Sorcin (SOluble Resistance-related Calcium bInding proteiN) is a calcium binding protein that plays a key role in multidrug resistance (MDR) in human cancers. This study aimed at understanding the binding mechanism and structural basis for the interaction of structurally and functionally unrelated chemotherapeutic agent, namely doxorubicin, etoposide, omacetaxine mepesuccinate and paclitaxel with Sorcin by utilizing docking and molecular dynamic simulation approaches. The docking evaluation of etoposide, omacetaxine mepesuccinate and paclitaxel have shown a high affinity binding with Sorcin at the Ca2+-binding C-terminal domain (SCBD) in a comparable mode and affinity of binding to doxorubicin. Moreover, all of the docked compounds were shown to interact both hydrophilically and hydrophobically with the same residues within the active pocket which is located at interface of the Sorcin and collectively formed by EF5 loop, G helix and EF4 loop. However, the MD simulations revealed that the dynamics of Sorcin structure is different in the presence of the compounds when compared and contrasted to the Apo Sorcin, particularly in the first 25 ns, after which each system gained considerable structure stability. The difference in dynamics might be the outcome of high N and C-terminal flexibility that seem not to disturb compounds binding conformation but more likely is affecting chemical interaction network by breaking and establishing old and new hydrogen bonds, respectively. https://www.selleckchem.com/products/AZD0530.html This detailed mechanistic understanding of different chemotherapeutic agents binding to Sorcin might be useful to open windows for designing and developing new inhibitors that are potentially capable of reversing the MDR in human cancers.Chemodynamic therapy (CDT) is an emerging tumour-specific therapeutic technology. However, the relatively insufficient catalytic activity of CDT agents in the tumour microenvironment (TME) limits their biomedical application. In addition, severe hypoxia and glutathione (GSH) overexpression in the TME greatly limit the antitumour efficiency of monotherapy. Herein, a cancer cell membrane-camouflaged and ultrasmall CeO2-decorated MnO2 (mMC) composite is developed for amplified CDT, photodynamic therapy (PDT) and photothermal therapy (PTT). Due to the homotypic targeting ability of cancer cell membranes, mMC nanoparticles preferentially accumulate in tumour tissue. In the TME, CeO2 acts as a highly efficient CDT agent to convert endogenous H2O2 to toxic reactive oxygen species (ROS) for killing cancer cells. Meanwhile, MnO2 irradiated with near-infrared (NIR) light displays prominent hyperthermia and ROS generation performance to perform PTT and PDT. Moreover, MnO2 can produce oxygen to ameliorate hypoxia and deplete GSH to relieve the antioxidant capability of tumours, which is beneficial to the simultaneous augmentation of PDT and CDT. Most importantly, the catalytic activity of CeO2 was greatly improved by hyperthermia. Consequently, a significantly enhanced therapeutic efficiency was obtained by the above multiple synergistic effects. This work provides a proof of concept for amplified tumour therapy by synchronously self-supplying oxygen, consuming GSH, and enhancing catalytic activity.The protozoan Plasmodium falciparum is the main aetiological agent of tropical malaria. Characteristic of the phylum is the presence of a plastid-like organelle which hosts several homologs of plant proteins, including a ferredoxin (PfFd) and its NADPH-dependent reductase (PfFNR). The PfFNR/PfFd redox system is essential for the parasite, while mammals share no homologous proteins, making the enzyme an attractive target for novel and much needed antimalarial drugs. Based on previous findings, three chemically reactive residues important for PfFNR activity were identified namely, the active-site Cys99, responsible for hydride transfer; Cys284, whose oxidation leads to an inactive dimeric form of the protein; and His286, which is involved in NADPH binding. These amino acid residues were probed by several residue-specific reagents and the two cysteines were shown to be promising targets for covalent inhibition. The quantitative and qualitative description of the reactivity of few compounds, including a repurposed drug, set the bases for the development of more potent and specific antimalarial leads.Atherosclerosis still remains the leading cause of morbidity and mortality worldwide, and deeper understanding of target signaling that protect from the atherosclerosis progression may provide novel therapeutic strategies. CDGSH iron-sulfur domain-containing protein 1 (CISD1) is a protein localized on the outer membrane of mitochondria, and plays key roles in regulating cell death and oxidative stress. However, its potential on atherosclerosis development and the underlying mechanisms are largely unknown. Here, in our study, we found markedly decreased CISD1 expression in lipid-laden THP1 macrophages. Notably, lentivirus (LV)-mediated CISD1 over-expression remarkably ameliorated lipid deposition in macrophages stimulated by ox-LDL. Furthermore, cellular total ROS and mitochondrial ROS generation, and impairment of mitochondrial membrane potential (MMP) were highly induced by ox-LDL in THP1 cells, while being considerably reversed upon CISD1 over-expression. Inflammatory response caused by ox-LDL was also significantly restrained in macrophages with CISD1 over-expression. Mechanistically, we found that CISD1 could interact with dynamin-related protein 1 (Drp1). Intriguingly, CISD1-improved mitochondrial dysfunction and inflammation in ox-LDL-treated macrophages were strongly abolished by Drp1 over-expression, indicating that Drp1 suppression might be necessary for CISD1 to perform its protective effects in vitro. In high fat diet (HFD)-fed apolipoprotein E-deficient (ApoE-/-) mice, tail vein injection of lentiviral vector expressing CISD1 remarkably decreased atherosclerotic lesion area, serum LDL cholesterol levels and triglyceride contents. Inflammatory response, cellular total and mitochondrial ROS production, and Drp1 expression levels in aorta tissues were also dramatically ameliorated in HFD-fed ApoE-/- mice, contributing to the inhibition of atherosclerosis in vivo. Therefore, improving CISD1 expression may be a novel therapeutic strategy for atherosclerosis treatment.
This study aimed to compare the efficacy between neoadjuvant chemotherapy (NACT) plus intensity-modulated radiotherapy (IMRT) and NACT plus concurrent chemoradiotherapy (CCRT) in patients with nasopharyngeal carcinoma (NPC).

Data from 603 patients with ascending (T4 and N0-1) or descending (T1-2&N3) NPC who were treated at Sun Yat-sen University Cancer Center between October 2009 and February 2012 were retrospectively analyzed. These patients were divided into two groups NACT+IMRT (n=302) and NACT+CCRT (n=301). The primary endpoint was overall survival (OS), which was analyzed using the Kaplan-Meier method, log-rank test, Cox proportional hazards model, and landmark analysis.

In univariate analysis, there was no significant difference in 5-year OS between the NACT+IMRT and NACT+CCRT groups (hazard ration [HR] 0.69; 95% confidence interval [CI] 0.47-1.01; P=0.057). However, after adjustment for age (<45years, ≥45years), gender, histological stage (I/II, III), T stage (1/2, 3, 4), and N stage (0/1,ng-term survival outcomes than those treated with NACT+CCRT, especially the patients younger than 45 years old or in stage T3/N2/N3. Additionally, NACT+IMRT may be a better option than NACT+CCRT in patients within the first 24 months.
Determine rates of intra-parotid and neck nodal metastasis, identify risk factors for recurrence, and report outcomes in patients with primary high-grade parotid malignancy who undergo total parotidectomy and neck dissection.

Retrospective review of patients undergoing total parotidectomy and neck dissection for high-grade parotid malignancy between 2005 and 2015. The presence and number of parotid lymph nodes, superficial and deep, as well as cervical lymph nodes involved with metastatic disease were assessed. Risk factors associated with metastatic spread to the parotid deep lobe were identified and recurrence rates reported.

75 patients with median follow-up time of 47months. 35 patients (46.7%) had parotid lymph node metastasis. Seven patients (9.3%) had deep lobe nodal metastasis without metastasis to the superficial lobe nodes. Nine patients (12%) had positive intra-parotid nodes without positive cervical nodes. Cervical nodal disease was identified in 49.3% patients (37/75). Local, parotid-bed reastasis. Rate of recurrence in the parotid bed, which may represent local or regional recurrence, was similar to regional cervical lymph node recurrence. Total parotidectomy and neck dissection should be considered high-grade parotid malignancy regardless of clinical nodal status.
Cochlear implantation (CI) has been shown to reduce vestibular function postoperatively in the implanted ear. The objective of this study was to identify the prevalence of preoperative vestibular weakness in CI candidates and identify any risk factors for postoperative dizziness.

Retrospective cohort study.

Patients who underwent CI and had preoperative videonystagmography (VNG) at the Silverstein Institute from January 1, 2017 to May 31, 2020 were evaluated. The primary endpoint was dizziness lasting more than one month postoperatively.

One hundred and forty nine patients were evaluated. Preoperative VNG revealed that 46 (30.9%) had reduced vestibular response (RVR) on one side and 32 (21.5%) had bilateral vestibular hypofunction (BVH). Postoperative dizziness occurred in 14 (9.4%) patients. Patients with postoperative dizziness were more likely to have abnormal preoperative VNG (RVR or BVH), compared to patients without postoperative dizziness (78.6% versus 49.6%, p = 0.0497). In cases of RVR, implantation of the weaker or stronger vestibular ear did not affect the postoperative dizziness (16.1% versus 6.7%, p=0.38). Postoperative VNG in patients with dizziness showed decreased caloric responses in the implanted ear (28.4 to 6.4 degrees/s, p=0.02).

Preoperative caloric weakness is prevalent in CI candidates and abnormal preoperative vestibular testing may be a predictor of postoperative dizziness. CI has the potential to cause vestibular injury and preoperative testing may aid in both counseling and decision-making.
Preoperative caloric weakness is prevalent in CI candidates and abnormal preoperative vestibular testing may be a predictor of postoperative dizziness. CI has the potential to cause vestibular injury and preoperative testing may aid in both counseling and decision-making.
Mothers from middle-income countries (MIC) are estimated to have higher rates of adverse childhood experiences (ACEs) and depression during pregnancy compared to mothers from high income countries. Prenatal depression can adversely impact on a mother's feelings towards her foetus and thus may be partially responsible for intergenerational transmission of risk associated with maternal ACEs. However, the extent to which prenatal depressive symptoms mediate the association between maternal ACEs and foetal attachment is unknown.

Data on foetal attachment, ACEs, and prenatal depression came from mothers in their third trimester of pregnancy (n=1,185) located across eight MICs, participating in the prospective birth cohort Evidence for Better Lives Study - Foundational Research (EBLS-FR). Data were from the baseline measurement.

Full-sample path mediation analyses, adjusting for relevant covariates, suggested a full mediating effect of prenatal depression. However, at the individual-country level, both positive and negative effects of ACEs on foetal attachment were observed after the inclusion of depressive symptoms as a mediator, suggesting cultural and geographical factors may influence a mother's empathic development after ACE exposure.