Impact of Anti-angiogenic Drugs on Severity of COVID-19 in Patients with Non-Small Cell Lung Cancer.

Introduction: The 2019 coronavirus disease (COVID-19) pandemic has reshaped oncology practice, but the impact of anti-angiogenic drugs on the severity of COVID-19 in patients with non-small cell lung cancer (NSCLC) remains unclear. Patients and Methods: We carried out a retrospective study involving 166 consecutive patients with NSCLC who were positive for COVID-19, aiming to determine the effects of anti-angiogenic drugs on disease severity, as defined by severe/critical symptoms, intensive care unit (ICU) admission/intubation, and mortality outcomes. Risk factors were identified using univariate and multivariate logistic regression models. Results: Of the participants, 73 had been administered anti-angiogenic drugs (termed the anti-angiogenic therapy (AT) group), while 93 had not (non-AT group). Comparative analyses showed no significant disparity in the rates of severe/critical symptoms (21.9% vs 35.5%, P = 0.057), ICU admission/intubation (6.8% vs 7.5%, P = 0.867), or death (11.0% vs 9.7%, P = 0.787) between these two groups. However, elevated risk factors for worse outcomes included age ≥ 60 (odds ratio (OR): 2.52, 95% confidence interval (CI): 1.07-5.92), Eastern Cooperative Oncology Group performance status of 2 or higher (OR: 21.29, 95% CI: 4.98-91.01), chronic obstructive pulmonary disease (OR: 7.25, 95% CI: 1.65-31.81), hypertension (OR: 2.98, 95% CI: 1.20-7.39), and use of immunoglobulin (OR: 5.26, 95% CI: 1.06-26.25). Conclusion: Our data suggests that the use of anti-angiogenic drugs may not exacerbate COVID-19 severity in NSCLC patients, indicating their potential safe application even during the pandemic period.

Anlotinib plus tislelizumab for recurrent metastatic pancreas ductal adenocarcinoma with germline BRCA2 mutation: A case report.

While combined immunotherapy and anti-angiogenic therapy have demonstrated efficacy in renal cell carcinoma, non-small cell lung cancer and hepatocellular carcinoma, the efficacy of first-line treatment for pancreatic ductal adenocarcinoma (PDAC) with germline BRCA2 mutation remains unproven. We described a BRCA2-mutated patient with PDAC who presented with posterior cardiac metastasis 8 months after surgery. After receiving four cycles of anlotinib combined with tislelizumab, abdominal CT scans indicated a complete response. The patient sustained this response for over 14 months on the combination regimen, with no reported adverse events. In conclusion, the combination of tislelizumab and anlotinib may offer a viable therapeutic option for recurrent metastatic BRCA2-mutated PDAC.

Exosome-transmitted podoplanin promotes tumor-associated macrophage-mediated immune tolerance in glioblastoma.

AIMS: Glioblastoma is the most frequent and aggressive primary brain tumor, characterized by rapid disease course and poor treatment responsiveness. The abundance of immunosuppressive macrophages in glioblastoma challenges the efficacy of novel immunotherapy. METHODS: Bulk RNA-seq and single-cell RNA-seq of glioma patients from public databases were comprehensively analyzed to illustrate macrophage infiltration patterns and molecular characteristics of podoplanin (PDPN). Multiplexed fluorescence immunohistochemistry staining of PDPN, GFAP, CD68, and CD163 were performed in glioma tissue microarray. The impact of PDPN on macrophage immunosuppressive polarization was investigated using a co-culture system. Bone marrow-derived macrophages (BMDMs) and OT-II T cells isolated from BALB/c and OT-II mice respectively were co-cultured to determine T-cell adherence. Pathway alterations were probed through RNA sequencing and western blot analyses. RESULTS: Our findings demonstrated that PDPN is notably correlated with the expression of CD68 and CD163 in glioma tissues. Additionally, macrophages phagocytosing PDPN-containing EVs (EVsPDPN ) from GBM cells presented increased CD163 expression and augmented secretion of immunoregulatory cytokine (IL-6, IL-10, TNF-α, and TGF-ß1). PDPN within EVs was also associated with enhanced phagocytic activity and reduced MHC II expression in macrophages, compromising CD4+ T-cell activation. CONCLUSIONS: This investigation underscores that EVsPDPN derived from glioblastoma cells contributes to M2 macrophage-mediated immunosuppression and is a potential prognostic marker and therapeutic target in glioblastoma.

Immunotherapy combined with rh-endostatin improved clinical outcomes over immunotherapy plus chemotherapy for second-line treatment of advanced NSCLC.

Background: Despite the fact that numerous clinical and preclinical studies have demonstrated the synergistic effects of combining antiangiogenic or chemotherapy with immunotherapy, no data have been found to indicate that combination therapy is more effective and safer as second-line therapy. Methods: We retrospectively compared the effectiveness and safety of ICIs plus rh-endostatin to ICIs plus chemotherapy in patients with advanced non-small cell lung cancer (NSCLC). The evaluation indicators of this study were progression-free survival (PFS), safety profile, objective response rate (ORR), disease control rate (DCR), and 1-year overall survival (OS). Results: The median PFS with immunotherapy plus rh-endostatin (IE) was 7.10 months (95% CI, 4.64 to 9.56) versus 5.13 months (95% CI, 4.29 to 5.97) with immunotherapy plus chemotherapy (IC) (HR, 0.56; 95%CI, 0.33 to 0.95). Treatment-related adverse events of grade 3 or 4 occurred in 7.5% of the IE group versus 25.0% of the IC group. The ORR in the IE group was 35.0% versus 20.8% in the IC group (P = 0.137), and the DCR in the IE group was 92.5% versus 77.1% in the IC group (P = 0.049). The 1-year OS rate for the IE group was 69.4%, which was higher than the 61.4% of the IC group. Conclusion: Our study showed that ICI therapy combined with endostatin therapy exhibits high efficacy and safety, suggesting that such a combination might be a viable treatment option for patients with pre-treated NSCLC in the future.

Efficacy and safety of immune checkpoint inhibitors combined with recombinant human endostatin and chemotherapy as the first-line treatment of advanced non-small-cell lung cancer.

Aim: To assess the efficacy and safety of combination of PD-1 inhibitors, recombinant human endostatin (Rh-endostatin) and chemotherapy as first-line treatment for advanced non-small-cell lung cancer (NSCLC). Methods: A total of 100 patients with advanced NSCLC were retrospectively reviewed and analyzed (58 in the group receiving PD-1 inhibitors plus Rh-endostatin and chemotherapy; 42 in the group receiving Rh-endostatin and chemotherapy). The primary end point was progression-free survival. Results: Patients in the group receiving PD-1 inhibitors plus Rh-endostatin and chemotherapy had significantly improved progression-free survival (10.2 vs 6.5 months; p < 0.001) and objective response rate (67.2 vs 42.9%; p = 0.015), with acceptable toxicity. Conclusion: Our study showed the superiority of combination therapy of PD-1 inhibitors and Rh-endostatin as first-line treatment for advanced NSCLC.

This study retrospectively analyzed the effectiveness and safety of PD-1 inhibitors combined with recombinant human endostatin (Rh-endostatin) and chemotherapy as first-line treatment for advanced non-small-cell lung cancer. Among them, 58 patients received a PD-1 inhibitor combined with Rh-endostatin and chemotherapy (treatment group), and 42 patients received Rh-endostatin combined with chemotherapy (control group). Patients in the treatment group had a significantly improved objective response rate (67.2 vs 42.9%; p = 0.015) and prolonged survival without their disease getting worse (10.2 vs 6.5 months; p < 0.001). No significant differences were found in the adverse events between the two groups.

Efficacy and safety analyses of epidermal growth factor receptor tyrosine kinase inhibitors combined with chemotherapy in the treatment of advanced non-small-cell lung cancer with an EGFR/TP53 co-mutation.

PURPOSE: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) combined with cytotoxic chemotherapy are highly effective in the treatment of advanced non-small-cell lung cancer (NSCLC) with EGFR mutations. The purpose of this study is to evaluate the efficacy and safety of this combination in advanced NSCLC patients with an EGFR/TP53 co-mutation. METHODS: Ninety-five advanced NSCLC patients with an EGFR/TP53 co-mutation were enrolled in this study. Treatments with either EGFR-TKI monotherapy (T group, n = 61) or EGFR-TKI combined with chemotherapy (TC group, n = 34) were evaluated in relation to objective response rate (ORR), disease control rate (DCR), median time to progression (TTP), and median overall survival (OS). RESULTS: There were no statistically significant differences in DCR between the treatment groups. The ORR was significantly improved in the TC group versus the T group (55.9% vs. 34.4%, P = 0.042). A higher median TTP was noted in TC group compared with T group (16.1 vs. 11.1 months, P = 0.002). Patients without brain metastases in TC group had a longer median OS than in T group (48.4 vs. 28.8 months, P = 0.003). However, there was a non-significant trend towards longer OS in TC group in the entire cohort (36.9 vs. 28.2 months, P = 0.078). Cox multivariate regression analysis showed that clinical stage, brain metastases, EGFR21 L858R mutation, and T790M status at first progression were independent risk factors for OS. However, the incidence of grade 3 or higher adverse events were higher in the TC group than in the T group (32.4% vs. 13.1%, P = 0.025). CONCLUSION: Our study indicates that EGFR-TKIs combined with chemotherapy could significantly improve the ORR and TTP of advanced NSCLC patients with an EGFR/TP53 co-mutation. Combination therapy may be a promising treatment for advanced NSCLC patients with an EGFR/TP53 co-mutation without brain metastases.

Intracranial hemorrhage after spinal surgery: a literature review.

Background and Objective: Intracranial hemorrhage following spinal surgery is an infrequent but severe complication. Due to its rarity, the etiology, clinical characteristics, and treatment have not yet been fully elucidated. This literature review analyzed the incidence, clinical manifestations, hemorrhage location, current therapeutic strategies, location of operation, and interval time between surgery and bleeding. The objectives of the article were to provide insights for clinicians to promptly identify and prevent potential cases of intracranial hemorrhage. Methods: The authors queried PubMed and Web of Science databases using predefined keywords and included published literature reporting on intracranial hemorrhage after spinal surgery. Relevant case reports, case series, and reviews describing the mechanism of intracranial hemorrhage after spinal surgery and meeting diagnostic criteria for intracranial hemorrhage related to spinal surgery were included. Clinico-demographc data, presentations symptoms, location, index surgery type, and neurological outcomes after brain hemorrhage. Oxford Centre Level of Evidence guidelines was used to evaluate the quality of included studies. Descriptive statistics were used to synthesize the results. Key Content and Findings: A total of 80 publications of level of evidence IV involving 108 patients with median age at diagnosis was 58.5 years (inter-quartile range: 6-85) were analyzed. The incidence of intracranial hemorrhage was 0.08-0.37% among patients who underwent spinal surgery, and this complication occurred predominantly within 48 hours postoperatively. The initial presentation included headache, reduced level of consciousness, dysarthria, nausea, vomiting, hearing loss, blurred vision, neck rigidity, and delayed recovery from anesthesia. More than half (58.3%) of patients improved, while 23.1% still experienced neurological dysfunctions, and 7.4% died. Conclusions: The present study is limited by the levels of evidence of the included studies. There is heterogeneity among cases with respect to patient demographics and medical history. Angiography is critical in assessing the presence and extent of underlying vascular diseases. Intracranial hemorrages may be caused by intraoperative or postoperative cerebrospinal fluid leakage that will lead to intracranial pressure change and induced by intracranial venous or arterial bleeding. The treatment strategies include conservative medical management and surgical treatment. Individualized treatment should be emphasized.

Hesperetin ameliorates glioblastoma by inhibiting proliferation, inducing apoptosis, and suppressing metastasis.

Background: Glioblastoma is the most common type of malignant tumor of the brain. Despite substantial improvements in therapy, the 5-year survival rate of patients with glioblastoma remains low. Antitumor drug development has encountered considerable obstacles, which can be attributed to metastasis and the blood-brain barrier (BBB). Hesperetin (HSP), derived from citrus fruits, exhibits several biological properties, including anticancer and anti-inflammatory activities. In addition, in vitro models have shown that HSP can easily cross the BBB. The purpose of the present study was to explore the effects and underlying mechanisms of HSP on glioblastoma cells. Methods: GL261 cell were cultured and treated with different dose HSP. The cell viability was assessed with Cell Counting Kit-8 (CCK-8) assay. The cell apoptosis was determined using an Annexin V/propidine iodide (PI) staining and Hoechst staining and detection assay, cell migration and invasion were observed on GL261 cells using Matrigel-coated Transwells and Wound-Healing assay. The expression of proteins was detected by Western blotting. Results: HSP suppressed cell proliferation and could induce apoptosis, the latter of which might be regulated through the Phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) and nuclear factor-kappa B (NF-κB) pathways. Furthermore, HSP inhibited cell migration and invasion by downregulating the expression of matrix metalloproteinase-2 (MMP-2) and MMP-9, and inhibited epithelial-mesenchymal transition (EMT) by upregulating the expression of E-cadherin while downregulating N-cadherin and vimentin expression. Conclusions: These findings suggest HSP to be an alternative preventive and therapeutic antiglioblastoma drug that may be especially useful for patients with recurrent glioblastoma.

Gold Nanocluster-Based Fluorometric Banoxantrone Assay Enabled by Photoinduced Electron Transfer.

Monitoring the blood concentration of banoxantrone (AQ4N) is important to evaluate the therapeutic efficacy and side effects of this new anticancer prodrug during its clinical applications. Herein, we report a fluorescence method for AQ4N detection through the modulation of the molecule-like photoinduced electron transfer (PET) behavior of gold nanoclusters (AuNCs). AQ4N can electrostatically bind to the surface of carboxylated chitosan (CC) and dithiothreitol (DTT) co-stabilized AuNCs and quench their fluorescence via a Coulomb interaction-accelerated PET process. Under optimized experimental conditions, the linear range of AQ4N is from 25 to 200 nM and the limit of detection is as low as 5 nM. In addition, this assay is confirmed to be reliable based on its successful use in AQ4N determination in mouse plasma samples. This work offers an effective strategy for AQ4N sensing based on fluorescent AuNCs and widens the application of AuNCs in clinical diagnosis and pharmaceutical analysis.

Establish a new parameter "horizontal view-axial angle" and explore its role in the treatment of atlantoaxial instability diseases.

Objective: The objective of the study is to establish a new parameter that can be clearly measured on x-ray images to complement the description of the sagittal alignment of the craniocervical junction. The authors anticipate that this new parameter will enhance surgeons' understanding of the sagittal alignment of the craniocervical junction and play a positive role in the guidance of intraoperative reduction and in the evaluation of postoperative outcomes of patients with atlantoaxial instability. Methods: From November 2018 to June 2020, a total of 159 asymptomatic subjects who underwent frontal and lateral cervical x-ray examination in the Second Affiliated Hospital of Soochow University were included in the study. Age, gender, previous spinal trauma, and disease history of each subject were recorded. After screening, 127 effective samples were finally obtained. When taking lateral cervical radiographs, all subjects placed their neck in a neutral position and looked straight ahead with both eyes. On the obtained lateral x-ray images, a straight line was drawn from the radix to the anterior clinoid process; another line was made along the posterior edge of the C2 vertebral body; and the angle between the two lines was measured, which was defined as the "horizontal view-axial angle." The angle formed by the tangent of the posterior edge of the C2 vertebra and C7 vertebral body is the "C2-C7 angle," which was used to describe the curvature of the lower cervical vertebra. The normal range of horizontal view-axial angle and its relationship with C2-7 angle were evaluated. Results: The average C2-C7 angle of male subjects was (14.0° ± 7.4°), while that of female subjects was (11.09° ± 7.36°). The average horizontal view-axial angle of male subjects was (92.79° ± 4.52°), and that of female subjects was (94.29° ± 4.50°). Pearson correlation test showed that there was a significant negative correlation between horizontal view-axis angle and C2-C7 angle. Conclusions: For patients with atlantoaxial instability diseases, the horizontal view-axis angle is expected to be a sagittal parameter to guide the intraoperative reduction and evaluate postoperative outcomes.

Clinical analysis of uterine torsion and fibroids in full-term pregnancy: A case report and review of the literature.

This study was performed to describe the clinical features, risk factors, and treatment methods of uterine torsion in pregnancy. The most common symptoms are abdominal pain, fetal heart rate changes, and failure of cervical dilatation and are often accompanied by complete or partial placental abruption. Preoperative diagnosis is challenging even with the use of ultrasound. Uterine torsion in the third trimester is correlated with the presence of multiple uterine fibroids. The causes of gravid uterine torsion vary and the clinical manifestations are nonspecific. Early diagnosis and improved detection approaches are the keys to treatment of patients with uterine torsion. However, the preoperative diagnosis remains difficult and the diagnosis is often made during cesarean section.

Inhibition of SLC1A5 sensitizes colorectal cancer to cetuximab.

Cetuximab resistance is a key barrier in treating metastatic colorectal cancer (mCRC). Targeting of metabolic resources import could resensitize drug-resistant cancer cells to anticancer treatments. Here we showed that the expression of the glutamine transporter solute carrier 1 family member 5 (SLC1A5) in clinical CRC samples of patients resisted to cetuximab was significantly higher than in those of patients responded to cetuximab. Inhibition of SLC1A5 by shRNA-mediated gene silencing or pharmacological inhibitor significantly suppressed the growth of CRC. Moreover, inhibition of SLC1A5 significantly enhanced the inhibitory efficacy of cetuximab on CRC proliferation both in vitro and in vivo. Mechanistically, SLC1A5 inhibition facilitated EGFR degradation through the ubiquitin-proteasome pathway, and decreased the expression of nuclear EGFR, both of which might have contribution to the improved response to cetuximab. This study provides the metabolic molecule SLC1A5 as a potential therapeutic target to increase the efficacy of cetuximab on CRC.

Ion channels or aquaporins as novel molecular targets in gastric cancer.

Gastric cancer (GC) is a common disease with few effective treatment choices and poor prognosis, and has the second-highest mortality rates among all cancers worldwide. Dysregulation and/or malfunction of ion channels or aquaporins (AQPs) are common in various human cancers. Furthermore, ion channels are involved in numerous important aspects of the tumor aggressive phonotype, such as proliferation, cell cycle, apoptosis, motility, migration, and invasion. Indeed, by localizing in the plasma membrane, ion channels or AQPs can sense and respond to extracellular environment changes; thus, they play a crucial role in cell signaling and cancer progression. These findings have expanded a new area of pharmaceutical exploration for various types of cancer, including GC. The involvement of multiple ion channels, such as voltage-gated potassium and sodium channels, intracellular chloride channels, 'transient receptor potential' channels, and AQPs, which have been shown to facilitate the pathogenesis of other tumors, also plays a role in GC. In this review, an overview of ion channel and aquaporin expression and function in carcinogenesis of GC is presented. Studies of ion channels or AQPs will advance our understanding of the molecular genesis of GC and may identify novel and effective targets for the clinical application of GC.

ELF5 in epithelial ovarian carcinoma tissues and biological behavior in ovarian carcinoma cells.

The expression of E74-like factor 5 (ELF5) in epithelial ovarian carcinoma tissues and its effects on biological behavior in ovarian carcinoma cells were assessed in search for a new approach for gene treatment of epithelial ovarian carcinoma. RT-PCR technology was applied to detect the expression of ELF5 mRNA in epithelial ovarian carcinoma (n=49), borderline ovarian epithelial tumor (n=19), benign ovarian epithelial tumor (n=31) and normal ovarian tissues (n=40). Then, we transfected recombinant plasmid pcDNA3.1­ELF5+EGFP into human ovarian carcinoma SKOV3 cells (recombinant plasmid group) in vitro and screened out stably transfected cells to conduct multiplication culture. Western blot analysis was performed to detect the expression of ELF5 protein in the different groups. Flow cytometry was employed to detect cell apoptosis and cycles. ELF5 mRNA in epithelial ovarian carcinoma and borderline ovarian epithelial tumor tissues were significantly lower (P<0.05) than those in benign ovarian epithelial tumor and normal ovarian tissues. ELF5 protein expression in the cells of recombinant plasmid group was significantly higher compared with empty plasmid and blank control groups. The capacity of cell reproductive recombinant plasmid group at each time point decreased (P<0.05). Flow cytometry detection showed that 67.03% of cells in recombinant plasmid group was blocked in G0/G1 phase (P<0.05), compared with empty plasmid group (37.17%) and blank control group (38.24%). Apoptotic rate of recombinant plasmid group was significantly lower (31.4±1.9%; P<0.05), compared with that of empty plasmid group (9.1±2.2%) and blank control group (8.7±1.5%), and the differences were statistically significant. In conclusion, ELF5 interfered with cell cycle of human ovarian carcinoma SKOV3 cells and promoted apoptosis of human ovarian carcinoma SKOV3 cells inhibiting their growth and invasive capacity; and thus providing a new approach to gene treatment of ovarian carcinoma.

Critical roles of mTOR Complex 1 and 2 for T follicular helper cell differentiation and germinal center responses.

T follicular helper (Tfh) cells play critical roles for germinal center responses and effective humoral immunity. We report here that mTOR in CD4 T cells is essential for Tfh differentiation. In Mtorf/f-Cd4Cre mice, both constitutive and inducible Tfh differentiation is severely impaired, leading to defective germinal center B cell formation and antibody production. Moreover, both mTORC1 and mTORC2 contribute to Tfh and GC B cell development but may do so via distinct mechanisms. mTORC1 mainly promotes CD4 T cell proliferation to reach the cell divisions necessary for Tfh differentiation, while Rictor/mTORC2 regulates Tfh differentiation by promoting Akt activation and TCF1 expression without grossly influencing T cell proliferation. Together, our results reveal crucial but distinct roles for mTORC1 and mTORC2 in CD4 T cells during Tfh differentiation and germinal center responses.

mTOR is critical for intestinal T-cell homeostasis and resistance to Citrobacter rodentium.

T-cells play an important role in promoting mucosal immunity against pathogens, but the mechanistic basis for their homeostasis in the intestine is still poorly understood. We report here that T-cell-specific deletion of mTOR results in dramatically decreased CD4 and CD8 T-cell numbers in the lamina propria of both small and large intestines under both steady-state and inflammatory conditions. These defects result in defective host resistance against a murine enteropathogen, Citrobacter rodentium, leading to the death of the animals. We further demonstrated that mTOR deficiency reduces the generation of gut-homing effector T-cells in both mesenteric lymph nodes and Peyer's patches without obviously affecting expression of gut-homing molecules on those effector T-cells. Using mice with T-cell-specific ablation of Raptor/mTORC1 or Rictor/mTORC2, we revealed that both mTORC1 and, to a lesser extent, mTORC2 contribute to both CD4 and CD8 T-cell accumulation in the gastrointestinal (GI) tract. Additionally, mTORC1 but not mTORC2 plays an important role regulating the proliferative renewal of both CD4 and CD8 T-cells in the intestines. Our data thus reveal that mTOR is crucial for T-cell accumulation in the GI tract and for establishing local adaptive immunity against pathogens.

Voltage-gated sodium channel Nav 1.7 promotes gastric cancer progression through MACC1-mediated upregulation of NHE1.

Voltage-gated sodium channels (VGSCs), which are aberrantly expressed in several human cancers, affect cancer cell behavior; however, their role in gastric cancer (GC) and the link between these channels and tumorigenic signaling remain unclear. The aims of this study were to determine the clinicopathological significance and role of the VGSC Nav 1.7 in GC progression and to investigate the associated mechanisms. Here, we report that the SCN9A gene encoding Nav 1.7 was the most abundantly expressed VGSC subtype in GC tissue samples and two GC cell lines (BGC-823 and MKN-28 cells). SCN9A expression levels were also frequently found to be elevated in GC samples compared to nonmalignant tissues by real-time PCR. In the 319 GC specimens evaluated by immunohistochemistry, Nav 1.7 expression was correlated with prognosis, and transporter Na(+) /H(+) exchanger-1 (NHE1) and oncoprotein metastasis-associated in colon cancer-1 (MACC1) expression. Nav 1.7 suppression resulted in reduced voltage-gated sodium currents, decreased NHE1 expression, increased extracellular pH and decreased intracellular pH, and ultimately, reduced invasion and proliferation rates of GC cells and growth of GC xenografts in nude mice. Nav 1.7 inhibition led to reduced MACC1 expression, while MACC1 inhibition resulted in reduced NHE1 expression in vitro and in vivo. Mechanistically, the suppression of Nav 1.7 decreased NF-κB p65 nuclear translocation via p38 activation, thus reducing MACC1 expression. Downregulation of MACC1 decreased c-Jun phosphorylation and subsequently reduced NHE1 expression, whereas the addition of hepatocyte growth factor (HGF), a c-Met physiological ligand, reversed the effect. These results indicate that Nav 1.7 promotes GC progression through MACC1-mediated upregulation of NHE1. Therefore, Nav 1.7 is a potential prognostic marker and/or therapeutic target for GC.

Elevated Orai1 and STIM1 expressions upregulate MACC1 expression to promote tumor cell proliferation, metabolism, migration, and invasion in human gastric cancer.

ORAI calcium release-activated calcium modulator 1 (Orai1)- and stromal interacting molecule 1 (STIM1)-mediated store-operated Ca(2+) entry (SOCE) have been increasingly implicated in tumor progression; however, its role in gastric cancer (GC) is not well elucidated. We aimed to determine whether SOCE influences GC prognosis and elucidate the underlying mechanisms. Orai1 and STIM1 expressions were higher in GC tissues compared to adjacent non-tumor tissues according to RT-PCR and western blotting. Higher Orai1 and/or STIM1 expression was associated with more advanced disease, more frequent recurrence, and higher mortality rates in our study of 327 GC patients. The disease-free survival rates of Stage I-III patients and the overall survival rates of Stage IV patients were significantly worse when the tumors had high Orai1 and/or STIM1 expressions. Orai1 and/or STIM1 knockdown caused significantly reduced tumor growth and metastasis in athymic mice. Orai1 and/or STIM1 knockdown lowered the proliferation, metabolism, migration, and invasion of two GC cell lines. Also, Orai1 and/or STIM1 knockdown changed the markers of the cell cycle and epithelial-mesenchymal transition (EMT). These effects were reversed by metastasis-associated in colon cancer-1 (MACC1) overexpression. In summary, the composite molecules of SOCE suggest a poor prognosis for GC by promoting tumor cell proliferation, metabolism, migration, and invasion by targeting MACC1.

Application of 'tying, binding and fixing operation' in surgical treatment of severe mixed hemorrhoids.

The aim of the present study was to examine the clinical value of 'tying, binding and fixing operation' in treating severe mixed hemorrhoids. A total of 160 patients with severe mixed hemorrhoids were selected and randomly divided into the experimental (n=80) and control (n=80) groups. The groups were treated using 'tying, binding and fixing operation' and Doppler ultrasound-guided hemorrhoidal artery ligation (DG-HAL), respectively. The results showed that the average operative time of the experimental group (35.57±6.17) was significantly higher than that of the control group (12.73±4.92). There was no significant difference of blood loss during the operation between the two groups (P>0.05). There was also no significant difference in improving the hemorrhage symptom between the two groups (P>0.05). In addition, concerning improvement of prolapse symptoms and reduction of the volume of hemorrhoids, the experimental group were significantly improved as compared to the control group. No anal function damage in the two groups was identified, and the length of stay in hospital for the two groups was not significantly different (P>0.05). However, the hospitalization cost in the experimental group (5,334.77±875.54) was significantly lower than that of the control group (8,551.81±1,806.54) and satisfaction degree was significantly higher than that of the control group. The incidences of perianal pain, anal edema and dysuria between two groups were not significantly different (P>0.05). There were 10 cases of secondary hemorrhage and 18 cases of infection in the experimental group, and 12 cases of secondary hemorrhage and 14 cases of infection in the control group, although the differences between the two groups were not statistically significant (P>0.05). The incidence rate of local hematoma in the experimental group (1.2%) was significantly lower than that in the control group (15.0%). The recurrence rate of the control group (22.5%) was also significantly higher than that of the experimental group (2.5%). In conclusion, tying, binding and fixing operation is a promising method that may be employed for the treatment of sever mixed hemorrhoids, and it is better than DG-HAL in improving the prolapse and reducing the volume of hemorrhoids.

Dominant Splice Site Mutations in PIK3R1 Cause Hyper IgM Syndrome, Lymphadenopathy and Short Stature.

The purpose of this research was to use next generation sequencing to identify mutations in patients with primary immunodeficiency diseases whose pathogenic gene mutations had not been identified. Remarkably, four unrelated patients were found by next generation sequencing to have the same heterozygous mutation in an essential donor splice site of PIK3R1 (NM_181523.2:c.1425 + 1G > A) found in three prior reports. All four had the Hyper IgM syndrome, lymphadenopathy and short stature, and one also had SHORT syndrome. They were investigated with in vitro immune studies, RT-PCR, and immunoblotting studies of the mutation's effect on mTOR pathway signaling. All patients had very low percentages of memory B cells and class-switched memory B cells and reduced numbers of naïve CD4+ and CD8+ T cells. RT-PCR confirmed the presence of both an abnormal 273 base-pair (bp) size and a normal 399 bp size band in the patient and only the normal band was present in the parents. Following anti-CD40 stimulation, patient's EBV-B cells displayed higher levels of S6 phosphorylation (mTOR complex 1 dependent event), Akt phosphorylation at serine 473 (mTOR complex 2 dependent event), and Akt phosphorylation at threonine 308 (PI3K/PDK1 dependent event) than controls, suggesting elevated mTOR signaling downstream of CD40. These observations suggest that amino acids 435-474 in PIK3R1 are important for its stability and also its ability to restrain PI3K activity. Deletion of Exon 11 leads to constitutive activation of PI3K signaling. This is the first report of this mutation and immunologic abnormalities in SHORT syndrome.