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Sequencing analysis was also performed for two predicted off-target genes (SLC25A13 and TECTB) in F99 and J76 cells.

Supplementary Figure 1 from Rho GTPase-Activating Protein Deleted in Liver Cancer Suppresses Cell Proliferation and Invasion in Hepatocellular Carcinoma

Administration of exercise mimetic drugs could be a novel therapeutic approach to combat comorbid neurodegeneration and metabolic syndromes. Adiponectin is an adipocyte-secreted hormone. In addition to its antidiabetic effect, adiponectin mediates the antidepressant effect of physical exercise associated with adult hippocampal neurogenesis. The antidiabetic effect of the adiponectin receptor agonist AdipoRon has been demonstrated, but its potential pro-cognitive and neurotrophic effects in the hippocampus under diabetic condition are still unclear. This study reported that chronic AdipoRon treatment for 2 weeks improved hippocampal-dependent spatial recognition memory in streptozotocin-induced diabetic mice. Besides, AdipoRon treatment increased progenitor cell proliferation and neuronal differentiation in the hippocampal dentate gyrus (DG) of diabetic mice. Furthermore, AdipoRon treatment significantly increased dendritic complexity, spine density, and N-methyl-D-aspartate receptor-dependent long-term potentiation (LTP) in the dentate region, and increased BDNF levels in the DG of diabetic mice. AdipoRon treatment activated AMPK/PGC-1α signalling in the DG, whereas increases in cell proliferation and LTP were not observed when PGC-1α signalling was pharmacologically inhibited. In sum, chronic AdipoRon treatment partially mimics the benefits of physical exercise for learning and memory and hippocampal neuroplasticity in the diabetic brain. The results suggested that AdipoRon could be a potential physical exercise mimetic to improve hippocampal plasticity and hence rescue learning and memory impairment typically associated with diabetes. Supplementary Information The online version contains supplementary material available at 10.1007/s12035-021-02441-7.

Background Ovarian cancer is characterised by frequent recurrence due to persistent presence of residual cancer stem cells (CSCs). Here, we identify and characterise tumour subsets from ascites-derived tumour cells with stemness, metastasis and metabolic switch properties and to delineate the involvement of pyruvate dehydrogenase kinase 4 (PDK4) in such process. Methods Ovarian cancer cells/cell lines derived from ascites were used for tumourspheres/ALDH+CD44+ subset isolation. The functional roles and downstream signalling of PDK4 were explored. Its association with clinical outcome of ovarian cancer was analysed. Results We demonstrated enhanced CSC characteristics of tumour cells derived from ovarian cancer ascites, concomitant with ALDH and CD44 subset enrichment and high PDK4 expression, compared to primary tumours. We further showed tumourspheres/ALDH+CD44+ subsets from ascites-derived tumour cells/cell lines with CSC properties and enhanced glycolysis. Clinically, PDK4 expression was correlated with aggressive features. Notably, blockade of PDK4 in tumourspheres/ALDH+CD44+ subsets led to inhibition of CSC characteristics, glycolysis and activation of STAT3/AKT/NF-κB/IL-8 (signal transducer and activator of transcription 3/protein kinases B/nuclear factor-κB/interleukin-8) signalling. Conversely, overexpression of PDK4 in ALDH−CD44– subsets exerted the opposite effects. Conclusion Ascites-derived ALDH+CD44+ tumour cell subsets endow stemness, metastatic and metabolic switch properties via PDK4-mediated STAT3/AKT/NF-κB/IL-8 signalling, suggesting PDK4 as a viable therapeutic molecular target for ovarian cancer management.

Introduction Coronary artery bypass grafting (CABG) is a crucial intervention in acute myocardial infarction (AMI), particularly when AMI is not amenable for management with primary percutaneous coronary intervention (PCI). To optimise outcome in these patients, surgical teams must consider a host of predictive factors, with the most prominent being the timing of CABG. Despite numerous studies exploring timing of CABG following AMI in the past, optimal surgical timing remains controversial. The mortality rates vary with timing of CABG, but confounding factors such as age, impaired pulmonary function, renal insufficiency, and poor left ventricular function may contribute to varied outcomes reported. Evidence acquisiton An electronic literature search of articles that discussed acute myocardial presentation and urgent in-patient or elective CABG was conducted. Evidence synthesis The evidence was synthesised based on each reported article and their outcomes. Conclusions Current literature suggests multiple factors can guide CABG timing including, type of AMI at initial presentation, distinctive pathological status and patient characteristics. Thus, there is a need for large, multi-centre studies to identify optimal CABG timing in complex coronary artery disease or failed PCI in patients with AMI. Future guidelines should emphasise patient cohorts by taking their risk factors into consideration. As such, a need for greater cardiac screening methods and development of scoring systems can aid in the optimisation of CABG timing.

Programmed cell death 1 ligand (PD-L1) blockade has been used therapeutically in the treatment of ovarian cancer, and potential combination treatment approaches are under investigation to improve the treatment response rate. The increased dependence on glutamine is widely observed in various type of tumors, including ovarian cancer. Kidney-type glutaminase (GLS), as one of the isotypes of glutaminase, is found to promote tumorigenesis. Here, we have demonstrated that the combined treatment with GLS inhibitor 968 and PD-L1 blockade enhances the immune response against ovarian cancer. Survival analysis using the Kaplan–Meier plotter dataset from ovarian cancer patients revealed that the expression level of GLS predicts poor survival and correlates with the immunosuppressive microenvironment of ovarian cancer. 968 inhibits the proliferation of ovarian cancer cells and enhances granzyme B secretion by CD8+ T cells as detected by XTT assay and flow cytometry, respectively. Furthermore, 968 enhances the apoptosis-inducing ability of CD8+ T cells toward cancer cells and improves the treatment effect of anti-PD-L1 in treating ovarian cancer as assessed by Annexin V apoptosis assay. In vivo studies demonstrated the prolonged overall survival upon combined treatment of 968 with anti-PD-L1 accompanied by increased granzyme B secretion by CD4+ and CD8+ T cells isolated from ovarian tumor xenografts. Additionally, 968 increases the infiltration of CD3+ T cells into tumors, possibly through enhancing the secretion of CXCL10 and CXCL11 by tumor cells. In conclusion, our findings provide a novel insight into ovarian cancer cells influence the immune system in the tumor microenvironment and highlight the potential clinical implication of combination of immune checkpoints with GLS inhibitor 968 in treating ovarian cancer.

Highlights • Penile gangrene is a presentation of calciphylaxis and is associated with high mortality rate. Calcium level may be normal at presentation. • Superficial biopsy of the penis should only be considered if diagnosis is equivocal. Punch biopsy is preferred over excision biopsy. • Overly aggressive surgical treatment of penile gangrene is associated to poor outcomes. Sodium thiosulfate may be effective in treating penile gangrene due to calciphylaxis. • Mechanism of sodium thiosulfate is unknown but may be related to improvement in blood flow in calcified blood vessels •Further studies are required., Penile gangrene is a rare but fatal complication of calciphylaxis in end-stage renal disease (ESRD). To date, there are no guidelines on its management, and outcomes are generally poor with high mortality rate. We present a case of a diabetic patient with ESRD presenting with dry gangrene of the glans penis due to calciphylaxis and successfully treated with intravenous sodium thiosulfate (STS) and early total parathyroidectomy. We further analysed existing literatures on cases that utilized STS in the treatment of penile calciphylaxis.

A subpopulation of cells within tumors has been suggested to possess the ability to initiate tumorigenesis and contribute to resistance to cancer therapy. Identification and isolation of this subpopulation in cancer cells can be achieved by detecting specific cell-surface markers. In this study, flow cytometry analysis revealed an abundant CD71+ subpopulation in human papillomavirus (HPV)-positive cervical cancer cells, while limited CD71+ cells were detected in HPV-negative cervical cancer cells. Furthermore, ectopic expression of the HPV-E6 protein in HPV-negative C33A cells enriched the CD71+subpopulation. The CD71+ subpopulation isolated from the C33A cell line and an HPV-E6–overexpressing clone exhibited enhanced transforming ability, proliferation, and resistance to irradiation. In contrast, suppression of CD71 in HPV-positive SiHa cells and the HPV-E6–overexpressing stable clone inhibited spheroid formation and in vitro and in vivo tumorigenicity and sensitized cells to irradiation treatment. CRISPR/Cas9 knockout of CD71 in SiHa cells also produced similar inhibitory effects on tumorigenicity. Double knockout of CD71 and CD55 reversed the oncogenic properties of the HPV-E6–overexpressing clone. These findings suggest that the HPV-E6 protein enriches the subpopulation of CD71+cells in cervical cancer, which exhibit cancer stem–like cell properties and are resistant to irradiation treatment. Targeting the CD71+ subpopulation in cervical cancer cells with siRNAs or CRISPR/Cas9 may provide new insights for the development of novel therapeutic approaches for treating cervical cancer. Implications: We describe the enrichment of CD71+ population by HPV-E6 protein in cervical cancer cells that promotes cancer aggressiveness and resistance to irradiation treatment.

Polyunsaturated fatty acids (PUFAs) play an essential role in brain development. Emerging data have suggested a possible link between an imbalance in PUFAs and cognitive behavioral deficits in offspring. A diet rich in high linoleic acid (HLA), typically from preconception to lactation, leads to an increase in the ratio of omega-6 (n-6) to omega-3 (n-3) fatty acids in the fetus. Arising research has suggested that a deficiency in omega-3 fatty acids is a potential risk factor for inducing autism spectrum disorder (ASD)-like behavioral deficits. However, the impact of a high n- diet during preconception, pregnancy, lactation, and post-weaning on the brain development of adolescent offspring are yet to be determined. This study examined whether consumption of an HLA diet during pregnancy, lactation, and post-weaning induced social and cognitive impairments in female and male offspring rats that resemble autistic phenotypes in humans. Female Wistar Kyoto rats were fed with either HLA or low linoleic acid (LLA) control diet for 10 weeks before mating, then continued with the same diet throughout the pregnancy and lactation period. Female and male offspring at 5 weeks old were subjected to behavioral tests to assess social interaction behavior and depression-/anxiety-like behavior. Our result showed that chronic consumption of an HLA diet did not affect sociability and social recognition memory, but induced depression-like behavior in male but not in female offspring.

AdipoRon, an adiponectin receptor agonist, elicits similar antidiabetic, anti-atherogenic, and anti-inflammatory effects on mouse models as adiponectin does. Since AdipoRon can cross the blood-brain barrier, its chronic effects on regulating hippocampal function are yet to be examined. This study investigated whether AdipoRon treatment promotes hippocampal neurogenesis and spatial recognition memory in a dose-dependent manner. Adolescent male C57BL/6J mice received continuous treatment of either 20 mg/kg (low dose) or 50 mg/kg (high dose) AdipoRon or vehicle intraperitoneally for 14 days, followed by the open field test to examine anxiety and locomotor activity, and the Y maze test to examine hippocampal-dependent spatial recognition memory. Immunopositive cell markers of neural progenitor cells, immature neurons, and newborn cells in the hippocampal dentate gyrus were quantified. Immunosorbent assays were used to measure the serum levels of factors that can regulate hippocampal neurogenesis, including adiponectin, brain-derived neurotrophic factor (BDNF), and corticosterone. Our results showed that 20 mg/kg AdipoRon treatment significantly promoted hippocampal cell proliferation and increased serum levels of adiponectin and BDNF, though there were no effects on spatial recognition memory and locomotor activity. On the contrary, 50 mg/kg AdipoRon treatment impaired spatial recognition memory, suppressed cell proliferation, neuronal differentiation, and cell survival associated with reduced serum levels of BDNF and adiponectin. The results suggest that a low-dose AdipoRon treatment promotes hippocampal cell proliferation, while a high-dose AdipoRon treatment is detrimental to the hippocampus function.

This systematic review aims to gather primary data from cancer institutions that have implemented changes to cancer service provision amid the COVID-19 outbreak to inform future intervention and health care facility response strategies. A comprehensive literature search was done on Global Health Medline and EMBASE using pertinent key words and MeSH terms relating to COVID-19 and Cancer service provision. A total of 72 articles were selected for inclusion in this systematic review. Following the narrative synthesis that was conducted of the literature, 6 core themes that encompassed common cancer service intervention adopted by institutions were identified: (1) Testing and Tracking, (2) Outreach and Communication, (3) Protection, (4) Social Distancing (5) Treatment Management, (6) Service Restructuring. Since cancer patients are a high-risk population amid the COVID-19 pandemic, these areas of targeted intervention can be used to inform necessary actions in institutions facing similar risks, based on previous learning from numerous cancer centers globally.

Background: Occult primary head and neck cancer constitutes 5-10% of all patients with carcinoma of unknown primary and presents as both a diagnostic challenge and management dilemma to clinicians. We present one case of papillary thyroid microcarcinoma where the only presenting sign was a painless enlarged cervical lymph node, with no evidence of the primary site of malignancy after initial evaluations. Case Presentation: A sixty-five-year-old female patient presented with a two-month history of painless swelling on the left side of the neck with no change in size. Ultrasonography detected a left level V lymph node and a left level IV lymph node with suspicious features for malignancy but did not detect any thyroid nodules. Excision biopsy of the lymph node and bilateral tonsillectomy revealed a diagnosis of metastatic papillary carcinoma with a primary from the thyroid. A repeat focused ultrasonography of the thyroid revealed two nodules. Total thyroidectomy and selective left neck dissection (levels IIVI) were performed. The final diagnosis was multifocal papillary thyroid carcinoma with metastasis to seven out of twenty-four lymph nodes excised. The TMN stage was pT1aN1bM0. The patient was discharged on postoperative day three uneventfully. Adjuvant radioactive iodine was planned for the patient at a dose of 100 mCi at one month postoperatively. Conclusion: Occult primary PTMC presenting as isolated cervical lymphadenopathy and diagnosed only on histology is a rare entity. When initial clinical and radiological evaluations reveal no thyroid abnormalities, FNAC and excision of lymph nodes are useful steps in establishing the diagnosis and primary site of the tumour. Total thyroidectomy with a therapeutic neck dissection is the appropriate next step in treatment for these patients. With postoperative radioactive iodine ablation and life-long suppressive thyroxine, the outcome is usually favourable for PTMC without high-risk characteristics.

Chemoradiotherapy (CRT) refers to the combined administration of both chemotherapy and radiotherapy as an anticancer treatment. Over the years, CRT has become an established treatment for a diverse range of locally advanced solid tumours. The rationale for CRT is based on the two concepts of spatial cooperation and in-field cooperation, whereby the end goal is to achieve synergistic antitumour effects from the combination of both treatment modalities. CRT offers notable patient survival benefits and local disease control without significant long-term toxicities. Although the enhancement of cytotoxic effects inevitably increases damage to normal tissues as well as tumour cells, if the damage to normal tissue is lesser than that to tumour cells, CRT is still deemed beneficial. Thus, the search to optimise dose, timings and fractionation of CRT is of particular interest. Considering the recent success achieved with anticancer immunotherapies including immune checkpoint inhibitors, the combination of CRT and immunotherapy has emerged as an exciting field of research with the potential for significant clinical benefit. This report outlines the rationale underlying CRT and discusses its advantages through clinical examples focusing on anal, cervical, non-small-cell lung cancer and bladder cancer.

High-caloric diet and physical inactivity predispose individuals to obesity and diabetes, which are risk factors of hippocampal neurodegeneration and cognitive deficits. Along with the adipose-hippocampus crosstalk, chronically inflamed adipose tissue secretes inflammatory cytokine could trigger neuroinflammatory responses in the hippocampus, and in turn, impairs hippocampal neuroplasticity under obese and diabetic conditions. Hence, caloric restriction and physical exercise are critical non-pharmacological interventions to halt the pathogenesis from obesity to hippocampal neurodegeneration. In response to physical exercise, peripheral organs, including the adipose tissue, skeletal muscles, and liver, can secret numerous exerkines, which bring beneficial effects to metabolic and brain health. In this review, we summarized how chronic inflammation in adipose tissue could trigger neuroinflammation and hippocampal impairment, which potentially contribute to cognitive deficits in obese and diabetic conditions. We also discussed the potential mechanisms underlying the neurotrophic and neuroprotective effects of caloric restriction and physical exercise by counteracting neuroinflammation, plasticity deficits, and cognitive impairments. This review provides timely insights into how chronic metabolic disorders, like obesity, could impair brain health and cognitive functions in later life.

Objective: There is wide variations in practice about the exact timing of coronary artery bypass grafting (CABG) post-acute myocardial infarction (AMI) and admission to hospital. This study aims to review current literature evidence to provide an up-to-date evaluation of the optimal CABG timing and parameters indicative of patient outcomes. Method: Electronic literature search was done to look into articles that discussed acute myocardial presentation and their referral for CABG either as urgent in-patient or as elective cases. The evidence was synthesised based on each reported article and their outcomes. Results: The timing of CABG following AMI have been explored in multiple studies, however there is no clear consensus on when to proceed with CABG following AMI and this remains controversial. The mortality rates vary with timing of CABG, but confounding factors such as age, poor pulmonary functions, renal insufficiency, poor left ventricular function and many others can all contribute to the variable reported outcomes. Conclusion: There is need for large, multi-centre study to identify optimal timings for CABG in cases of complex coronary artery diseases or failed PCI in patients with acute MI. Upcoming guidelines should emphasize patient cohorts by taking their risk factors into consideration.

Human papillomavirus (HPV) is the etiological agent of cervical cancer; however, the mechanisms underlying HPV-mediated carcinogenesis remain poorly understood. Here, we showed that nuclear receptor related-1 protein (Nurr1) was upregulated in primary cervical cancer tissue-derived spheroid cells and HPV-positive cell lines, and Nurr1 upregulation was correlated with cancer grade. Nurr1 promoted cell proliferation, migration, invasion, and anchorage-independent cell growth. In addition to its effect on cancer aggressiveness, Nurr1 enhanced the self-renewal ability of cells in vitro and in vivo, underscoring the importance of Nurr1 in maintaining the stemness of cancer stem-like cells (CSLCs). Mechanistically, Nurr1 independently activated the MEK/ERK and PI3K/Akt/mTOR signaling cascades. The MEK inhibitor trametinib (GSK) and PI3K/mTOR dual inhibitor dactolisib (BEZ) were shown to abrogate Nurr1-augmented tumorigenesis by upregulating p21 and p27 expression and by suppressing MMP9 and KLF4 expression. We provided further evidence that BEZ, but not GSK, could abolish Nurr1-enhanced radioresistance, suggesting its potential value for radiosensitizing CSLCs in the clinical setting. This study highlights the unprecedented roles of Nurr1 and elucidates mechanisms by which Nurr1 promotes tumor progression and radioresistance, providing a novel therapeutic strategy for cervical cancer treatment.

As the world continues to study and understand coronavirus disease (COVID-19), existing investigations and tests have been used to try and detect the virus to slow viral transmission and its global spread. A ‘gold-standard’ investigation has not yet been identified for detection and monitoring. Initially, computed tomography (CT) was the mainstay investigation as it shows the disease severity and recovery, and its images change at different stages of the disease. However, CT has been found to have limited sensitivity and negative predictive value in the early stages of the disease, and the value of its use has come under debate due to whether its images change the treatment plan, the risk of radiation, as well as its practicality with infection control. Therefore, there has been a shift to the use of other imaging modalities and tests, such as chest X-rays and ultrasound. Furthermore, the use of nucleic acid-based testing such as reverse-transcriptase polymerase chain reaction (RT-PCR) have proven useful with direct confirmation of COVID-19 infection. In this study, we aim to review and analyse current literature to compare RT-PCR, immunological biomarkers, chest radiographs, ultrasound and chest CT scanning as methods of diagnosing COVID-19.