Cadmium modulates steatosis, fibrosis, and oncogenic signaling in liver cancer cells by activating notch and AKT/mTOR pathways.

Cadmium (Cd) is an environmental pollutant that increases hepatotoxicity and the risk of liver diseases. In the current study, we investigated the effect of a physiologically relevant, low concentration of Cd on the regulation of liver cancer cell proliferation, steatosis, and fibrogenic/oncogenic signaling. Exposure to low concentrations of Cd increased endogenous reactive oxygen species (ROS) production and enhanced cell proliferation in a human bipotent progenitor cell line HepaRG and hepatocellular carcinoma (HCC) cell lines. Acute exposure of Cd increased Jagged-1 expression and activated Notch signaling in HepaRG and HCC cells HepG2 and SK-Hep1. Cd activated AKT/mTOR signaling by increasing phosphorylation of AKT-S473 and mTOR-S-4448 residues. Moreover, a low concentration of Cd also promoted cell steatosis and induced fibrogenic signaling in HCC cells. Chronic exposure to low concentrations of Cd-activated Notch and AKT/mTOR signaling induced the expression of pro-inflammatory cytokines tumor necrosis factor-alpha (TNFα) and its downstream target TNF-α-Induced Protein 8 (TNFAIP8). RNA-Seq data revealed that chronic exposure to low concentrations of Cd modulated the expression of several fatty liver disease-related genes involved in cell steatosis/fibrosis in HepaRG and HepG2 cells. Collectively, our data suggest that low concentrations of Cd modulate steatosis along with fibrogenic and oncogenic signaling in HCC cells by activating Notch and AKT/mTOR pathways.

Tumor immunosuppressive microenvironment modulating hydrogels for second near-infrared photothermal-immunotherapy of cancer.

Immunotherapy has recently been seen as a hopeful therapeutic device to inhibit tumor growth and metastasis, while the curative efficacy is limited by intrinsic immunosuppressive tumor microenvironment. Herein, we reported a tumor immunosuppressive microenvironment modulating hydrogel (TIMmH) platform to achieve second near-infrared (NIR-II) photothermal therapy (PTT) combined immunotherapy for durable inhibition of breast cancer. This TIMmH platform was synthesized through co-loading of NIR-II photothermal nanoagent and an immunoadjuvant cytosine-phosphateguanosine oligodeoxynucleotides (CpG ODNs) into the alginate hydrogel (ALG). Upon the administration of ALG into the tumor, the TIMmH was in situ formed via the coordination effect with Ca2+, locally encapsulating the semiconducting polymer nanoparticles (SPIIN) and CpG in the colloid, achieving to prolong the accumulation time and prevent the premature damage and release of immunotherapeutic agents. Upon 1064-nm photoirradiation, the TIMmHSD was able to elevate the intratumoral temperature for the ablation of tumors, which could induce the apoptosis of tumor cells and achieve thermal immune activation by regulating of an immunosuppressive microenvironment. The TIMmH-mediated combined treatment effectively suppressed the growths of breast cancers, and even acquired a sustained inhibition of the lung metastasis. This study provides a novel tumor immunosuppressive microenvironment modulating hydrogel platform with NIR-II photoexcited capacity for the safe, effective and durable lung metastasis-inhibiting breast cancer treatment.

Surgical Management of Hirschsprung's Disease: A Comparative Study Between Conventional Laparoscopic Surgery, Transumbilical Single-Site Laparoscopic Surgery, and Robotic Surgery.

Background: Hirschsprung's disease (HD) is a commonly digestive malformation in children that usually requires surgery. This study aims to evaluate the short-term efficacy of conventional laparoscopic surgery (CLS), transumbilical single-hole laparoscopic surgery (TU-LESS), and robotic surgery (RS) in the treatment of Hirschsprung's disease. Methods: 90 patients with Hirschsprung's disease undergone laparoscopic surgery at our center between 2015 and 2019, divided into three groups (group CLS, TU-LESS and RS), were retrospectively analysed. Results: CLS and TU-LESS group showed no significant difference in operation duration (P > 0.05) but shorter operation duration than the RS group (P < 0.05). RS group had highest overall SCAR scores, while TU-LESS group had the lowest one (P < 0.05). Other parameters such as operative blood loss, hospital stays, recovery time of digestive function, postoperative complications had no significant difference among the three groups (P > 0.05). Conclusion: The three surgical methods for HD revealed similar efficacy, where TU-LESS and CLS spent less time than RS; TU-LESS led to the most aesthetic effect, followed by CLS and RS.

Expression Level of Keratin 7 in Epithelial Ovarian Cancer and Malignant Metastasis of Benign Epithelial Ovarian Tumors.

It was to investigate the diagnostic value of keratin 7 (KRT7) in malignant metastasis of epithelial ovarian cancer and benign epithelial ovarian tumors. From January 2018 to January 2019, 30 fresh tissues of benign epithelial ovarian tumors, 30 fresh tissues of borderline tumors, 30 fresh tissues of metastatic ovarian were collected in The First Affiliated Hospital of Fujian Medical University, and 30 fresh tissues of normal ovarian tissues were collected as the control group. Federation of gynecology and obstetrics (FIGO) staging criteria: 25 cases of stage I, 26 cases of stage II, 16 cases of stage III, and 23 cases of stage IV. The relative expression of KRT7 was detected by real-time fluorescence quantitative PCR, and the relationship between KRT7 expression and epithelial ovarian cancer grading was analyzed. The results showed that the positive expression rate of KRT7 was 12.1% in normal ovarian tissues, 28.4% in benign epithelial ovarian tumors, 53.5% in borderline tumors, and 24.2% in metastatic ovarian cancer. With the increase of tumor stage malignancy, the relative expression of KRT7 decreased significantly, but there was no significant difference between stage I and stage II, stage III and stage IV (P > 0.05). The difference between stage I and stage III, and stage IV was significant (P < 0.05). Patients with epithelial ovarian cancer had a significant difference compared with the control group (P < 0.05). In summary, compared with the control group, the expression of KRT7 in patients with benign epithelial ovarian tumors and borderline tumors was significantly decreased. The expression level of KRT7 in benign epithelial ovarian tumors was lower than that in borderline tumors. The expression of KRT7 was related to the occurrence, development, and deterioration of ovarian cancer, which provided a basis for targeted therapy of tumors.

Role of Autophagy in Cadmium-Induced Hepatotoxicity and Liver Diseases.

Cadmium (Cd) is a toxic pollutant that is associated with several severe human diseases. Cd can be easily absorbed in significant quantities from air contamination/industrial pollution, cigarette smoke, food, and water and primarily affects the liver, kidney, and lungs. Toxic effects of Cd include hepatotoxicity, nephrotoxicity, pulmonary toxicity, and the development of various human cancers. Cd is also involved in the development and progression of fatty liver diseases and hepatocellular carcinoma. Cd affects liver function via modulation of cell survival/proliferation, differentiation, and apoptosis. Moreover, Cd dysregulates hepatic autophagy, an endogenous catabolic process that detoxifies damaged cell organelles or dysfunctional cytosolic proteins through vacuole-mediated sequestration and lysosomal degradation. In this article, we review recent developments and findings regarding the role of Cd in the modulation of hepatotoxicity, autophagic function, and liver diseases at the molecular level.

Emerging Roles of Impaired Autophagy in Fatty Liver Disease and Hepatocellular Carcinoma.

Autophagy is a conserved catabolic process that eliminates dysfunctional cytosolic biomolecules through vacuole-mediated sequestration and lysosomal degradation. Although the molecular mechanisms that regulate autophagy are not fully understood, recent work indicates that dysfunctional/impaired autophagic functions are associated with the development and progression of nonalcoholic fatty liver disease (NAFLD), alcoholic fatty liver disease (AFLD), and hepatocellular carcinoma (HCC). Autophagy prevents NAFLD and AFLD progression through enhanced lipid catabolism and decreasing hepatic steatosis, which is characterized by the accumulation of triglycerides and increased inflammation. However, as both diseases progress, autophagy can become impaired leading to exacerbation of both pathological conditions and progression into HCC. Due to the significance of impaired autophagy in these diseases, there is increased interest in studying pathways and targets involved in maintaining efficient autophagic functions as potential therapeutic targets. In this review, we summarize how impaired autophagy affects liver function and contributes to NAFLD, AFLD, and HCC progression. We will also explore how recent discoveries could provide novel therapeutic opportunities to effectively treat these diseases.

Perivenous Stellate Cells Are the Main Source of Myofibroblasts and Cancer-Associated Fibroblasts Formed After Chronic Liver Injuries.

BACKGROUND AND AIMS: Studies of the identity and pathophysiology of fibrogenic HSCs have been hampered by a lack of genetic tools that permit specific and inducible fate-mapping of these cells in vivo. Here, by single-cell RNA sequencing of nonparenchymal cells from mouse liver, we identified transcription factor 21 (Tcf21) as a unique marker that restricted its expression to quiescent HSCs. APPROACH AND RESULTS: Tracing Tcf21+ cells by Tcf21-CreER (Cre-Estrogen Receptor fusion protein under the control of Tcf21 gene promoter) targeted ~10% of all HSCs, most of which were located at periportal and pericentral zones. These HSCs were quiescent under steady state but became activated on injuries, generating 62%-67% of all myofibroblasts in fibrotic livers and ~85% of all cancer-associated fibroblasts (CAFs) in liver tumors. Conditional deletion of Transforming Growth Factor Beta Receptor 2 (Tgfbr2) by Tcf21-CreER blocked HSC activation, compromised liver fibrosis, and inhibited liver tumor progression. CONCLUSIONS: In conclusion, Tcf21-CreER-targeted perivenous stellate cells are the main source of myofibroblasts and CAFs in chronically injured livers. TGF-ß signaling links HSC activation to liver fibrosis and tumorigenesis.

MicroRNA-205-5p inhibits skin cancer cell proliferation and increase drug sensitivity by targeting TNFAIP8.

Tumor necrosis factor-α-induced protein 8 (TNFAIP8) is a member of the TIPE/TNFAIP8 family which regulates tumor growth and survival. Our goal is to delineate the detailed oncogenic role of TNFAIP8 in skin cancer development and progression. Here we demonstrated that higher expression of TNFAIP8 is associated with basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and melanoma development in patient tissues. Induction of TNFAIP8 expression by TNFα or by ectopic expression of TNFAIP8 in SCC or melanoma cell lines resulted in increased cell growth/proliferation. Conversely, silencing of TNFAIP8 decreased cell survival/cell migration in skin cancer cells. We also showed that miR-205-5p targets the 3'UTR of TNFAIP8 and inhibits TNFAIP8 expression. Moreover, miR-205-5p downregulates TNFAIP8 mediated cellular autophagy, increased sensitivity towards the B-RAFV600E mutant kinase inhibitor vemurafenib, and induced cell apoptosis in melanoma cells. Collectively our data indicate that miR-205-5p acts as a tumor suppressor in skin cancer by targeting TNFAIP8.

TNFAIP8 drives metabolic reprogramming to promote prostate cancer cell proliferation.

Tumor necrosis factor-α-induced protein 8 (TNFAIP8) is a member of TIPE/TNFAIP8 family, has been involved in the development and progression of various human cancers. We hypothesized that TNFAIP8 promotes prostate cancer (PCa) progression via regulation of oxidative phosphorylation (OXPHOS) and glycolysis. Ectopic expression of TNFAIP8 increased PCa cell proliferation/migration/spheroid formation by enhancing cell metabolic activities. Mechanistically, TNFAIP8 activated the PI3K-AKT pathway and up-regulated PCa cell survival. TNFAIP8 was also found to regulate the expression of glucose metabolizing enzymes, enhancing glucose consumption, and endogenous ATP production. Treatment with a glycolysis inhibitor, 2-deoxyglucose (2-DG), reduced TNFAIP8 mediated glucose consumption, ATP production, spheroid formation, and PCa cell migration. By maintaining mitochondrial membrane potential, TNFAIP8 increased OXPHOS and glycolysis. Moreover, TNFAIP8 modulates the production of glycolytic metabolites in PCa cells. Collectively, our data suggest that TNFAIP8 exerts its oncogenic effects by enhancing glucose metabolism and by facilitating metabolic reprogramming in PCa cells. Therefore, TNFAIP8 may be a biomarker associated with prostate cancer and indicate a potential therapeutic target.

TNFAIP8 regulates autophagy, cell steatosis, and promotes hepatocellular carcinoma cell proliferation.

Tumor necrosis factor-α-induced protein 8 (TNFAIP8) expression has been linked to tumor progression in various cancer types, but the detailed mechanisms of TNFAIP8 are not fully elucidated. Here we define the role of TNFAIP8 in early events associated with development of hepatocellular carcinoma (HCC). Increased TNFAIP8 levels in HCC cells enhanced cell survival by blocking apoptosis, rendering HCC cells more resistant to the anticancer drugs, sorafenib and regorafenib. TNFAIP8 also induced autophagy and steatosis in liver cancer cells. Consistent with these observations, TNFAIP8 blocked AKT/mTOR signaling and showed direct interaction with ATG3-ATG7 proteins. TNFAIP8 also exhibited binding with fatty acids and modulated expression of lipid/fatty-acid metabolizing enzymes. Chronic feeding of mice with alcohol increased hepatic levels of TNFAIP8, autophagy, and steatosis but not in high-fat-fed obese mice. Similarly, higher TNFAIP8 expression was associated with steatotic livers of human patients with a history of alcohol use but not in steatotic patients with no history of alcohol use. Our data indicate a novel role of TNFAIP8 in modulation of drug resistance, autophagy, and hepatic steatosis, all key early events in HCC progression.

Initiating palliative care consultation for acute critically ill patients in the emergency department intensive care unit.

BACKGROUND: Little is known about the characteristics of patients needing palliative care consultation in the emergency department (ED). This study aimed to investigate the impacts of initiating screening in acute critically ill patients needing palliative care on mortality, health care resources, and end-of-life (EOL) care in the intensive care unit in ED (EICU). METHODS: We conducted an analysis study in Taipei Veterans General Hospital. From February 1 to July 31, 2018, acute critically ill patients in EICU were recruited. The primary outcomes were inhospital mortality and EOL care. The secondary outcomes included clinical characteristics and health care utilization. RESULTS: A total of 796 patients were screened, with 396 eligible and 400 noneligible patients needing palliative care consultations. The mean age was 74.8 ± 17.1 years, and 62.6% of the patients were male. According to logistic regression analysis, clinical predictors, including age (adjusted odds ratio [AOR], 1.028; 95% CI, 1.015-1.042), respiratory distress and/or respiratory failure (AOR, 2.670; 95% CI, 1.829-3.897), the Acute Physiology and Chronic Health Evaluation II score (AOR, 1.036; 95% CI, 1.009-1.064), Charlson Comorbidity Index score (AOR, 1.212; 95% CI, 1.125-1.306), and Glasgow Coma Scale (AOR, 0.843; 95% CI, 0.802-0.885), were statistically more significant in eligible patients than in noneligible patients. The inhospital mortality rate was significantly higher in eligible patients than that in noneligible patients (40.7% vs 11.5%, p < 0.01). Eligible patients have a higher ratio in both vasopressor and narcotic use and withdrawal of endotracheal tube than noneligible patients (p < 0.05). CONCLUSION: Our study results demonstrated that initiating palliative consultation for acute critically ill patients in ED had an impact on the utilization of health care resources and quality of EOL care. Further assessments of the viewpoints of ED patients and their family on palliative care consultations and hospice care are required.

Interhemispheric Connectivity Potentiates the Basolateral Amygdalae and Regulates Social Interaction and Memory.

Impaired interhemispheric connectivity is commonly found in various psychiatric disorders, although how interhemispheric connectivity regulates brain function remains elusive. Here, we use the mouse amygdala, a brain region that is critical for social interaction and fear memory, as a model to demonstrate that contralateral connectivity intensifies the synaptic response of basolateral amygdalae (BLA) and regulates amygdala-dependent behaviors. Retrograde tracing and c-FOS expression indicate that contralateral afferents widely innervate BLA non-randomly and that some BLA neurons innervate both contralateral BLA and the ipsilateral central amygdala (CeA). Our optogenetic and electrophysiological studies further suggest that contralateral BLA input results in the synaptic facilitation of BLA neurons, thereby intensifying the responses to cortical and thalamic stimulations. Finally, pharmacological inhibition and chemogenetic disconnection demonstrate that BLA contralateral facilitation is required for social interaction and memory. Our study suggests that interhemispheric connectivity potentiates the synaptic dynamics of BLA neurons and is critical for the full activation and functionality of amygdalae.

Rituximab increases the risk of hepatitis B virus reactivation in non-Hodgkin lymphoma patients who are hepatitis B surface antigen-positive or have resolved hepatitis B virus infection in a real-world setting: a retrospective study.

BACKGROUND: Hepatitis B virus (HBV) reactivation with a hepatitis flare is a common complication in lymphoma patients treated with immunotherapy and/or chemotherapy. Anti-HBV prophylaxis is suggested for non-Hodgkin lymphoma (NHL) patients undergoing rituximab therapy, even those with resolved HBV infection. Since anti-HBV prophylaxis for patients with resolved HBV infection is not covered by national health insurance in Taiwan, a proportion of these patients receive no prophylaxis. In addition, late HBV reactivation has emerged as a new issue in recent reports, and no consensus has been reached for the optimal duration of antiviral prophylaxis. Thus, the aim of our study was to investigate the incidence and outcomes of HBV reactivation in NHL patients in a real-world setting and to study the frequency of late HBV reactivation. MATERIALS: Non-Hodgkin lymphoma patients who received rituximab and/or chemotherapy at our institute between January 2011 and December 2015 and who were hepatitis B surface antigen (HBsAg)- or hepatitis B core antibody (HBcAb)-positive were reviewed retrospectively. RESULTS: A total of 388 patients were screened between January 2011 and December 2015. In total, 196 patients were excluded because HBsAg was not assessed, HBcAb was negative or not assessed, or they were not treated with immunosuppressive therapy. Finally, the retrospective study included 62 HBsAg-positive NHL patients and 130 NHL patients with resolved HBV infection (HBsAg-negative and HBcAb-positive). During a median 30.5-month follow-up period, seven patients experienced HBV reactivation, five of whom had a hepatitis flare. The incidence of HBV reactivation did not significantly differ between the HBsAg-positive patients and the resolved HBV infection population without anti-HBV prophylaxis (4.8% vs. 3.1%, P = 0.683). All patients with HBV reactivation were exposed to rituximab. Notably, late HBV reactivation was not uncommon (two of seven patients with HBV reactivation events, 28.6%). Hepatitis B virus reactivation did not influence the patients' overall survival. An age ≥65 years and an advanced disease stage were independent risk factors for poorer overall survival. CONCLUSION: The incidence of HBV reactivation was similar between the HBsAg-positive patients with antiviral prophylaxis and the resolved HBV infection population without anti-HBV prophylaxis. All HBV reactivation events occurred in NHL patients exposed to rituximab. Late reactivation was not uncommon. The duration of regular liver function monitoring for more than 1 year after immunosuppressive therapy or after withdrawal of prophylactic antiviral therapy should be prolonged. Determining the exact optimal duration of anti-HBV prophylaxis is warranted in a future prospective study for NHL patients treated with rituximab-containing therapy.

Systematic Analysis of Drug Vulnerabilities Conferred by Tumor Suppressor Loss.

In addition to oncogene inhibition, targeting tumor suppressor deficiency could provide potential venues for precision cancer medicine. However, the full spectrum of drug vulnerability conferred by tumor suppressor loss remains unclear. We systematically analyzed how loss of 59 common tumor suppressors each affected cellular sensitivity to 26 different types of anticancer therapeutics. The experiments were performed in a one-gene, one-drug manner, and through such a large gene-drug iteration study, we were able to generate a drug sensitivity map that describes numerous examples of drug resistance or hypersensitivity conferred by tumor suppressor loss. We further delineated the mechanisms of several gene-drug interactions, showing that loss of tumor suppressors could modify drug sensitivity at various steps of drug action. This systematic drug sensitivity map highlights potential drug vulnerabilities associated with tumor suppressor loss, which may help expand precision cancer medicine on the basis of tumor suppressor status.

Luteinizing hormone signaling restricts hematopoietic stem cell expansion during puberty.

The number and self-renewal capacity of hematopoietic stem cells (HSCs) are tightly regulated at different developmental stages. Many pathways have been implicated in regulating HSC development in cell autonomous manners; however, it remains unclear how HSCs sense and integrate developmental cues. In this study, we identified an extrinsic mechanism by which HSC number and functions are regulated during mouse puberty. We found that the HSC number in postnatal bone marrow reached homeostasis at 4 weeks after birth. Luteinizing hormone, but not downstream sex hormones, was involved in regulating HSC homeostasis during this period. Expression of luteinizing hormone receptor (Lhcgr) is highly restricted in HSCs and multipotent progenitor cells in the hematopoietic hierarchy. When Lhcgr was deleted, HSCs continued to expand even after 4 weeks after birth, leading to abnormally elevated hematopoiesis and leukocytosis. In a murine acute myeloid leukemia model, leukemia development was significantly accelerated upon Lhcgr deletion. Together, our work reveals an extrinsic counting mechanism that restricts HSC expansion during development and is physiologically important for maintaining normal hematopoiesis and inhibiting leukemogenesis.