicates of two GAPDH bands featured in Fig. 3B, although different conditions were represented by these figures. Furthermore, the protein bands featured in the two lanes in the left p62 panel in Fig. 1D, when flipped horizontally, looked remarkably similar to the Cyclin B lanes featured in the right-hand gel of Fig. 3B. Finally, the same protein bands were also strikingly similar to bands featured in Fig. 4B, albeit in a different experimental context. The Editor of Molecular Medicine Reports has investigated this matter, and we were able to confirm that the two sets of data bands featured in this trio of figures were indeed the same ones, beyond all reasonable doubt. Consequently, the Editor has decided that this article should be retracted from the publication on the basis of an overall lack of confidence in the presented data. The Editor apologizes to the readership of the Journal for any inconvenience caused. [the original article was published in Molecular Medicine Reports 11: 1214-1220, 2015; DOI: 10.3892/mmr.2014.2853].

[Precise investigation of digital guide plates applied to implant surgery of anterior teeth].

OBJECTIVE: To study the precision of digital guide plates applied to the implant surgery of anterior teeth. METHODS: Fifty patients scheduled to receive implant restoration treatment in anterior teeth were enrolled in this study and divided into two groups (n=25, each group): those who were given routine implant restoration treatment (control group, 45 implants) and those who received implant restoration treatment using a digital guide plate (test group, 51 implants). After implantation, planned and placed implants were superimposed using digital software, and deviations (corona, apex, depth, degree) were analyzed. Esthetic parameters were assessed at 1 week (baseline), 6 month, and 1 year post final restoration. Pink esthetic (PES) and white esthetic (WES) scores were respectively used to evaluate the soft tissue and restoration esthetic outcome. RESULTS: The deviation parameters in the test group were significantly lower than those in the control group (P<0.05). PES and WES values recorded for the control group at 1 week, 6 month, and 1 year post final restoration were significantly lower than those in the test group (P<0.05). CONCLUSIONS: The digital guide plate can improve the accuracy of the three-dimensional position of implants in the maxillary esthetic zone. As such, this device may play an important role in obtaining the ideal aesthetic effects of maxillary anterior teeth.

A Phase Ib Study of Pembrolizumab as Second-Line Therapy for Chinese Patients With Advanced or Metastatic Melanoma (KEYNOTE-151).

BACKGROUND: Pembrolizumab shows robust antitumor activity and favorable safety in metastatic melanoma. KEYNOTE-151 evaluated pembrolizumab in Chinese patients, who have more aggressive melanoma subtypes than other populations. METHODS: Chinese patients aged ≥18years with advanced melanoma previously treated with one line of therapy received pembrolizumab 2 mg/kg every 3 weeks for 35 cycles or until confirmed disease progression, intolerable toxicity, or study withdrawal. Primary end points were objective response rate (ORR) per RECIST v1.1 by blinded independent central review and safety. Key secondary end points included duration of response (DOR) and progression-free survival (PFS) per RECIST v1.1 and overall survival (OS). RESULTS: Median age was 52 years (N=103); 37.9% had acral and 14.6% had mucosal melanoma. Median follow-up was 7.9months at data cutoff (December 27, 2017). ORR was 16.7% (95% CI, 10.0-25.3%) (1 complete, 16 partial responses). Disease control rate was 38.2%. ORR was 15.8% for acral, 13.3% for mucosal melanoma. Median DOR was 8.4months; 65.6% of patients had response duration ≥6months. Median PFS was 2.8months (95% CI, 2.7-3.5months); 6-month rate was 20.4%. Median OS was 12.1months (95% CI, 9.6months-not reached); 6-month rate, 75.7%; 12-month rate, 50.6%. Treatment-related AEs (TRAEs) occurred in 87 (84.5%) patients; 9 (8.7%) experienced grade 3/4 TRAE and 2 (1.9%) discontinued because of TRAE; none died. Two deaths occurred that were unrelated to treatment. CONCLUSIONS: Pembrolizumab was well tolerated and provided clinically meaningful antitumor activity as second-line therapy in Chinese patients with advanced melanoma.

Multiple Primary Malignant Tumors - A Clinical Analysis of 15,321 Patients with Malignancies at a Single Center in China.

Background: Multiple primary malignant tumors (MPMTs) are defined as two or more histologically distinct malignancies in one individual, standard treatments for MPMTs are not well established, we aimed to clinical analyze the factors influence the treatment efficacy of MPMTs. Methods: This study retrospectively analyzed 15,321 malignant tumor patients at the Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, China, between March 2006 and June 2016. The survival analysis was performed with SPSS version 22.0 (SPSS Inc., Chicago, IL, USA) with Kaplan-Meier methodology. Results: The prevalence of MPMTs in our study was 1.09% (167/15321), with a male to female ratio of 2.34:1. Specifically, 98 patients harbored synchronous MPMTs, and 69 patients harbored metachronous MPMTs. The most common cancer pairs were digestive-digestive tumor (43 patients, 25.75%), digestive-lung cancer (32 patients, 19.16%), and head & neck-digestive tumor (11 patients, 6.59%). Among patients with synchronous and metachronous first primary cancers, 65.86% received surgery. 33.33% (27/81) of the patients with synchronous MPMTs received simultaneous resection. Of the 69 patients with metachronous MPMTs, 31.88% (22/69) were treated with surgery alone, 62.32% (43/69) received chemotherapy and/or radiotherapy for the first primary tumor, and 44.93% (31/69) received surgery for the other primary tumor. 98.20% (164/167) of patients with MPMTs were effectively followed up, the overall 2- and 5-year survival rates were 54.3% and 31.4%, respectively, with a median survival time of 28.0 months. Conclusions: The early diagnosis of rare MPMTs should not be neglected in patients not only when treated for a primary malignancy but also during long-term follow-up. Effective treatment for MPMTs may yield promising curative effect and warrants further investigation.

Thermal Radiofrequency Ablation as an Adjuvant Therapy for Patients With Colorectal Liver Metastasis.

Radiofrequency ablation (RFA) is a minimally invasive technology for the treatment of liver malignancies and is used as an adjuvant therapy in patients with colorectal liver metastasis (CLM). This study enrolled a total of 49 CLM patients who underwent RFA treatment. Univariate and multivariate analyses were performed using the log-rank test and Cox proportional hazard model, respectively. Univariate analysis showed that OS was closely correlated with tumor size, frequency of RFA treatment, resection of the liver lesion, and CEA levels before RFA (p < 0.05). Multivariate analysis revealed that resection of CLM lesions after RFA, frequency of RFA treatment, and serum CEA levels before RFA were independent risk factors for the survival of CLM patients (p < 0.05). Tumor lesion size, resection of the liver lesion after RFA, frequency of RFA treatment, and serum CEA levels before RFA may be important prognostic factors of CLM patients treated with RFA therapy.

Histone deacetylase 2 regulates doxorubicin (Dox) sensitivity of colorectal cancer cells by targeting ABCB1 transcription.

PURPOSE: Histone deacetylases (HDACs) have been shown to regulate cell cycle, differentiation, and apoptosis of colorectal cancer (CRC) cells, while their roles in drug sensitivity remain unclear. The objectives of the present study were to investigate the effects of HDAC2 on drug resistance of CRC cells. METHODS: We measured the expression of class I HDACs (HDAC1, 2, 3, 8) in CRC and human normal colonic epithelial cells. Additionally, we inhibited HDAC2 via siRNA or overexpressed it via pcDNA/HDAC2 transfection to evaluate its roles in doxorubicin (Dox) sensitivity. RESULTS: Our present study showed HDAC2 was significantly increased in CRC cell lines as compared to human normal colonic epithelial cells. Silencing of HDAC2 can obviously enhance the sensitivity of HCT-116 and SW480 cells to dDox. Further, knockdown of HDAC2 can significantly (p < 0.05) downregulate the expression of ABCB1, while not ABCG2, ABCC1, ABCA1, or ABCC2. Inhibition of HDAC2 decreased ABCB1 promoter activities and the phosphorylation of c-fos and c-Jun, which can directly interact with the ABCB1 promoter and then promote its transcription. Overexpression of HDAC2 by pcDNA/HDAC2 transfection significantly increased the sensitivity of CRC cells to Dox and upregulated the levels of P-gp, p-c-fos, and p-c-Jun. CONCLUSIONS: Our data revealed that HDAC2 can regulate Dox sensitivity of CRC cells by targeting ABCB1 transcription. It suggested that HDAC2 might be an important target for CRC therapy. Further, the combination of HDAC2-specific inhibitor and anticancer drugs including Dox might be an efficiency approach to elevate the treatment outcome of CRC.

Autophagy-associated immune responses and cancer immunotherapy.

Autophagy is an evolutionarily conserved catabolic process by which cellular components are sequestered into a double-membrane vesicle and delivered to the lysosome for terminal degradation and recycling. Accumulating evidence suggests that autophagy plays a critical role in cell survival, senescence and homeostasis, and its dysregulation is associated with a variety of diseases including cancer, cardiovascular disease, neurodegeneration. Recent studies show that autophagy is also an important regulator of cell immune response. However, the mechanism by which autophagy regulates tumor immune responses remains elusive. In this review, we will describe the role of autophagy in immune regulation and summarize the possible molecular mechanisms that are currently well documented in the ability of autophagy to control cell immune response. In addition, the scientific and clinical hurdles regarding the potential role of autophagy in cancer immunotherapy will be discussed.

MicroRNA-26a regulates insulin sensitivity and metabolism of glucose and lipids.

Type 2 diabetes (T2D) is characterized by insulin resistance and increased hepatic glucose production, yet the molecular mechanisms underlying these abnormalities are poorly understood. MicroRNAs (miRs) are a class of small, noncoding RNAs that have been implicated in the regulation of human diseases, including T2D. miR-26a is known to play a critical role in tumorigenesis; however, its function in cellular metabolism remains unknown. Here, we determined that miR-26a regulates insulin signaling and metabolism of glucose and lipids. Compared with lean individuals, overweight humans had decreased expression of miR-26a in the liver. Moreover, miR-26 was downregulated in 2 obese mouse models compared with control animals. Global or liver-specific overexpression of miR-26a in mice fed a high-fat diet improved insulin sensitivity, decreased hepatic glucose production, and decreased fatty acid synthesis, thereby preventing obesity-induced metabolic complications. Conversely, silencing of endogenous miR-26a in conventional diet-fed mice impaired insulin sensitivity, enhanced glucose production, and increased fatty acid synthesis. miR-26a targeted several key regulators of hepatic metabolism and insulin signaling. These findings reveal miR-26a as a regulator of liver metabolism and suggest miR-26a should be further explored as a potential target for the treatment of T2D.

MicroRNAs-mediated cell fate in triple negative breast cancers.

MicroRNAs (miRNAs) are small non-coding RNAs that function as major modulators of posttranscriptional protein-coding gene expression in diverse biological processes including cell survival, cell cycle arrest, senescence, autophagy, and differentiation. The control of miRNAs plays an important role in cancer initiation and metastasis. Triple negative breast cancer (TNBC) is a distinct breast cancer subtype, which is defined by the absence of estrogen receptor (ER), progesterone receptor (PR) and epidermal growth factor receptor 2 (HER2/neu). Due to its high recurrence rate and poor prognosis, TNBC represents a challenge for breast cancer therapy. In recent years, a large number of microRNAs have been identified to play a crucial role in TNBC and some of them were found to be correlated with worse prognosis of TNBC. Thus, understanding the novel function of miRNAs may allow us to develop promising therapeutic targets for the treatment of TNBC patients.

p53 suppresses stress-induced cellular senescence via regulation of autophagy under the deprivation of serum.

The tumor suppressor p53 is widely known for its ability to induce cell cycle arrest or cell death, therefore preventing neoplastic progression. Previous studies have demonstrated novel roles for p53 in the regulation of autophagy and senescence. p53 can not only exert cell cycle­arresting and senescence­promoting or suppressing functions, but can also induce autophagic flux, particularly under conditions of nutrient deprivation. The present study demonstrated that p53 was capable of activating autophagy, which permits cell survival under conditions of serum starvation, and suppresses cellular senescence through inhibition of the mammalian target of rapamycin pathway. These results suggest that active autophagy may be a potential mechanism by which p53 suppresses cellular senescence, in response to serum starvation. The findings of the present study provide a potential mechanism for suppression of senescence by p53.