Identifying Lymph Nodes and Their Statuses from Pretreatment Computer Tomography Images of Patients with Head and Neck Cancer Using a Clinical-Data-Driven Deep Learning Algorithm.

BACKGROUND: Head and neck cancer is highly prevalent in Taiwan. Its treatment mainly relies on clinical staging, usually diagnosed from images. A major part of the diagnosis is whether lymph nodes are involved in the tumor. We present an algorithm for analyzing clinical images that integrates a deep learning model with image processing and attempt to analyze the features it uses to classify lymph nodes. METHODS: We retrospectively collected pretreatment computed tomography images and surgery pathological reports for 271 patients diagnosed with, and subsequently treated for, naïve oral cavity, oropharynx, hypopharynx, and larynx cancer between 2008 and 2018. We chose a 3D UNet model trained for semantic segmentation, which was evaluated for inference in a test dataset of 29 patients. RESULTS: We annotated 2527 lymph nodes. The detection rate of all lymph nodes was 80%, and Dice score was 0.71. The model has a better detection rate at larger lymph nodes. For those identified lymph nodes, we found a trend where the shorter the short axis, the more negative the lymph nodes. This is consistent with clinical observations. CONCLUSIONS: The model showed a convincible lymph node detection on clinical images. We will evaluate and further improve the model in collaboration with clinical physicians.

Chlorpyrifos induces neuronal cell death via both oxidative stress and Akt activation downstream-regulated CHOP-triggered apoptotic pathways.

Chlorpyrifos (CPF) is one of the most abundant and widely used organophosphate pesticides for agricultural, industrial, and household purposes in the world. Epidemiological studies have reported that CPF can induce neurotoxic impairments in mammalian, which is linked to an important risk factor for development of neurodegenerative diseases (NDs). However, limited information is available on CPF-induced neurotoxicity, with the underlying exact mechanism remains unclear. In this study, CPF exposure (10-400 µM) significantly reduced Neuro-2a cell viability and induced apoptotic events, including the increase in caspase-3 activity, apoptotic cell population, and cleavage of caspase-3/-7 and PARP. Exposure of Neuro-2a cells to CPF also triggered CHOP activation. Transfection with CHOP-specific siRNA markedly suppressed the expression of CHOP, and attenuated cytotoxicity and apoptotic events in CPF-exposed Neuro-2a cells. Furthermore, CPF exposure obviously evoked the phosphorylation of Akt as well as ROS generation in a time-dependent manner. Pretreatment with LY294002 (an Akt inhibitor) effectively attenuated the CPF-induced Akt phosphorylation, CHOP activation, and apoptotic events, but not that ROS production. Of note, buffering the ROS generation with antioxidant N-acetylcysteine effectively prevented the CPF-induced ROS generation, CHOP activation, and apoptotic events, but not that the Akt phosphorylation. Collectively, these findings indicate that CPF exposure exerts neuronal cytotoxicity via the independent pathways of ROS generation and Akt activation downstream-regulated CHOP-triggered apoptosis, ultimately leading to neuronal cell death.

Fully Convolutional Network for the Semantic Segmentation of Medical Images: A Survey.

There have been major developments in deep learning in computer vision since the 2010s. Deep learning has contributed to a wealth of data in medical image processing, and semantic segmentation is a salient technique in this field. This study retrospectively reviews recent studies on the application of deep learning for segmentation tasks in medical imaging and proposes potential directions for future development, including model development, data augmentation processing, and dataset creation. The strengths and deficiencies of studies on models and data augmentation, as well as their application to medical image segmentation, were analyzed. Fully convolutional network developments have led to the creation of the U-Net and its derivatives. Another noteworthy image segmentation model is DeepLab. Regarding data augmentation, due to the low data volume of medical images, most studies focus on means to increase the wealth of medical image data. Generative adversarial networks (GAN) increase data volume via deep learning. Despite the increasing types of medical image datasets, there is still a deficiency of datasets on specific problems, which should be improved moving forward. Considering the wealth of ongoing research on the application of deep learning processing to medical image segmentation, the data volume and practical clinical application problems must be addressed to ensure that the results are properly applied.

Norketamine, the Main Metabolite of Ketamine, Induces Mitochondria-Dependent and ER Stress-Triggered Apoptotic Death in Urothelial Cells via a Ca2+-Regulated ERK1/2-Activating Pathway.

Ketamine-associated cystitis is characterized by suburothelial inflammation and urothelial cell death. Norketamine (NK), the main metabolite of ketamine, is abundant in urine following ketamine exposure. NK has been speculated to exert toxic effects in urothelial cells, similarly to ketamine. However, the molecular mechanisms contributing to NK-induced urothelial cytotoxicity are almost unclear. Here, we aimed to investigate the toxic effects of NK and the potential mechanisms underlying NK-induced urothelial cell injury. In this study, NK exposure significantly reduced cell viability and induced apoptosis in human urinary bladder epithelial-derived RT4 cells that NK (0.01-0.5 mM) exhibited greater cytotoxicity than ketamine (0.1-3 mM). Signals of mitochondrial dysfunction, including mitochondrial membrane potential (MMP) loss and cytosolic cytochrome c release, were found to be involved in NK-induced cell apoptosis and death. NK exposure of cells also triggered the expression of endoplasmic reticulum (ER) stress-related proteins including GRP78, CHOP, XBP-1, ATF-4 and -6, caspase-12, PERK, eIF-2α, and IRE-1. Pretreatment with 4-phenylbutyric acid (an ER stress inhibitor) markedly prevented the expression of ER stress-related proteins and apoptotic events in NK-exposed cells. Additionally, NK exposure significantly activated JNK, ERK1/2, and p38 signaling and increased intracellular calcium concentrations ([Ca2+]i). Pretreatment of cells with both PD98059 (an ERK1/2 inhibitor) and BAPTA/AM (a cell-permeable Ca2+ chelator), but not SP600125 (a JNK inhibitor) and SB203580 (a p38 inhibitor), effectively suppressed NK-induced mitochondrial dysfunction, ER stress-related signals, and apoptotic events. The elevation of [Ca2+]i in NK-exposed cells could be obviously inhibited by BAPTA/AM, but not PD98059. Taken together, these findings suggest that NK exposure exerts urothelial cytotoxicity via a [Ca2+]i-regulated ERK1/2 activation, which is involved in downstream mediation of the mitochondria-dependent and ER stress-triggered apoptotic pathway, consequently resulting in urothelial cell death. Our findings suggest that regulating [Ca2+]i/ERK signaling pathways may be a promising strategy for treatment of NK-induced urothelial cystitis.

Z-Ligustilide Induces c-Myc-Dependent Apoptosis via Activation of ER-Stress Signaling in Hypoxic Oral Cancer Cells.

Z-ligustilide (or ligustilide) is found in Angelica sinensis (Oliv.) Diels and may exert potential benefits in cancer treatment. Previous research has reported that ligustilide has anti-cancer effects on several types of cancer cells. However, studies of ligustilide on oral cancer cells have not been reported, especially under hypoxic conditions. This study focuses on the molecular mechanism of ligustilide-induced apoptosis in hypoxic oral cancer cells. We found that in hypoxic TW2.6 cells, ligustilide inhibited cell migration and induced caspase-dependent apoptosis. Accumulation of c-Myc accompanied by BH3-only members suggests that ligustilide may induce c-Myc-dependent apoptosis. In addition, we reported that ligustilide has an effect on ER-stress signaling. By using inhibitors of c-Myc, IRE1α, and ER-stress inhibitors, we found that cell morphologies or cell viability were rescued to some degree. Moreover, ligustilide is able to increase the expression of γ-H2AX and enhance the occurrence of DNA damage in oral cancer cells after radiation treatment. This result suggests that ligustilide has potential as a radiation sensitizer. Altogether, we propose that ligustilide may induce c-Myc-dependent apoptosis via ER-stress signaling in hypoxic oral cancer cells.

The Role of Cytokines and Chemokines in Severe Acute Respiratory Syndrome Coronavirus 2 Infections.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in countless infections and caused millions of deaths since its emergence in 2019. Coronavirus disease 2019 (COVID-19)-associated mortality is caused by uncontrolled inflammation, aberrant immune response, cytokine storm, and an imbalanced hyperactive immune system. The cytokine storm further results in multiple organ failure and lung immunopathology. Therefore, any potential treatments should focus on the direct elimination of viral particles, prevention strategies, and mitigation of the imbalanced (hyperactive) immune system. This review focuses on cytokine secretions of innate and adaptive immune responses against COVID-19, including interleukins, interferons, tumor necrosis factor-alpha, and other chemokines. In addition to the review focus, we discuss potential immunotherapeutic approaches based on relevant pathophysiological features, the systemic immune response against SARS-CoV-2, and data from recent clinical trials and experiments on the COVID-19-associated cytokine storm. Prompt use of these cytokines as diagnostic markers and aggressive prevention and management of the cytokine storm can help determine COVID-19-associated morbidity and mortality. The prophylaxis and rapid management of the cytokine storm appear to significantly improve disease outcomes. For these reasons, this study aims to provide advanced information to facilitate innovative strategies to survive in the COVID-19 pandemic.

Breast-conserving surgery with whole breast radiation therapy has a subsequent lower mood disorder incidence rate than total mastectomy in early-stage breast cancer patients: a nationwide population-based longitudinal study.

PURPOSE: Breast-conserving surgery (BCS) followed by whole breast radiation therapy (BCS-WBRT) or total mastectomy without WBRT (TM-no-WBRT) is the primary treatment for early stage breast cancer patients. Our study aimed to identify which early stage breast cancer treatment strategies had a subsequent lower incidence rate of mood disorder over a period of 10 years after the primary treatment. METHODS: This retrospective cohort study consisted of newly diagnosed early stage breast cancer patients in Taiwan from 2000 to 2013 using the National Health Insurance Research Database in Taiwan. We used a 1:1 propensity score matching by age to enrol patients into the BCS-WBRT and TM-no-WBRT groups. Statistical analyses were performed to calculate the hazard ratio and cumulative incidence rate. RESULTS: Our study consisted of 876 BCS-WBRT patients and 1949 TM-no-WBRT patients. After propensity score matching, each study group included 876 patients. The results showed that the mood disorder incidence rate was lower in the BCS-WBRT group than in the TM-no-WBRT group. Multivariate Cox regression analysis revealed that the BCS-WBRT group had a decreased risk of developing mood disorder (adjusted hazard ratio 0.69, 95% CI 0.53-0.90, p < 0.01). Furthermore, the Kaplan-Meier analysis showed that the BCS-WBRT group had a lower cumulative incidence rate of mood disorder, especially depression, after undergoing 10 years of primary treatment (p = 0.004). CONCLUSION: Our results indicated that BCS-WBRT was associated with a lower risk of development of mood disorder over a 10-year period compared to TM-no-WBRT in early stage breast cancer patients. Our findings may provide helpful information, along with other clinical data, for breast cancer patients as they choose the type of appropriate surgery for treatment.

Androgen deprivation therapy for prostate cancer and the risk of thyroid diseases.

BACKGROUND: Androgen deprivation therapy (ADT) is the major treatment for metastatic prostate cancer (PCa), but few studies have investigated the effects of ADT on thyroid diseases. METHODS: This population-based, nationwide cohort study utilized the Taiwan National Health Insurance Research Database (NHIRD) with 17,192 PCa patients between 1997 and 2013. We used the Cox proportional hazards models and propensity score-matched analysis to analyze the association between ADT and the development of thyroid diseases. RESULTS: A total of 17,192 newly diagnosed men with PCa were selected from the NHIRD. There were 6200 ADT users and 6200 non-ADT users after 1:1 propensity score matching. There was a significantly decreased risk of thyroid diseases among ADT users compared with non-ADT users (adjusted hazard ratio (aHR): 0.79, 95% confidence interval (CI): 0.65-0.95, p < 0.001). Further analysis showed a significantly decreased risk of thyroid diseases with increasing ADT duration (p < 0.001). CONCLUSIONS: The result showed that ADT use in men with PCa was associated with a decreased risk of thyroid disease development.

Aspirin and Primary Cancer Risk Reduction in Ischemic Cardiac or Cerebrovascular Disease Survivors: A Nationwide Population-Based Propensity-Matched Cohort Study.

Ischemic cardiac or cerebrovascular disease (ICCD) survivors represent a subpopulation with a high cancer risk. Antiplatelet medications, such as aspirin, remain a fundamental therapy for the secondary prevention of ischemic attack in these patients. We conducted a population-based cohort study to investigate the association of long-term low-dose aspirin use with the risk of primary cancer in ICCD survivors. Patients aged ≥20 years with newly diagnosed ICCD (n = 98,519) between January 2000 and December 2013 were identified from the Taiwan National Health Insurance Research Database. The aspirin user and nonuser groups (each n = 24,030) were propensity-matched (1:1) for age, sex, comorbidities, prior medications, ICCD diagnosis year, and year of index dates. The incidence rate of primary cancer was significantly lower in the user group (6.49/1000 person-years) than in the nonuser group (14.04/1000 person-years). Multivariate Cox regression analysis indicated that aspirin use was an independent factor associated with a reduced risk of primary cancer (aHR (95% confidence interval) = 0.42 (0.38−0.45)) after adjustment. Kaplan−Meier curve analysis revealed that the cumulative incidence rate of primary cancer was significantly lower (p < 0.0001) in the user group than in the nonuser group over the 14-year follow-up period. Subgroup analyses demonstrated that this anticancer effect increased with duration of treatment and with similar estimates in women and men. In addition, aspirin use was associated with a reduced risk for seven out of the ten most common cancers in Taiwan. These findings suggest the anticancer effect of aspirin in ICCD survivors and provide information for assessing the benefit-to-risk profile of aspirin as an antiplatelet medication in these patients.

Medical Utilization of Emergency Departments among Patients with Prostate Cancer: A Nationwide Population-Based Study in Taiwan.

(1) Background: In Taiwan, prostate cancer is a major malignancy with an increasing incidence among men. This study explores the medical utilization of emergency departments among patients with prostate cancer in Taiwan. (2) Methods: This nationwide, population-based study was conducted via a cross-sectional method based on the Registry for Catastrophic Illness Patient Database from Taiwan's National Health Insurance Research Database. Patients with newly diagnosed prostate cancer between 1997 and 2013 were enrolled in the study and divided into four treatment-related groups. The rate of emergency department presentation, disease categorization of emergency department visits, emergency department-related medical expenditures, and temporal trends were investigated. (3) Results: A total of 18,728 patients with prostate cancer were identified between 1997 and 2013, for whom 13,098 emergency department visits were recorded. The number of emergency department visits increased during the study period. The incidence rate for the medical utilization of emergency department visits was 822 per 1000 people during the study period. The incidence rates for patients with prostate cancer in the radical prostatectomy, radiotherapy, androgen deprivation therapy, and chemotherapy groups were 549, 1611, 1101, and 372, respectively. The average medical expenditure per emergency department visit was TWD 3779.8 ± 5116.2, and the expenditure was recorded for the chemotherapy group at TWD 4690.8 ± 7043.3. The most common disease diagnoses among patients with prostate cancer who presented to the emergency department were injury/poisoning (16.79%), genitourinary disorders (10.66%), and digestive disorders (10.48%). (4) Conclusions: This nationwide population-based study examined the emergency department visits of patients with prostate cancer in Taiwan, providing useful information for improving the quality of medical care.

Association between Helicobacter pylori infection and mortality risk in prostate cancer patients receiving androgen deprivation therapy: A real-world evidence study.

PURPOSE: Helicobacter pylori (H. pylori) is a major risk factor for gastric cancer and may affect androgen activity in men. The association between H. pylori and androgen deprivation therapy (ADT) in patients with prostate cancer (PCa) remains unclear. METHODS: This retrospective cohort study linked National Health Insurance (NHI) data to Taiwan Cancer Registry (TCR) and Taiwan Death Registry (TDR) between 1995 and 2016. PCa patients who received ADT were classified into H. pylori infection and non-H. pylori infection groups. The outcomes were overall mortality, prostate cancer-specific mortality, and castration-resistant prostate cancer (CRPC). Propensity score matching was adopted for the primary analysis and inverse probability of treatment weighting (IPTW) was used for the sensitivity analysis. RESULTS: Of the 62,014 selected PCa patients, 23,701 received ADT, of whom 3516 had H. pylori infections and 20,185 did not. After matching, there were 3022 patients in the H. pylori infection group and 6044 patients in the non-H. pylori infection group. The mean follow-up period for the matched cohort was 4.8 years. Compared to the non-H. pylori group, the H. pylori group was significantly associated with decreased risks of all-cause mortality (hazard ratio [HR] 0.90; 95% confidence interval [CI] 0.84-0.96) and prostate cancer-specific mortality (HR 0.88; 95% CI 0.81-0.95) in the matched analysis. CONCLUSIONS: H. pylori infection was associated with a reduced risk of mortality in PCa patients receiving ADT.

Association between Androgen Deprivation Therapy and Risk of Dementia in Men with Prostate Cancer.

The risk of dementia after androgen deprivation therapy (ADT) in patients with advanced prostate cancer (PCa) remains controversial. This study aimed to evaluate the association between ADT and the incidence of dementia in patients with PCa. We identified patients newly diagnosed with PCa in the National Health Insurance Database of Taiwan from 1 January 2002 to 30 June 2016 and in The Health Improvement Network of the United Kingdom (UK) from 1 January 1998 to 31 March 2018. We classified patients with PCa into ADT and ADT-naïve groups. Propensity score (PS) methods were used to minimize the differences in characteristics between the groups. We performed a Cox proportional hazard model to obtain the adjusted hazard ratio (HR) to compare the incidence of dementia between the groups. Our ADT group comprised 8743 and 73,816 patients in Taiwan and the UK, respectively, which were matched 1:1 to ADT-naïve patients by PS. The incidence rates of dementia in the ADT group were 2.74 versus 3.03 per 1000 person-years in the ADT naïve groups in Taiwan, and 2.81 versus 2.79 per 1000 person-years in the UK. There was no statistical difference between ADT and ADT-naïve groups (adjusted HR: 1.12; 95% confidence interval (CI): 0.87-1.43 in Taiwan and adjusted HR: 1.02; 95% CI: 0.85-1.23 in the UK). We found no association between the incidence of dementia and ADT in patients with advanced PCa in either database. Further studies are warranted to evaluate other possible triggers of incident dementia in patients receiving ADT for advanced PCa.

Preterm Labor Using Tocolysis as a Possible Risk Factor for Postpartum Depression: A 14-Year Population-Based Study in Taiwan.

Postpartum depression (PPD) is associated with negative physical and mental health outcomes for the mother and infant. Women often experience elevated symptoms of PPD, and the incidence of PPD has increased in recent years. There were lack of studies to investigate the effects of medications during pregnancy. Herein, we focused on the most common obstetric medical therapies used in labor and determined whether the medical therapies cause mental stress in pregnant women. This 14-year retrospective population-based nationwide study was based on the National Health Insurance Research Database. Univariate and multivariate logistic regression analyses were used to evaluate unadjusted and adjusted odds ratios and 95% confidence intervals for each tocolytic and uterotonic treatments during pregnancy and common medical illnesses. In comparing the effects of tocolytic and uterotonic medications on maternal PPD, tocolysis with the injection form of ritodrine resulted in a significantly higher risk of PPD based on multivariate analysis. This study supports existing research demonstrating an association between tocolysis with ritodrine and PPD. Ritodrine treatment for preterm labor was a significant risk factor for PPD, especially the injection form. This information provides obstetricians and health policy providers to pay attention to maternal mental health outcomes among high-risk pregnant women.

Arsenic induces autophagy-dependent apoptosis via Akt inactivation and AMPK activation signaling pathways leading to neuronal cell death.

Inorganic arsenic (As3+), a well-known worldwide industrial and environmental pollutant, has been linked to neurodegenerative disorders (NDs). Autophagy plays an important role in controlling neuronal cell survival/death. However, limited information is available regarding the toxicological mechanism at the interplay between autophagy and As3+-induced neurotoxicity. The present study found that As3+ exposure induced a concomitant activation of apoptosis and autophagy in Neuro-2a cells, which was accompanied with the increase of phosphatidylserine exposure on outer membrane leaflets and apoptotic cell population, and the activation of caspase-3, -7, and PARP as well as the elevation of protein expressions of LC3-II, Atg-5, and Beclin-1, and the accumulation of autophagosome. Pretreatment of cells with autophagy inhibitor 3-MA, but not that of Z-VAD-FMK (a pan-caspase inhibitor), effectively prevented the As3+-induced autophagic and apoptotic responses, indicating that As3+-triggered autophagy was contributing to neuronal cell apoptosis. Furthermore, As3+ exposure evoked the dephosphorylation of Akt. Pretreatment with SC79, an Akt activator, could significantly attenuated As3+-induced Akt inactivation as well as autophagic and apoptotic events. Expectedly, inhibition of Akt signaling with LY294002 obviously enhanced As3+-triggered autophagy and apoptosis. Exposure to As3+ also dramatically increased the phosphorylation level of AMPKα. Pretreatment of AMPK inhibitor (Compound C) could markedly abrogate the As3+-induced phosphorylated AMPKα expression, and autophagy and apoptosis activation. Taken together, these results indicated that As3+ exerted its cytotoxicity in neuronal cells via the Akt inactivation/AMPK activation downstream-regulated autophagy-dependent apoptosis pathways, which ultimately lead to cell death. Our findings suggest that the regulation of Akt/AMPK signals may be a promising intervention to against As3+-induced neurotoxicity and NDs.

Androgen deprivation therapy and the risk of subsequent keratitis.

OBJECTIVES: The objective of the study was to determine the risk of subsequent keratitis in prostate cancer (PCa) patients treated with androgen deprivation therapy (ADT). MATERIALS AND METHODS: Three thousand three hundred and nine patients with PCa were identified using data from Taiwan's National Health Insurance Research Database for 2001 through 2013. Among those patients, 856 treated with ADT comprised the study group, while 856 non-ADT-treated patients matched with 1:1 propensity-score-matched analysis comprised the control group. The demographic characteristics and comorbidities of all the patients were analyzed, and Cox proportional hazards regression was utilized to determine the hazard ratios (HRs) for subsequent keratitis. RESULTS: A total of 157 (9.2%) patients had newly diagnosed keratitis. Compared to the non-ADT-treated patients, the ADT-treated patients had a reduced risk of subsequent keratitis, with an adjusted HR of 0.38 (95% confidence interval: 0.27-0.55; P < 0.001). CONCLUSION: ADT treatment apparently decreased the risk of subsequent keratitis in the investigated PCa patients, but the clinical significance of this finding should be further assessed in additional studies.

Adaptive support ventilation attenuates postpneumonectomy acute lung injury in a porcine model.

OBJECTIVES: An optimal ventilation strategy that causes as little mechanical stress and inflammation as possible is critical for patients undergoing pneumonectomy. The aim of this study was to determine whether adaptive support ventilation (ASV) can provide protective ventilation to the remaining lung after pneumonectomy with minimal mechanical stress and less inflammation than volume-control ventilation (VCV). METHODS: In this study, 15 pigs were randomly allocated to 3 groups (n = 5 for each group): the control group, the VCV group and the ASV group. After left pneumonectomy, the VCV group was treated with the volume-control set to 20 ml/kg, and the ASV group with the mode set to achieve 60% of the minute ventilation of 2 lungs. RESULTS: The ASV group had lower alveolar strain than the VCV group. The ASV group exhibited less lung injury and greater alveolar fluid clearance than the VCV group (13.3% vs -17.8%; P ≤ 0.018). Ventilator-induced lung injury was associated with changes in the cytokine levels in the exhaled breath condensate, differential changes in plasma and changes in the cytokines in the bronchoalveolar lavage fluid. Expression of 3 microRNAs (miR449b-3p, P ≤ 0.001; miR451-5p, P = 0.027; and miR144-5p, P = 0.008) was increased in the VCV group compared with the ASV group. CONCLUSIONS: The ASV mode was capable of supporting rapid, shallow breathing patterns to exert lung-protective effects in a porcine postpneumonectomy model. Further investigation of microRNAs as biomarkers of ventilator-induced lung injury is warranted.

Decreased Risk of Renal Calculi in Patients Receiving Androgen Deprivation Therapy for Prostate Cancer.

Renal calculi are common, with male predilection and androgen exposure potentially increasing the risk of renal calculi. Systemic effects of androgen deprivation therapy (ADT) have been observed but the influence of ADT on renal calculi in prostate cancer (PCa) patients is not fully understood. We conducted this population-based study to evaluate the impact of ADT on the subsequent risk of renal calculi. We used the National Health Insurance Research Database of Taiwan to analyze the incidences of renal calculi in ADT patients and non-ADT patients from 2001 to 2013. In total, 3309 patients with PCa were selected. After matching with 1:1 propensity-score analysis, 758 ADT patients with 758 matched non-ADT controls were enrolled in the final analysis. Demographic characteristics were analyzed and Cox regression analysis for calculating the hazard ratios (HR) was performed for the subsequent risk of renal calculi. Finally, 186 (186/1516, 12.3%) patients with diagnosed renal calculi were detected. ADT patients had a lower risk of subsequent renal calculi with an adjusted HR of 0.38 (7% vs. 17.5%, 95% confidence interval (CI) 0.28-0.53; p < 0.001) in comparison with the non-ADT group. The Kaplan-Meier curve showed significant differences of cumulative incidences of renal calculi. In conclusion, ADT patients had approximately one-third lower risk of subsequent renal calculi. Further studies are warranted to evaluate the clinical significance.

Androgen deprivation therapy for prostate cancer and the risk of hematologic disorders.

PURPOSE: This study aimed to investigate the association between androgen deprivation therapy (ADT) and the risk of subsequently developing hematologic disorders in patients with prostate cancer. MATERIALS AND METHODS: This population-based nationwide cohort study utilized data from the Taiwan National Health Insurance Research Database between 1997 and 2013. The patients were divided into three groups-those who received ADT only (ADT-only group), those who had radiotherapy (RT) only (RT-only group), and those treated with radical prostatectomy (RP) only (RP-only group). The study outcome was newly diagnosed hematologic disorder, including anemia and hematologic malignancy. Propensity score-matched, Cox regression, and Kaplan-Meier curve analyses were performed to investigate the risk of subsequently developing hematologic disorders after ADT. RESULTS: Of the 17,168 patients with prostate cancer who were included in the study, 13,318 met the inclusion and exclusion criteria. After propensity score matching, 1,797, 1,797, and 1,797 patients treated with ADT only, RT only, and RP only, respectively, who had a median follow-up period of 4.32 years were included in the study cohort. Compared with the patients treated with RP only, those who received ADT and RT were significantly at increased risk of subsequently developing hematologic disorders (ADT: adjusted hazard ratio [aHR]: 1.60, 95% confidence interval [CI]: 1.29-1.97; RT: aHR, 1.98, 95% CI: 1.62-2.42) according to the Cox regression analysis. Based on the Kaplan-Meier curve analysis, patients with bone metastasis who received ADT only had the lowest cumulative probabilities of not developing hematologic disorders. Moreover, a significantly increased risk of hematologic disorders was observed with the increasing duration of ADT (P for trend < .001). CONCLUSIONS: The use of ADT in patients with prostate cancer may increase the risk of subsequently developing hematologic disorders.

Cr(VI) induces ROS-mediated mitochondrial-dependent apoptosis in neuronal cells via the activation of Akt/ERK/AMPK signaling pathway.

Hexavalent chromium (Cr(VI)), a well-known toxic industrial and environmental pollutant, has been shown to cause serious toxic and health effects. However, limited information is available on Cr(VI)-induced neurotoxic potential, with the underlying toxicological mechanisms remain mostly unclear. The present study demonstrated that the mitochondria-dependent apoptosis pathway was involved in Cr(VI)-induced SH-SY5Y cell (the human neuroblastoma cell line) death, which was accompanied by the appearance of cell shrinkage, increased mitochondrial membrane potential (MMP) depolarization and cytochrome c release, and the activation of caspase cascades and poly (ADP-ribose) polymerase (PARP). Cr(VI) treatment also increased the generation of intracellular reactive oxygen species (ROS). Pretreatment of SH-SY5Y cells with antioxidant N-acetylcysteine (NAC) effectively attenuated ROS production and reversed these Cr(VI)-induced cytotoxicity and apoptotic responses. Furthermore, exposure to Cr(VI) significantly increased the phosphorylation levels of Akt, extracellular regulated kinase (ERK)1/2, and AMP-activated protein kinase (AMPK)α. NAC and the pharmacological inhibitor of Akt (LY294002), ERK1/2 (PD980590), and AMPKα (Compound C) markedly abrogated the Cr(VI)-induced activation of Akt, ERK1/2, and AMPKα signal, respectively, with the concomitant inhibition of mitochondrial dysfunction and caspase activation. Additionally, all these inhibitors suppressed Cr(VI)-induced phosphorylation of Akt, ERK1/2, and AMPKα and of each other. Collectively, these results suggest that Cr(VI) exerts its cytotoxicity on neuronal cells by inducing mitochondria-dependent apoptosis through the interdependent activation of Akt, ERK1/2, and AMPKα, which are mainly mediated by ROS generation.

Enzymatic degradation of ginkgolic acid by laccase immobilized on novel electrospun nanofiber mat.

BACKGROUND: Ginkgo biloba leaf extract contains many active ingredients that are beneficial for health. However, ginkgolic acid, one of the major components found in G. biloba extract, may cause serious allergic and toxic side effects. The purpose of this study is to immobilize the laccase system on the electrospun nylon fiber mat (NFM) to hydrolyze the ginkgolic acid in G. biloba leaf extract efficiently. RESULTS: Novel electrospinning technology successfully produced high-quality nanoscopic fiber mats made of a mixture of multi-walled carbon nanotube and nylon 6,6. Laccase that was immobilized onto the NFM exhibited much higher efficiency in the catalyzation of 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt (ABTS) than nylon 6,6 pellets. After being immobilized onto the NFM, the pH and temperature stability of laccase were significantly improved. The NFM-immobilized laccase could maintain more than 50% of its original activity even after 40 days of storage or 10 operational cycles. The kinetic parameters, including rate constant (K), the time (τ50) in which 50% of ginkgolic acid hydrolysis was reached, the time (τcomplete) required to achieve complete ginkgolic acid hydrolysis, Km and Vmax were determined, and were 0.07 ± 0.01 min-1 , 8.97 ± 0.55 min, 45.45 ± 2.79 min, 0.51 ± 0.09 mM and 0.49 ± 0.03 mM min-1 mg-1 , respectively. CONCLUSION: The result successfully demonstrated the strong potential of using novel electrospun nanofiber mats as enzyme immobilization platforms, which could significantly enhance enzyme activity and stability. © 2020 Society of Chemical Industry.