Omega-3 Fatty Acid-Enriched Fish Oil and Selenium Combination Modulates Endoplasmic Reticulum Stress Response Elements and Reverses Acquired Gefitinib Resistance in HCC827 Lung Adenocarcinoma Cells.

Non-small cell lung cancer (NSCLC)-carrying specific epidermal growth factor receptor (EGFR) mutations can be effectively treated by a tyrosine kinase inhibitor such as gefitinib. However, the inevitable development of acquired resistance leads to the eventual failure of therapy. In this study, we show the combination effect of omega-3 fatty acid-enriched fish oil (FO) and selenium (Se) on reversing the acquired gefitinib-resistance of HCC827 NSCLC cells. The gefitinib-resistant subline HCC827GR possesses lowered proapoptotic CHOP (CCAAT/enhancer-binding protein homologous protein) and elevated cytoprotective GRP78 (glucose regulated protein of a 78 kDa molecular weight) endoplasmic reticulum (ER) stress response elements, and it has elevated ß-catenin and cyclooxygenase-2 (COX-2) levels. Combining FO and Se counteracts the above features of HCC827GR cells, accompanied by the suppression of their raised epithelial-to-mesenchymal transition (EMT) and cancer stem markers, such as vimentin, AXL, N-cadherin, CD133, CD44, and ABCG2. Accordingly, an FO and Se combination augments the gefitinib-mediated growth inhibition and apoptosis of HCC827GR cells, along with the enhanced activation of caspase -3, -9, and ER stress-related caspase-4. Intriguingly, gefitinib further increases the elevated ABCG2 and cancer stem-like side population in HCC827GR cells, which can also be diminished by the FO and Se combination. The results suggest the potential of combining FO and Se in relieving the acquired resistance of NSCLC patients to targeted therapy.

Enantio- and Diastereoselective Hydrofluorination of Enals by N-Heterocyclic Carbene Catalysis.

In contrast to well-established asymmetric hydrogenation reactions, enantioselective protonation is an orthogonal approach for creating highly valuable methine chiral centers under redox-neutral conditions. Reported here is the highly enantio- and diastereoselective hydrofluorination of enals by an asymmetric ß-protonation/α-fluorination cascade catalyzed by N-heterocyclic carbenes (NHCs). The two nucleophilic sites of a homoenolate intermediate, generated from enals and an NHC, are sequentially protonated and fluorinated. The results show that controlling the relative rates of protonation, fluorination, and esterification is crucial for this transformation, and can be accomplished using a dual shuttling strategy. Structurally diverse carboxylic acid derivatives with two contiguous chiral centers are prepared in a single step with excellent d.r. and ee values.

Enantioselective ß-Protonation of Enals via a Shuttling Strategy.

Remote asymmetric protonation is a longstanding challenge due to the small size of protons. Reactions involving electron-deficient olefins pose a further difficulty due to the electrophilic nature of these substrates. We report a shuttling system that delivers a proton in a highly enantioselective manner to the ß-carbon of enals using a chiral N-heterocyclic carbene (NHC) catalyst. Choices of a Brønsted base shuttle and a Brønsted acid cocatalyst are critical for highly stereoselective ß-protonation of the homoenolate intermediate and regeneration of the NHC catalyst results in functionalization of the carbonyl group. Thioesters with a ß-chiral center were prepared in a redox-neutral transformation with an excellent yield and ee.

Leptin OB3 peptide suppresses leptin-induced signaling and progression in ovarian cancer cells.

BACKGROUND: Obesity and its comorbidities constitute a serious health burden worldwide. Leptin plays an important role in diet control; however, it has a stimulatory potential on cancer cell proliferation. The OB3 peptide, a synthetic peptide, was shown to be more active than leptin in regulating metabolism but with no mitogenic effects in cancer cells. METHODS: In this study, we investigated the proliferative effects, gene expressions and signaling pathways modulated by leptin and OB3 in human ovarian cancer cells. In addition, an animal study was performed. RESULTS: Leptin, but not OB3, induced the proliferation of ovarian cancer cells. Interestingly, OB3 blocked the leptin-induced proliferative effect when it was co-applied with leptin. Both leptin and OB3 activated the phosphatidylinositol-3-kinase (PI3K) signal transduction pathway. In addition, leptin stimulated the phosphorylation of signal transducer and activator of transcription-3 (STAT3) Tyr-705 as well as estrogen receptor (ER)α, and the expression of ERα-responsive genes. Interestingly, all leptin-induced signal activation and gene expressions were blocked by the co-incubation with OB3 and the inhibition of extracellular signal-regulated kinase (ERK)1/2. Coincidently, leptin, but not OB3, increased circulating levels of follicle-stimulating hormone (FSH) which is known to play important roles in the initiation and proliferation of ovarian cancer cells. CONCLUSIONS: In summary, our findings suggest that the OB3 peptide may prevent leptin-induced ovarian cancer initiation and progression by disrupting leptin-induced proliferative signals via STAT3 phosphorylation and ERα activation. Therefore, the OB3 peptide is a potential anticancer agent that might be employed to prevent leptin-induced cancers in obese people.

Highly Enantioselective Aza-Michael Reaction between Alkyl Amines and ß-Trifluoromethyl ß-Aryl Nitroolefins.

The aza-Michael addition reaction is a vital transformation for the synthesis of functionalized chiral amines. Despite intensive research, enantioselective aza-Michael reactions with alkyl amines as the nitrogen donor have not been successful. We report the use of chiral N-heterocyclic carbenes (NHCs) as noncovalent organocatalysts to promote a highly selective aza-Michael reaction between primary alkyl amines and ß-trifluoromethyl ß-aryl nitroolefins. In contrast to classical conjugate-addition reactions, a strategy of HOMO-raising activation was used. Chiral trifluoromethylated amines were synthesized in high yield (up to 99 %) with excellent enantioselectivity (up to 98 % ee).

Risk for suicidal behaviors associated with alcohol and energy drink use in the US Army.

PURPOSE: Suicidal behaviors have increased in the US Army since 2005. To identify potential interventions for suicide risk, we examined the relationship between alcohol and energy drink use, independently and in combination, and rates of seriously considering and/or attempting suicide in US Army soldiers. METHODS: This study used the DoD Survey of Health Related Behaviors Among Active Duty Military Personnel (DoD HRB), which sampled 10,400 Army soldiers, with 5,927 responses representing 508,088 soldiers. Use of energy drinks in combination with alcohol (A/ED) and average daily amount of alcohol consumption over the past 30 days and history of seriously considering and/or attempting suicide in the past year were assessed via self-report questions. RESULTS: Six percent of Army service members reported either seriously considering and/or attempting suicide in the past year. Twenty-six percent of soldiers reported A/ED. Those who reported the highest level of alcohol use were more likely to have seriously considered and/or attempted suicide. Soldiers who reported daily A/ED were over three times more likely to have reported suicidal ideation or attempts, and even after adjusting for overall alcohol consumption and energy drink use alone remained approximately two times (OR = 1.99) more likely to report suicidality. CONCLUSIONS: Combination alcohol and energy drink use and heavy alcohol use contribute to suicidality and may be targets for potential intervention to address suicide risk.

Pd-Catalyzed cascade Heck cyclization/carbonylation of indoles with aryl formates: enantioselective construction of indolo[2,1-a]isoquinolines.

An efficient palladium-catalyzed cascade cyclization/carbonylation of indoles with aryl formates to access ester-functionalized indolo[2,1-a]isoquinoline scaffolds has been developed. In addition, an asymmetric variant is also achieved using a chiral phosphine ligand, affording the indolo[2,1-a]isoquinoline products in good yields and enantioselectivities.

The cancer marker neutrophil gelatinase-associated lipocalin is highly expressed in human endometrial hyperplasia.

Recently, endometrial hyperplasia was identified as presenting a higher risk for progressing to endometrial carcinoma more readily than adenomyosis. The Lcn-2 gene encodes neutrophil gelatinase-associated lipocalin (NGAL), which promotes cell proliferation and serves as a cancer marker in some cancers. In our current study, we investigated the relationship between the expression of NGAL and that of pathogenic cytokines and cancer-related genes including cyclooxygenase-2 (COX-2), E-cadherin, ß-catenin, and vimentin in patients with endometrial disorders. NGAL expression was examined by Western blotting, immunohistochemistry, and reverse-transcription polymerase chain reaction (RT-PCR) in hyperplasia and adenomyosis biopsy samples. Immunohistochemistry demonstrated the occurrence of NGAL in glandular epithelial cells but not in the stromal cells of hyperplasia biopsy samples. NGAL protein and mRNA expression were significantly greater in endometrial hyperplasia than in endometrial adenomyosis. Although our data showed no difference in pathogenic cytokines between patients with endometrial hyperplasia and endometrial adenomyosis, we observed high expression levels of COX-2, ß-catenin, vimentin, and E-cadherin in patients with endometrial hyperplasia. NGAL mRNA expression correlated positively with COX-2 and E-cadherin mRNA expression (r = 0.41 and r = 0.57, respectively), but correlated negatively with vimentin and ß-catenin mRNA expression (r = -0.42 and r = -0.61, respectively). Our data suggest that NGAL is up-regulated in patients with endometrial hyperplasia to prevent the transition from hyperplasia to carcinoma.

Pd-Catalyzed Cascade Intramolecular Heck Cyclization/Dearomatization of Indoles for the Construction of Two All-Carbon Quaternary Centers.

A facile Pd-catalyzed cascade of intramolecular Heck cyclization/alkylpalladium activated dearomatization of aryl alkyne-tethered indole is described. In this single step two nonadjacent all-carbon quaternary centers, two nitrogen-containing heterocycles, and three C(sp2)-C(sp3) bonds are efficiently furnished. These products could also undergo 5-to-6 ring migration-expansion reaction under Brønsted-acid conditions to transform into the benzo[c]carbazole skeletons.

Combinatorial Analysis of Circulating Biomarkers and Maternal Characteristics for Preeclampsia Prediction in the First and Third Trimesters in Asia.

We aim to establish a prediction model for pregnancy outcomes through a combinatorial analysis of circulating biomarkers and maternal characteristics to effectively identify pregnant women with higher risks of preeclampsia in the first and third trimesters within the Asian population. A total of two hundred and twelve pregnant women were screened for preeclampsia through a multicenter study conducted in four recruiting centers in Taiwan from 2017 to 2020. In addition, serum levels of sFlt-1/PlGF ratio, miR-181a, miR-210 and miR-223 were measured and transformed into multiples of the median. We thus further developed statistically validated algorithmic models by designing combinations of different maternal characteristics and biomarker levels. Through the performance of the training cohort (0.848 AUC, 0.73−0.96 95% CI, 80% sensitivity, 85% specificity, p < 0.001) and the validation cohort (0.852 AUC, 0.74−0.98 95% CI, 75% sensitivity, 87% specificity, p < 0.001) from one hundred and fifty-two women with a combination of miR-210, miR-181a and BMI, we established a preeclampsia prediction model for the first trimester. We successfully identified pregnant women with higher risks of preeclampsia in the first and third trimesters in the Asian population using the established prediction models that utilized combinatorial analysis of circulating biomarkers and maternal characteristics.

Responding to Repeated Disasters: Time to Recovery in Public Health Workers.

OBJECTIVE: In times of repeated disaster events, including natural disasters and pandemics, public health workers must recover rapidly to respond to subsequent events. Understanding predictors of time to recovery and developing predictive models of time to recovery can aid planning and management. METHODS: We examined 681 public health workers (21-72 y, M(standard deviation [SD]) = 48.25(10.15); 79% female) 1 mo before (T1) and 9 mo after (T2) the 2005 hurricane season. Demographics, trauma history, social support, time to recover from previous hurricane season, and predisaster work productivity were assessed at T1. T2 assessed previous disaster work, initial emotional response, and personal hurricane injury/damage. The primary outcome was time to recover from the most recent hurricane event. RESULTS: Multivariate analyses found that less support (T1; odds ratio [OR] = .74[95% confidence interval [CI] = .60-.92]), longer previous recovery time (T1; OR = 5.22[95%CI = 3.01-9.08]), lower predisaster work productivity (T1; OR = 1.98[95%CI = 1.08-3.61]), disaster-related personal injury/damage (T2; OR = 3.08[95%CI = 1.70-5.58]), and initial emotional response (T2; OR = 1.71[95%CI = 1.34-2.19]) were associated with longer recovery time (T2). CONCLUSIONS: Recovery time was adversely affected in disaster responders with a history of longer recovery time, personal injury/damage, lower work productivity following prior hurricanes, and initial emotional response, whereas responders with social support had shorter recovery time. Predictors of recovery time should be a focus for disaster preparedness planners.

Longitudinal Study of Hurricane Preparedness Behaviors: Influence of Collective Efficacy.

OBJECTIVE: Community characteristics, such as collective efficacy, a measure of community strength, can affect behavioral responses following disasters. We measured collective efficacy 1 month before multiple hurricanes in 2005, and assessed its association to preparedness 9 months following the hurricane season. METHODS: Participants were 631 Florida Department of Health workers who responded to multiple hurricanes in 2004 and 2005. They completed questionnaires that were distributed electronically approximately 1 month before (6.2005-T1) and 9 months after (6.2006-T2) several storms over the 2005 hurricane season. Collective efficacy, preparedness behaviors, and socio-demographics were assessed at T1, and preparedness behaviors and hurricane-related characteristics (injury, community-related damage) were assessed at T2. Participant ages ranged from 21-72 (M(SD) = 48.50 (10.15)), and the majority were female (78%). RESULTS: In linear regression models, univariate analyses indicated that being older (B = 0.01, SE = 0.003, P < 0.001), White (B = 0.22, SE = 0.08, P < 0.01), and married (B = 0.05, SE = 0.02, p < 0.001) was associated with preparedness following the 2005 hurricanes. Multivariate analyses, adjusting for socio-demographics, preparedness (T1), and hurricane-related characteristics (T2), found that higher collective efficacy (T1) was associated with preparedness after the hurricanes (B = 0.10, SE = 0.03, P < 0.01; and B = 0.47, SE = 0.04, P < 0.001 respectively). CONCLUSION: Programs enhancing collective efficacy may be a significant part of prevention practices and promote preparedness efforts before disasters.

Maternal and fetal outcomes of the pregnant woman with COVID-19: The first case report in Taiwan.

OBJECTIVE: A real-Taiwan experience to deal with near-term pregnant woman infected by severe acute respiratory syndrome coronavirus 2, SARS-CoV-2 (coronavirus disease 2019, COVID-19) is extremely limited. We described the first case in Taiwan. CASE REPORT: A 30-year-old woman, primigravida had a laboratory-confirmed COVID-19 infection at 36 gestational weeks (GW). She was asymptomatic. Ten days later, she was hospitalized and receive a selective cesarean section with a term baby weighted 3142 gm (Apgar score 8 and 9 at 1st and 5th minute, respectively) at 38 GW. No evidence of in utero and direct transmission was found and newborn was free of COVID-19. CONCLUSION: It is still uncertain whether timing or mode of delivery is appropriate in SARS-CoV-2 infected pregnant woman in near term, but we suggested that a selective delivery time at 38 GW or later, regardless of which mode of delivery is finally decided, can be considered.

Posttraumatic Stress Disorder and Mental Distress Following the 2004 and 2005 Florida Hurricanes.

OBJECTIVE: Community characteristics, such as perceived collective efficacy, a measure of community strength, can affect mental health outcomes following disasters. We examined the association of perceived collective efficacy with posttraumatic stress disorder (PTSD) and frequent mental distress (14 or more mentally unhealthy days in the past month) following exposure to the 2004 and 2005 hurricane seasons. METHODS: Participants were 1486 Florida Department of Health workers who completed anonymous questionnaires that were distributed electronically 9 months after the 2005 hurricane season. Participant ages ranged from 20 to 79 years (mean, 48; SD, 10.7), and the majority were female (79%), white (75%), and currently married (64%). Fifty percent had a BA/BS degree or higher. RESULTS: In 2 separate logistic regression models, each adjusted for individual sociodemographics, community socioeconomic characteristics, individual injury/damage, and community storm damage, lower perceived collective efficacy was significantly associated with a greater likelihood of having PTSD (OR, 0.93; 95% CI, 0.90-0.96), and lower collective efficacy was significantly associated with frequent mental distress (OR, 0.94; 95% CI, 0.92-0.96). CONCLUSIONS: Programs enhancing community collective efficacy may be a significant part of prevention practices and possibly lead to a reduction in the rate of PTSD and persistent distress postdisaster. (Disaster Med Public Health Preparedness. 2019;13:44-52).

Effect of Aerobic Exercise on Treg and Th17 of Rats with Ischemic Cardiomyopathy.

Immune activation and inflammation participate in the progression of chronic heart failure (CHF). Th17 cells and CD4+CD25+ regulatory T (Treg) cells both come from naive Th cells and share reciprocal development pathways but exhibit opposite effects. We hypothesized that the Th17/Treg balance was impaired in patients with CHF, and exercise can improve it. Rats with ischemic cardiomyopathy were prepared by ligaturing the left anterior descending branch of the left coronary artery. Rats in training group were trained with treadmill; Th17 cells increased significantly while Treg cells significantly decreased in s by flow cytometry, and the peripheral blood level of IL-6, IL-17, and TNF-α was obviously elevated by ELISA assay. We found that Th17/Treg balance is impaired in CHF rats, suggesting Th17/Treg imbalance potentially plays a role in the pathogenesis of CHF. Exercise can improve Th17/Treg imbalance, which also improves cardiac function of CHF.

Crosstalk between integrin αvß3 and ERα contributes to thyroid hormone-induced proliferation of ovarian cancer cells.

Ovarian cancer is the leading cause of death in gynecological diseases. Thyroid hormone promotes proliferation of ovarian cancer cells via cell surface receptor integrin αvß3 that activates extracellular regulated kinase (ERK1/2). However, the mechanisms are still not fully understood. Thyroxine (T4) at a physiologic total hormone concentration (10-7 M) significantly increased proliferating cell nuclear antigen (PCNA) abundance in these cell lines, as did 3, 5, 3'-triiodo-L-thyronine (T3) at a supraphysiologic concentration. Thyroid hormone (T4 and T3) treatment of human ovarian cancer cells resulted in enhanced activation of the Ras/MAPK(ERK1/2) signal transduction pathway. An MEK inhibitor (PD98059) blocked hormone-induced cell proliferation but not ER phosphorylation. Knock-down of either integrin αv or ß3 by RNAi blocked thyroid hormone-induced phosphorylation of ERK1/2. We also found that thyroid hormone causes elevated phosphorylation and nuclear enrichment of estrogen receptor α (ERα). Confocal microscopy indicated that both T4 and estradiol (E2) caused nuclear translocation of integrin αv and phosphorylation of ERα. The specific ERα antagonist (ICI 182,780; fulvestrant) blocked T4-induced ERK1/2 activation, ERα phosphorylation, PCNA expression and proliferation. The nuclear co-localization of integrin αv and phosphorylated ERα was inhibited by ICI. ICI time-course studies indicated that mechanisms involved in T4- and E2-induced nuclear co-localization of phosphorylated ERα and integrin αv are dissimilar. Chromatin immunoprecipitation results showed that T4-induced binding of integrin αv monomer to ERα promoter and this was reduced by ICI. In summary, thyroid hormone stimulates proliferation of ovarian cancer cells via crosstalk between integrin αv and ERα, mimicking functions of E2.

Early Intervention for Post-Traumatic Stress Disorder, Depression, and Quality of Life in Mortuary Affairs Soldiers Postdeployment.

U.S. Army mortuary affairs (MA) soldiers experience stressors of deployment and exposure to the dead, increasing risk for post-traumatic stress and depression. This study examines Troop Education for Army Morale, a postdeployment early intervention based on Psychological First Aid. MA soldiers (N = 126) were randomized to intervention or comparison groups 1-month postdeployment. Intervention sessions were held at 2, 3, 4, and 7 months. Assessments of post-traumatic stress disorder (PTSD), depression, and quality of life (QOL) were conducted at 1, 2, 3, 4, 7, and 10 months for both groups. At baseline, 25.0% of the total sample had probable PTSD (17-item PTSD Checklist M = 35.4, SD = 16.9) and 23.6% had probable depression (9-item Patient Health Questionnaire Depression Scale M = 7.8, SD = 6.9). Over 10 months, PTSD and depression symptoms decreased and QOL improved for the total sample. At study conclusion, intervention and comparison groups were not different. Intervention group males showed a transient symptom increase at 2 to 3 months. Males attended fewer intervention sessions than females. Lower attendance was associated with more symptoms and lower QOL. Higher attendance was associated with greater intervention benefits. Findings highlight the need for better understanding postdeployment interventions and facilitating attendance. Further intervention for MA soldiers is indicated.

Highly enantioselective sulfa-Michael addition reactions using N-heterocyclic carbene as a non-covalent organocatalyst.

We report the first asymmetric sulfa-Michael addition (SMA) reactions using a chiral N-heterocyclic carbene (NHC) as a non-covalent organocatalyst. We demonstrate that a triazolium salt derived NHC functions as an excellent Brønsted base to promote enantioselective carbon-sulfur bond formation. The reaction is applicable to a wide range of thiols and electrophilic olefins. Notably, quaternary chiral centers bearing both an S atom and a CF3 group were synthesized with excellent asymmetric control. Mechanistic studies suggest that the facial discrimination is likely to be guided by non-covalent interactions: hydrogen bonding and π-π stacking.

EphA2 is a biomarker of hMSCs derived from human placenta and umbilical cord.

OBJECTIVE: The heterogeneous nature of mesenchymal stem cells (MSCs) and the absence of known MSC-specific biomarkers make it challenging to define MSC phenotypes and characteristics. In this study, we compared the phenotypic and functional features of human placenta-derived MSCs with those of human dermal fibroblasts in vitro in order to identify a biomarker that can be used to increase the purity of MSCs in a primary culture of placenta-derived cells. MATERIALS AND METHODS: Liquid chromatography-tandem mass spectrometry analysis was used to analyze and compare the proteome of human placenta-derived MSCs with that of fibroblasts. Quantitative real-time polymerase chain reaction, immunofluorescence, and flow cytometry were used to determine expression levels of EphA2 in placenta-derived MSCs. EphA2-positive cells were enriched by magnetic-activated cell sorting or with a cell sorter. An shRNA-mediated EphA2 knockdown was used to assess the role of EphA2 in MSC response to Tumor necrosis factor (TNF)-α stimulation. RESULTS: Analysis of proteomics data from MSCs and fibroblasts resulted in the identification of the EphA2 surface protein biomarker, which could reliably distinguish MSCs from fibroblasts. EphA2 was significantly upregulated in placenta-derived MSCs when compared to fibroblasts. EphA2 played an important role in MSC migration in response to inflammatory stimuli, such as TNF-α. EphA2-enriched MSCs were also more responsive to inflammatory stimuli in vitro when compared to unsorted MSCs, indicating a role for EphA2 in the immunomodulatory functionality of MSCs. CONCLUSION: EphA2 can be used to distinguish and isolate MSCs from a primary culture of placenta-derived cells. EphA2-sorted MSCs exhibited superior responsiveness to TNF-α signaling in an inflammatory environment compared with unsorted MSCs or MSC-like cells.