Multidrug resistance-associated protein 3 confers resistance to chemoradiotherapy for rectal cancer by regulating reactive oxygen species and caspase-3-dependent apoptotic pathway

This study aimed to clarify the role of multidrug resistance-associated protein 3 (MRP3) in resistance to neoadjuvant chemoradiotherapy and long-term prognosis of advanced rectal cancer. Immunohistochemistry was used to measure MRP3 expression in biopsy specimens of 144 stage II–III rectal cancer patients who received preoperative chemoradiotherapy. The effect of MRP3 expression on short-term pathological response and postoperative long-term prognosis were assessed using the Cox proportional hazards model. Short interfering RNAs targeting MRP3 were synthesized and used to transfect human colorectal carcinoma cell lines. The effect of MRP3 down-regulation on cell proliferation and apoptosis in response to 5-fluorouracil and/or irradiation were examined in vitro and in xenograft mouse models, respectively. The content of intracellular reactive oxygen species and the activity of caspase-3-dependent apoptotic pathway in response to irradiation were further evaluated. High expression (immunoreactive score > 6) of MRP3 significantly predicted poor pathological response to chemoradiotherapy (tumor regression grade ≤ 2 vs. ≥3, p = 0.002) in univariate analysis and unfavorable long-term prognosis (5-year overall survival: HR = 1.612, 95% CI, 1.094–2.375, p = 0.016; 5-year disease-free survival: HR = 1.513, 95% CI, 1.041–2.200, p = 0.030) in multivariate Cox analysis. MRP3 down-regulation significantly increased 5-fluorouracil or irradiation-induced cell apoptosis and attenuated tumor growth following irradiation in animal models. MRP3 inhibition significantly reduced intracellular reactive oxygen species exporting from cells following irradiation, and increased expression of cleaved poly ADP-ribose polymerase and caspase-3. Aberrant expression of MRP3 in rectal cancer confers chemo-radioresistance. MRP3 might be a predictive factor and an attractive target in treating advanced rectal cancer.     

Efficacy of Therapies for Postural Tachycardia Syndrome: A Systematic Review and Meta-analysis

Objective

To identify the evidence base and evaluate the efficacy of each treatment for postural tachycardia syndrome (POTS) in light of a recent consensus statement highlighting the lack of treatment options with clear benefit to risk ratios for this debilitating condition.

Regulatory role of leukocyte common antigen‐related molecule (LAR) in thymocyte differentiation

The strength of interaction between the antigenic peptide‐loaded MHC (MHC/p) and the TCR determines T‐cell fate in the thymus. A high avidity interaction between the TCR and the MHC/p induces apoptosis of self‐reactive T cells (negative selection), whereas a moderate avidity interaction rescues thymocytes from apoptosis and permits further differentiation to mature T cells (positive selection). Leukocyte common antigen‐related molecule (LAR), a receptor‐like protein tyrosine phosphatase, is expressed on immature thymocytes, but its role in thymocyte differentiation has not yet been fully elucidated. We analyzed LAR‐deficient mice and demonstrated that LAR deficiency affected the differentiation and expansion of immature thymocytes as well as positive and negative selection. Furthermore, LAR deficiency resulted in a lower Ca²⁺ response. The results indicate that LAR is an important modulator of TCR signaling that controls thymocyte differentiation.     

A dual-perspective analysis of the hospital and payer-borne burdens of selected in-hospital surgical complications in low anterior resection for colorectal cancer

Objectives: The economic burden of surgical complications is borne in distinctly different ways by hospitals and payers. This study quantified the incidence and economic burden – from both the hospital and payer perspective – of selected major colorectal surgery complications in patients undergoing low anterior resection (LAR) for colorectal cancer.

Methods: Retrospective, observational study of patient undergoing LAR for colorectal cancer between 1/1/2010 and 7/1/2015. Analyses were replicated in two large healthcare administrative databases: Premier (hospital discharge and billing data; hospital perspective) and Optum (insurance claims data; payer perspective). Multivariable analyses evaluated the association between infection (surgical site or bloodstream), anastomotic leak, and bleeding complications and the following outcomes: hospital length of stay (LOS), non-home discharge, 90-day all-cause readmission, index admission costs to the hospital, index admission payer expenditures, and index admission +90-day post-discharge payer expenditures.

Results: 9,738 eligible LAR patients were included (7,479 in Premier; 2,259 in Optum). Overall, the incidences of infection, anastomotic leak, and bleeding complications were 6.4%, 10.6%, and 10.9%, respectively, during the index hospitalization. Each complication was associated with statistically significant longer LOS, higher risk of non-home discharge, higher risk of 90-day readmission, greater costs to the hospital, and higher payer expenditures.

Conclusions: In-hospital infection, anastomotic leak, and bleeding were associated with a substantial economic burden, for both hospitals and payers, in patients undergoing LAR for colorectal cancer. This study provides information which may be used to quantify the potential economic value and impact of innovations in surgical care and delivery that reduce the incidence and burden of these complications.     

Resolution of refractory chemotherapy-induced diarrhea (CID) with octreotide long-acting formulation in cancer patients: 11 case studies

Purpose Subcutaneous (SC) octreotide has been shown to effectively relieve chemotherapy-induced diarrhea (CID) refractory to conventional therapy but requires t.i.d. injections. A microencapsulated, long-acting formulation (LAR) of octreotide has been developed for once-monthly intramuscular (IM) dosing. Efficacy in resolving severe diarrhea and preventing further episodes of diarrhea in cancer patients was explored.Patients and methods Patients with advanced cancer who developed CID and failed conventional antidiarrheal therapy (loperamide + diphenoxylate-atropine) received octreotide LAR IM. The starting dose was either 20 or 30 mg with possible dose escalation from 20 to 30 mg and from 30 to 40 mg. Treatment was repeated every 28 days during chemotherapy.Results Complete resolution of diarrhea within 1 to 4 weeks from injection time was seen in all cases with octreotide LAR 30 mg. With a subsequent prophylactic injection once every 28 days, CID was limited to NCI grade 1. This resulted in increased patient quality of life (QOL) and allowed better patient compliance with therapy. Therapy could then be completed at full dose and on schedule after resolution of often debilitating diarrhea.Conclusion The ability of octreotide LAR 30 mg to speed the resolution of CID and limit further episodes of diarrhea to infrequent NCI grade 1 controlled with loperamide (prn) suggests that long-acting somatostatin homologues have the potential to be useful in the secondary prevention of diarrhea in patients undergoing chemotherapy.     

Septic shock in a patient infected with Rickettsia sibirica mongolitimonae,Spain

In 1996, the first human case of infection by Rickettsia sibirica subsp. mongolitimonae was described in France. Subsequently, other human cases were reported in the same country. The acronym LAR (lymphangitis-associated rickettsiosis) has been proposed to designate this disease because lymphangitis is one of the main clinical manifestations. Later, a few more cases were described in Portugal, South Africa, Egypt, Greece and Spain. We report a case of R. sibirica mongolitimonae infection as a cause of septic shock in a Spanish patient living in La Rioja (northern Spain). In addition, the broad clinical spectrum of this tick-borne disease is discussed.     

Oleanolic acid derivative NPLC441 potently stimulates glucose transport in 3T3-L1 adipocytes via a multi-target mechanism

The natural product oleanolic acid (OA) has been discovered to exhibit varied pharmacological functions including anti-inflammation, anti-tumor and anti-diabetes, while appropriate synthetic oleanolic acid derivatives seem to possess more potent activities. Here we identified a new oleanolic acid derivative, 3-β-(2-carboxybenzoyloxy)-oleanolic acid (NPLC441), which functioned as a competitive PTP1B inhibitor and enhanced insulin-stimulated phosphorylation of IR and AKT in HepG2 cells. As an RXRα antagonist, it could selectively activate LXRα:RXRα heterodimer and increase the promoter activities of ABCA1 and ABCG1 genes in transient transfection assays. Quantitative RT-PCR and Western blot analyses suggested that NPLC441 could up-regulate GLUT4 expression in 3T3-L1 adipocytes, and such effect was further proved to be dependent on LXRα:RXRα activation. Moreover, 2-deoxyglucose uptake technology-based characterization demonstrated that this compound could stimulate glucose uptake in 3T3-L1 adipocytes. Finally, NPLC441 was observed to be able to suppress 11β-HSD₁ expression in HepG2 cells, following the discovery that activation of LXRα:RXRα could repress the expression of 11β-HSD₁. Compared with NPLC441, OA showed no effects on the transactivation of either LXRα:RXRα heterodimer or RXRα-LBD. Our work is thus expected to provide a new insight into the anti-diabetic application for oleanolic acid derivatives via multi-target mechanism, and NPLC441 could be used as a potential lead compound for further research.     

儿童肝母细胞瘤预后影响因素分析

目的：回顾性分析儿童肝母细胞瘤预后影响因素。方法：对2011-2019年首诊于上海儿童医学中心的120例肝母细胞瘤患儿进行回顾性分析,记录患儿年龄、性别、PRETEXT分期、病理类型、远处转移、治疗前血清AFP水平、治疗前LAR水平、治疗方案及治疗后随访结果。所有患儿依据上海儿童医学中心分组标准分为标准危险组与高度危险组,并采用不同的化疗方案。采用单因素分析和多因素分析方法研究影响儿童肝母细胞瘤无事件生存期和总体生存期的危险因素。结果：120例患儿中,男性73例,女性47例；发病中位年龄为16个月,3岁以内患儿为103例,3岁以上患儿为17例；标准危险组为39例,高度危险组为81例;伴远处转移为20例,不伴远处转移为100例；治疗前血清甲胎蛋白(AFP)≤100ng/ml 为2例,AFP＞100ng/ml 为118例；治疗前乳酸脱氢酶与白蛋白比值(LAR)≤31.6为 92例,LAR＞31.6为28例。随访时间29.0 (10.3, 62.8)个月,患儿5年无事件生存率(EFS)和5年总体生存率(OS)分别为79.8±4.1%和84.9±3.7%。多因素回归分析表明肝母细胞瘤患儿独立危险因素包括年龄(EFS: HR=1.029, 95%CI 1.015-1.042; OS: HR=1.030, 95%CI 1.014-1.046)、治疗前AFP≤100ng/ml(EFS: HR=18.10, 95%CI 3.20-102.53; OS: HR=19.82, 95%CI 3.26-120.56)、伴远处转移(EFS: HR=3.13, 95%CI 1.07-9.20; OS: HR=4.36, 95%CI 1.22-15.60)以及治疗前LAR＞31.6(EFS: HR=5.77, 95%CI 1.89-17.66; OS: HR=7.69, 95%CI 1.91-31.02)(P＜0.05)。结论：肝母细胞瘤患儿发病年龄较大、远处转移、AFP≤100ng/ml、LAR＞31.6是影响肝母细胞瘤预后独立危险因素, LAR可作为一种判断儿童肝母细胞瘤预后的生物标志物。