Glucose starvation induces resistance to metformin through the elevation of mitochondrial multidrug resistance protein 1

Metformin, a drug for type 2 diabetes mellitus, has shown therapeutic effects for various cancers. However, it had no beneficial effects on the survival rate of human malignant mesothelioma (HMM) patients. The present study was performed to elucidate the underlying mechanism of metformin resistance in HMM cells. Glucose‐starved HMM cells had enhanced resistance to metformin, demonstrated by decreased apoptosis and autophagy and increased cell survival. These cells showed abnormalities in mitochondria, such as decreased ATP synthesis, morphological elongation, altered mitochondrial permeability transition pore and hyperpolarization of mitochondrial membrane potential (MMP). Intriguingly, Mdr1 was significantly upregulated in mitochondria but not in cell membrane. The upregulated mitochondrial Mdr1 was reversed by treatment with carbonyl cyanide m‐chlorophenyl hydrazone, an MMP depolarization inducer. Furthermore, apoptosis and autophagy were increased in multidrug resistance protein 1 knockout HMM cells cultured under glucose starvation with metformin treatment. The data suggest that mitochondrial Mdr1 plays a critical role in the chemoresistance to metformin in HMM cells, which could be a potential target for improving its therapeutic efficacy.     

Safety and Efficacy of the Moderate Sedation During Flexible Bronchoscopic Procedure: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Moderate sedatives have been increasingly used to improve patient comfort during flexible bronchoscopy (FB). However, routine use of moderate sedation during FB is controversial because its efficacy and safety are not well established.This study aims to evaluate the efficacy and safety of moderate sedation during FB.A search was made of Medline, EMBASE, and the Cochrane Library to May 2014.Randomized controlled trials (RCTs) and quasi-RCTs were included.The main analysis was designed to examine the efficacy of moderate sedation during FB in sedation than no-sedation.The willingness to repeat FB was significantly more in sedation than no-sedation (odds ratio [OR] 2.30; 95% confidence interval [CI] 1.11–4.73; P = 0.02; I² = 22.5). The duration of FB was shorter in sedation group than no-sedation group (standardized mean difference [SMD] −0.21; 95% CI −0.38 to −0.03; P = 0.02; I² = 78.3%). Event of hypoxia was not significantly different between sedation and no-sedation groups (OR 0.86; 95% CI 0.42–1.73; P = 0.67; I² = 0%). The SpO₂ during procedure was not different between sedation and no-sedation groups (SMD −0.14; 95% CI −0.37 to 0.08; P = 0.21; I² = 49.9%). However, in subgroup analysis without supplemental oxygen, the SpO₂ was significantly lower in sedation than no-sedation group (SMD −0.45; 95% CI −0.78 to −0.11; P = 0.01; I² = 0.0%).According to this meta-analysis, moderate sedation in FB would be useful in patients who will require repeated bronchoscopies as well as safe in respiratory depression. To our knowledge, although the various sedative drugs are already used in the real field, this analysis was the first attempt to quantify objective results. We anticipate more definite and studies designed to elucidate standardized outcomes for moderate sedation in FB.     

Pseudocystic pilomatricoma: A new variant and review of the literature

A classic pilomatricoma, which usually presents with an asymptomatic, solitary, firm, subcutaneous nodule in the head, neck, or extremities of the paediatric population, is easily diagnosed based on its characteristic clinical and histopathological features. However, its variants often pose particular diagnostic challenges to clinicians due to their rarity and diverse clinicopathological features. We present a new pseudocystic variant, manifesting as solid lesions floating in a fluid‐filled sac.     

Clinicopathologic characteristics of paranasal sinus fungus ball: retrospective,multicenter study in Korea

European Archives of Oto-Rhino-Laryngology - Fungus ball (FB) is the most common type of fungal rhinosinusitis and the prevalence of FB has increased over the past 10 years. The aim of...     

Exposure to ambient air pollution and the incidence of lung cancer and breast cancer in the Ontario Population Health and Environment Cohort

Lung and female breast cancers are highly prevalent worldwide. Although the association between exposure to ambient fine particulate matter (PM_2.5) and lung cancer has been recognized, there is less evidence for associations with other common air pollutants such as nitrogen dioxide (NO₂) and ozone (O₃). Even less is known about potential associations between these pollutants and breast cancer. We conducted a population-based cohort study to investigate the associations of chronic exposure to PM_2.5, NO₂, O₃ and redox-weighted average of NO₂ and O₃ (O_x) with incident lung and breast cancer, using the Ontario Population Health and Environment Cohort (ONPHEC), which includes all long-term residents aged 35–85 years who lived in Ontario, Canada, 2001–2015. Incident lung and breast cancers were ascertained using the Ontario Cancer Registry. Annual estimates of exposures were assigned to the residential postal codes of subjects for each year during follow-up. We used Cox proportional-hazards models adjusting for personal- and neighborhood-level covariates. Our cohorts for lung and breast cancer analyses included ~4.9 million individuals and ~2.5 million women, respectively. During follow-up, 100,146 incident cases of lung cancer and 91,146 incident cases of breast cancer were diagnosed. The fully adjusted analyses showed positive associations of lung cancer incidence with PM_2.5 (hazard ratio [HR] = 1.02 [95% CI: 1.01–1.05] per 5.3 μg/m³) and NO₂ (HR = 1.05 [95% CI: 1.03–1.07] per 14 ppb). No associations with lung cancer were observed for O₃ or O_x. Relationships between PM_2.5 and NO₂ with lung cancer exhibited a sublinear shape. We did not find compelling evidence linking air pollution to breast cancer.     

Sonodynamic Therapy: Advances and Challenges in Clinical Translation

Sonodynamic therapy (SDT) consists of the synergetic interaction between ultrasound and a chemical agent. In SDT, the cytotoxicity is triggered by ultrasonic stimuli, notably through cavitation. The unique features of SDT are relevant in the clinical context more than ever: the need for efficacy, accuracy, and safety while being noninvasive and preserving the patient's quality of life. However, despite the promising results of this technique, only a few clinical reports describe the use of SDT. The objective of this article is to provide an extensive overview of the clinical and preclinical research conducted in vivo on SDT, to identify the limitations, and to detail the developed strategies to overcome them.