Key gp120 Glycans Pose Roadblocks to the Rapid Development of VRC01-Class Antibodies in an HIV-1-Infected Chinese Donor.

VRC01-class antibodies neutralize diverse HIV-1 strains by targeting the conserved CD4-binding site. Despite extensive investigations, crucial events in the early stage of VRC01 development remain elusive. We demonstrated how VRC01-class antibodies emerged in a Chinese donor by antigen-specific single B cell sorting, structural and functional studies, and longitudinal antibody and virus repertoire analyses. A monoclonal antibody DRVIA7 with modest neutralizing breadth was isolated that displayed a subset of VRC01 signatures. X-ray and EM structures revealed a VRC01-like angle of approach, but less favorable interactions between the DRVIA7 light-chain CDR1 and the N terminus with N276 and V5 glycans of gp120. Although the DRVIA7 lineage was unable to acquire broad neutralization, longitudinal analysis revealed a repertoire-encoded VRC01 light-chain CDR3 signature and VRC01-like neutralizing heavy-chain precursors that rapidly matured within 2 years. Thus, light chain accommodation of the glycan shield should be taken into account in vaccine design targeting this conserved site of vulnerability.

Insulin resistance is more frequent in type 1 diabetes patients with long disease duration.

AIMS: To investigate the clinical status of insulin resistance (IR) and its correlation with disease duration in patients with type 1 diabetes (T1D). MATERIALS AND METHODS: Cross-sectional data from a T1D cohort were obtained (n = 923). IR-related metabolic disorders including hypertension, obesity, and dyslipidemia were used as outcome variables to explore the cut-off point for estimated glucose disposal rate (eGDR) by restricted cubic spline (RCS) curve. Regression models were used for multivariate analysis of the clinical factors associated with IR. The correlation between the status of IR and diabetes duration was depicted with the RCS curve. RESULTS: IR-related metabolic disorders were observed in 39.4% of patients, with 9.1% meeting the criteria for metabolic syndrome. Specifically, patients with ≥10 years of T1D were more likely to have IR-related metabolic disorders (54.7% vs. 36.9%, p < 0.05). The presence of IR, defined as an eGDR ≤9.0 mg/kg/min, was observed in 42.2% of patients. Patients with IR had a longer diabetes duration (3.5 vs. 2.7, years, p = 0.003) and higher insulin dose (0.5 vs. 0.4, units per kg per day, p < 0.001). Moreover, the presence of IR showed a gradual increase during 10 years' disease duration and further analysis showed that diabetes duration ≥10 years was a key element behind the development of IR and IR-related metabolic disorders. CONCLUSIONS: The status of IR is common in T1D patients, especially in those with ≥10 years of disease duration. Therapies targeting balancing glycaemic control and IR are needed to decrease the future risk of cardiovascular diseases in T1D. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT03610984 (cohort study of patients with type 1 diabetes).

Fat-to-muscle ratio is associated with insulin resistance and cardiometabolic disorders in adults with type 1 diabetes mellitus.

AIMS: This study aimed to investigate the correlation of the fat-to-muscle ratio (FMR) with insulin resistance (IR) and cardiometabolic disorders (CMD) in patients with type 1 diabetes mellitus (T1DM). MATERIALS AND METHODS: We retrospectively recruited 420 adults with T1DM [52.6% men, median age 32.4 (24.5, 43.0) years]. Body composition was assessed by bioelectrical impedance analysis and FMR was calculated. The characteristics of the overall participants were compared between tertiles of FMR. Logistic regression analyses were performed to assess the association of FMR tertiles with IR and cardiometabolic risk factors. RESULTS: Median age and median haemoglobin A1c of all participants were 32.4 (24.5, 43.0) years and 7.4 (6.5, 8.7)%, respectively. The prevalence of IR and CMD was 18% and 38.6%. The FMR significantly differed between men and women [0.39 (0.31, 0.53) vs. 0.74 (0.63, 0.92), respectively, p < .001]. The proportion of IR and CMD gradually increased as the FMR increased. The multivariable-adjusted odd ratios for IR and CMD in FMR tertile 3 compared with tertile 1 were 4.8 [95% confidence interval (CI): (1.9, 12.1)] and 9.7 (95% CI: 4.2, 22.3), respectively, in men. For women, the corresponding odd ratios were 4.0 (95% CI: 1.2, 12.9) for IR and 5.8 (95% CI: 2.4, 13.6) for CMD. CONCLUSIONS: FMR is associated with IR and CMD in adults with T1DM and could be used as a promising parameter for targeting treatment in T1DM.

Poorly differentiated cluster grade-a vital predictor for lymph node metastasis and oncological outcomes in patients with T1 colorectal cancer: a retrospective study.

BACKGROUND: T1 colorectal cancers have a low lymph node metastasis rate and good prognosis. Thus, endoscopic resection is an attractive choice. This study aimed to describe the value of poorly differentiated cluster grade in identifying endoscopically curable T1 colorectal cancers. METHODS: We included 183 T1 colorectal cancer patients who underwent curative resection. Univariate and multivariate logistic regressions were used to identify lymph node metastasis predictors. The Akaike information criterion was used to determine whether poorly differentiated cluster grade was the best predictor. Backward regression was used to screen the variables. Survival analyses were conducted to determine the prognostic predictive power of poorly differentiated cluster grade. Correlations among predictors and concordance between our pathologists were also investigated. RESULTS: Poorly differentiated cluster grade was an independent predictor for lymph node metastasis (adjusted odds ratio [OR]G 3 = 0.001; 95% confidence interval [95% CI]G 3 = < 0.001, 0.139) in T1 colorectal cancer patients; moreover, it had the best predictive value (AIC = 61.626) among all indicators. It was also screened for inclusion in the predictive model. Accordingly, a high poorly differentiated cluster grade independently indicated shorter overall survival (hazard ratio [HR]G 2 = 4.315; 95% CIG 2 = 1.506, 12.568; HRG 3 = 5.049; 95% CIG 3 = 1.326, 19.222) and disease-free survival (HRG 3 = 6.621; 95% CIG 3 = 1.472, 29.786). CONCLUSIONS: Poorly differentiated cluster grade is a vital reference to manage T1 colorectal cancer. It could serve as an indicator to screen endoscopically curable T1 colorectal cancers.

Identifying Patients at High Risk of Chronic Pain After Video-Assisted Thoracoscopic Surgery Using Thermal Quantitative Sensory Testing.

OBJECTIVE: To examine whether perioperative thermal quantitative sensory testing could be used to identify patients at high risk of chronic pain after video-assisted thoracoscopic surgery (VATS). DESIGN: A single-center, prospective, observational study. SETTING: At the Peking University People's Hospital. PARTICIPANTS: A total of 111 patients scheduled to undergo VATS were enrolled. INTERVENTIONS: Quantitative sensory testing was conducted at the anterior intercostal incision prior to surgery and after chest tube removal. MEASUREMENTS AND MAIN RESULTS: The patient's chronic pain was assessed at 3 months after surgery using a questionnaire. The incidence of chronic pain was 35 out of 107 evaluable patients (32.7%). Among the 35 patients with chronic pain, 26 had features characteristic of neuropathic pain (74.3%). Compared to the patients without chronic pain, subjects with chronic pain had a significantly greater perioperative change in cold pain threshold (CPT; p = 0.032), but not cold detection threshold, warm detection threshold, and hot pain threshold . In the multivariate regression, perioperative CPT change was associated with chronic pain after VATS (odds ratio = 1.043, p = 0.026). CONCLUSIONS: Chronic pain after VATS is typically neuropathic. The change in perioperative CPT at the incision site may help to identify patients at higher risk of chronic pain after VATS.

Safety and immunogenicity of COVID-19 vaccination in patients with non-alcoholic fatty liver disease (CHESS2101): A multicenter study.

BACKGROUND & AIMS: The development of COVID-19 vaccines has progressed with encouraging safety and efficacy data. Concerns have been raised about SARS-CoV-2 vaccine responses in the large population of patients with non-alcoholic fatty liver disease (NAFLD). The study aimed to explore the safety and immunogenicity of COVID-19 vaccination in NAFLD. METHODS: This multicenter study included patients with NAFLD without a history of SARS-CoV-2 infection. All patients were vaccinated with 2 doses of inactivated vaccine against SARS-CoV-2. The primary safety outcome was the incidence of adverse reactions within 7 days after each injection and overall incidence of adverse reactions within 28 days, and the primary immunogenicity outcome was neutralizing antibody response at least 14 days after the whole-course vaccination. RESULTS: A total of 381 patients with pre-existing NAFLD were included from 11 designated centers in China. The median age was 39.0 years (IQR 33.0-48.0 years) and 179 (47.0%) were male. The median BMI was 26.1 kg/m2 (IQR 23.8-28.1 kg/m2). The number of adverse reactions within 7 days after each injection and adverse reactions within 28 days totaled 95 (24.9%) and 112 (29.4%), respectively. The most common adverse reactions were injection site pain in 70 (18.4%), followed by muscle pain in 21 (5.5%), and headache in 20 (5.2%). All adverse reactions were mild and self-limiting, and no grade 3 adverse reactions were recorded. Notably, neutralizing antibodies against SARS-CoV-2 were detected in 364 (95.5%) patients with NAFLD. The median neutralizing antibody titer was 32 (IQR 8-64), and the neutralizing antibody titers were maintained. CONCLUSIONS: The inactivated COVID-19 vaccine appears to be safe with good immunogenicity in patients with NAFLD. LAY SUMMARY: The development of vaccines against coronavirus disease 2019 (COVID-19) has progressed rapidly, with encouraging safety and efficacy data. This study now shows that the inactivated COVID-19 vaccine appears to be safe with good immunogenicity in the large population of patients with non-alcoholic fatty liver disease.

microRNA-107 protects against inflammation and endoplasmic reticulum stress of vascular endothelial cells via KRT1-dependent Notch signaling pathway in a mouse model of coronary atherosclerosis.

Coronary atherosclerosis is a long-term, sustained, and evolving inflammatory disease manifested with the remodeling of the coronary arteries. The purpose of this study is to explore the potential role of microRNA-107 (miR-107) in vascular endothelial cells (VECs) in coronary atherosclerosis by regulating the KRT1 gene and the Notch signaling pathway. A mouse model of coronary atherosclerosis was established. The relationship between miR-107 and KRT1 was analyzed and verified by dual-luciferase reporter assay. The functional role of miR-107 in coronary atherosclerosis was determined using ectopic expression and depletion. Blood lipid levels and atherosclerotic index (AI) were measured in atherosclerotic mice. Expression pattern of miR-107, KRT1, Notch signaling pathway, inflammatory/anti-inflammatory factors, and endoplasmic reticulum (ER) stress-related genes was evaluated by means of reverse transcription quantitative polymerase chain reaction, western blot analysis, and enzyme-linked immunosorbent assay. Meanwhile, cell-cycle distribution and cell apoptosis in VECs were assessed by flow cytometry. Atherosclerotic mice exhibited higher blood lipid levels, AI, apoptotic index, and KRT1-positive expression as well as inhibited Notch signaling pathway when compared with normal mice. The miR-107 was revealed to bind to KRT1; miR-107 upregulation or KRT1 silencing resulted in reductions in blood lipid levels and AI, inhibition in cell apoptosis, inflammation, and ER stress. Restored miR-107 or downregulated KRT1 activated the Notch signaling pathway. These results supported the notion that miR-107-targeted KRT1 inhibition activated the Notch pathway, thereby, protecting against the coronary atherosclerosis. Findings in this study might provide a novel biomarker for the coronary atherosclerosis treatment.

[Research advance in chondrogenic differentiation of adipose-derived stem cells].

Articular cartilage lesions due to injury or other pathology are often difficult to heal, and the outcomes of the clinical treatment widely used today are far from satisfaction. Adipose-derived stem cells (ADSCs) are multipotent stem cells from adipose tissue. Tissue engineering based on the ability of ADSCs to differentiate into chondrocytes provides a new idea for the repair and regeneration of articular cartilage defects. The method for inducing the differentiation of ADSCs into chondrocytes in vitro who have been quite well established, which mainly include the use of growth factors and scaffolds to mimic the in vivo microenvironment, thereby promoting the differentiation of ADSCs into chondrocytes.

Early Env-specific CTLs effectively suppress viral replication in SHIV controller macaques.

Early immunological events in acute HIV infection are thought to fundamentally influence long-term disease outcomes. Though the contribution of Gag-specific CD8 T cell responses to early viral control is well established, little is known about the role of Env-specific CD8 T cell responses in controlling viral replication during acute infection. In a macaque simian-human immunodeficiency virus (SHIV) model, some macaques who were able to control SHIV replication after ART interruption showed expansion of Env-specific CD8 T cell responses during acute infection, compared to macaques who progressed to viral rebound. To better understand the function of early Env-specific CD8 T cells, we isolated, expanded and examined their ability to act as effectors in vitro. We observed that Env-specific CD8 T cell clones have the capacity to directly recognize and kill SHIV-infected CD4 T cells, but failed to reduce viral replication in SHIV-infected macrophages. Our data suggest that early Env-specific CD8 T cell responses during acute SHIV infection contribute substantially to the control of viral replication. The T-cell clones composing of Env-specific effector cells demonstrates in vitro phenotypic and functional characteristics with the potentials to provide longlasting clinical benefit of in vivo HIV study.

Identification of suh gene and evidence for involvement of notch signaling pathway on gonadal differentiation of Yellow River carp (Cyprinus carpio).

The suh gene is crucial in Notch pathway and regulates mammalian gonad development. In this study, the sequences of suh1 and suh2 genes in Yellow River carp (Cyprinus carpio) were verified. The partial 5'-flanking regions of suh1 and suh2 were analyzed and several potential transcription factor-binding sites were identified. Phylogenetic, gene structure, and chromosome synteny analyses revealed that carp suh1 and suh2 were orthologs and homologous to vertebrate suh. Investigation of the expression profiles of suh1 and suh2 with qPCR showed that these genes were abundant in the brain and gonad of carp, with suh1 exhibiting sexual dimorphism expression pattern in gonad. To study the relationship between gonad differentiation and Notch signaling, primordial gonads were exposed to DAPT, an inhibitor of Notch signaling, in vitro and in vivo. The results revealed a significant downregulation of suh1 and other Notch genes in vitro. In addition, expression of male-biased genes, such as amh, dmrt1, etc., was downregulated, whereas that of female-biased genes, such as foxl2, gdf9, etc., was upregulated. When the primordial gonads were subjected to long-term DAPT exposure, an increased proportion of ovary and delay in testis development were observed. These results suggest that suh gene may have a conservative function between teleosts and mammals. Furthermore, Notch signaling was found to be involved in gonad differentiation in Yellow River carp, and DAPT was noted to inhibit and enhance the expression of male- and female-biased genes, respectively, and induce the increase in number of females.

Interleukin-21 administration leads to enhanced antigen-specific T cell responses and natural killer cells in HIV-1 vaccinated mice.

Interleukin-21 (IL-21), which belongs to IL-2 γ chain receptor cytokine family, is as an important regulator of immune responses. In this study, we developed a novel strategy for immunizing mice with a DNA/vaccinia/protein vaccine in the presence or absence of mouse IL-21 (mIL-21) to evaluate whether mIL-21 could enhance immune responses. Our results demonstrated that co-immunization with mIL-21 did not increase significantly the capacity of vaccine induced antibodies to bind to HIV-1 GP140. An effect of mIL-21 in adjusting the efficacy of HIV-1 vaccine through enhancing Th1 type immune response was however observed. The frequencies of HIV-1-specific cytokine-producing CD4+ T and CD4+ TEM cells, especially multifunctional T cell responses, were significantly increased by co-administrating with mIL-21. A significant increase was also observed in the frequency of NK cells in mIL-21 adjuvant groups. Taken together, combination of mIL-21 with HIV-1 vaccines led to distinct enhancement of NK cells and T cell immune responses associated with immune protection.

Insulin resistance-related features are associated with cognitive decline: a cross-sectional study in adult patients with type 1 diabetes.

BACKGROUND: To investigate the associations between insulin resistance (IR)-related features and cognitive function in type 1 diabetes (T1D). METHODS: A total of 117 adult patients with T1D were recruited in this cross-sectional study. IR-related features include overweight/obesity/central obesity, hypertension, atherogenic dyslipidemia, and decreased estimated insulin sensitivity (eIS). The Wechsler Memory Scale-Chinese Revision, Wisconsin Card Sorting Test, and Sustained Attention to Response Task was used to assess memory, executive function and sustained attention, respectively. A z-score was generated from each test, and a composite measure of global cognitive performance was calculated by averaging the z-scores of all tests. Cognitive differences were measured between T1D patients with and without IR-related features. The associations between IR-related features and and cognitive performance were analyzed using: logistic regression, partial correlation, and multivariate linear regression analysis. RESULTS: A total of 53 (45.3%) T1D patients were defined as having IR-related features. Individuals with IR-related features displayed worse overall cognitive scores compared to those without and had a 4-fold increase in the risk for having global cognitive z-score < 0. Among the IR-related features, higher triglyceride (TG) and lower eIS showed linear correlation with lower global cognitive performance. And the subsequent regression analysis identified eIS as the factor independently associated with global cognitive performance. CONCLUSIONS: We have provided evidence linking IR-related features to deteriorated cognitive function in adult patients with T1D. And eIS showed an independent positive correlation with global cognitive performance. Although no causal relationship can be drawn, IR emerges as an important factor reflecting cognitive function. TRIAL REGISTRATION: ClinicalTrials.gov NCT03610984.

A polysomnographic study of slow-wave sleep loss in elderly patients with epilepsy.

Objective: The primary objective is to explore what causes slow-wave sleep loss in elderly patients with epilepsy. The secondary objective is to identify the PSG characteristics in elderly patients with epilepsy. The clinical demographics, sleep architecture, sleep-related events, and interictal epileptiform discharges are to be evaluated in the objectives. Methods: The video electroencephalography (VEEG) and polysomnogram (PSG) data from 44 elderly patients with epilepsy and 52 elderly patients with sleep disorders but without definite central nervous system diseases were analysed. This was a case-control study. The differences in the PSG sleep architecture parameters (total sleep time (TST), sleep efficiency, wake after sleep onset, etc.) and sleep-related events (apnea hypopnea index, oxygen desaturation index (ODI), periodic limb movement index, etc.) between the epilepsy and control groups. As Additionally, these parameters were assessed within the elderly patients with epilepsy, comparing the slow-wave sleep existence and slow-wave sleep loss groups, using VEEG and PSG. Results: The epileptic group exhibited significantly lower TST (343.477 ± 96.3046min vs 389.115 ± 61.5727min, p < 0.05), rapid eye movement (%) (13.011 ± 7.5384 vs 16.992 ± 6.7025, p < 0.05), non-rapid eye movement stage 3 (%) (1.35[0,7.225] vs 3.65[0.425,13.75], p < 0.05), and sleep efficiency (%) (69.482 ± 14.1771% vs 77.242 ± 10.6171%, p < 0.05). Conversely, the ODI (25.6[9.825,51.775] events/hour vs 16.85[5.3,30.425] events/hour, p < 0.05) and spontaneous arousal index (4.0455[2.1805,6.9609] events/hour vs 2.9709[1.4747,5.0554] events/hour, p < 0.05) were significantly higher in elderly patients with epilepsy. The prevalence of obstructive sleep apnea-hypopnea syndrome (OSAHS) was significantly higher in the slow-wave sleep loss group than in the slow-wave sleep existence group (100% vs 77.8%, p < 0.05). The incidence of slow-wave sleep loss was lower in patients with epilepsy aged between 75 and 85 years compared to those aged between 65 and 75 years. Conclusion: Elderly patients with epilepsy exhibit higher levels of ODI and spontaneous arousal index. Our findings indicate that OSAHS could be a contributing factor to slow-wave sleep loss in this population. The incidence of slow-wave sleep loss was lower in patients aged above 75 years among elderly patients with epilepsy.

Immunomodulatory Function of Pien Tze Huang in T Cell-Mediated Anti-tumor Activity against B16-F10, MC38 and Hep1-6 Tumor Models.

OBJECTIVE: To investigate the anti-tumor effects of Pien Tze Huang (PZH) in mouse models of B16-F10 melanoma, MC38 colorectal cancer, Hep1-6 hepatocellular carcinoma and chemically induced hepatocellular carcinoma model. METHODS: Various tumor models, including B16-F10, MC38 and Hep1-6 tumor hypodermic inoculation models, B16-F10 and Hep1-6 pulmonary metastasis models, Hep1-6 orthotopic implantation model, and chemically induced hepatocellular carcinoma model, were utilized to evaluate the anti-tumor function of PZH. Tumor growth was assessed by measuring tumor size and weight of solid tumors isolated from C57BL/6 mice. For cell proliferation and death of tumor cells in vitro, as well as T cell activation markers, cytokine production and immune checkpoints analysis, single-cell suspensions were prepared from mouse spleen, lymph nodes, and tumors after PZH treatment. RESULTS: PZH demonstrated significant therapeutic efficacy in inhibiting tumor growth (P<0.01). Treatment with PZH resulted in a reduction in tumor size in subcutaneous MC38 colon adenocarcinoma and B16-F10 melanoma models, and decreased pulmonary metastasis of B16-F10 melanoma and Hep1-6 hepatoma (P<0.01). However, in vitro experiments showed that PZH only had slight impact on the cell proliferation and survival of tumor cells (P>0.05). Nevertheless, PZH exhibited a remarkable ability to enhance T cell activation and the production of interferon gamma, tumor necrosis factor alpha, and interleukin 2 in CD4+ T cells in vitro (P<0.01 or P<0.05). Importantly, PZH substantially inhibited T cell exhaustion and boosted cytokine production by tumor-infiltrating CD8+ T cells (P<0.01 or P<0.05). CONCLUSION: This study has confirmed a novel immunomodulatory function of PZH in T cell-mediated anti-tumor immunity, indicating that PZH holds promise as a potential therapeutic agent for cancer treatment.

Overexpression of microRNA gga-miR-1650 decreases the replication of avian leukosis virus subgroup J in infected cells.

MicroRNAs (miRNAs) are a class of small regulatory non-coding RNAs that modulate gene expression at the post-transcriptional level, playing a crucial role in cell differentiation and development. Recently, some reports have demonstrated that a number of cellular miRNAs play a role during viral infection. In this study, a luciferase-reporter system carrying the 5' untranslated region (5' UTR) and 3' UTR of avian leukosis virus subgroup J (ALV-J) was used to determine whether cellular miRNAs are involved in ALV-J infection. The miRNA gga-miR-1650 was screened for its potential interaction with the 5' UTR of ALV-J and the ability to suppress luciferase-reporter activity. A mutational analysis of predicted gga-miR-1650-binding sites showed that the 5' and 3' ends of gga-miR-1650 contributed to the interaction between gga-miR-1650 and its target located at the 5' UTR. Overexpression of miRNA gga-miR-1650 was shown to downregulate the expression of the Gag protein and influence the replication of ALV-J through binding to the 5' UTR. Overall, this report provides the basis for the development of new strategies for anti-ALV-J intervention.

Circ_0000285 regulates nasopharyngeal carcinoma progression through miR-1278/FNDC3B axis.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is cancer with high mortality and poor prognosis. Circular RNAs (circRNAs) have been identified in a wide variety of cancers. But the functional mechanism of circ_000285 in NPC remains unclear. PURPOSE: To decipher the biological function and molecular mechanism of circ_000285 in NPC. METHODS: Quantitative PCR (RT-qPCR) was applied for detecting the expression of circ_0000285, miR-1278, and FNDC3B. Western blot was used to measure the protein levels of Fibronectin type III domain containing 3B (FNDC3B), Bcl2 associated X (Bax), and B cell leukemia/lymphoma 2 (Bcl2). Cell proliferation, migration, and invasion were analyzed by colony formation, 5-ethynyl-2'-deoxyuridine (EdU), and transwell assays. Cell apoptosis was detected by flow cytometry assays. ELISA assay was used to analyze Caspase-3 activity. Bioinformatics was used to predict, and the target relationship between miR-1278 and circ_0000285 or FNDC3B was verified by luciferase reporter assay. Tumor xenograft models were established to examine how circ_0000285 functions during the mediation of NPC tumor growth in vivo. RESULTS: Increased circ_0000285 and FNDC3B expressions, and a decreased miR-1278 expression were observed in NPC tissues and cell lines. Knockdown of circ_0000285 inhibited NPC cell proliferation, migration, invasion, and while promoting NPC cell apoptosis in vitro. Circ_0000285 knockdown-mediated anti-tumor effects in NPC cells could be largely reversed by silencing of miR-1278 or overexpression of FNDC3B. Circ_0000285 could up-regulate FNDC3B expression by sponging miR-1278 in NPC cells. Knockdown of circ_0000285 could inhibit tumor growth in vivo. CONCLUSION: Circ_0000285 upregulates FNDC3B expression by adsorbing miR-1278 to promote NPC development.

Biology of breast cancer brain metastases and novel therapies targeting the blood brain barrier: an updated review.

Brain metastasis (BM) is a critical cause of morbidity and mortality in patients with breast cancer (BC). Compared with other cancer cells, BC cells (BCs) exhibit special features in the metastatic process. However, the underlying mechanisms are still unclear, especially the crosstalk between tumour cells and the microenvironment. To date, novel therapies for BM, including targeted therapy and antibody‒drug conjugates, have been developed. Due to an improved understanding of the blood‒brain barrier (BBB) and blood-tumour barrier (BTB), the development and testing of therapeutic agents in clinical phases have substantially increased. However, these therapies face a major challenge due to the low penetration of the BBB or BTB. As a result, researchers have increasingly focused on finding ways to promote drug penetration through these barriers. This review provides an updated overview of breast cancer brain metastases (BCBM) and summarizes the newly developed therapies for BCBM, especially drugs targeting the BBB or BTB.

Radionecrosis mimicking pseudo­progression in a patient with lung cancer and brain metastasis following the combination of anti­PD­1 therapy and stereotactic radiosurgery: A case report.

Brain metastases (BMs) usually develop in patients with non-small cell lung cancer. In addition to systemic therapy, radiation therapy and surgery, anti-programmed cell death-ligand 1 (PD-L1) therapy is another promising clinical anticancer treatment modality. However, the optimal timing and drug-drug interactions of anti-PD-L1 therapy with other combined treatments remain to be elucidated. Treatment with anti-PD-L1 therapy is associated with an increased risk of radionecrosis (RN) regardless of tumor histology. The present study described a case of RN in a patient with lung adenocarcinoma and with BM who received anti-PD-L1 therapy. Before anti-PD-L1 treatment, the patient received whole brain radiotherapy. During durvalumab treatment, the intracranial metastases regressed. The progression of intracranial lesions 9 months later prompted a second-line of therapy with PD-L1 inhibitor durvalumab and stereotactic radiotherapy (SRT). Despite stereotactic irradiation, the lesions progressed further, leading to surgical resection. On examination, RN was detected, but there was no evidence of metastatic lung cancer. The aim of the present study was to present the longitudinal change in magnetic resonance imaging in RN following STR and anti-PD-L1 combined therapy. The atypical image of RN is conditionally important for making an accurate preoperative diagnosis.

Asiaticoside Suppresses Gastric Cancer Progression and Induces Endoplasmic Reticulum Stress through the miR-635/HMGA1 Axis.

Objective: Gastric cancer is a prevalent malignant tumor with high morbidity and poor prognosis. Asiaticoside (AC) has antitumor effects, while its role in gastric cancer is elusive. Thus, this study investigated the effect of AC on gastric cancer progression. Methods: Cell viability and migration were determined using the CCK-8 and Transwell migration assay. Endoplasmic reticulum stress was detected through measuring the expressions of GRP78, Chop, and hnRNPA1 by Western blot. The luciferase assay confirmed the relationship between miR-635 and High Mobility Group AT-Hook 1 (HMGA1). The effect of AC on tumor growth was evaluated by establishing a xenograft tumor. The survival rate of mice was analyzed by Kaplan-Meier analysis. Results: AC suppressed gastric cancer cell viability and restrained cell migration. AC inhibited the expressions of the cell proliferation marker PCNA and EMT-related marker N-cadherin and increased E-cadherin expression. AC elevated the levels of GRP78 and Chop and suppressed the level of hnRNPA1. In addition, AC restrained gastric cancer proliferation and migration ability and induced endoplasmic reticulum stress by upregulating miR-635 expression. Furthermore, HMGA1 was proven to be a target of miR-635. AC constrained gastric cancer cell proliferation and migration and promoted endoplasmic reticulum stress by regulating HMGA1. Moreover, AC suppressed in vivo tumor growth and improved the survival time of mice. Additionally, AC elevated the expressions of miR-635, E-cadherin, GRP78, and Chop and inhibited Ki-67, HMGA1, N-cadherin, and hnRNPA1 expressions in tumor tissues of mice. Conclusion: AC suppressed gastric cancer progression and induced endoplasmic reticulum stress via the miR-635/HMGA1 axis, providing a valuable drug against gastric cancer.

Using Glycated Albumin and Stimulated C-Peptide to Define Partial Remission in Type 1 Diabetes.

Objective: To propose a new definition of partial remission (PR) for patients with type 1 diabetes (T1D) of all-ages using insulin dose and glycated albumin (GA), and find the optimal cut-off values for stimulated C-peptide to diagnose PR in different age-groups. Research Design and Methods: Patients with newly diagnosed T1D (n=301) were included. GA/insulin dose was used to diagnose PR, and insulin dose-adjusted glycated albumin (IDAGA) was proposed to facilitate clinical application. The optimal diagnostic levels of IDAGA and stimulated C-peptide were determined in different age-groups (≤ 12y, 12-18y and ≥ 18y). Furthermore, the diagnostic consistency between different PR definitions was studied. Results: GA≤ 23%/insulin dose ≤ 0.5u/kg/day was used to define PR, and IDAGA (GA (%) + 40 * insulin dose(u/kg/day)) ≤ 40 was feasible in all age-groups. Whereas, the optimal diagnostic level showed difference for stimulated C-peptide (265.5, 449.3 and 241.1 pmol/L for the ≤ 12y, 12-18y and ≥ 18y age-group, respectively). About 40% of patients met the PR definition by stimulated C-peptide but not GA/insulin dose or IDAGA, who showed dyslipidemia and higher insulin resistance. Conclusions: A new definition of the PR phase is proposed using GA/insulin dose, and the calculated IDAGA≤ 40 applies to all age-groups. The stimulated C-peptide to diagnose PR is the highest in the 12-18y age-group, which reflects the effect of puberty on metabolism. For patients with insulin resistance, it is not recommended to use stimulated C-peptide alone to diagnose PR.