Prognostic risk stratification value of MACC1 expression in patients with gastric cancer.

BACKGROUND: The prognostic significance of metastasis-associated in colon cancer-1 (MACC1) has been explored in a variety of malignancies. However, its clinical relevance in patients with gastric cancer (GC) is limited, also remains controversial. METHOD: In this study, we retrospectively evaluated the prognostic value of lesion MACC1 expression in 347 GC patients. Lesion MACC1 expression was analyzed with immunohistochemistry and grouped as MACC1low (n = 172) and MACC1high (n = 175) cases. RESULTS: Data revealed that the degree of MACC1 expression is not related to patient sex, age and disease stage (all p > 0.05). Survival analysis showed that only post-operation advanced pT (p = 0.018), pN (p < 0.001), pM (p = 0.001) and AJCC stages (p < 0.001) are significantly associated with shorter survival, while no obvious difference was observed between MACC1low and MACC1high cases (p = 0.158). However, we found that survival for female (p = 0.032), older (p = 0.028), and early disease stage (pT stage I + II, p = 0.033) patients with MACC1high are remarkably worse than those with MACC1low. CONCLUSION: In summary, our findings revealed that, though MACC1 expression is not associated with the survival of the whole cohort, the prognostic risk stratification value of lesion MACC1 expression in subgroups of patients with gastric cancer should be noted.

Filamin A facilitates NLRP3 inflammasome activation during arsenic-induced nonalcoholic steatohepatitis.

Prolonged exposure to arsenic can cause nonalcoholic steatohepatitis (NASH). The NOD-like receptor protein 3 (NLRP3) inflammasome plays an essential role in the process of NASH. However, the mechanism by which arsenic promotes NLRP3 expression remains unclear. Three-month NaAsO2 gavage led to the nuclear factor-κB (NF-κB) signaling pathway activation and NASH. Additionally, NaAsO2 upregulated the level of Filamin A (FLNA) and pyroptosis, thereby activating the NLRP3 inflammasome in SD rat liver. Using FLNA siRNA, NASH-associated inflammation and pyroptosis were clearly mitigated by reducing activation of the NLRP3 inflammasome. Furthermore, arsenic treatment facilitated activation of the NF-κB signaling pathway and promoted p-p65 translocation into the nucleus. Chromatin immunoprecipitation (Ch-IP) assay indicated that FLNA promoted p65 binding to the NLRP3 gene and upregulated the transcription of NLRP3, ultimately leading to pyroptosis and NASH. Our findings indicate that FLNA and pyroptosis are strongly associated with NASH induced by NaAsO2. Collectively, the findings of this study indicated that FLNA mediates NF-κB signaling pathway-induced activation of the NLRP3 inflammasome and ultimately activates pyroptosis and NASH upon NaAsO2 exposure. This information may be useful for improving therapeutic strategies against arsenic-induced NASH.

Glioblastomas with and without peritumoral fluid-attenuated inversion recovery (FLAIR) hyperintensity present morphological and microstructural differences on conventional MR images.

OBJECTIVES: Glioblastoma (GB) without peritumoral fluid-attenuated inversion recovery (FLAIR) hyperintensity is atypical and its characteristics are barely known. The aim of this study was to explore the differences in pathological and MRI-based intrinsic features (including morphologic and first-order features) between GBs with peritumoral FLAIR hyperintensity (PFH-bearing GBs) and GBs without peritumoral FLAIR hyperintensity (PFH-free GBs). METHODS: In total, 155 patients with pathologically diagnosed GBs were retrospectively collected, which included 110 PFH-bearing GBs and 45 PFH-free GBs. The pathological and imaging data were collected. The Visually AcceSAble Rembrandt Images (VASARI) features were carefully evaluated. The first-order radiomics features from the tumor region were extracted from FLAIR, apparent diffusion coefficient (ADC), and T1CE (T1-contrast enhanced) images. All parameters were compared between the two groups of GBs. RESULTS: The pathological data showed more alpha thalassemia/mental retardation syndrome X-linked (ATRX)-loss in PFH-free GBs compared to PFH-bearing ones (p < 0.001). Based on VASARI evaluation, PFH-free GBs had larger intra-tumoral enhancing proportion and smaller necrotic proportion (both, p < 0.001), more common non-enhancing tumor (p < 0.001), mild/minimal enhancement (p = 0.003), expansive T1/FLAIR ratio (p < 0.001) and solid enhancement (p = 0.009), and less pial invasion (p = 0.010). Moreover, multiple ADC- and T1CE-based first-order radiomics features demonstrated differences, especially the lower intensity heterogeneity in PFH-free GBs (for all, adjusted p < 0.05). CONCLUSIONS: Compared to PFH-bearing GBs, PFH-free ones demonstrated less immature neovascularization and lower intra-tumoral heterogeneity, which would be helpful in clinical treatment stratification. CLINICAL RELEVANCE STATEMENT: Glioblastomas without peritumoral FLAIR hyperintensity show less immature neovascularization and lower heterogeneity leading to potential higher treatment benefits due to less drug resistance and treatment failure. KEY POINTS: • The study explored the differences between glioblastomas with and without peritumoral FLAIR hyperintensity. • Glioblastomas without peritumoral FLAIR hyperintensity showed less necrosis and contrast enhancement and lower intensity heterogeneity. • Glioblastomas without peritumoral FLAIR hyperintensity had less immature neovascularization and lower tumor heterogeneity.

Impact of Sample Processing and Storage Conditions on RNA Quality of Fresh-Frozen Cancer Tissues.

Background: A biobank is a central resource that supports basic and clinical research. RNA quality of fresh-frozen tissue specimens in the biobank is highly associated with the success of downstream applications. Therefore, it is very important to evaluate the impact of tissue processing and storage conditions on RNA quality. Methods: A total of 238 surgically removed tissue specimens, including esophagus, lung, liver, stomach, colon, and rectal cancer, were used to evaluate RNA quality. Two tissue homogenization methods, manual and TissueLyser, were compared and the impacts of temperature fluctuation, tissue types, storage period, and clinicopathological parameters on RNA quality were analyzed. Results: RNA integrity was not influenced by tissue homogenization methods and tissue types. However, RNA integrity number (RIN) values were significantly correlated with temperature fluctuation. When the power of a -80°C freezer was cut off, RNA integrity of frozen tissues was not significantly affected until the temperature increased to 0°C. When the temperature rose to room temperature and remained for 4 hours, RNA integrity was almost completely destroyed. In addition, various cancer tissues with short-term storage at -80°C (<5 years) or high tumor differentiation had higher RINs. Conclusions: Tissue processing and storage conditions affected RNA quality of fresh-frozen cancer tissues. It is necessary to keep storage temperature stable and keep specimens at ultralow temperatures during homogenization. Also, for a biobank containing multiple types of cancer tissue samples, it is better to store them in liquid nitrogen if the storage duration is more than 5 years.

Prevalence of human papillomavirus DNA and p16INK4a positivity in vulvar cancer and vulvar intraepithelial neoplasia: a systematic review and meta-analysis.

BACKGROUND: Human papillomavirus (HPV) DNA and p16INK4a positivity have crucial roles in the pathogenesis of vulvar cancer and vulvar intraepithelial neoplasia. We aimed to examine the pooled prevalence of HPV DNA and p16INK4a positivity in vulvar cancer and vulvar intraepithelial neoplasia worldwide. METHODS: In this systematic review and meta-analysis, we searched PubMed, Embase, and the Cochrane Library databases for studies published between Jan 1, 1986, and May 6, 2022, that reported the prevalence of HPV DNA, or p16INK4a positivity, or both, in histologically verified vulvar cancer or vulvar intraepithelial neoplasia. Studies on a minimum of five cases were included. Study-level data were extracted from the published studies. Random effect models were used to examine the pooled prevalence of HPV DNA and p16INK4a positivity in both vulvar cancer and vulvar intraepithelial neoplasia, which were further investigated using stratified analyses by histological subtype, geographical region, HPV DNA or p16INK4a detection method, tissue sample type, HPV genotype, publication year, and age at diagnosis. Additionally, meta-regression was applied to explore sources of heterogeneity. FINDINGS: We retrieved 6393 search results, of which 6233 were excluded for being duplicates or after application of our inclusion and exclusion criteria. We also identified two studies from manual searches of references lists. 162 studies were eligible for inclusion in the systematic review and meta-analysis. The prevalence of HPV in vulvar cancer (91 studies; n=8200) was 39·1% (95% CI 35·3-42·9) and in vulvar intraepithelial neoplasia (60 studies; n=3140) was 76·1% (70·7-81·1). The most predominant HPV genotype in vulvar cancer was HPV16 (78·1% [95% CI 73·5-82·3]), followed by HPV33 (7·5% [4·9-10·7]). Similarly, HPV16 (80·8% [95% CI 75·9-85·2]) and HPV33 (6·3% [3·9-9·2]) were also the most two predominant HPV genotypes in vulvar intraepithelial neoplasia. The distribution of type-specific HPV genotypes in vulvar cancer among geographical regions was different, with HPV16 varying between regions, showing a high prevalence in Oceania (89·0% [95% CI 67·6-99·5]) and a low prevalence in South America (54·3% [30·2-77·4]). The prevalence of p16INK4a positivity in patients with vulvar cancer was 34·1% (95% CI 30·9-37·4; 52 studies; n=6352), and it was 65·7% (52·5-77·7; 23 studies; n=896) in patients with vulvar intraepithelial neoplasia. Furthermore, among patients with HPV-positive vulvar cancer, p16INK4a positivity prevalence was 73·3% (95% CI 64·7-81·2), compared with 13·8% (10·0-18·1) in HPV-negative vulvar cancer. The prevalence of double positivity for HPV and p16INK4a was 19·6% (95% CI 16·3-23·0) in vulvar cancer and 44·2% (26·3-62·8) in vulvar intraepithelial neoplasia. Most analyses had large heterogeneity (I2>75%). INTERPRETATION: The high prevalence of HPV16 and HPV33 in vulvar cancer and vulvar intraepithelial neoplasia emphasised the importance of nine-valent HPV vaccination in preventing vulvar neoplasm. Additionally, this study highlighted the potential clinical significance of double positivity for HPV DNA and p16INK4a in vulvar neoplasm. FUNDING: Taishan Scholar Youth Project of Shandong Province, China.

AS3MT facilitates NLRP3 inflammasome activation by m6A modification during arsenic-induced hepatic insulin resistance.

N6-methyladenosine (m6A) messenger RNA methylation is the most widespread gene regulatory mechanism affecting liver functions and disorders. However, the relationship between m6A methylation and arsenic-induced hepatic insulin resistance (IR), which is a critical initiating event in arsenic-induced metabolic syndromes such as type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD), remains unclear. Here, we showed that arsenic treatment facilitated methyltransferase-like 14 (METTL14)-mediated m6A methylation, and that METTL14 interference reversed arsenic-impaired hepatic insulin sensitivity. We previously showed that arsenic-induced NOD-like receptor protein 3 (NLRP3) inflammasome activation contributed to hepatic IR. However, the regulatory mechanisms underlying the role of arsenic toward the post-transcriptional modification of NLRP3 remain unclear. Here, we showed that NLRP3 mRNA stability was enhanced by METTL14-mediated m6A methylation during arsenic-induced hepatic IR. Furthermore, we demonstrated that arsenite methyltransferase (AS3MT), an essential enzyme in arsenic metabolic processes, interacted with NLRP3 to activate the inflammasome, thereby contributing to arsenic-induced hepatic IR. Also, AS3MT strengthened the m6A methylase association with NLRP3 to stabilize m6A-modified NLRP3. In summary, we showed that AS3MT-induced m6A modification critically regulated NLRP3 inflammasome activation during arsenic-induced hepatic IR, and we identified a novel post-transcriptional function of AS3MT in promoting arsenicosis.

Dynamic changes of soluble HLA-G and cytokine plasma levels in cervical cancer patients: potential role in cancer progression and immunotherapy.

PURPOSE: Chronic inflammation has been proven to be an important factor in carcinogenesis. Cytokines are the central mediators in the inflammatory microenvironment, and their release may be influenced by soluble HLA-G (sHLA-G). The aim of this study was to monitor the dynamic process of these soluble factors in patients with cervical cancer at Taizhou Hospital of Zhejiang Province, trying to understand their relationship with diagnosis, treatment, and prognosis. METHODS: We quantified plasma levels of sHLA-G and 12 cytokines using ELISA and flow cytometry, respectively, in the peripheral blood of patients with cervical cancer divided into three groups: preoperation, postoperation and clinical relapse. Healthy women were used as the control group. Data were analysed by non-parametric tests, receiver-operating characteristic (ROC) curves, and Kaplan-Meier plotter (log-rank test). RESULTS: In this study, our findings showed that preoperation plasma levels of sHLA-G and the cytokines IL-6, IL-10, and IFN-γ in cervical cancer patients had a good discriminatory effect between cervical cancer patients and healthy women. It should be noted that plasma levels of sHLA-G, IL-6, and IL-10 were significantly decreased within 30 days after radical hysterectomy (P < 0.05). A positive correlation was observed between IL-6 and IL-10, IL-8 and IL-17 levels preoperatively. In contrast, sHLA-G levels were negatively correlated with IL-10 but not with other cytokines. An increased survival rate in patients with cervical cancer was associated with IL-5 < 1.70 pg/mL, IL-17 < 2.30 pg/mL, and IFN-α < 2.26 pg/mL preoperatively. In addition, our findings showed that the levels of cytokines IL-6, IL-8, IL-12p70, IL-17, and IFN-γ may be related to 5-year relapse rates and/or the metastasis of cervical cancer. CONCLUSION: The current findings enhance our understanding of the dynamic process (preoperation, postoperation and clinical relapse) of sHLA-G and these cytokines in the plasma of patients with cervical cancer from diagnosis to prognosis. These biomarkers may play a potential therapeutic target role of such dynamic changes in the immunotherapy for cervical cancer.

Pre-operative neutrophil-to-lymphocyte ratio is an independent prognostic factor in patients with gastric cancer.

OBJECTIVE: To evaluate the prognostic significance of peripheral lymphocyte count and its derived inflammatory markers, such as neutrophil-to-lymphocyte ratio (NLR), in a cohort of patients with gastric cancer (GC). METHODS: In this retrospective study, the clinical characteristics and follow-up information, both pre- and post-operative within one week of laboratory findings, of 338 patients with GC who underwent radical gastrectomy were retrieved, and their prognostic significance was evaluated. RESULTS: Both lower pre- and post-operative lymphocyte counts and higher NLR and SSI were significantly related to advanced tumour (pT) and disease stages (American Joint Committee on Cancer [AJCC]) in patients with GC. Log-rank survival analysis showed that, in addition to traditional pT, pN, pM, and AJCC stages, both lower pre- (p = 0.041) and post-operative (p = 0.002) lymphocyte counts and higher NLR (ppre < 0.001 and ppost = 0.008) and SSI (ppre = 0.014 and ppost = 0.145) were associated with worse survival. Cox proportional hazards analysis revealed that pre-operative NLR (p = 0.018; hazard ratio = 1.778) was an independent predictor of prognosis in patients with GC. Moreover, when the pre-operative NLR was divided into NLRlow and NLRhigh, NLRhigh showed stratified prognostic value for patient sex (male, p = 0.001; female, p = 0.044), age (younger, p = 0.005; older, p = 0.005), and AJCC stage III (p = 0.007). CONCLUSION: Pre-operative NLR is an independent prognostic factor for patients with GC and has stratified prognostic value for patients with AJCC stage III GC.

Prognostic significance of the immune checkpoint HLA-G/ILT-4 in the survival of patients with gastric cancer.

OBJECTIVE: Human leukocyte antigen-G (HLA-G) and its receptors, including immunoglobulin-like transcripts (ILT)-2 and ILT-4, are closely associated with cancer development and clinical outcomes of patients. However, the clinical significance of HLA-G and ILT-2/-4 in gastric cancer (GC) is limited. METHODS: In this study, the percentage of HLA-G-, ILT-2 and ILT-4 positive tumor cells in 127 GC lesion suspensions of tumor cells gated for epithelialcelladhesionmolecule(EpCAM) was determined using multicolor flow cytometry and their clinical significance was evaluated. RESULTS: Our data showed that the median percentages of HLA-G-, ILT-2, and ILT-4 expressing GC cells were 18.0%, 67.80%, and 1.42%, respectively, and co-expression of HLA-G/ILT-2, HLA-G/ILT-4, and ILT-2/ILT-4 was 16.9%, 1.42%, and 1.70%, respectively. Kaplan-Meier survival results revealed that besides post-operation N status (p = 0.006), M status (p = 0.001), and AJCC clinical stage (p < 0.001), only high percentage of ILT-4+ GC cells was a significant factor for worse survival of patients with GC (overall survival [OS]: 42.9 months vs. 84.5 months; p = 0.031). However, among female patients with GC (n = 31), high percentage of either HLA-G+ (OS: 18.5 months vs. 89.3 months; p = 0.001) or ILT-4+ (OS: 17.9 months vs. 85.8 months; p = 0.002) GC cells was markedly associated with a poor prognosis. CONCLUSION: Our findings revealed that among HLA-G, ILT-2, and ILT-4, only a high percentage of ILT-4+ GC cells was significantly related to poor prognosis in the entire cohort of patients with GC. However, high percentage of HLA-G+ and ILT-4+ GC cells is associated with poor clinical outcome among female patients with GC.

Assessment of dynamic hepatic and renal imaging changes in COVID-19 survivors using T1 mapping and IVIM-DWI.

PURPOSE: To explore the imaging changes of the liver and kidneys in COVID-19 survivors using variable flip angle (VFA) T1 mapping and intravoxel incoherent motion-diffusion weighted imaging (IVIM-DWI). METHODS: This prospective study included 37 discharged COVID-19 participants and 24 age-matched non-COVID-19 volunteers who underwent abdominal MRI with VFA T1 mapping and IVIM-DWI sequencing as a COVID-19 group and control group, respectively. Among those discharged COVID-19 participants, 23 patients underwent two follow-up MRI scans, and were enrolled as the 3-month follow-up group and 1-year follow-up group, respectively. The demographics, clinical characteristics, and laboratory tests were collected. Imaging parameters of the liver and kidneys were measured. All collected values were compared among different groups. RESULTS: The 3-month follow-up group had the lowest hepatic T1 value, which was significantly lower than the value in the control group (P < 0.001). Additionally, the 3-month follow-up group had the highest hepatic ADC and D values, cortical ADC and f values, which were significantly higher than those in the control group (for all, P < 0.05). The hepatic D value in the 1-year follow-up group decreased significantly in comparison with that in the 3-month follow-up group (P = 0.001). Compared to non-severe patients, severe cases had significantly higher hepatic D* and f*D* values (P = 0.031, P = 0.015, respectively). CONCLUSION: The dynamic alterations of hepatic and renal imaging parameters detected with T1 mapping and IVIM-DWI suggested that COVID-19 survivors might develop mild, non-symptomatic liver and kidney impairments, of which liver impairment could probably relieve over time and kidney impairment might be long-existing.

Performances of clinical characteristics and radiological findings in identifying COVID-19 from suspected cases.

BACKGROUND: To identify effective factors and establish a model to distinguish COVID-19 patients from suspected cases. METHODS: The clinical characteristics, laboratory results and initial chest CT findings of suspected COVID-19 patients in 3 institutions were retrospectively reviewed. Univariate and multivariate logistic regression were performed to identify significant features. A nomogram was constructed, with calibration validated internally and externally. RESULTS: 239 patients from 2 institutions were enrolled in the primary cohort including 157 COVID-19 and 82 non-COVID-19 patients. 11 features were selected by LASSO selection, and 8 features were found significant using multivariate logistic regression analysis. We found that the COVID-19 group are more likely to have fever (OR 4.22), contact history (OR 284.73), lower WBC count (OR 0.63), left lower lobe involvement (OR 9.42), multifocal lesions (OR 8.98), pleural thickening (OR 5.59), peripheral distribution (OR 0.09), and less mediastinal lymphadenopathy (OR 0.037). The nomogram developed accordingly for clinical practice showed satisfactory internal and external validation. CONCLUSIONS: In conclusion, fever, contact history, decreased WBC count, left lower lobe involvement, pleural thickening, multifocal lesions, peripheral distribution, and absence of mediastinal lymphadenopathy are able to distinguish COVID-19 patients from other suspected patients. The corresponding nomogram is a useful tool in clinical practice.

Prognostic Significance of Immune Checkpoints HLA-G/ILT-2/4 and PD-L1 in Colorectal Cancer.

Immune checkpoint inhibitors (ICIs) have become a promising area of research for cancer treatment. In addition to the well-known ICIs targeting PD-1/PD-L1, HLA-G/ILT-2/-4 is relatively new immune checkpoint that has been evaluated in early clinical trials in patients with advanced solid tumors. In this study, the expression of HLA-G (n=157), ILT-2/4 (n=82), and PD-L1 (n=70) in epithelial cell adhesion molecule (EpCAM)-positive colorectal cancer (CRC) cells was analyzed by multicolor flow cytometry, and the prognostic significance of these molecules was evaluated. In EpCAM+ CRC cells, the median percentages of HLA-G, ILT-2, ILT-4, and PD-L1 were 14.90%, 67.70%, 8.55% and 80.30%, respectively. In addition, a positive correlation was observed between them (all p<0.001). Higher levels of these immune checkpoint proteins are associated with lymph node metastasis. In addition to the AJCC stage (p=0.001), Kaplan-Meier survival analysis showed that higher levels of HLA-G (p=0.041), ILT-2 (p=0.060), ILT-4 (p<0.001), PD-L1 (p=0.012), HLA-GILT4 (p<0.001) and ILT-2ILT-4 (p<0.001) were significantly associated with shorter survival of CRC patients. When CRC patients were stratified by early and advanced AJCC stages, HLA-G levels were only related to the survival among CRC patients with early disease stage (p=0.024), while ILT-4 levels were significant for both CRC patients with early (p=0.001) and advanced (p=0.020) disease stages. Multivariate cox regression analysis revealed that advanced AJCC stage (HR=2.435; p=0.005) and higher ILT-4 levels (HR=2.198; p=0.063) were independent risk factors for poor outcomes in patients with CRC. In summary, among the immune checkpoints, HLA-G/ILT-2/4 and PD-L1, ILT-4 is the most significant prognostic indicator of CRC. This finding indicated that a combination of immunotherapy strategies, such as ILT-4 blockade, could improve the clinical outcomes in patients with cancer. Moreover, multicolor flow cytometry can be employed as a reliable and efficient, alternative to immunohistochemistry, for evaluating the immune checkpoint proteins expressed in tumor lesions.

Peripheral immunological features of COVID-19 patients in Taizhou, China: A retrospective study.

BACKGROUND: Abnormal peripheral immunological features are associated with the progression of coronavirus disease 2019 (COVID-19). METHODS: Clinical and laboratory data were retrieved in a cohort of 146 laboratory-confirmed COVID-19 patients. Potential risk factors for the development of severe COVID-19 were evaluated. RESULTS: On admission, lymphocytes, CD3+, CD4+ and CD8+ T cells, eosinophils, and albumin and pre-albumin were dramatically lower, whereas neutrophils, and interleukin (IL)-10, C-reactive protein (CRP), aspartate aminotransferase (AST) and gamma-glutamyltransferase (GGT) were significantly higher in severe cases. By the second week after discharge, all variables improved to normal levels. Covariate logistic regression results showed that the CD8+ cell count and CRP level were independent risk factors for severe COVID-19. CONCLUSION: Lower peripheral immune cell subsets in patients with severe disease recovered to normal levels as early as the second week after discharge. CD8+ T cell counts and CRP levels on admission are independent predictive factors for severe COVID-19.

Bufalin inhibits human diffuse large B-cell lymphoma tumorigenesis by inducing cell death through the Ca2+/NFATC1/cMYC pathway.

The 5-year survival rate of diffuse large B-cell lymphoma (DLBCL) can reach 60%. However, nearly half of patients undergo relapse/refractory issues with a survival period of less than 2 years. New therapeutic approaches are therefore needed to improve chemotherapy efficacy and patient survival. Bufalin (BF), isolated from the traditional Chinese medicine Chansu, has been reported to play an anticancer role in multiple cancer cell types. However, there are few reports of the effects of BF on the growth of DLBCL. In the present study, we demonstrated that BF exerts antitumor activity in DLBCL cells, both in vitro and in vivo. Treatment of DLBCL cells with BF resulted in increased proliferation and apoptosis in a dose- and time-dependent manner. Daily intraperitoneal injection of 1.5 mg/kg BF significantly delayed DLBCL xenograft growth in NOD/SCID mice without affecting body weight. Bioinformatics analysis showed that BF may regulate NFATC1 protein and affect expression of its downstream gene, cMYC. Our results suggest that BF can attenuate NFATC1 translocation by reducing the intracellular calcium concentration; BF may also have a low synergistic effect with cyclosporin A. In conclusion, we demonstrated that BF exerts antitumor activity that is mediated at least in part by the Ca2+/NFATC1/cMYC pathway. Our findings suggest that BF can be effectively applied as a novel potential therapeutic agent for DLBCL.

Intratumor Heterogeneity of HLA-G Expression in Cancer Lesions.

Signaling pathway between human leukocyte antigen (HLA)-G and immune inhibitory receptors immunoglobulin-like transcript (ILT)-2/4 has been acknowledged as one of immune checkpoints, and as a potential target for cancer immunotherapy. Like other immune checkpoints, inter- and even intratumor heterogeneity of HLA-G could render a rather complexity for HLA-G-target immunotherapy. However, little information for intratumor heterogeneity of HLA-G is available. In this study, HLA-G expression in a serial section of colorectal cancer (CRC) lesions from three CRC patients (each sample with serial section of 50 slides, 10 randomized slides for each antibody), three different locations within a same sample (five CRC), and three case-matched blocks that each includes 36 esophageal cancer samples, were evaluated with immunohistochemistry using anti-HLA-G antibodies (mAbs 4H84, MEM-G/1 and MEM-G/2 probing for all denatured HLA-G isoforms, 5A6G7, and 2A12 probing for denatured HLA-G5 and HLA-G6 isoforms). Our results revealed that, in addition to the frequently observed inter-tumor heterogeneity, intratumor heterogeneous expression of HLA-G is common in different areas within a tumor in CRC and esophageal cancer samples included in this study. Moreover, percentage of HLA-G expression probed with different anti-HLA-G antibodies also varies dramatically within a tumor. Given HLA-G has been considered as an important immune checkpoint, intratumor heterogeneity of HLA-G expression, and different specificity of anti-HLA-G antibodies being used among studies, interpretation and clinical significance of HLA-G expression in cancers should be with caution.

High SYT7 expression is associated with poor prognosis in human non-small cell lung carcinoma.

Synaptotagmin 7 (SYT7) can encode a single-pass 46-kDa transmembrane protein which located on human chromosome 11q12.2. It has been reported to be dysregulated in several cancers; however, there are few reports on the role of SYT7 in non-small cell lung carcinoma (NSCLC). The purpose of our study was to investigate the expression of SYT7 in NSCLC and its relationship with the prognosis of NSCLC. Differences in SYT7 expression were explored by using a public database and tissue samples. The prognostic value of SYT7 and its expression correlation with clinical parameters were evaluated by statistical analysis. Our current study found that elevated mRNA and protein levels of SYT7 in NSCLC tissues compared to adjacent normal tissues. The high expression of SYT7 in NSCLC patients was positively correlated with tumour differentiation (P = 0.031) and pT (P = 0.041). The higher SYT7 expression had a shorter survival time than those with lower SYT7 expression in NSCLC patients. Furthermore, multivariate analysis demonstrated that the expression of SYT7 was an unfavourable independent prognostic factor for NSCLC (P = 0.044). In conclusion, SYT7 was upregulated in NSCLC tissues and maybe a prognostic and diagnostic factor of NSCLC.

IL-7R gene variants are associated with breast cancer susceptibility in Chinese Han women.

BACKGROUND: Interleukin 7 receptor (IL-7R) is a member of the type I cytokine receptor family, which affects the occurrence of various tumors by forming a signaling complex with its ligand Interleukin 7 (IL-7). This study aimed to explore the potential relationships of IL-7R polymorphisms with breast cancer susceptibility in the Chinese Han women. METHODS: Five polymorphisms of IL-7R gene (rs969129, rs10213865, rs10053847, rs118137916, and rs6451231) form 553 patients and 550 healthy individuals among the Chinese Han women were genotyped using Agena MassARRAY platform. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated to evaluate the relationship. RESULTS: The resulted of this study showed that rs10213865 was related to an increased breast cancer risk in allele (P = 0.045), dominant (P = 0.040), and log-additive (P = 0.029) models. As for rs969129, an increased risk of breast cancer was found in the allele (P = 0.018), co-dominant (P = 0.017), recessive (P = 0.034), and additive (P = 0.019) models. Rs6451231 was related to an increased risk of breast cancer under allele (P = 0.018), co-dominant (P = 0.021), and log-additive (P = 0.019) models. Age stratified analysis revealed that rs6451231 could enhance risk of breast cancer among the individuals older than 52 years. Furthermore, there was a significant correlation between haplotype Crs969129Grs10213865Ars10053847Grs118137916 and the decreased risk of breast cancer (P = 0.010). CONCLUSIONS: This study firstly proved that IL-7R polymorphisms were significantly correlated with an increased susceptibility of breast cancer in the Chinese Han women.

Mask wearing in pre-symptomatic patients prevents SARS-CoV-2 transmission: An epidemiological analysis.

OBJECTIVES: Pandemic COVID-19 has become a seriously public health priority worldwide. Comprehensive strategies including travel restrictions and mask-wearing have been implemented to mitigate the virus circulation. However, detail information on community transmission is unavailable yet. METHODS: From January 23 to March 1, 2020, 127 patients (median age: 46 years; range: 11-80) with 71 male and 56 female, were confirmed to be infected with the SARS-CoV-2 in Taizhou, Zhejiang, China. Epidemiological trajectory and clinical features of these COVID-19 cases were retrospectively retrieved from electronic medical records and valid individual questionnaire. RESULTS: The disease onset was between January 9 to February 14, 2020. Among them, 64 patients are local residents, and 63 patients were back home from Wuhan from January 10 to 24, 2020 before travel restriction. 197 local residents had definite close-contact with 41 pre-symptomatic patients back from Wuhan. 123 and 74 of them contact with mask-wearing or with no mask-wearing pre-symptomatic patients back from Wuhan, respectively. Data showed that incidence of COVID-19 was significantly higher for local residents close-contact with no mask-wearing Wuhan returned pre-symptomatic patients (19.0% vs. 8.1%, p < 0.001). Among 57 close-contact individuals, 21 sequential local COVID-19 patients originated from a pre-symptomatic Wuhan returned couple, indicated dense gathering in congested spaces is a high risk for SARS-CoV-2 transmission. CONCLUSIONS: Our findings provided valuable details of pre-symptomatic patient mask-wearing and restriction of mass gathering in congested spaces particularly, are important interventions to mitigate the SARS-CoV-2 transmission.