The discriminatory diagnostic value of multimodal ultrasound combined with blood cell analysis for granulomatous lobular mastitis and invasive ductal carcinoma of the breast.

OBJECTIVE: To explore the discriminatory diagnostic value of multimodal ultrasound(US) combined with blood cell analysis(BCA) for Granulomatous Lobular Mastitis (GLM) and Invasive Ductal Carcinoma(IDC) of the breast. METHODS: A total of 157 breast disease patients were collected and divided into two groups based on postoperative pathological results: the GLM group(57 cases with 57 lesions) and the IDC group(100 cases with 100 lesions). Differences in multimodal ultrasound features and the presence of BCA were compared between the two groups. The receiver operating characteristic(ROC) curve was used to calculate the optimal cutoff values, sensitivity, specificity, 95% confidence interval(CI), and the area under the curve(AUC) for patient age, lesion size, lesion resistive index(RI), and white blood cell(WBC) count in BCA. Sensitivity, specificity, positive predictive value, negative predictive value, diagnostic accuracy, and AUC were calculated for different diagnostic methods. RESULTS: There were statistically significant differences(P <  0.05) observed between GLM and IDC patients in terms of age, breast pain, the factors in Conventional US(lesion size, RI, nipple delineation, solitary/multiple lesions, margin, liquefaction area, growth direction, microcalcifications, posterior echogenicity and abnormal axillary lymph nodes), the factors in CEUS(contrast agent enhancement intensity, enhancement pattern, enhancement range, and crab-like enhancement) and the factors in BCA(white blood cells, neutrophils, lymphocytes and monocytes). ROC curve analysis results showed that the optimal cutoff values for distinguishing GLM from IDC were 40.5 years for age, 7.15 cm for lesion size, 0.655 for lesion RI, and 10.525*109/L for white blood cells. The diagnostic accuracy of conventional US combined with CEUS(US-CEUS) was the highest(97.45%). The diagnostic performance AUCs for US-CEUS, CEUS, and US were 0.965, 0.921 and 0.832, respectively. CONCLUSION: Multifactorial analysis of multimodal ultrasound features and BCA had high clinical application value in the differential diagnosis of GLM and IDC.

Dysregulated microRNAs as a biomarker for diagnosis and prognosis of hepatitis B virus-associated hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a malignancy with a high incidence and fatality rate worldwide. Hepatitis B virus (HBV) infection is one of the most important risk factors for its occurrence and development. Early detection of HBV-associated HCC (HBV-HCC) can improve clinical decision-making and patient outcomes. Biomarkers are extremely helpful, not only for early diagnosis, but also for the development of therapeutics. MicroRNAs (miRNAs), a subset of non-coding RNAs approximately 22 nucleotides in length, have increasingly attracted scientists' attention due to their potential utility as biomarkers for cancer detection and therapy. HBV profoundly impacts the expression of miRNAs potentially involved in the development of hepatocarcinogenesis. In this review, we summarize the current progress on the role of miRNAs in the diagnosis and treatment of HBV-HCC. From a molecular standpoint, we discuss the mechanism by which HBV regulates miRNAs and investigate the exact effect of miRNAs on the promotion of HCC. In the near future, miRNA-based diagnostic, prognostic, and therapeutic applications will make their way into the clinical routine.

Study on the Efficacy of "Information Platform + Self-Care Model" on the Health Status of Discharged Patients Following Vaginal Natural Orifice Transluminal Endoscopic Surgery.

Objective: To discuss the impact of the "information platform + self-care model" on the health status of discharged patients following vaginal natural orifice transluminal endoscopic surgery (vNOTES). Methods: Patients underwent vNOTES at a tertiary specialized women's and children's hospital in Chengdu. They were randomly assigned to one of two groups-the intervention group (29 patients) and the control group (29 patients). The control group received standard education after discharge, while the intervention group received guidance based on an "information platform + self-care model" on discharge; a questionnaire survey was conducted for both groups one month after discharge. Results: The quality of life score in the intervention group was higher than that in the control group, and the difference was statistically significant (P < 0.05); the scores of the intervention group on dimensions such as vitality, general health perceptions, physical role functioning, social role functioning, emotional role functioning, and mental health, except for physical functioning (Z = 0.034, P = 0.973) and bodily pain (Z = 1.470, P = 0.141), were higher than those in the control group one month after discharge, and the difference was statistically significant (P < 0.05). There was no patient (0) in the intervention group who had an unscheduled visit/admission, and there was 1 patient (3.6%) in the control group who had unscheduled visit/admission; there were no statistical differences between the two groups in the number of patients who had an unscheduled visit/admission 1 month after discharge (P = 0.491). Conclusion: The application of the "information platform + self-care model" can, to a certain extent, improve the health status of patients following vNOTES after discharge, and it can also reduce unscheduled visits/admissions, but more research with a larger sample size is required.

Autophagy and its therapeutic potential in diabetic nephropathy.

Diabetic nephropathy (DN), the leading cause of end-stage renal disease, is the most significant microvascular complication of diabetes and poses a severe public health concern due to a lack of effective clinical treatments. Autophagy is a lysosomal process that degrades damaged proteins and organelles to preserve cellular homeostasis. Emerging studies have shown that disorder in autophagy results in the accumulation of damaged proteins and organelles in diabetic renal cells and promotes the development of DN. Autophagy is regulated by nutrient-sensing pathways including AMPK, mTOR, and Sirt1, and several intracellular stress signaling pathways such as oxidative stress and endoplasmic reticulum stress. An abnormal nutritional status and excess cellular stresses caused by diabetes-related metabolic disorders disturb the autophagic flux, leading to cellular dysfunction and DN. Here, we summarized the role of autophagy in DN focusing on signaling pathways to modulate autophagy and therapeutic interferences of autophagy in DN.

CDK4/6 inhibition triggers ICAM1-driven immune response and sensitizes LKB1 mutant lung cancer to immunotherapy.

Liver kinase B1 (LKB1) mutation is prevalent and a driver of resistance to immune checkpoint blockade (ICB) therapy for lung adenocarcinoma. Here leveraging single cell RNA sequencing data, we demonstrate that trafficking and adhesion process of activated T cells are defected in genetically engineered Kras-driven mouse model with Lkb1 conditional knockout. LKB1 mutant cancer cells result in marked suppression of intercellular adhesion molecule-1 (ICAM1). Ectopic expression of Icam1 in Lkb1-deficient tumor increases homing and activation of adoptively transferred SIINFEKL-specific CD8+ T cells, reactivates tumor-effector cell interactions and re-sensitises tumors to ICB. Further discovery proves that CDK4/6 inhibitors upregulate ICAM1 transcription by inhibiting phosphorylation of retinoblastoma protein RB in LKB1 deficient cancer cells. Finally, a tailored combination strategy using CDK4/6 inhibitors and anti-PD-1 antibodies promotes ICAM1-triggered immune response in multiple Lkb1-deficient murine models. Our findings renovate that ICAM1 on tumor cells orchestrates anti-tumor immune response, especially for adaptive immunity.

Better performance of PIVKA-II for detecting hepatocellular carcinoma in patients with chronic liver disease with normal total bilirubin.

BACKGROUND: Serum protein induced by vitamin K absence or antagonist-II (PIVKA-II) is a promising biomarker for hepatocellular carcinoma (HCC) surveillance. AIM: To identify the contributing factors related to the abnormal elevation of PIVKA-II level and assess their potential influence on the performance of PIVKA-II in detecting HCC. METHODS: This study retrospectively enrolled in 784 chronic liver disease (CLD) patients and 267 HCC patients in Mengchao Hepatobiliary Hospital of Fujian Medical University from April 2016 to December 2019. Logistic regression and the area under the receiver operating characteristic curve (AUC) were used to evaluate the influencing factors and diagnostic performance of PIVKA-II for HCC, respectively. RESULTS: Elevated PIVKA-II levels were independently positively associated with alcohol-related liver disease, serum alkaline phosphatase (ALP), and total bilirubin (TBIL) for CLD patients and aspartate aminotransferase (AST) and tumor size for HCC patients (all P < 0.05). Serum PIVKA-II were significantly lower in patients with viral etiology, ALP ≤ 1 × upper limit of normal (ULN), TBIL ≤ 1 × ULN, and AST ≤ 1 × ULN than in those with nonviral disease and abnormal ALP, TBIL, or AST (all P < 0.05), but the differences disappeared in patients with early-stage HCC. For patients with TBIL ≤ 1 × ULN, the AUC of PIVKA-II was significantly higher compared to that in patients with TBIL > 1 × ULN (0.817 vs 0.669, P = 0.015), while the difference between ALP ≤ 1 × ULN and ALP > 1 × ULN was not statistically significant (0.783 vs 0.729, P = 0.398). These trends were then more prominently perceived in subgroups of patients with viral etiology and HBV alone. CONCLUSION: Serum PIVKA-II has better performance in detecting HCC at an early stage for CLD patients with normal serum TBIL.

PARP Inhibition Induces Synthetic Lethality and Adaptive Immunity in LKB1-Mutant Lung Cancer.

Contradictory characteristics of elevated mutational burden and a "cold" tumor microenvironment (TME) coexist in liver kinase B1 (LKB1)-mutant non-small cell lung cancers (NSCLC). The molecular basis underlying this paradox and strategies tailored to these historically difficult to treat cancers are lacking. Here, by mapping the single-cell transcriptomic landscape of genetically engineered mouse models with Kras versus Kras/Lkb1-driven lung tumors, we detected impaired tumor-intrinsic IFNγ signaling in Kras/Lkb1-driven tumors that explains the inert immune context. Mechanistic analysis showed that mutant LKB1 led to deficiency in the DNA damage repair process and abnormally activated PARP1. Hyperactivated PARP1 attenuated the IFNγ pathway by physically interacting with and enhancing the poly(ADP-ribosyl)ation of STAT1, compromising its phosphorylation and activation. Abrogation of the PARP1-driven program triggered synthetic lethality in NSCLC on the basis of the LKB1 mutation-mediated DNA repair defect, while also restoring phosphorylated STAT1 to favor an immunologically "hot" TME. Accordingly, PARP1 inhibition restored the disrupted IFNγ signaling and thus mounted an adaptive immune response to synergize with PD-1 blockade in multiple LKB1-deficient murine tumor models. Overall, this study reveals an unexplored interplay between the DNA repair process and adaptive immune response, providing a molecular basis for dual PARP1 and PD-1 inhibition in treating LKB1-mutant NSCLC. SIGNIFICANCE: Targeting PARP exerts dual effects to overcome LKB1 loss-driven immunotherapy resistance through triggering DNA damage and adaptive immunity, providing a rationale for dual PARP and PD-1 inhibition in treating LKB1-mutant lung cancers.

Canonical WNT Signaling Activated by WNT7B Contributes to L-HBs-Mediated Sorafenib Resistance in Hepatocellular Carcinoma by Inhibiting Mitophagy.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer death globally, with hepatitis B virus (HBV) infection accounting for over half of all cases. HBV leads to the development of HCC according to a body of literature. Our previous research and other studies also suggest that HBV causes chemotherapeutic treatment resistance, however, the mechanism is uncertain. The WNT family, which encodes secreted signaling molecules, has been linked to carcinogenesis in a variety of malignancies, including HCC. However, little is known regarding WNT7B, a WNT ligand, in the development of HCC and HBV-induced chemoresistance. In this study, the bioinformatics analysis and immunohistochemistry (IHC) staining of clinical samples revealed that WNT7B was overexpressed in HBV-associated HCC tissues versus nontumor liver tissues, which was related to HCC patient survival. Further study in vitro showed that WNT7B and its receptor frizzled-4 (FZD4) were upregulated in response to large hepatitis B surface antigens (L-HBs). L-HBs increased canonical WNT signaling in HCC cells through WNT7B/FZD4. According to functional experiments, WNT7B enhanced the cell proliferation and metastasis in HCC. In vivo and in vitro studies investigated whether L-HBs induced sorafenib resistance by WNT7B in HCC. Interestingly, L-HBs suppressed sorafenib-induced mitophagy by increasing WNT7B/CTNNB1 signaling, resulting in chemoresistance. The findings revealed that WNT7B could be a promising molecular therapeutic target as well as a predictor of sorafenib resistance in HBV-related HCC. The suppression of HBV structural proteins such as L-HBs may play a crucial role in systemic chemotherapy resistance in HBV-associated HCC.

Multimetallic CuCoNi Oxide Nanowires In Situ Grown on a Nickel Foam Substrate Catalyze Persulfate Activation via Mediating Electron Transfer.

In situ growth of nanostructures on substrates is a strategy for designing highly efficient catalytic materials. Herein, multimetallic CuCoNi oxide nanowires are synthesized in situ on a three-dimensional nickel foam (NF) substrate (CuCoNi-NF) by a hydrothermal method and applied to peroxydisulfate (PDS) activation as immobilized catalysts. The catalytic performance of CuCoNi-NF is evaluated through the degradation of organic pollutants such as bisphenol A (BPA) and practical wastewater. The results indicate that the NF not only plays an important role as the substrate support but also serves as an internal Ni source for material fabrication. CuCoNi-NF exhibits high activity and stability during PDS activation as it mediates electron transfer from BPA to PDS. CuCoNi-NF first donates electrons to PDS to arrive at an oxidized state and subsequently deprives electrons from BPA to return to the initial state. CuCoNi-NF maintains high catalytic activity in the pH range of 5.2-9.2, adapts to a high ionic strength up to 100 mM, and resists background HCO3- and humic acid. Meanwhile, 76.6% of the total organic carbon can be removed from packaging wastewater by CuCoNi-NF-catalyzed PDS activation. This immobilized catalyst shows promising potential in wastewater treatment, well addressing the separation and recovery of conventional powdered catalysts.

Exosomes as potential diagnosis and treatment for liver cancer.

BACKGROUND: Liver cancer is the fourth most significant cause of cancer-related death. Lack of early diagnosis strategy and a scarcity of efficient therapy constitute the main reasons for its lethality. Exosomes, which contain various bioactive molecules, are characterized by high biocompatibility, low immunogenicity, and high transport efficiency. As a result, exosomes have become a research hotspot and present significant potential for cancer diagnosis biomarkers, biotherapeutics, therapy targets, drug carriers and therapeutic agents. AIM: To explore the potential of exosomes in the diagnosis and treatment of liver cancer. METHODS: We conducted a systematic literature search via PubMed and Web of Science. The following keywords were used: "exosomal biomarkers", "exosomal therapy", "exosomal therapy", and "liver cancer" or "HCC". The duplicate data were deleted by EndNote software. Literature search focused on full-texts and references of each article were carefully checked. One author (Xiao-Cui Wei) screened the literature that met the following inclusion criteria: (1) Detection of exosomes or their contents in clinical samples (body fluid or tissue); or (2) Exosomes served as drug carriers or therapeutic factors. Two authors (Xiao-Cui Wei and Li-Juan Liu) independently reviewed all retained literature and analyzed the information. RESULTS: A total of 1295 studies were identified using the systematic literature search. Of these, 835 duplicate studies were removed. A further 402 irrelevant studies were excluded due to being irrelevant, including other diseases, review articles, the literature containing neither clinical samples nor animal experiments, exosome-independent studies, methods for detecting exosomes, or articles in Chinese. Finally, 58 published papers were retained and analyzed in the study. It showed a list of potential exosomal biomarkers that were upregulated in the blood samples of patients with liver cancer. Those downregulated in exosomes might serve as possible biotherapeutics. Some exosomes derived from cells in vitro were used for cytology or animal experiments to explore the mechanism of these exosome contents in disease. These contents might serve as potential targets for liver cancer. Additionally, we also discussed that exosomes serve as drug carriers or therapeutic factors. CONCLUSION: Exosomes might serve as potential biomarkers or therapeutic biotargets in liver cancer and have the potential to act as drug carriers and self-treatment factors for liver cancer patients.

Airflow obstruction, impaired lung function and risk of sudden cardiac death: a prospective cohort study.

BACKGROUND: Growing evidence suggests that compromised lung health may be linked to cardiovascular disease. However, little is known about its association with sudden cardiac death (SCD). OBJECTIVES: We aimed to assess the link between impaired lung function, airflow obstruction and risk of SCD by race and gender in four US communities. METHODS: A total of 14 708 Atherosclerosis Risk in Communities (ARIC) study participants who underwent spirometry and were asked about lung health (1987-1989) were followed. The main outcome was physician-adjudicated SCD. Fine-Gray proportional subdistribution hazard models with Firth's penalised partial likelihood correction were used to estimate the HRs. RESULTS: Over a median follow-up of 25.4 years, 706 (4.8%) subjects experienced SCD. The incidence of SCD was inversely associated with FEV1 in each of the four race and gender groups and across all smoking status categories. After adjusting for multiple measured confounders, HRs of SCD comparing the lowest with the highest quintile of FEV1 were 2.62 (95% CI 1.62 to 4.26) for white males, 1.80 (95% CI 1.03 to 3.15) for white females, 2.07 (95% CI 1.05 to 4.11) for black males and 2.62 (95% CI 1.21 to 5.65) for black females. The above associations were consistently observed among the never smokers. Moderate to very severe airflow obstruction was associated with increased risk of SCD. Addition of FEV1 significantly improved the predictive power for SCD. CONCLUSIONS: Impaired lung function and airflow obstruction were associated with increased risk of SCD in general population. Additional research to elucidate the underlying mechanisms is warranted.

Proliferating cell nuclear antigen clamp associated factor, a potential proto-oncogene with increased expression in malignant gastrointestinal tumors.

Gastrointestinal (GI) cancers, including malignancies in the gastrointestinal tract and accessory organs of digestion, represent the leading cause of death worldwide due to the poor prognosis of most GI cancers. An investigation into the potential molecular targets of prediction, diagnosis, prognosis, and therapy in GI cancers is urgently required. Proliferating cell nuclear antigen (PCNA) clamp associated factor (PCLAF), which plays an essential role in cell proliferation, apoptosis, and cell cycle regulation by binding to PCNA, is a potential molecular target of GI cancers as it contributes to a series of malignant properties, including tumorigenesis, epithelial-mesenchymal transition, migration, and invasion. Furthermore, PCLAF is an underlying plasma prediction target in colorectal cancer and liver cancer. In addition to GI cancers, PCLAF is also involved in other types of cancers and autoimmune diseases. Several pivotal pathways, including the Rb/E2F pathway, NF-κB pathway, and p53-p21 cascade, are implicated in PCLAF-mediated diseases. PCLAF also contributes to some diseases through dysregulation of the p53 pathway, WNT signal pathway, MEK/ERK pathway, and PI3K/AKT/mTOR signal cascade. This review mainly describes in detail the role of PCLAF in physiological status and GI cancers. The signaling pathways involved in PCLAF are also summarized. Suppression of the interaction of PCLAF/PCNA or the expression of PCLAF might be potential biological therapeutic strategies for GI cancers.

Mutated DNA Damage Repair Pathways Are Prognostic and Chemosensitivity Markers for Resected Colorectal Cancer Liver Metastases.

Deficiency of the DNA damage repair (DDR) signaling pathways is potentially responsible for genetic instability and oncogenesis in tumors, including colorectal cancer. However, the correlations of mutated DDR signaling pathways to the prognosis of colorectal cancer liver metastasis (CRLM) after resection and other clinical applications have not been fully investigated. Here, to test the potential correlation of mutated DDR pathways with survival and pre-operative chemotherapy responses, tumor tissues from 146 patients with CRLM were collected for next-generation sequencing with a 620-gene panel, including 68 genes in 7 DDR pathways, and clinical data were collected accordingly. The analyses revealed that 137 of 146 (93.8%) patients had at least one mutation in the DDR pathways. Mutations in BER, FA, HRR and MMR pathways were significantly correlated with worse overall survival than the wild-types (P < 0.05), and co-mutated DDR pathways showed even more significant correlations (P < 0.01). The number of mutated DDR pathways was also proved an independent stratifying factor of overall survival by Cox multivariable analysis with other clinical factors and biomarkers (hazard ratio = 9.14; 95% confidence interval, 1.21-68.9; P = 0.032). Additionally, mutated FA and MMR pathways were positively and negatively correlated with the response of oxaliplatin-based pre-operative chemotherapy (P = 0.0095 and 0.048, respectively). Mutated DDR signaling pathways can predict pre-operative chemotherapy response and post-operative survival in CRLM patients.

Prevalence and Clinical Characteristics of Myelinated Retinal Nerve Fibres in a Chinese Teleophthalmology System.

Purpose: To investigate the prevalence and clinical characteristics of myelinated retinal nerve fibre (MRNF) in a large teleophthalmology system.Methods: All records between January 2015 and December 2015 from Daheng Prust teleophthalmology system were reviewed by 2 ophthalmologists independently. MRNF was classified into continuous group and discontinuous group according to the relationship between MRNF patches and optic disc. The number, total area and location of MRNF patches were analysed. Concomitant ocular diseases were documented.Results: Out of 51469 subjects, MRNF was detected in 304 eyes of 263 subjects with a prevalence rate of 0.51 ± 7.1% per subject and 0.30 ± 5.4% per eye. Among 304 eyes with MRNF, 239 (78.6%) eyes were in continuous group and 65 (21.4%) eyes were in discontinuous group. Single MRNF patch was found in 249 (81.9%) eyes and multiple MRNF patches were found in 55 (18.1%) eyes. MRNF of small size was found in 150 (49.3%) eyes. The ratios of multiple MRNF patches and small-sized MRNF in the continuous group were significantly higher than those in the discontinuous group (P = .014 and P < .001). In continuous group, the MRNF patches were located most frequently in the superior region (68.6%) of the optic disc; In discontinuous group, the MRNF patches were located most frequently in the inferotemporal region (38.5%) of the retina. Epiretinal membrane (12 eyes, 3.9%) was the most common concomitant ocular disease.Conclusion: MRNF is uncommon in China. MRNF usually presents unilaterally and as a single small whitish patch that is connected with optic disc.

Spontaneous intracapsular hemorrhage of a giant hepatic cavernous hemangioma: a rare case report and literature review.

BACKGROUND: Hepatic cavernous hemangioma is the most common type of benign liver tumor. Although ruptures and hemorrhages of hepatic hemangioma are rare complications, they are associated with high mortality. Most practitioners only pay more attention to abdominal hemorrhages caused by the rupture of hepatic hemangiomas. However, spontaneous intracapsular hemorrhages can often be neglected and poorly understood. CASE PRESENTATION: A 65-year-old man was referred to our institution with right upper quadrant pain, which had occurred suddenly and without a history of recent trauma. The blood test results were normal. Magnetic resonance imaging (MRI) of the abdomen showed a cystic mass in the right liver lobe. Considering the possibility of hepatic cystadenoma with hemorrhage, the patient underwent a right hepatic lobectomy. The pathological findings unexpectedly revealed intratumoral hemorrhage of hepatic hemangioma. The patient recovered well and was discharged eight days after surgery. CONCLUSIONS: Intracapsular hemorrhage of hepatic cavernous hemangioma is challenging to diagnose and has a high potential risk of rupture. MRI is beneficial for diagnosing subacute internal hemorrhage cases, and it is recommended to undergo surgery for patients with a definitive diagnosis.

Hepatitis B core antigen modulates exosomal miR-135a to target vesicle-associated membrane protein 2 promoting chemoresistance in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors. The association of hepatitis B virus (HBV) infection with HCC is hitherto documented. Exosomal miRNAs contribute to cancer progression and chemoresistance. HBV X protein has been known to modulate miRNAs that facilitate cell proliferation and the process of hepatocarcinogenesis. However, there has been no report on hepatitis B core antigen (HBc) regulating exosomal miRNAs to induce drug resistance of HCC cells. AIM: To elucidate the mechanism by which HBc promotes Doxorubicin hydrochloride (Dox) resistance in HCC. METHODS: Exosomes were isolated by ultracentrifugation. The morphology and size of exosomes were evaluated by Dynamic Light Scattering (DLS) and transmission electron microscopy (TEM). The miRNAs differentially expressed in HCC were identified using The Cancer Genome Atlas (TCGA) database. The level of miR-135a-5p in patient tissue samples was detected by quantitative polymerase chain reaction. TargetScan and luciferase assay were used to predict and prove the target gene of miR-135a-5p. Finally, we identified the effects of miR-135a-5p on anti-apoptosis and the proliferation of HCC in the presence or absence of Dox using flow cytometry, Cell counting kit 8 (CCK-8) assay and western blot. RESULTS: We found that HBc increased the expression of exosomal miR-135a-5p. Integrated analysis of bioinformatics and patient samples found that miR-135a-5p was increased in HCC tissues in comparison with paracancerous tissues. Bioinformatic analysis and in vitro validation identified vesicle-associated membrane protein 2 (VAMP2) as a novel target gene of miR-135a-5p. Functional assays showed that exosomal miR-135a-5p induced apoptosis protection, cell proliferation, and chemotherapy resistance in HCC. In addition, the rescue experiment demonstrated that VAMP2 reversed apoptosis protection, cell growth, and drug resistance by miR-135a-5p. Finally, HBc promoted HCC anti-apoptosis, proliferation, and drug resistance and prevented Dox-induced apoptosis via the miR-135a-5p/VAMP2 axis. CONCLUSION: These data suggested that HBc upregulated the expression of exosomal miR-135a-5p and promoted anti-apoptosis, cell proliferation, and chemical resistance through miR-135a-5p/VAMP2. Thus, our work indicated an essential role of the miR-135a-5p/VAMP2 regulatory axis in chemotherapy resistance of HCC and a potential molecular therapeutic target for HCC.

TRPC1 inhibits the proliferation and migration of estrogen receptor-positive Breast cancer and gives a better prognosis by inhibiting the PI3K/AKT pathway.

PURPOSE: Previous studies have indicated that transient receptor potential (TRP) channels can influence cancer development. The TRPC subfamily consists of seven subtypes, TRPC1 - TRPC7. Interestingly, the expression levels of TRPC1 have been shown to be totally different in different breast cancer cell lines. Nevertheless, the underlying mechanism remains unknown. In this study, we explore the significance of TRPC1 expression in breast cancer. METHODS: Immunohistochemical TRPC1 staining was performed in 278 samples. TRPC1 expression in different breast tissues were examined. Then, the influence of TRPC1 on migration, invasion and proliferation was explored. We analyzed the protein of TRPC1 by Western blot to prove which pathway may be involved in. Finally, we use online database to predict the prognosis of TRPC1 in breast cancer. RESULTS: Through immunohistochemistry and in vitro experiments, we found that the expression level of TRPC1 was higher in breast cancer cells as compared with that in normal breast epithelial cells. Moreover, the expression level of TRPC1 was different between estrogen receptor-positive (ER +) and -negative (ER -) breast cancer. It was shown that TRPC1 inhibited MCF7 cell proliferation, migration, and invasion in vitro. Western blotting revealed that TRPC1 inhibited the PI3K/AKT pathway and epithelium-mesenchymal transformation, leading to subsequent inhibition of cell proliferation and metastasis. In luminal A and luminal B patients, those with high TRPC1 expression had a better prognosis. On the contrary, in basal-like and triple-negative breast cancer (TNBC) subtypes, patients with high-TRPC1 expression had a worse prognosis. CONCLUSIONS: We confirmed that TRPC1 was high expression in breast cancer. Overexpression of TRPC1 inhibits proliferation and migration of ER + breast cancer and gives a better prognosis by inhibiting PI3K/AKT pathway activation. TRPC1 may be an independent prognostic predictor in breast cancer patients.

Inactivation of endothelial ZEB1 impedes tumor progression and sensitizes tumors to conventional therapies.

Current antiangiogenic therapy is limited by its cytostatic property, scarce drug delivery to the tumor, and side toxicity. To address these limitations, we unveiled the role of ZEB1, a tumor endothelium-enriched zinc-finger transcription factor, during tumor progression. We discovered that the patients who had lung adenocarcinomas with high ZEB1 expression in tumor endothelium had increased prevalence of metastases and markedly reduced overall survival after the diagnosis of lung cancer. Endothelial ZEB1 deletion in tumor-bearing mice diminished tumor angiogenesis while eliciting persistent tumor vascular normalization by epigenetically repressing TGF-ß signaling. This consequently led to improved blood and oxygen perfusion, enhanced chemotherapy delivery and immune effector cell infiltration, and reduced tumor growth and metastasis. Moreover, targeting vascular ZEB1 remarkably potentiated the anticancer activity of nontoxic low-dose cisplatin. Treatment with low-dose anti-programmed cell death protein 1 (anti-PD-1) antibody elicited tumor regression and markedly extended survival in ZEB1-deleted mice, conferring long-term protective anticancer immunity. Collectively, we demonstrated that inactivation of endothelial ZEB1 may offer alternative opportunities for cancer therapy with minimal side effects. Targeting endothelium-derived ZEB1 in combination with conventional chemotherapy or immune checkpoint blockade therapy may yield a potent and superior anticancer effect.

A ZEB1/p53 signaling axis in stromal fibroblasts promotes mammary epithelial tumours.

Accumulating evidence indicates that the zinc-finger transcription factor ZEB1 is predominantly expressed in the stroma of several tumours. However, the role of stromal ZEB1 in tumour progression remains unexplored. In this study, while interrogating human databases, we uncover a remarkable decrease in relapse-free survival of breast cancer patients expressing high ZEB1 levels in the stroma. Using a mouse model of breast cancer, we show that ZEB1 inactivation in stromal fibroblasts suppresses tumour initiation, progression and metastasis. We associate this with reduced extracellular matrix remodeling, immune cell infiltration and decreased angiogenesis. ZEB1 deletion in stromal fibroblasts increases acetylation, expression and recruitment of p53 to FGF2/7, VEGF and IL6 promoters, thereby reducing their production and secretion into the surrounding stroma. Importantly, p53 ablation in ZEB1 stroma-deleted mammary tumours sufficiently recovers the impaired cancer growth and progression. Our findings identify the ZEB1/p53 axis as a stroma-specific signaling pathway that promotes mammary epithelial tumours.

Discovery of a natural small-molecule compound that suppresses tumor EMT, stemness and metastasis by inhibiting TGFß/BMP signaling in triple-negative breast cancer.

BACKGROUND: The transforming growth factor ß (TGFß) and bone morphogenetic protein (BMP) signaling pathways are both constitutively activated in triple-negative breast cancer (TNBC). We are interested in isolating the naturally-derived small-molecule inhibitor that could simultaneously targeting TGFß/BMP pathways and further studying its anti-proliferative/-metastatic effects as well as the underlying mechanisms in multiple tumor models. METHODS: Multiple in vitro cell-based assays are used to examine the compound's inhibitory efficacy on TNBC cell growth, stemness, epithelial-mesenchymal transition (EMT), invasion and migration by targeting TGFß/BMP signaling pathways. Transgenic breast cancer mouse model (MMTV-PyMT), subcutaneous xenograft and bone metastasis models are used to examine ZL170's effects on TNBC growth and metastasis potentials in vivo. RESULTS: ZL170 dose-dependently inhibits cell proliferation, EMT, stemness, invasion and migration in vitro via specifically targeting canonical TGFß/BMP-SMADs pathways in TNBC cells. The compound significantly hinders osteolytic bone metastasis and xenograft tumor growth without inflicting toxicity on vital organs of tumor-bearing nude mice. ZL170 strongly inhibits primary tumor growth and lung metastases in MMTV-PyMT transgenic mice. ZL170-treated tumors exhibit impaired TGFß/BMP signaling pathways in both epithelial and stromal compartments, thereby creating a suppressive tumor microenvironment characterized by reduced extracellular matrix deposition and decreased infiltration of stromal cells. CONCLUSIONS: ZL170 inhibits tumor EMT, stemness and metastasis and could be further developed as a potent anti-metastatic agent used in combination with cytotoxic drugs for treatment of TNBC and other advanced metastatic cancers.