Synergic effect of combined xenogeneic mesenchymal stem cells and ceftriaxone on acute septic arthritis.

BACKGROUND: This study tested the hypothesis that combined ceftriaxone (Cef) and human umbilical cord-derived mesenchymal stem cells (HUCDMSCs) was better than either therapy for alleviating acute septic arthritis (ASA). METHODS AND RESULTS: Adult-male C57BL/6 mice were categorized into control group (Clt), group A (ASA only), group B [ASA + Cef (5 mg/kg, IM per day, at days 2 to 16 after ASA induction)], group C [ASA + HUCDMSCs (5 × 105 per mice at days 2, 3, 4 after ASA induction)], and group D (ASA + Cef + HUCDMSCs). Animals were euthanized by day 28. The result demonstrated that the body weight was significantly lower, whereas the ratio of kidney or spleen weight to WB, circulatory WBC count, bacterial colony-formation-unit from circulatory/kidney extraction were significantly higher in group A than in other groups (all P < .001). The proinflammatory cytokines (IL-6/TNF-α) of knee joint fluid were lowest in Clt and significantly and progressively reduced from groups A to D, whereas the circulatory levels of these 2 parameters at the time points of days 3/7/28 exhibited an identical pattern as knee joint fluid among the groups (all P-value < .0001). The scores of vertebral-bone destructions/inflamed synovium were lowest in Clt, highest in group A, significantly higher in group C than in groups B/D, and significantly higher in group C than in group D (all P < .0001). CONCLUSION: Combined antibiotics and Cef and HUCDMSCs was superior to just one therapy for suppressing circulatory and tissue levels of inflammation and knee joint destruction in ASA.

Cardiomyocyte-specific overexpression of GPR22 ameliorates cardiac injury in mice with acute myocardial infarction.

BACKGROUND: The activation of G protein-coupled receptors (GPCR) signaling by external stimuli has been implicated in inducing cardiac stress and stress responses. GPR22 is an orphan GPCR expressed in brains and hearts, while its expression level is associated with cardiovascular damage in diabetes. Previous studies have suggested a protective role of GPR22 in mechanical cardiac stress, as loss of its expression increases susceptibility to heart failure post-ventricular pressure overload. However, the involvement and underlying signaling of GPR22 in cardiac stress response to ischemic stress remains unexplored. METHODS: In this study, we used cultured cells and a transgenic mouse model with cardiomyocyte-specific GPR22 overexpression to investigate the impact of ischemic stress on GPR22 expression and to elucidate its role in myocardial ischemic injury. Acute myocardial infarction (AMI) was induced by left coronary artery ligation in eight-week-old male GPR22 transgenic mice, followed by histopathological and biochemical examination four weeks post-AMI induction. RESULTS: GPR22 expression in H9C2 and RL-14 cells, two cardiomyocyte cell lines, was decreased by cobalt chloride (CoCl2) treatment. Similarly, reduced expression of myocardial GPR22 was observed in mice with AMI. Histopathological examinations revealed a protective effect of GPR22 overexpression in attenuating myocardial infarction in mice with AMI. Furthermore, myocardial levels of Bcl-2 and activation of PI3K-Akt signaling were downregulated by ischemic stress and upregulated by GPR22 overexpression. Conversely, the expression levels of caspase-3 and phosphorylated ERK1/2 in the infarcted myocardium were downregulated with GPR22 overexpression. CONCLUSION: Myocardial ischemic stress downregulates cardiac expression of GPR22, whereas overexpression of GPR22 in cardiomyocytes upregulates Akt signaling, downregulates ERK activation, and mitigates ischemia-induced myocardial injury.

Trained immunity induced by high-salt diet impedes stroke recovery.

A high-salt diet (HSD) elicits sustained sterile inflammation and worsens tissue injury. However, how this occurs after stroke, a leading cause of morbidity and mortality, remains unknown. Here, we report that HSD impairs long-term brain recovery after intracerebral hemorrhage, a severe form of stroke, despite salt withdrawal prior to the injury. Mechanistically, HSD induces innate immune priming and training in hematopoietic stem and progenitor cells (HSPCs) by downregulation of NR4a family and mitochondrial oxidative phosphorylation. This training compromises alternative activation of monocyte-derived macrophages (MDMs) without altering the initial inflammatory responses of the stroke brain. Healthy mice transplanted with bone marrow from HSD-fed mice retain signatures of reduced MDM reparative functions, further confirming a persistent form of innate immune memory that originates in the bone marrow. Loss of NR4a1 in macrophages recapitulates HSD-induced negative impacts on stroke outcomes while gain of NR4a1 enables stroke recovery in HSD animals. Together, we provide the first evidence that links HSD-induced innate immune memory to the acquisition of persistent dysregulated inflammatory responses and unveils NR4a1 as a potential therapeutic target.

Incidence, prescription patterns and risk factors of antipsychotic initiation in elderly stroke survivors.

OBJECTIVES: Epidemiological data regarding antipsychotic initiation in elderly patients with stroke are limited. We aimed to investigate the incidence, prescription patterns and determinants of antipsychotic initiation in elderly patients with stroke. METHODS: We conducted a retrospective cohort study to identify patients aged above 65 years who had been admitted for stroke from the National Health Insurance Database (NHID). The index date was defined as the discharge date. The incidence and prescription pattern of antipsychotics were estimated using the NHID. To evaluate the determinants of antipsychotic initiation, the cohort identified from the NHID was linked to the Multicenter Stroke Registry (MSR). Demographics, comorbidities and concomitant medications were obtained from the NHID. Information including smoking status, body mass index, stroke severity and disability was retrieved by linking to the MSR. The outcome was antipsychotic initiation after the index date. Hazard ratios for antipsychotic initiation were estimated using the multivariable Cox model. RESULTS: In terms of prognosis, the first 2 months after a stroke was the highest-risk period for antipsychotic use. A high burden of coexisting diseases carried an increased risk of antipsychotic use; in particular, chronic kidney disease (CKD) had the highest adjusted hazard ratio (aHR = 1.73; 95% CI 1.29-2.31) as compared with other risk factors. Furthermore, stroke severity and disability were significant risk factors for antipsychotic initiation. CONCLUSIONS: Our study indicated that elderly stroke patients with chronic medical conditions, particularly CKD, and a higher stroke severity and disability were at greater risk of psychiatric disorders during the first 2 months after a stroke. CLINICAL TRIAL REGISTRATION: NA.

HSD3B1 Expression Is Upregulated by Interleukin 4 in HT-29 Colon Cancer Cells via Multiple Signaling Pathways.

3ß-Hydroxysteroid dehydrogenase/isomerase is essential for the synthesis of active steroid hormones. Interleukin 4 (IL4) induces the expression of HSD3B1 in various human cancer cell lines. Here, we demonstrated that administration of IL4 to an HT-29 colon cancer cell line induced high expression of HSD3B1 at the mRNA and protein levels. In the HT-29 cells, IL4 stimulated the activity of signal transducer and activator of transcription 6 (STAT6) and promoted its binding to the STAT6-binding site in the HSD3B1 promoter. The STAT6 inhibitor significantly suppressed HSD3B1 induction by IL4 in a dose-dependent manner. Moreover, inhibition of the PI3-kinase/AKT pathway strongly suppressed the IL4-induced HSD3B1 expression. Glycogen synthase kinase 3 (GSK3), a downstream target of AKT, had a stimulatory effect on the IL4-induced HSD3B1 expression. However, IL4 stimulated the phosphorylation of AKT, which inhibited the GSK3 activity at the early stage. Hence, GSK3 potentiated the HSD3B1 levels at the late stage of the IL4 stimulation. Additionally, inhibitors of mitogen-activated protein kinases (MAPKs), ERK1/2 and p38, but not of JNK, partly reduced the HSD3B1 expression following the IL4 stimulation. We further demonstrated that IL4 potently promoted steroid synthesis. Our results indicate that IL4 induces HSD3B1 expression via multiple signaling pathways in HT-29 cells and may play a role in the regulation of steroid synthesis.

Comparison of afatinib and erlotinib combined with bevacizumab in untreated stage IIIB/IV epidermal growth factor receptor-mutated lung adenocarcinoma patients: a multicenter clinical analysis study.

Background: Although bevacizumab in combination with afatinib or erlotinib is an effective and safe first-line therapy for advanced epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC), there are very few clinical data comparing afatinib and erlotinib combined with bevacizumab. We performed a retrospective multicenter analysis for the comparison of two combination therapies. Methods: Between May 2015 and October 2020, data of 135 stage IIIB/IV EGFR-mutated NSCLC patients receiving first-line afatinib or erlotinib combined with bevacizumab combination therapy in Linkou, Keelung, Chiayi, and Kaohsiung Chang Gung Memorial Hospitals were retrieved and retrospectively analyzed. Results: In all, 67 patients received afatinib plus bevacizumab, and 68 patients received erlotinib plus bevacizumab. Afatinib combined with bevacizumab had an objective response rate (ORR) of 82.1% and a disease control rate (DCR) of 97.0%, and the ORR and DCR were 83.8 and 95.6%, respectively, in the erlotinib combined with bevacizumab group (p = 0.798 and p = 1.000). The median progression-free survival was 20.7 and 20.3 months for the afatinib plus bevacizumab group and the erlotinib plus bevacizumab group, respectively [hazard ratio (HR) = 1.02; 95% confidence interval (CI), 0.891-1.953; p = 0.167). The overall survival was 41.9 and 51.0 months for the afatinib plus bevacizumab group and erlotinib plus bevacizumab group, respectively (HR = 1.42; 95% CI, 0.829-2.436; p = 0.201). The secondary EGFR-T790M mutation rates after disease progression were 44% in the afatinib plus bevacizumab group and 58.8% in the erlotinib plus bevacizumab group (p = 0.165). Skin toxicity was the most frequent treatment-related adverse event (AE) in both treatment groups. Diarrhea, an AE, occurred significantly more frequently in the afatinib plus bevacizumab group than in the erlotinib plus bevacizumab group (p < 0.05). Conclusion: Afatinib combined with bevacizumab was equally as effective as erlotinib combined with bevacizumab for untreated advanced EGFR-mutated NSCLC. Prospective clinical studies that explore bevacizumab combined with afatinib or erlotinib for advanced EGFR-mutated NSCLC are warranted.

Dose-dependent benefits of iron-magnetic nanoparticle-coated human umbilical-derived mesenchymal stem cell treatment in rat intracranial hemorrhage model.

BACKGROUND: This study tested whether two doses of human umbilical-derived mesenchymal stem cells (hUC-MSCs) were superior to one dose for protecting the brain against intracranial hemorrhage (ICH) induced by intracranial injection collagenase and the capacity of ironic-magnetic-nanoparticles (Ir-MNa) coated hUC-MSCs tracked by MRI. METHODS AND RESULTS: Adult male SD rats (n = 40) were equally categorized into group 1 (sham-operated-control), group 2 (ICH), group 3 [ICH + Ir-MNa-coated hUC-MSCs/1.2 × 106 cells with an extracorporeal magnet over rat head (eCMag)/administered by left internal carotid artery (LICA) at post-3 h ICH], and group 4 (ICH + Ir-MNa-coated hUC-MSCs/1.2 × 106 cells with an eCMag/administered post-3 h ICH by LICA and 24 h by IV) and euthanized by day 28. The result showed that by day 28 after ICH induction the neurological function was severely impaired in group 2 than in group 1 that was significantly improved in group 3 and further significantly improved in group 4, whereas ICH volume exhibited an opposite pattern of neurological impairment among the groups (all p < 0.0001). Brain MRI demonstrated that by 4 h after ICH, Ir-MNa-coated hUC-MSCs were abundantly identified in ischemic area in group 4. The protein expressions of inflammatory (TNF-α/MMP-9/IL-1ß/iNOS)/oxidative-stress (NOX-1/NOX-2/oxidized protein)/apoptotic (caspase-3/mitochondrial Bax/PARP)/fibrotic (Smad3/TGF-ß)/mitochondrial-damaged (cytosolic-cytochrome-C) biomarkers displayed an identical pattern of neurological impairment among the groups (all p < 0.0001). The cellular expressions of inflammation (CD68+/CD11b+)/brain edema (AQP4+) biomarkers exhibited an identical pattern, whereas the neuronal-myelin (Doublecortin+/NeuN/nestin) biomarkers displayed an opposite pattern of neurological impairment (all p < 0.0001). CONCLUSION: Two doses of hUC-MSCs were superior to just one dose for protecting the brain against ICH-induced damage and Ir-MNa-coated hUC-MSCs offered a well adopted method for tracking hUC-MSCs homing into the brain.

Combined levosimendan and Sacubitril/Valsartan markedly protected the heart and kidney against cardiorenal syndrome in rat.

BACKGROUND: Cardiorenal syndrome (CRS) remains the leading cause of death in hospitalized patients for all disease entities. Sacubitril/Valsartan (Sac/Val) therapy has been proved to improve prognostic outcome in patients with heart failure or chronic kidney disease. This study tested the hypothesis that combined levosimendan and Sac/Val was superior to just one therapy on protecting the heart and kidney against simultaneous heart and kidney ischemia (I) (for 50-min)-reperfusion (R) (for 7-days) (i.e., double IR) injury (defined as CRS). METHODS AND RESULTS: Adult-male Spraque-Dawley rats (n = 40) were equally categorized into group 1 (sham-operated control), group 2 (double IR), group 3 [double IR+levosimendan (10 mg/kg by intra-peritoneum administration at 30 min/followed by days 1-5 once daily after IR procedure)], group 4 [double IR+Sac/Val (10 mg/kg, orally at 30 min/followed by days 1-5 twice daily after IR procedure)], and group 5 (double IR+Sac/Val+levosimendan). By day 7 after double-IR, the left-ventricular-ejection fraction (LVEF)/left-ventricular-fraction-shortening (LVFS) were highest in group 1, lowest in group 2 and significantly higher in group 5 than in groups 3/4, but they showed no difference between groups 3/4, whereas the circulatory heart-failure (brain-natriuretic peptide)/proinflammatory (suppression of tumorigenicity-2) biomarkers, blood-urea-nitrogen/creatinine and ratio of urine protein to creatinine (all p < 0.0001) exhibited an opposite pattern of LVEF among the groups. The protein expressions of inflammatory (tumor necrosis factor-α/interleukin-1ß/matrix metalloproteinase-9)/oxidative-stress (NOX-1/NOX-2/NOX-4)/apoptotic (mitochondrial-Bax/caspase-3/poly-(ADP-ribose)-polymerase)/fibrotic (Smad3/transforming growth factor-ß)/mitochondrial-damaged (cytosolic-cytochrome-C)/myocardial-hypertrophic (ß-MHC) biomarkers in LV myocardium exhibited an opposite pattern of LVEF among the groups (all p < 0.0001). The cellular expressions of inflammatory (CD68)/DNA-damaged (γ-H2AX) biomarkers and infarct/fibrotic areas in LV myocardium and kidney displayed an opposite pattern of LVEF among the groups (all p < 0.0001). CONCLUSION: Combined levosimendan and Sac/Val was superior to merely one therapy on protecting the heart and kidney as well as preserving their functions against double IR injury.

Melatonin and hyperbaric oxygen therapies suppress colorectal carcinogenesis through pleiotropic effects and multifaceted mechanisms.

Colorectal cancer (CRC) is the third most common cancer worldwide. Colorectal carcinogenesis is frequently induced by hypoxia to trigger the reprogramming of cellular metabolism and gain of malignant phenotypes. Previously, hyperbaric oxygen (HBO) therapy and melatonin have been reported to alter the hypoxic microenvironment, resulting in inhibiting cancer cell survival. Accordingly, this study tested the hypothesis whether HBO and melatonin effectively inhibited CRC carcinogenesis. In vitro results indicated that melatonin therapy significantly suppressed the malignant phenotypes, including colony formation, growth, invasion, migration and cancer stemness with dose-dependent manners in CRC cell lines through multifaceted mechanisms. Similar to in vitro study, in vivo findings further demonstrated the melatonin, HBO and combined treatments effectively promoted apoptosis (cleaved-caspase 3/ cleaved-PARP) and arrested tumor proliferation, followed by inhibiting colorectal tumorigenesis in CRC xenograft tumor model. Moreover, melatonin, HBO and combined treatments modulated multifaceted mechanisms, including decreasing HIF-1α expression, alleviating AKT activation, repressing glycolytic metabolism (HK-2/PFK1/PKM2/LDH), restraining cancer stemness pathway (TGF-ß/p-Smad3/Oct4/Nanog), reducing inflammation (p-NFκB/ COX-2), diminishing immune escape (PD-L1), and reversing expression of epithelial mesenchymal transition (E-cadherin/N-cadherin/MMP9). In conclusion, melatonin and HBO therapies suppressed colorectal carcinogenesis through the pleiotropic effects and multifaceted mechanisms, suggesting melatonin and HBO treatments could be novel therapeutic strategies for CRC treatment.

Additional benefit of induced pluripotent stem cell-derived mesenchymal stem cell therapy on sepsis syndrome-associated acute kidney injury in rat treated with antibiotic.

BACKGROUND: This study tested whether human induced-pluripotent stem-cell-derived mesenchymal-stem-cells (iPS-MSCs) would offer an additional benefit to the rodent with acute kidney injury (AKI) (ischemia for 1 h followed by reperfusion for 120 h) associated sepsis syndrome (SS) (by cecal-ligation-puncture immediately after AKI-induction) undergoing ciprofloxacin therapy. RESULTS: Male-adult SD rats (n = 80) were categorized into group 1 (sham-operated-control, n = 10), group 2 (AKI + SS, n = 24), group 3 (AKI + SS + ciprofloxacin/3 mg/kg, orally for 120 h, n = 12), group 4 (AKI + SS + iPS-MSCs/1.2 × 106/intravenously administered by 3 h after AKI, n = 12), group 5 (AKI + SS + iPS-MSCs/1.2 × 106/intravenously administered by 18 h after AKI, n = 12), group 6 (AKI + SS + iPS-MSCs/1.2 × 106/intravenously administered by 3 h after AKI induction + ciprofloxacin, n = 10] and euthanized by 120 h. The result showed that the mortality was significantly higher in group 2 than in other groups (all p < 0.01). The creatinine level was highest in group 2, lowest in group 1, significantly lower in group 6 than in groups 3, 4 and 5, (all p < 0.0001), but it showed no difference among the latter 3 groups. Flow cytometric analysis showed that the circulatory inflammatory cells (Ly6G/CD11b/c), early (AN-V+/PI-)/late (AN-V+/PI+) apoptosis, and circulatory/splenic immune cells (CD3+/CD4+, CD3+/CD8a+) were highest in group 2, lowest in group 1, significantly lower in group 6 than in groups 3/4/5 and significantly lower in group 4 than in groups 3/5 (all p < 0.0001), but they showed no difference between groups 3/5. Protein expressions of oxidative-stress (NOX-1/NOX2/oxidized protein), apoptotic (cleaved-caspase3/cleaved-PARP/mitochondrial-Bax), fibrotic (TGF-ß/Smad3), inflammatory (MMP-9/IL-6/TNF-α) and autophagic (Atg5/Beclin) biomarkers in kidney exhibited an identical pattern of circulatory inflammatory cells (all p < 0.0001). CONCLUSION: Combined iPS-MSCs-ciprofloxacin therapy was superior to either one alone for protecting AKI complicated by SS.

Developing a Prediction Model for 7-Year and 10-Year All-Cause Mortality Risk in Type 2 Diabetes Using a Hospital-Based Prospective Cohort Study.

Leveraging easily accessible data from hospitals to identify high-risk mortality rates for clinical diabetes care adjustment is a convenient method for the future of precision healthcare. We aimed to develop risk prediction models for all-cause mortality based on 7-year and 10-year follow-ups for type 2 diabetes. A total of Taiwanese subjects aged ≥18 with outpatient data were ascertained during 2007-2013 and followed up to the end of 2016 using a hospital-based prospective cohort. Both traditional model selection with stepwise approach and LASSO method were conducted for parsimonious models' selection and comparison. Multivariable Cox regression was performed for selected variables, and a time-dependent ROC curve with an integrated AUC and cumulative mortality by risk score levels was employed to evaluate the time-related predictive performance. The prediction model, which was composed of eight influential variables (age, sex, history of cancers, history of hypertension, antihyperlipidemic drug use, HbA1c level, creatinine level, and the LDL /HDL ratio), was the same for the 7-year and 10-year models. Harrell's C-statistic was 0.7955 and 0.7775, and the integrated AUCs were 0.8136 and 0.8045 for the 7-year and 10-year models, respectively. The predictive performance of the AUCs was consistent with time. Our study developed and validated all-cause mortality prediction models with 7-year and 10-year follow-ups that were composed of the same contributing factors, though the model with 10-year follow-up had slightly greater risk coefficients. Both prediction models were consistent with time.

Memantine Protects against Paclitaxel-Induced Cognitive Impairment through Modulation of Neurogenesis and Inflammation in Mice.

Chemotherapy-induced cognitive impairment (CICI) is an adverse side effect of cancer treatment with increasing awareness. Hippocampal damage and related neurocognitive impairment may mediate the development of CICI, in which altered neurogenesis may play a role. In addition, increased inflammation may be related to chemotherapy-induced hippocampal damage. Memantine, an uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist that may enhance neurogenesis and modulate inflammation, may be useful for treating CICI. To test this hypothesis, paclitaxel was administered to eight-week-old male B6 mice to demonstrate the relationship between CICI and impaired neurogenesis, and then, we evaluated the impact of different memantine regimens on neurogenesis and inflammation in this CICI model. The results demonstrated that both the pretreatment and cotreatment regimens with memantine successfully reversed impaired neurogenesis and spatial memory impairment in behavior tests. The pretreatment regimen unsuccessfully inhibited the expression of peripheral and central TNF-α and IL-1ß and did not improve the mood alterations following paclitaxel treatment. However, the cotreatment regimen led to a better modulatory effect on inflammation and restoration of mood disturbance. In conclusion, this study illustrated that impaired neurogenesis is one of the mechanisms of paclitaxel-induced CICI. Memantine may serve as a potential treatment for paclitaxel-induced CICI, but different treatment strategies may lead to variations in the treatment efficacy.

Comparative safety of antipsychotic medications in elderly stroke survivors: A nationwide claim data and stroke registry linkage cohort study.

BACKGROUND: Antipsychotics remain the first choice of treatment for post-stroke psychosis, despite an increased risk of mortality reported in elderly patients. We aimed to compare the mortality risk among antipsychotics in elderly patients with stroke using the stroke registry for external adjustment. METHODS: We conducted a retrospective cohort study to identify patients aged above 65 years who were admitted for stroke in the National Health Insurance Database (NHID) from 2002 to 2014. The first date of antipsychotic use after the stroke hospitalization was defined as the index date. Covariates including diseases, medications and external information on smoking, BMI, stroke severity and disability, that were unavailable in the NHID were obtained from the linked Multicenter Stroke Registry (MSR) and used for propensity score calibration (PSC). The main outcome was one-year all-cause mortality. RESULTS: Stroke patients in the NHID prescribed with haloperidol, quetiapine and risperidone numbered 22,235, 28,702 and 8 663, respectively. In the PSC-adjusted analyses, haloperidol [adjusted hazard ratio (aHR) = 1.22; 95% CI 1.18-1.27] and risperidone (aHR = 1.31; 95% CI 1.24-1.38) users had a higher mortality risk than quetiapine users. When the dosage was higher than 0.5 defined daily dose (DDD), haloperidol and risperidone users had a significant mortality risk as compared with those taking a lower dose. CONCLUSIONS: In post-stroke elderly patients, quetiapine would pose less mortality risk than risperidone and haloperidol at doses higher than 0.5 DDD. When haloperidol or risperidone is indicated, starting with a lower dose is suggested to avoid excess risk.

A Real-World Analysis of Patients with Untreated Metastatic Epidermal Growth Factor Receptor (EGFR)-Mutated Lung Adenocarcinoma Receiving First-Line Erlotinib and Bevacizumab Combination Therapy.

INTRODUCTION: The clinical features of patients with metastatic epidermal growth factor receptor (EGFR)-mutated lung adenocarcinoma receiving first-line therapy based on erlotinib combined with bevacizumab are unclear. Here, we sought to analyze the clinical features of this patient group. METHODS: Data were analyzed for the period from January 2015 to August 2019 for 49 patients with metastatic EGFR-mutated lung adenocarcinoma receiving first-line erlotinib-and-bevacizumab combination therapy from the Linkou and Kaohsiung Chang Gung Memorial Hospitals. RESULTS: The combination of erlotinib and bevacizumab showed an 83.7% objective response rate and a 97.9% disease control rate. The median progression-free survival (PFS) and overall survival (OS) were 22.0 [95% CI (19.7-22.33)] and 47.6 [95% CI (38.87-56.37)] months, respectively, for all patients. The secondary EGFR-T790M mutation rate in the patients with acquired resistance to the combination was 72.4%. No predictive factor associated with the appearance of secondary EGFR-T790M mutations was found. The most frequent adverse event (AE) caused by the combination therapy was dermatitis (100%), and most of the AEs were manageable and grades 1 and 2. CONCLUSION: Erlotinib combined with bevacizumab is an effective and safe therapy for untreated metastatic EGFR-mutated lung adenocarcinoma. The combination does not alter secondary EGFR-T790M mutations in patients with acquired resistance and is feasible in real-world clinical practice.

Synergic effect of combined cyclosporin and melatonin protects the brain against acute ischemic reperfusion injury.

BACKGROUND: This study tested whether combined cyclosporin-A (CsA) and melatonin (Mel) was superior to either one on protecting the brain against ischemia (occluded left-middle-cerebral-artery for 90-min)-reperfusion (for 14 days) injury. METHODS AND RESULTS: Neuro-2a cells (N2a) were categorized into groups 1 (N2a), 2 (N2a-IR), 3 (N2a-IR-Mel), 4 (N2a-IR-CsA) and 5 (N2a-IR-CsA-Mel). in vitro results showed the protein expressions of cytosolic-cytochrome-C/mitochondrial-Bax/cleaved-capase-3/NOX-1/NOX-2 and flow-cytometric results of ROS (DCFDA/Mito-SOX) were highest in group 2, lowest in group 1, significantly lower in group 5 than in groups 3/4, but they showed no difference in groups 3/4 (all p < 0.001). Male-adult-SD rats (50) were equally categorized into groups 1 (sham-operated-control), 2 (IR), 3 (IR-CsA/20.0 mg/kg at 0.5/24/48 h intraperitoneally after IR), 4 (IR-Mel/50.0 mg/kg intraperitoneally at 30 min and 30 mg/kg at 6/24/48 h after IR) and 5 (IR-CsA-Mel). The brain-infarct-area (BIA) (at day-3 by TTC-stain) was lowest in group 1, highest in group 2, significantly lower in group 5 than groups 3/4, but it showed no difference between groups 3/4 whereas the brain-infarct-volume (at day 14 by MRI) was similar as BIA except for significantly lower in group 4 than in group 3 (all p < 0.0001). By day 14, microscopic finding showed the numbers of glial+/GFAP+/AQP + cells expressed an identical trend whereas the number of NeuN + cells exhibited an opposite pattern of BIA among the groups (all p < 0.0001). The protein expressions of oxidative-stress (NOX-1/NOX-2/p22phox/oxidized-protein), inflammatory (TNF-α/p-NF-κB/MMP-9), apoptotic (mitochondrial-Bax/caspase-3/PARP) and mitochondrial-damaged (Cyclophilin-D/DRP1/cytosolic-cytochrome-C) biomarkers displayed an identical pattern of BIA among the five groups (all p < 0.0001). CONCLUSION: Combined CsA-Mel was superior to either CsA or Mel on protecting the brain against IR injury.

Smoking Paradox in Stroke Survivors?: Uncovering the Truth by Interpreting 2 Sets of Data.

Background and Purpose- The observation that smokers with stroke could have better outcome than nonsmokers led to the term "smoking paradox." The controversy of such a complex claim has not been fully settled, even though different case mix was noted. Analyses were conducted on 2 independent data sets to evaluate and determine whether such a paradox truly exists. Methods- Taiwan Stroke Registry with 88 925 stroke cases, and MJ cohort with 541 047 adults participating in a medical screening program with 1630 stroke deaths developed during 15 years of follow-up (1994-2008). Primary outcome for stroke registry was functional independence at 3 months by modified Rankin Scale score ≤2, for individuals classified by National Institutes of Health Stroke Scale score at admission. For MJ cohort, mortality risk by smoking status or by stroke history was assessed by hazard ratio. Results- A >11-year age difference in stroke incidence was found between smokers and nonsmokers, with a median age of 60.2 years for current smokers and 71.6 years for nonsmokers. For smokers, favorable outcome in mortality and in functional assessment in 3 months with modified Rankin Scale score ≤2 stratified by the National Institutes of Health Stroke Scale score was present but disappeared when age and sex were matched. Smokers without stroke history had a ≈2-fold increase in stroke deaths (2.05 for ischemic stroke and 1.53 for hemorrhagic stroke) but smokers with stroke history, 7.83-fold increase, overshadowing smoking risk. Quitting smoking at earlier age reversed or improved outcome. Conclusions- "The more you smoke, the earlier you stroke, and the longer sufferings you have to cope." Smokers had 2-fold mortality from stroke but endured stroke disability 11 years longer. Quitting early reduced or reversed the harms.

Accumulation and phytotoxicity of perfluorooctanoic acid and 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)propanoate in Arabidopsis thaliana and Nicotiana benthamiana.

2,3,3,3-Tetrafluoro-2-(heptafluoropropoxy)propanoate (known as GenX) has been used as an alternative to perfluorooctanoic acid (PFOA) which was phased out of formulations for industrial and consumer product applications in 2015. While the effects of GenX on lab animals have been studied, little is known about its effects on plants. This study examined and compared the accumulation and toxicity of GenX and PFOA in the model plants Arabidopsis thaliana and Nicotiana benthamiana. Both plants showed reduction in biomass and root growth following exposure to PFOA or GenX in a dosage-dependent manner. The bioaccumulation factors (BFs) of GenX and PFOA were plant species-dependent, with higher BFs in A. thaliana compared to N. bethanminana. Additionally, GenX and PFOA were more readily accumulated into shoot tissues of A. thaliana than in N. bethanminana. Exposure to GenX also caused a reduction in chlorophyll content (18%) and total phenolic compounds (26%). However, GenX exposure increased superoxide dismutase activity and H2O2 content (1.6 and 2.6 folds increase, respectively) in N. benthamiana. Overall, our result suggest that GenX is bioaccumulative, and that its accumulation likely inhibits plant growth and photosynthesis as well as inducing oxidative stress.

Oral vinorelbine plus cisplatin with concomitant radiotherapy as induction therapy for stage III non-small cell lung cancer: Results of a single-arm prospective cohort study.

BACKGROUND: Concurrent chemoradiotherapy (CCRT) is an optimal recommended treatment for stage III non-small cell lung cancer (NSCLC). Herein, we aimed to investigate the efficacy and safety of oral vinorelbine plus cisplatin with concomitant radiotherapy for stage III NSCLC. METHODS: This prospective, open-label, single-arm, observational cohort study was performed between January 2010 and September 2016. Patients were treated with two cycles of chemotherapy with 60 mg/m2 intravenous cisplatin on day 1 and 50 mg/m2 oral vinorelbine on days 1, 8, and 15; radiotherapy was administered concurrently from day 1 when chemotherapy was initiated. A total dose of 66-70 Gy radiotherapy was delivered in daily fractions of 2 Gy for 6.5-7 consecutive weeks. The tumor response was assessed after completing concomitant treatment. RESULTS: A total of 58 patients were enrolled and analyzed; 31 patients had stage IIIA NSCLC and 27 had stage IIIB NSCLC. After induction CCRT, 31 patients achieved an objective response (complete response in one and partial response in 30; the response rate was 53.4%). The median progression-free survival was 6.73 months (95% confidence interval [CI], 5.42-7.91), duration of response was 12.30 months (95% CI, 5.59-19.01), and overall survival was 24.83 months (95% CI, 19.26-30.21). No treatment-related mortality was observed, and neutropenia was the most common grade 3 and 4 treatment-related toxicity (11 patients; 18.9%). CONCLUSIONS: CCRT with the weekly regimen of oral vinorelbine plus triweekly cisplatin was effective and safe for stage III NSCLC.

The training in SHARE communication course by physicians increases the signing of do-not-resuscitate orders for critical patients in the emergency room (cross-sectional study).

BACKGROUND: Communication skills may be an important skill for the front-line emergency physicians. AIM: This study aimed to investigate the effect of training in a SHARE communication course by emergency physicians on patient notification and signing of do-not-resuscitate (DNR) orders for critical patients in the emergency room. DESIGN: From a total of 29 attending physicians in the emergency department, 19 physicians had been trained in the SHARE communication course. An observation form designed based on the SHARE training was completed by two observers who noted the communication process between physicians and patients and family members during patient notification and signing a DNR order. To assess the influence of physicians trained in a SHARE communication course on the signing of DNR orders, a propensity score-matched population was created to reduce the potential selection bias of patients and family members. SETTING: Level 1 trauma medical center in southern Taiwan. RESULTS: There were 145 individuals enrolled in the study, of which 93 signed the DNR order, and 52 did not sign it. Analysis from 23 matched pairs from this population revealed that significantly more family members would sign a DNR order if the physician had been trained in the SHARE communication course than when they did not receive this training (78.3% vs. 39.1%, respectively, p = 0.017). The overall score of the observation form for physicians was higher in those individuals who had signed a DNR order than in those who did not sign it (29.48 ±â€¯3.72 vs. 26.13 ±â€¯3.52, respectively, p = 0.003), especially when the physician had chosen a quiet environment (1.35 ±â€¯0.65 vs. 0.87 ±â€¯0.69, respectively, p = 0.020), understood the patient's wishes and confirmed them (1.78 ±â€¯0.42 vs. 1.30 ±â€¯0.70, respectively, p = 0.008), and expressed concern (1.48 ±â€¯0.79 vs. 0.96 ±â€¯0.77, respectively, p = 0.028). In addition, a feedback survey about the feelings experienced by these physicians during the process of patient notification did not reveal a significant difference during the communication with those who had or had not signed DNR orders. CONCLUSION: The training in a SHARE communication course can improve the communication skills of emergency physicians in patient notification and signing of DNR orders for critical patients.

Diagnostic pitfalls and therapeutic outcomes of the macrofollicular variant of papillary thyroid carcinoma.

BACKGROUND: The macrofollicular variant of papillary thyroid cancer (MFVPTC) is a rare histological variant of papillary thyroid cancer (PTC), with only 71 cases reported through 2014. This study analyzed the clinical, preoperative thyroid ultrasonography (US), and fine needle aspiration cytology (FNAC) features; and therapeutic outcomes of 11 patients with MFVPTC. METHODS: The records of 393 patients with histologically diagnosed follicular variant of papillary thyroid carcinoma (FVPTC), including 11 with MFVPTC, were retrospectively reviewed. Preoperative thyroid US findings, clinical presentation, treatment outcomes, and survival rates were analyzed. RESULT: Mean tumor size was significantly greater in patients with MFVPTC than that in those with FVPTC (4.2 ± 2.1 cm vs. 2.9 ± 1.7 cm; p = 0.016). No patient with MFVPTC had lymph node involvement, but one had a micrometastasis to the lung, which responded well to therapeutic radioiodine. All MFVPTC lesions were isoechoic on US. Eight nodules had calcifications and eight had irregular margins. FNAC showed that these tumors had low cellularity, absence or focal presence of enlarged clear nuclei, and subtle or focal nuclear features of PTC. Cells were, arranged in microfollicular pattern, with abundant colloid background. Multifocal PTCs were detected in the opposite lobe of two patients. All 11 patients with MFVPTC had excellent outcomes. No patient experienced recurrence, and survival rates were high. CONCLUSIONS: Malignant US criteria combined with FNAC features have a low preoperative diagnostic rate for MFVPTC. Surgery is recommended for patients with thyroid nodules larger than 4 cm and those with subtle and focal atypical nuclei in FNAC.