Distinct cytokine profiles across trajectories of self-perceived cognitive impairment among early-stage breast cancer survivors.

The aim of the current study is to identify distinct cytokine profiles in relation to self-perceived cognitive trajectories. In our study cohort (n = 128), early-stage breast cancer patients were categorized into no impairment reported, acute, delayed, persistent and intermittent cognitive decline respectively. Pro-inflammatory cytokines were elevated compared to baseline; with TNF-α implicated in the acute cognitive trajectory while IL-6 and IL-8 were involved in the persistent cognitive trajectory. Our findings help to further our understanding of cytokine profiles implicated in cancer-related cognitive impairment (CRCI) and support the use of cytokine levels as biomarkers of cognitive decline over time

Magnesium Isoglycyrrhizinate Ameliorates Fibrosis and Disrupts TGF-β-Mediated SMAD Pathway in Activated Hepatic Stellate Cell Line LX2

Liver fibrosis is a histological change often attributed to the activation of hepatic stellate cells (HSCs) and the excessive formation of scar tissues in the liver. Advanced stages of the disease frequently lead to cirrhosis. Magnesium isoglycyrrhizinate (MgIG) has been accepted as a hepatoprotective drug with the potential of alleviating inflammatory conditions and thus promote liver recovery from viral- or drug-induced injury. While MgIG has been empirically integrated into the clinics to treat some liver diseases, its anti-fibrotic effect and the associated mechanisms remain poorly characterized. Herein, we demonstrated that 1 mg/ml MgIG attenuated the production of αSMA and collagen-1 in activated HSCs using TGF-β1-induced human HSCs LX2 as the fibrotic cell model. We found that MgIG exerts an inhibitory effect on the TGF-β-SMAD signaling pathway by arresting the binding of downstream transcription factors SMAD2/3 and SMAD4. Furthermore, MgIG was shown to suppress proliferation and induce senescence of activated LX2 cells. Protein expression of p27 and enzymatic activity of senescence-associated β-galactosidase were elevated upon exposure to MgIG. In addition, we observed that exposure of activated LX2 cells to MgIG reduces TGF-β-induced apoptosis. Interestingly, a lower toxicity profile was observed when human fetal hepatocytes LO2 were exposed to the same concentration and duration of the drug, suggesting the specificity of MgIG effect toward activated HSCs. Overall, hepatoprotective concentrations of MgIG is shown to exert a direct effect on liver fibrosis through inhibiting TGF-β-signaling, in which SMAD2/3 pathway could be one of the mechanisms responsible for the fibrotic response, thereby restoring the surviving cells toward a more quiescent phenotype. This provides critical mechanistic insights to support an otherwise empirical therapy

Klotho-beta overexpression as a novel target for suppressing proliferation and fibroblast growth factor receptor-4 signaling in hepatocellular carcinoma

<p>Abstract</p> <p>Background</p> <p>We had previously demonstrated overexpression of fibroblast growth factor receptor-4 (FGFR4) in hepatocellular carcinoma (HCC). However, additional molecular mechanisms resulting in amplified FGFR4 signaling in HCC remain under-studied. Here, we studied the mechanistic role of its co-receptor klotho-beta (KLB) in driving elevated FGFR4 activity in HCC progression.</p> <p>Results</p> <p>Quantitative real-time PCR analysis identified frequent elevation of KLB gene expression in HCC tumors relative to matched non-tumor tissue, with a more than two-fold increase correlating with development of multiple tumors in patients. KLB-silencing in Huh7 cells decreased cell proliferation and suppressed FGFR4 downstream signaling. While transient repression of KLB-FGFR4 signaling decreased protein expression of alpha-fetoprotein (AFP), a HCC diagnostic marker, prolonged inhibition enriched for resistant HCC cells exhibiting increased liver stemness.</p> <p>Conclusions</p> <p>Elevated KLB expression in HCC tissues provides further credence to the oncogenic role of increased FGFR4 signaling in HCC progression and represents a novel biomarker to identify additional patients amenable to anti-FGFR4 therapy. The restricted tissue expression profile of KLB, together with the anti-proliferative effect observed with KLB-silencing, also qualifies it as a specific and potent therapeutic target for HCC patients. The enrichment of a liver stem cell-like population in response to extended KLB-FGFR4 repression necessitates further investigation to target the development of drug resistance.</p

The role of head-up cardiopulmonary resuscitation in sudden cardiac arrest: a systematic review and meta-analysis

BACKGROUND: Head-up cardiopulmonary resuscitation (HU-CPR) is an experimental treatment for sudden cardiac arrest (SCA), where cardiopulmonary resuscitation (CPR) is performed in a ramped position. We evaluated whether HU-CPR improved survival and surrogate outcomes as compared to standard CPR (S-CPR). METHODS: Studies reporting on HU-CPR in SCA were searched for in PubMed, Embase and Cochrane Library from inception to May 1st 2021. Outcomes included neurologically-intact survival, 24-hour-survival, intracranial pressure (ICP), cerebral perfusion pressure (CerPP) and brain blood flow (BBF). Risk of bias was assessed using the GRADE assessment tool and Newcastle Ottawa Scale. Fixed- and random-effects models were used to estimate the pooled effects of HU-CPR at 30 degrees. RESULTS: Thirteen articles met the criteria for inclusion (11 animal-only studies, one before-and-after human-only study, one study that utilized human- and animal-cadavers). Among animal studies, the most common implementation of HU-CPR was a 30-degree upward tilt of the head and thorax (n=7), while four studies investigated controlled sequential elevation (CSE). Two animal studies reported improved cerebral performance category (CPC) scores at 24-hour. The pooled effect on 24-hour survival was not statistically significant (P=0.37). The lone human study reported doubled return of spontaneous circulation (ROSC) (17.9% versus 34.2%, P<0.0001). The pooled effect on ROSC in three porcine studies was OR =3.63 (95% CI: 0.72–18.39). Pooled effects for surrogate physiological outcomes of intracranial cranial pressure (MD −14.08, 95% CI: −23.21 to −4.95, P=0.003), CerPP (MD 14.39, 95% CI: 3.07–25.72, P=0.01) and BBF (MD 0.14, 95% CI: 0.02–0.27, P=0.03), showed statistically significant benefit. DISCUSSION: Overall, HU-CPR improved neurologically-intact survival at 24-hour, ROSC and physiological surrogate outcomes in animal models. Despite promising preclinical data, and one human observational study, clinical equipoise remains surrounding the role of HU-CPR in SCA, necessitating clarification with future randomized human trials

Replication and Meta-analysis of the Association between BDNF Val66Met Polymorphism and Cognitive Impairment in Patients Receiving Chemotherapy.

Cancer-related cognitive impairment (CRCI) adversely affects cancer patients. We had previously demonstrated that the BDNF Val66Met genetic polymorphism is associated with lower odds of subjective CRCI in the multitasking and verbal ability domains among breast cancer patients receiving chemotherapy. To further assess our previous findings, we evaluated the association of BDNF Val66Met polymorphism with subjective and objective CRCI in a temporally separate cohort of patients and pooled findings from both the original (n = 145) and current (n = 193) cohorts in a meta-analysis. Subjective CRCI was assessed using FACT-Cog. Objective CRCI was evaluated using computerized neuropsychological tests. Genotyping was carried out using Sanger sequencing. The association of BDNF Val66Met genotypes and CRCI was examined with logistic regression. A fixed-effect meta-analysis was conducted using the inverse variance method. In the meta-analysis (n = 338), significantly lower odds of CRCI were associated with Met allele carriers based on the global FACT-Cog score (OR = 0.52, 95% CI 0.29-0.94). Furthermore, Met allele carriers were at lower odds of developing impairment in the domains of memory (OR = 0.34, 95% CI: 0.17-0.70), multitasking (OR = 0.33, 95% CI: 0.18-0.59), and verbal ability (OR = 0.46, 95% CI: 0.24-0.88). Consistent with the previous study, lower odds of subjective CRCI among patients with the BDNF Met allele was observed after adjusting for potential confounders in the multitasking (OR = 0.30, 95% CI: 0.14-0.67) domain. In conclusion, carriers of the BDNF Met allele were protected against global subjective CRCI, particularly in the domains of memory, multitasking, and verbal ability. Our findings further contribute to the understanding of CRCI pathophysiology

Induction of apoptosis and regulation ofMicroRNA expression by (2E,6E)-2,6-bis-(4-hydroxy-3-methoxybenzylidene)- cyclohexanone (BHMC) treatment on MCF-7 breast cancer cells

(2E,6E)-2,6-bis-(4-hydroxy-3-methoxybenzylidene)-cyclohexanone (BHMC) is a synthetic curcumin analogue, which has been reported to possess anti-tumor, anti-metastatic, and anti-invasion properties on estrogen receptor (ER) negative breast cancer cells in vitro and in vivo. However, the cytotoxic effects of BHMC on ER positive breast cancer cells were not widely reported. This study was aimed to investigate the cytotoxic potential of BHMC on MCF-7 cells using cell viability, cell cycle, and apoptotic assays. Besides, microarray and quantitative polymerase chain reaction (qPCR) were performed to identify the list of miRNAs and genes, which could be dysregulated following BHMC treatment. The current study discovered that BHMC exhibits selective cytotoxic effects on ER positive MCF-7 cells as compared to ER negative MDA-MB-231 cells and normal breast cells, MCF-10A. BHMC was shown to promote G2/M cell cycle arrest and apoptosis in MCF-7 cells. Microarray and qPCR analysis demonstrated that BHMC treatment would upregulate several miRNAs like miR-3195 and miR-30a-3p and downregulate miRNAs such as miR-6813-5p and miR-6132 in MCF-7 cells. Besides, BHMC administration was also found to downregulate few tumor-promoting genes like VEGF and SNAIL in MCF-7. In conclusion, BHMC induced apoptosis in the MCF-7 cells by altering the expressions of apoptotic-regulating miRNAs and associated genes