Phase II investigational oral drugs for the treatment of radio/chemotherapy induced oral mucositis

Introduction: Oral mucositis is a significant unmet clinical need for many cancer patients. The biological complexity of mucositis’ pathogenesis provides a number of mechanistic targets suitable as pharmacologic targets. The diversity of targets has stimulated drug development in search of an effective intervention. In this paper, we review a range of agents that are currently being evaluated.

Areas covered: Drugs for management of oral mucositis vary in formulation, route of administration and biological target. Most propose to interrupt the initiation of injury by suppressing activation of the innate immune response or countering oxidative stress, or minimizing downstream inflammatory responses. Overwhelmingly, the population most studied is patients being treated with concomitant chemoradiation for cancers of the head and neck as this is the cohort that most consistently suffers severe mucositis for long periods of time. The Phase 2 pipeline is robust. Preliminary data reported for a number of agents is optimistic. Genomics may be important in interpreting and comparing responses to agents across widely demographically diverse populations.

Expert opinion: Oral mucositis remains a significant toxicity for patients undergoing cancer treatment. Incremental reports of successes have been noted for a number of targeted agents.     

《政府会计制度》与《医院会计制度》会计科目衔接方法研究

为了建立健全政府会计核算体系,实现权责发生制政府综合财务报告制度,国家财政部制定了适用于各级各类行政事业单位统一的会计制度——政府会计制度,此制度适用于各级各类行政单位和事业单位,包括医院及基层医疗卫生机构。文章从《政府会计制度》与《医院会计制度》衔接的前期准备工作、新账科目设置与衔接方法进行了研究。     

新时期公立医院党建工作的实践与思考

随着医药卫生体制改革的不断深入,公立医院党建工作面临许多新情况新问题,如何正确应对和解决这些问题、推动党建工作进一步改进创新,已成为医院改革发展需要面对的重要课题。通过总结思考北京协和医院开展党建工作的经验做法,对新时期加强公立医院党建工作提供了借鉴和启示。     

基于新制度主义视角的药品集中招标采购制度研究

目的：为完善我国药品招标采购政策提供参考。方法：分析相关文献和数据,并基于新制度主义视角,从制度的合法性、路径依赖以及权力与利益的博弈三个方面,分析我国药品招标采购制度运行过程中出现问题的原因。结果与结论：我国药品招标采购制度实施过程中存在招标评价指标不合理,药品质量难以保障;招标采购分离、量价不挂钩;医疗机构回款较慢等问题。建议均衡各个利益集团的利益,完善医疗机构补偿机制,优化综合招标评价体系,落实招标采购合一、带量采购,规范政府在招标采购制度中的现代施政原则。     

Mutations in PLS1, encoding fimbrin,cause autosomal dominant nonsyndromic hearing loss

Nonsyndromic hearing loss (NSHL), a common sensory disorder, is characterized by high clinical and genetic heterogeneity (i.e., approximately 115 genes and 170 loci so far identified). Nevertheless, almost half of patients submitted for genetic testing fail to receive a conclusive molecular diagnosis. We used next‐generation sequencing to identify causal variants in PLS1 (c.805G>A, p.[E269K]; c.713G>T, p.[L238R], and c.383T>C, p.[F128S]) in three unrelated families of European ancestry with autosomal dominant NSHL. PLS1 encodes Plastin 1 (also called fimbrin), one of the most abundant actin‐bundling proteins of the stereocilia. In silico protein modeling suggests that all variants destabilize the structure of the actin‐binding domain 1, likely reducing the protein's ability to bind F actin. The role of PLS1 gene in hearing function is further supported by the recent demonstration that Pls1^?/? mice show a hearing loss phenotype similar to that of our patients. In summary, we report PLS1 as a novel gene for autosomal dominant NSHL, suggesting that this gene is required for normal hearing in humans and mice.     

Bacterial adhesion and host cell factors leading to effector protein injection by type III secretion system

Type III secretion systems (T3SS) play a crucial role for virulence in many Gram-negative bacteria. After tight bacterial contact to host cells, the T3SS injects effector proteins into the host cells, which leads to cell invasion, tissue destruction and/or immune evasion. Over the last decade several attempts were made to characterize the host-cell interactions which precede and determine effector protein injection during infection. The development of the TEM-β-lactamase reporter was an important breakthrough to achieve this goal. By this means it was demonstrated that during infection with many Gram-negative pathogens such as Salmonella, Pseudomonas or Yersinia the main targets of T3SS are leukocytes of the myeloid lineage such as neutrophils, macrophages or dendritic cells. This is due to the recruitment of these cells to the site of infection, but also due to the specific interplay between bacterial and host cells. Comprehensive studies on Yersinia pestis, Yersinia enterocolitica and Yersinia pseudotuberculosis effector translocation show that adhesins such as Invasin (Inv), Yersinia adhesin A (YadA) and attachment and invasion locus (Ail) are critical for effector translocation. Here, mainly the complex interaction of YadA and Ail with various host cell receptor repertoires on leukocytes and the modulatory effects of serum factors direct effector translocation predominantly towards myeloid cells. The current understanding suggests that mostly protein based interactions between bacteria and host determine host cell specific effector translocation during Yersinia infection. However, for Shigella dysenteriae infection it was shown that glycan-glycan interactions can also play a critical role for the adhesion preceding effector translocation. In addition, the Shigella infection model revealed that the activation status of cells is a further criterium directing effector translocation into a distinct cell population. In this review the current understanding of the complex and species-specific interaction between bacteria and host cells leading to type III secretion is discussed.     

Immune phenotype predicts new onset diabetes after kidney transplantation

Few data are available concerning immune factors involved in the occurrence of new onset diabetes after transplantation (NODAT). Our objective was to determine an immune profile associated with the subsequent development of NODAT. The secondary objective was to build a predictive model of NODAT. We studied a prospective cohort of incident kidney transplant patients to determine whether pre-transplant immune characteristics could be associated with the occurrence of NODAT. 818 patients were included. We observed a significant inverse correlation between BMI and recent thymic emigrants (RTE) % at transplant time (p < 0.001). 177 (17.3%) of 677 non-diabetic patients experienced NODAT in the first year post-transplant. In multivariate analysis, age, body mass index (BMI), use of Tacrolimus, use of anti-thymocyte globulins (ATG), higher B cell count, and lower recent thymic emigrants (RTE) % were associated with NODAT. A differential effect of immune profile was observed in ATG-treated patients and non-ATG-treated patients. B cell count predicts NODAT only in non-ATG-treated patients whereas lower RTE% was associated with NODAT only in ATG-treated patients. Tacrolimus sparing and B cell depletion may efficiently prevent NODAT in selected patients. We identified an immune profile associated with the occurrence of post-transplant diabetes. Further studies should better precise the exact mechanisms involved in this association. Trial registration NCT02843867, registered July 8, 2016 – retrospectively registered https://clinicaltrials.gov/ct2/show/record/NCT02843867.     

Return of the lysergamides. Part IV: Analytical and pharmacological characterization of lysergic acid morpholide (LSM‐775)

Lysergic acid diethylamide (LSD) is perhaps one of the best‐known psychoactive substances and many structural modifications of this prototypical lysergamide have been investigated. Several lysergamides were recently encountered as ‘research chemicals’ or new psychoactive substances (NPS). Although lysergic acid morpholide (LSM‐775) appeared on the NPS market in 2013, there is disagreement in the literature regarding the potency and psychoactive properties of LSM‐775 in humans. The present investigation attempts to address the gap of information that exists regarding the analytical profile and pharmacological effects of LSM‐775. A powdered sample of LSM‐775 was characterized by X‐ray crystallography, nuclear magnetic resonance spectroscopy (NMR), gas chromatography mass spectrometry (GC–MS), high mass accuracy electrospray MS/MS, high performance liquid chromatography (HPLC) diode array detection, HPLC quadrupole MS, and GC solid‐state infrared analysis. Screening for receptor affinity and functional efficacy revealed that LSM‐775 acts as a nonselective agonist at 5‐HT_1A and 5‐HT_2A receptors. Head twitch studies were conducted in C57BL/6J mice to determine whether LSM‐775 activates 5‐HT_2A receptors and produces hallucinogen‐like effects in vivo. LSM‐775 did not induce the head twitch response unless 5‐HT_1A receptors were blocked by pretreatment with the antagonist WAY‐100,635 (1 mg/kg, subcutaneous). These findings suggest that 5‐HT_1A activation by LSM‐775 masks its ability to induce the head twitch response, which is potentially consistent with reports in the literature indicating that LSM‐775 is only capable of producing weak LSD‐like effects in humans.     

Detection of the recently emerged synthetic cannabinoid 5F–MDMB‐PICA in ‘legal high’ products and human urine samples

Indole or indazole‐based synthetic cannabinoids (SCs) bearing substituents derived from valine or tert‐leucine are frequently abused new psychoactive substances (NPS). The emergence of 5F–MDMB‐PICA (methyl N‐{[1‐(5‐fluoropentyl)‐1H–indol‐3‐yl]carbonyl}‐3‐methylvalinate) on the German drug market is a further example of a substance synthesized in the context of scientific research being misused by clandestine laboratories by adding it to ‘legal high’ products. In this work, we present the detection of 5F–MDMB‐PICA in several legal high products by gas chromatography–mass spectrometry (GC–MS) analysis. To detect characteristic metabolites suitable for a proof of 5F–MDMB‐PICA consumption by urine analysis, pooled human liver microsome (pHLM) assays were performed and evaluated using liquid chromatography–tandem mass spectrometry (LC–MS/MS) and liquid chromatography quadrupole time‐of‐flight mass spectrometry (LC‐QToF‐MS) techniques to generate reference spectra of the in vitro phase I metabolites. The in vivo phase I metabolism was investigated by the analysis of more than 20 authentic human urine specimens and compared to the data received from the pHLM assay. Biotransformation of the 5‐fluoropentyl side chain and hydrolysis of the terminal methyl ester bond are main phase I biotransformation steps. Two of the identified main metabolites formed by methyl ester hydrolysis or mono‐hydroxylation at the indole ring system were evaluated as suitable urinary biomarkers and discussed regarding the interpretation of analytical findings. Exemplary analysis of one urine sample for 5F–MDMB‐PICA phase II metabolites showed that two of the main phase I metabolites are subject to extensive glucuronidation prior to renal excretion. Therefore, conjugate cleavage is reasonable for enhancing sensitivity. Commercially available immunochemical pre‐tests for urine proved to be unsuitable for the detection of 5F–MDMB‐PICA consumption. Copyright © 2017 John Wiley & Sons, Ltd.