Oral squamous cell carcinomas: state of the field and emerging directions / 国际口腔科学杂志·英文版

Oral squamous cell carcinoma (OSCC) develops on the mucosal epithelium of the oral cavity. It accounts for approximately 90% of oral malignancies and impairs appearance, pronunciation, swallowing, and flavor perception. In 2020, 377,713 OSCC cases were reported globally. According to the Global Cancer Observatory (GCO), the incidence of OSCC will rise by approximately 40% by 2040, accompanied by a growth in mortality. Persistent exposure to various risk factors, including tobacco, alcohol, betel quid (BQ), and human papillomavirus (HPV), will lead to the development of oral potentially malignant disorders (OPMDs), which are oral mucosal lesions with an increased risk of developing into OSCC. Complex and multifactorial, the oncogenesis process involves genetic alteration, epigenetic modification, and a dysregulated tumor microenvironment. Although various therapeutic interventions, such as chemotherapy, radiation, immunotherapy, and nanomedicine, have been proposed to prevent or treat OSCC and OPMDs, understanding the mechanism of malignancies will facilitate the identification of therapeutic and prognostic factors, thereby improving the efficacy of treatment for OSCC patients. This review summarizes the mechanisms involved in OSCC. Moreover, the current therapeutic interventions and prognostic methods for OSCC and OPMDs are discussed to facilitate comprehension and provide several prospective outlooks for the fields.

Repurposing econazole as a pharmacological autophagy inhibitor to treat pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is characterized by the highest mortality among carcinomas. The pathogenesis of PDAC requires elevated autophagy, inhibition of which using hydroxychloroquine has shown promise. However, current realization is impeded by its suboptimal use and unpredictable toxicity. Attempts to identify novel autophagy-modulating agents from already approved drugs offer a rapid and accessible approach. Here, using a patient-derived organoid model, we performed a comparative analysis of therapeutic responses among various antimalarial/fungal/parasitic/viral agents, through which econazole (ECON), an antifungal compound, emerged as the top candidate. Further testing in cell-line and xenograft models of PDAC validated this activity, which occurred as a direct consequence of dysfunctional autophagy. More specifically, ECON boosted autophagy initiation but blocked lysosome biogenesis. RNA sequencing analysis revealed that this autophagic induction was largely attributed to the altered expression of activation transcription factor 3 (ATF3). Increased nuclear import of ATF3 and its transcriptional repression of inhibitor of differentiation-1 (ID-1) led to inactivation of the AKT/mammalian target of rapamycin (mTOR) pathway, thus giving rise to autophagosome accumulation in PDAC cells. The magnitude of the increase in autophagosomes was sufficient to elicit ER stress-mediated apoptosis. Furthermore, ECON, as an autophagy inhibitor, exhibited synergistic effects with trametinib on PDAC. This study provides direct preclinical and experimental evidence for the therapeutic efficacy of ECON in PDAC treatment and reveals a mechanism whereby ECON inhibits PDAC growth.

Functional metabolomics reveal the role of AHR/GPR35 mediated kynurenic acid gradient sensing in chemotherapy-induced intestinal damage

Intestinal toxicity induced by chemotherapeutics has become an important reason for the interruption of therapy and withdrawal of approved agents. In this study, we demonstrated that chemotherapeutics-induced intestinal damage were commonly characterized by the sharp upregulation of tryptophan (Trp)-kynurenine (KYN)-kynurenic acid (KA) axis metabolism. Mechanistically, chemotherapy-induced intestinal damage triggered the formation of an interleukin-6 (IL-6)-indoleamine 2,3-dioxygenase 1 (IDO1)-aryl hydrocarbon receptor (AHR) positive feedback loop, which accelerated kynurenine pathway metabolism in gut. Besides, AHR and G protein-coupled receptor 35 (GPR35) negative feedback regulates intestinal damage and inflammation to maintain intestinal integrity and homeostasis through gradually sensing kynurenic acid level in gut and macrophage, respectively. Moreover, based on virtual screening and biological verification, vardenafil and linagliptin as GPR35 and AHR agonists respectively were discovered from 2388 approved drugs. Importantly, the results that vardenafil and linagliptin significantly alleviated chemotherapy-induced intestinal toxicity

Strategy and practice of standardized residency training management during the national outbreak of COVID-19 / 中华医学教育探索杂志

The national outbreak of coronavirus disease 2019 (COVID-19) has brought a severe challenge to the management of standardized residency training (SRT). To protect SRT residents from being infected by 2019 novel coronavirus (2019-nCoV), to guarantee the training program well carried out, and to prevent psychological health problems are conundrums to the management of SRT. In this article, the specific countermeasures are introduced from the following aspects: perfecting the management system, implementing quarantine and life support, conducting epidemic prevention and control training, turning training patterns suitable to epidemic prevention, and maintaining the psychological health of the residents. And we expect to provide references for SRT management under the public health emergency in the future.

The effects of hypertension on the risk of recurrence among TOAST subtype of ischemic stroke / 医学研究生学报

Objective The relationship between hypertension ( HTN) and ischemic stroke recurrence is unclear , but there may be different effects of HTN on the risk of recurrence .This study aims to explore whether HTN contributes differently to the recur-rence among subtypes of ischemic stroke ( IS) . Methods We eventually enrolled 1114 patients with ischemic stroke from Jul 2008 to Dec 2012 registered in Nanjing Stroke Registry Program (NSRP) in this study.All the patients were classified according to Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria: 315 (28.3%) patiwnts were classified as Large-artery atheroselerosis (LAA), 212 (19.0%) as cardioembolism (CE), 266 (23.9%) as small-artery occlusion (SAO), and 321 (28.8%) as other de-termined and undetermined etiologies ( Other) .The association between HTN and stroke recurrence in patients with different IS sub-types was analyzed using multivariate Cox regression analysis . Results The average follow-up duration was (19.4 ±10.3) months. Of 1114 patients with IS, 158 (14.2%) patients experienced a recurrent stroke .Patients with HTN had a significantly higher stroke recurrence rate than those without (16.5%vs 10.5%, P<0.05).Multivariate Cox regression analysis indicated that HTN increased the risk of ischemic stroke recurrence (HR=1.722, 95%CI:1.181-2.512, P=0.005).After stratification by TOAST subtypes, analysis revealed an association between HTN and stroke recurrence in LAA( HR=3 .767, 95%CI:1.866-7.585, P=0.001) and SAO (HR=3.530, 95%CI:1.156-12.740, P=0.028), but not in the other subtypes (CE: HR=0.773, 95%CI:0.370-1.615, P=0.493;Other:HR=1.498, 95%CI:0.590-3.807, P=0.395). Conclusion HTN is an independent risk factor for recurrent ischemic stroke and is related to the recurrent ischemic stroke in patients with large-artery and small-vessel disease .