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We found that MITA1 was highly upregulated in the gefitinib-resistant NSCLC cells, indicating the regulatory role of MITA1 in gefitinib resistance. Mechanistically, upregulated MITA1 led to gefitinib resistance by suppressing apoptosis, increasing cell viability, and inducing autophagy. Furthermore, these results were true when tested in the presence of bafilomycin A1. Our results suggest that MITA1 by inducing autophagy could be a key regulator of gefitinib resistance in NSCLC.The blood-brain barrier (BBB) is the most critical obstacle in the treatment of central nervous system disorders, such as glioma, the most typical type of brain tumor. To overcome the BBB and enhance drug-penetration abilities, we used angiopep-2-modified liposomes to deliver arsenic trioxide (ATO) across the BBB, targeting the glioma. Angiopep-2-modified calcium arsenite-loaded liposomes (A2-PEG-LP@CaAs), with uniformly distributed hydrodynamic diameter (96.75 ± 0.57 nm), were prepared using the acetate gradient method with high drug-loading capacity (7.13 ± 0.72%) and entrapment efficiency (54.30 ± 9.81%). In the acid tumor microenvironment, arsenic was responsively released, thereby exerting an anti-glioma effect. The anti-glioma effect of A2-PEG-LP@CaAs was investigated both in vitro and in vivo. As a result, A2-PEG-LP@CaAs exhibited a potent, targeted anti-glioma effect mediated by the lipoprotein receptor-related (LRP) receptor, which is overexpressed in both the BBB and glioma. Therefore, A2-PEG-LP@CaAs could dramatically promote the anti-glioma effect of ATO, as a promising strategy for glioma therapy.To help fight COVID-19, new molecular tools specifically targeting critical components of the causative agent of COVID-19, SARS-Coronavirus-2 (SARS-CoV-2), are desperately needed. The SARS-CoV-2 nucleocapsid protein is critical for viral replication, integral to viral particle assembly, and a major diagnostic marker for infection and immune protection. Currently the limited available antibody reagents targeting the nucleocapsid protein are not specific to SARS-CoV-2 nucleocapsid protein, and sequences for these antibodies are not publicly available. In this work we developed and characterized a series of new mouse monoclonal antibodies against the SARS-CoV-2 nucleocapsid protein, with a specific clone, mBG86, targeting only SARS-CoV-2 nucleocapsid protein. The monoclonal antibodies were validated in ELISA, Western blot, and immunofluorescence analyses. The variable regions from six select clones were cloned and sequenced, and preliminary epitope mapping of the sequenced clones was performed. Overall, these new antibody reagents will be of significant value in the fight against COVID-19.Age-related decrease in testosterone levels is a potential risk factor for cognitive decline in older men. However, observational studies and clinical trials have reported inconsistent results on the effects of testosterone on individual cognitive domains. Null findings may be attributed to factors that studies have yet to consider. In particular, individual variations in polyglutamine (CAG) length in the androgen receptor (AR) gene could alter androgenic activity in brain regions associated with cognitive processes including memory and executive functions. However, the role of AR CAG repeat length as a moderator of the relationship between testosterone levels and cognition has not been investigated. Therefore, we aimed to examine the relationship between baseline calculated free testosterone (cFT) levels, change in cFT levels over 18 months and CAG repeat length on cognitive performance in memory, executive function, language, attention and processing speed domains. EGFR inhibitors cancer These relationships were examined in 304 cognitively normal older male participants of the Australian Imaging, Biomarkers and Lifestyle (AIBL) Study of Ageing. In the attention and processing speed domain, a short CAG repeat length appears to exacerbate the effects of low baseline cFT levels that are also lower than expected at follow-up. These results highlight that individual variations in AR CAG repeat length should be considered in future studies and clinical trials that examine the complex relationship between testosterone and cognition.The prejunctional norepinephrine transporter (NET) is responsible for the clearance of released norepinephrine (NE) back into the sympathetic nerve terminal. NET regulation must be tightly controlled as variations could have important implications for neurotransmission. Thus far, the effects of sympathetic neuronal activity on NET function have been unclear. Here, we optically monitor single-terminal cardiac NET activity ex vivo in response to a broad range of sympathetic postganglionic action potential (AP) firing frequencies. Isolated murine left atrial appendages were loaded with a fluorescent NET substrate [Neurotransmitter Transporter Uptake Assay (NTUA)] and imaged with confocal microscopy. Sympathetic APs were induced with electrical field stimulation at 0.2-10 Hz (0.1-0.2 ms pulse width). Exogenous NE was applied during the NTUA uptake- and washout phases to investigate substrate competition and displacement, respectively, on transport. Single-terminal NET reuptake rate was rapidly suppressed in a frequency-dependent manner with an inhibitory EF50 of 0.9 Hz. At 2 Hz, the effect was reversed by the α2-adrenoceptor antagonist yohimbine (1 μM) (p  less then  0.01) with no further effect imposed by the muscarinic receptor antagonist atropine (1 μM). Additionally, high exogenous NE concentrations abolished NET reuptake (1 μM NE; p  less then  0.0001) and displaced terminal specific NTUA during washout (1-100 μM NE; p  less then  0.0001). We have also identified α2-adrenoceptor-induced suppression of NET reuptake rate during resting stimulation frequencies, which could oppose the effect of autoinhibition-mediated suppression of exocytosis and thus amplify the effects of sympathetic drive on cardiac function.Nod-like receptor pyrin containing (NLRP)3 inflammasome-mediated neuroinflammation is involved in the pathology of Parkinson's disease (PD), but the roles of other inflammasomes in PD remain unclear. The NLRP3 inhibitor MCC950 exerts neuroprotective effects in several neurological diseases. Using a 1-methyl-4-phenyl-1,2,3,6-tetrahydro pyridine (MPTP)-induced mouse model with or without intraperitoneal MCC950 administration, we assessed whether specifically the NLRP3 inflammasome is activated in the nigrostriatal system and whether MCC950 has therapeutic potential in this PD model. Western blots were used to determine the nigrostriatal expression of inflammasome-specific proteins, including NLRP1, NLRP2, NLRP3, nod-like receptor CARD containing 4 (NLRC4), and absent in melanoma 2 (AIM2). The pole, hanging, and swimming tests were used to assess functional deficits, western blots and immunostainings were used to analyze dopaminergic neuronal degeneration, as well as activation of glial cells and the NLRP3 inflammasome. NLRP3 expression in the nigrostriatal system of MPTP-induced mice was significantly increased compared to control, whereas NLRP1, NLRP2, NLRC4, and AIM2 expression in the nigrostriatal system, as well as NLRP3 expression in the cerebral cortex and hippocampus, were similar in the two groups. Furthermore, MPTP-induced mice exhibited behavioral dysfunctions, dopaminergic neuronal degeneration, and activation of glial cells and the NLRP3 inflammasome. MCC950 treatment of MPTP-induced mice improved behavioral dysfunctions, reduced dopaminergic neuronal degeneration, and inhibited the activation of glial cells and the NLRP3 inflammasome. In conclusion, these findings indicated that NLRP3, not NLRP1, NLRP2, NLRC4, and AIM2, may be the key inflammasome that promotes MPTP-induced pathogenesis. MCC950 protects against MPTP-induced nigrostriatal damage and may be a novel promising therapeutic approach in treating MPTP-induced PD.
The authors estimated changes of stressed blood volume (SBV) induced by splanchnic nerve block (SNB) in patients with either decompensated or ambulatory heart failure with reduced ejection fraction (HFrEF).

The splanchnic vascular capacity is a major determinant of the SBV, which in turn determines cardiac filling pressures and may be modifiable through SNB.

We analyzed data from 2 prospective, single-arm clinical studies in decompensated HFrEF (splanchnic HF-1; resting hemodynamics) and ambulatory heart failure (splanchnic HF-2; exercise hemodynamics). Patients underwent invasive hemodynamics and short-term SNB with local anesthetics. SBV was simulated using heart rate, cardiac output, central venous pressure, pulmonary capillary wedge pressure, systolic and diastolic systemic arterial and pulmonary artery pressures, and left ventricular ejection fraction. SBV is presented as ml/70kg body weight.

Mean left ventricular ejection fraction was 21 ± 11%. In patients with decompensated HFrEF (n=11), the mery heart failure. SNB reduced the estimated SBV in decompensated and ambulatory heart failure. The reduction in estimated SBV was maintained throughout exercise. (Splanchnic Nerve Anesthesia in Heart Failure, NCT02669407; Abdominal Nerve Blockade in Chronic Heart Failure, NCT03453151).
The goal of this study was to describe outcomes of patients with bridge to heart transplantation (BTT) after changes were made to the donor heart allocation system.

Left ventricular assist devices (LVADs) have been used as a BTT. On October 18, 2018, the donor heart allocation system in the United States was updated.

This study identified adults in the United Network for Organ Sharing database with durable, continuous-flow LVAD at listing or implanted while listed between April 2017 and April 2020. Baseline recipient and donor characteristics, waitlist survival, and post-transplantation outcomes were compared pre- and post-allocation system change.

A total of 1,794 patients met inclusion criteria 983 in the pre-change period and 814 afterward. The number of patients listed with LVAD decreased nationally over time from 102 in April 2017 to 12 in April 2020 (p<0.001). The proportion of patients with LVAD at time of transplant decreased from 47% to 14%. Before the change, the majority were Status 1A (eadily and dramatically after the allocation system change. Although time to transplant decreased, there was an increase in post-transplant mortality. These data suggest that the risks and benefits of LVAD implantation as a BTT have changed under the new allocation system and that the appropriate indication for this treatment strategy warrants a re-evaluation.
The goal of this study was to evaluate differences in clinical and patient-reported outcomes between women and men hospitalized for acute HF.

Among patients hospitalized for heart failure (HF), it is unclear if symptom burden, response to therapy, and patient-reported quality of life (QOL) are different in women as compared with men.

The ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated HeartFailure) trial randomized 7,141 patients hospitalized for HF with reduced or preserved ejection fraction (EF) to receive nesiritide or placebo in addition to standard care. Clinical endpoints included 30-day mortality and rehospitalization and 180-day mortality. Patient-reported QOL was assessed at baseline, discharge, and 30days using the EuroQOL 5 dimensions (EQ-5D) survey.

Among 7,141 total patients, 4,697 (65.8%) were men and 2,444 (34.2%) were women. Among patients with EF≤40%, women were less likely to receive angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker and beta-blocker therapy, and less likely to have an implantable cardioverter-defibrillator (all p<0.
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