Childhood adversity and suicidal ideation in older Korean adults: unraveling the mediating mechanisms of mental health, physical health, and social relationships.

BACKGROUND: Suicide rates in older adults are much higher than those in younger age groups. Given the rapid increase in the proportion of older adults in Korea and the high suicide rate of this age group, it is worth investigating the mechanism of suicidal ideation for older adults. Generally, adverse childhood experiences are positively associated with suicidal ideation; however, it is not fully understood what mediating relationships are linked to the association between these experiences and current suicidal ideation. METHODS: The data from 685 older Korean adults were analyzed utilizing logistic regression, path analyses, and structural equation modeling. Based on our theoretical background and the empirical findings of previous research, we examined three separate models with mental health, physical health, and social relationship mediators. After that, we tested a combined model including all mediators. We also tested another combined model with mediation via mental health moderated by physical health and social relationships. RESULTS: The univariate logistic regression results indicated that childhood adversity was positively associated with suicidal ideation in older adults. However, multivariate logistic regression results demonstrated that the direct effect of childhood adversity became nonsignificant after accounting all variables. Three path models presented significant mediation by depression and social support in the association between childhood adversity and suicidal ideation. However, combined structural equation models demonstrated that only mediation by a latent variable of mental health problems was statistically significant. Social relationships moderated the path from mental health problems to suicidal ideation. CONCLUSIONS: Despite several limitations, this study has clinical implications for the development of effective strategies to mitigate suicidal ideation. In particular, effectively screening the exposure to adverse childhood experiences, early identification and treatment of depressive symptoms can play a crucial role in weakening the association between childhood adversity and suicidal ideation in older adults.

Comparison of Xpert Xpress SARS-CoV-2 Assay Compared with Standard M nCoV Real-Time PCR: Prospective Study.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), can be diagnosed using rapid real-time polymerase chain reaction (PCR), real-time reverse transcription PCR (rRT-PCR), or rapid antigen testing. Among these, rRT-PCR is considered the gold standard assay. The Xpert Xpress SARS-CoV-2 assay is a rapid, real-time PCR test; approved by the Korean Disease Control and Prevention Agency in 2020. Current performance of the Xpert assay (Xpert) with the STANDARD M nCoV Real-Time Detection kit (SD) were determined. METHODS: All samples used by the SD test team were immediately transferred to the Xpert test team within 24 hours. Both tests were conducted between April 2023 and July 2023. Exclusion criteria were studies which show either inconclusive, invalid, or erroneous results. Positive rate, sensitivity, specificity, overall concordance rate, positive concordance rate, discordance rate, false-positive rate, and false-negative rates of the Xpert assay with the STANDARD M nCoV Real-Time Detection kit were determined. RESULTS: Samples from 347 patients (174 men and 173 women) with a median age of 60 years (range; 6 - 90 years) were included. Positive rate, sensitivity, specificity, overall concordance rate, positive concordance rate, discordance rate, false-positive rate, and false-negative rates of the Xpert assay were 11.2%, 82.1%, 95.0%, 93.9%, 6.6%, 6.1%, 41.0%, and 1.6%, respectively. CONCLUSIONS: COVID-19 results from Xpert should be confirmed through rRT-PCR because of low sensitivity (82.1%) and high false-positive rate (41.0%).

Comparison of Positive/Inconclusive Xpert Xpress SARS-CoV-2 with the Standard M nCoV Real-Time Detection.

BACKGROUND: COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), can be diagnosed using rapid real-time PCR, real-time reverse transcription PCR (rRT-PCR), or rapid antigen testing. Among these, rRT-PCR is considered the gold standard assay. The Xpert Xpress SARS-CoV-2 assay is a rapid real-time PCR test, approved by the Korean Disease Control and Prevention Agency in 2020. The overall concordance and positive concordance rates of the Xpert assay with the STANDARD M nCoV Real-Time Detection kit were determined. METHODS: All samples with positive or inconclusive Xpert test results from July 2021 to February 2023 that underwent confirmatory testing using the reference rRT-PCR assay were included in the analysis. RESULTS: Samples from 224 patients (93 men and 131 women) with a median age of 59 years (range 15 - 90 years) were included. Of 212 samples that tested positive using Xpert, 112 (52.8%) were true positves and 100 (47.2%) were false positives on rRT-PCR testing. The overall concordance and positive concordance rates were 52.8% (112/212) and 54.5% (112/224), respectively. In the Xpert positive group, the samples had a lower Ct value for the E gene than the N2 gene. The Ct values for the E and N2 genes were significantly lower in the positive group than in the inconclusive group. CONCLUSIONS: Positive or inconclusive Xpert results should be confirmed by the gold standard rRT-PCR for early control of this disease. Furthermore, Korea's policy should be reconsidered given the high false-positive rate of the rapid real-time PCR Xpert Xpress SARS-CoV-2 assay.

Parent-to-child aggression, intimate partner aggression, conflict resolution, and children's social-emotional competence in early childhood.

Early childhood is critical to the development of children's social-emotional competence, which predicts peer relations and school adjustment in later periods of childhood. The effects of experiencing or witnessing aggression on children's social-emotional development are well known, yet the role of conflict resolution within the family has not been sufficiently studied. Social information processing models suggests that children who experience positive forms of conflict resolution within the family are likely to generalize these experiences and related skills outside the family, and thus develop greater social-emotional competence. In this longitudinal study, 128 parents (representing 79 families) participated in four quarterly telephone interviews in which they described aggressive conflicts that occurred in their family for which their children were present, including the degree to which each conflict was resolved. They also reported on the frequency of intimate partner aggression (IPA) and parent-to-child aggression (PCA) that occurred while the child was in toddlerhood and preschool as well as children's social-emotional competence at the end of the study. Multi-level models reveal that parents' reports of positive conflict resolution mitigated the concurrent and longitudinal negative effects of children's exposure to both IPA and PCA on their social-emotional competence. These findings reinforce prevention scientists' emphasis on conflict resolution skills as an essential component of parent education programs.

La primera infancia es fundamental para el desarrollo de la competencia socioemocional de los niños, la cual predice las relaciones entre pares y la adaptación escolar en periodos posteriores de la niñez. Se conocen muy bien los efectos que producen el sufrir o ser testigos de agresión en el desarrollo socioemocional de los niños, sin embargo, aún no se ha estudiado de manera suficiente el papel que desempeña la resolución de conflictos dentro de la familia. Los modelos de procesamiento de la información social sugieren que los niños que viven formas positivas de resolución de conflictos dentro de la familia son propensos a generalizar estas experiencias y las habilidades afines fuera de la familia y, por lo tanto, a desarrollar una mayor competencia socioemocional. En este estudio longitudinal, 128 padres (que representaban 79 familias) participaron en cuatro entrevistas telefónicas cada tres meses en las cuales describieron conflictos agresivos que hubo en su familia en los cuales sus hijos estuvieron presentes, incluido el grado en el cual se resolvió cada conflicto. También informaron la frecuencia de agresión en la pareja y de agresión de padres a hijos que tuvo lugar durante sus primeros años de vida y en la etapa del preescolar, así como la competencia socioemocional de los niños al final del estudio. Los modelos multinivel indican que los informes de los padres sobre la resolución positiva de los conflictos mitigaron los efectos negativos longitudinales y simultáneos de la exposición de los niños a la agresión en la pareja y a la agresión de padres a hijos en su competencia socioemocional. Estos resultados refuerzan el énfasis en las habilidades de resolución de conflictos de los científicos de la prevención como componente esencial de los programas de educación para padres.

Impact of the COVID-19 Pandemic on Parent, Child, and Family Functioning.

To quantify the impact of the COVID-19 pandemic and public health interventions on parent and child mental health and family relationships, we examined change in individual and family functioning in a sample of parents enrolled in a prevention trial; we examined change before the pandemic (2017-2019) when children were an average of 7 years old to the first months after the imposition of widespread public health interventions in the United States (2020) with paired t tests and HLM models. We examined moderation by parent gender, education, family income, and coparenting conflict. We found large deteriorations from before the pandemic to the first months of the pandemic in child internalizing and externalizing problems and parent depression, and a moderate decline in coparenting quality. Smaller changes were found for parent anxiety and parenting quality. Mothers and families with lower levels of income were at particular risk for deterioration in well-being. Results indicate a need for widespread family support and intervention to prevent potential family "scarring," that is, prolonged, intertwined individual mental health and family relationship problems.

Para cuantificar el efecto de la pandemia de la COVID-19 y de las intervenciones de salud pública en la salud mental de los padres y los niños y en las relaciones familiares, analizamos los cambios en el funcionamiento individual y familiar en una muestra de padres inscriptos en un ensayo de prevención; estudiamos el cambio antes de la pandemia (2017-2019) cuando los niños tenían un promedio de 7 años hasta los primeros meses después de la imposición de las intervenciones generalizadas de salud pública en los Estados Unidos (2020) con pruebas t apareadas y modelos lineales jerárquicos. Analizamos la moderación por género, educación, ingresos familiares y conflicto de cocrianza de los padres. Hallamos grandes deterioros desde antes de la pandemia hasta los primeros meses de la pandemia en problemas de interiorización y exteriorización de los niños y depresión de los padres, y una disminución moderada de la calidad de la cocrianza. También encontramos cambios más pequeños en la ansiedad de los padres y la calidad de la crianza. Las madres y las familias con niveles más bajos de ingresos estuvieron en riesgo particular de deterioro del bienestar. Los resultados indican la necesidad de apoyo familiar generalizado y de intervenciones para prevenir posibles «secuelas¼ familiares, p. ej.: salud mental individual interconectada y prolongada y problemas en las relaciones familiares.

Building long-term family resilience through universal prevention: 10-year parent and child outcomes during the COVID-19 pandemic.

As the COVID-19 pandemic has been highly stressful for parents and children, it is clear that strategies that promote long-term family resilience are needed to protect families in future crises. One such strategy, the Family Foundations program, is focused on promoting supportive coparenting at the transition to parenthood. In a randomized trial, we tested the long-term intervention effects of Family Foundations on parent, child, and family well-being one to two months after the imposition of a national shelter-in-place public health intervention in 2020. We used regression models to test intervention impact on outcomes reported on by parents in a standard questionnaire format and a series of 8 days of daily reports. We also tested moderation of intervention impact by parent depression and coparenting relationship quality. Relative to control families, intervention families demonstrated significantly lower levels of individual and family problems (general parent hostility, harsh and aggressive parenting, coparenting conflict, sibling relationship conflict, and children's negative mood and behavior problems), and higher levels of positive family relationship quality (positive parenting, couple relationship quality, sibling relations, and family cohesion). For some outcomes, including coparenting conflict, harsh parenting, and child behavior problems, intervention effects were larger for more vulnerable families-that is, families with higher pre-pandemic levels of parent depression or lower levels of coparenting relationship quality. We conclude that targeted family prevention programming is able to promote healthy parent and child functioning during unforeseen future periods of acute stress. The long-term benefits of a universal approach to family support at the transition to parenthood indicate the need for greater investment in the dissemination of effective approaches.

Dado que la pandemia de COVID-19 ha sido muy estresante para padres e hijos, está claro que se necesitan estrategias que promuevan la resiliencia familiar a largo plazo para proteger a las familias en crisis futuras. Una de esas estrategias, el programa Family Foundations, se centra en promover la crianza compartida de apoyo en la transición a la paternidad. En un ensayo aleatorizado, probamos los efectos de la intervención a largo plazo de Family Foundations en el bienestar de los padres, el niño y la familia uno o dos meses después de la imposición de una intervención nacional de salud pública de refugio en el lugar en 2020. Usamos modelos de regresión para evaluar el impacto de la intervención en los resultados informados por los padres en un formato de cuestionario estándar y una serie de 8 días de informes diarios. También probamos la moderación del impacto de la intervención por la depresión de los padres y la calidad de la relación de coparentalidad. En relación con las familias de control, las familias de intervención demostraron niveles significativamente más bajos de problemas individuales y familiares (hostilidad general de los padres, crianza dura y agresiva, conflicto de crianza conjunta, conflicto de relaciones entre hermanos y problemas de comportamiento y estado de ánimo negativos de los niños) y niveles más altos de calidad de relación familiar positiva (crianza positiva, calidad de la relación de pareja, relaciones entre hermanos y cohesión familiar). Para algunos resultados, incluido el conflicto de crianza compartida, la crianza severa y los problemas de comportamiento infantil, los efectos de la intervención fueron mayores para las familias más vulnerables, es decir, familias con niveles más altos de depresión de los padres prepandémicos o niveles más bajos de calidad de la relación de crianza compartida. Concluimos que los programas de prevención familiar específicos pueden promover el funcionamiento saludable de padres e hijos durante períodos futuros imprevistos de estrés agudo. Los beneficios a largo plazo de un enfoque universal del apoyo familiar en la transición a la paternidad indican la necesidad de una mayor inversión en la difusión de enfoques eficaces.

Analytical Performance and Comparability of Three New Coagulation Analyzers.

BACKGROUND: Analytical performance should be evaluated before a new coagulation analyzer is adopted in a clinical laboratory. The objective of this study was to evaluate analytical performances of three new coagulation analyzers (STA-R Max3, CN-6000, and Cobas t511) and compare them based on the following four coagulation parameters: prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen, and D-dimer. METHODS: A total of 427 plasma samples, including fresh and frozen/thawed plasma spanning wide ranges. Each of the manufacturers' quality control samples were used for the evaluation. Analytical performances were evaluated. Parameters considered were precision, carryover, verification of analytical measurement range, auto-dilution, and reference range according to the CLSI guidelines (H57-A). The results of each parameter were compared between STA-R compact (currently in use) and three new analyzers using fresh plasma. The results were compared among three new analyzers using fresh and frozen/thawed plasma, and samples with interferences of hemolysis/icterus/ lipemia (H/I/L). RESULTS: Analytical performances were excellent for all analyzers within each manufacturer's target based on results of precision, carryover, linearity, and verifications of auto-dilution, and reference range. Results for four parameters (PT/aPTT/fibrinogen/D-dimer) with the three new analyzers using fresh samples were well-correlated with those of STA-R Compact except for D-dimer tests (Pearson's r: 0.84 to 1.00). Good correlations were observed between the new analyzers with the total samples (fresh and frozen/thawed samples) (Pearson's r, 0.86 to 0.97). However, weaker correlation and/or higher mean bias% were observed for aPTT and D-dimer with total samples and for four parameters with normal samples rather than abnormal samples across the three analyzers. Differences were more prominent with H/I/L samples, especially between STA-R Max3 and CN-6000 or Cobas t511 for PT, aPTT, and D-dimers. CONCLUSIONS: With excellent analytical performances, the three new coagulation analyzers demonstrated good correlations, although high variabilities were seen for aPTT and D-dimers. High variability in comparison analysis might be mainly attributed to differences in reference and reportable ranges of each parameter across the three different analyzers.

Serotonergic sensitivity alleles moderate relations between attachment security at age three and socioemotional competence at age five.

Children with higher socioemotional competence are more likely to build constructive relationships with others and experience more positive adjustment outcomes in later periods. Securely attached children are likely to develop better socioemotional competence, but genetic moderation of associations between attachment and later socioemotional competence has received less attention. Using structural equation modeling, this study analyzed data collected from 1,337 children (51% male) born from 1998 to 2000 in the Fragile Families and Child Wellbeing study. The results demonstrated that relations between attachment security at age 3 years and their social competence at age 5 years differed by two serotonin transporter variants (5-HTTLPR, STin2). Effect sizes of these interactions were larger than effect sizes of main effects and the benefit of having sensitive alleles was consistently supported. This implies that having more secure attachment in the early developmental period is advantageous especially for children with minor alleles who have greater environmental sensitivity.

Coparenting Intervention for Expectant Parents Affects Relationship Quality: A Pilot Study.

Research has shown that the transition to parenthood is a particularly challenging period of life which is often associated with a decline in relationship quality and an increase in mental health problems. Emerging parents often experience difficulties in coping with new tasks and challenges in the relationship, resulting in inadequate mutual support, stress, conflicts and even depressive symptoms. To support expectant parents in establishing an effective and strong coparenting alliance, we have employed an educational coparenting intervention to teach important coparenting skills. The intervention was a non-randomized case-control study with 126 expectant parents. The intervention group participated in a five-session intervention, whereas the control group received an information booklet and had an optional meeting postpartum. The purpose of this study was to ease the transition to parenthood in order to prevent postpartum conflict and depression. Parents in the intervention group (n = 34 couples) showed significantly fewer conflicts postpartum than before (Z = -3.28, p = 0.00), and scored better in postnatal delegated dyadic coping (ß = 0.25, p = 0.00, R2 = 0.32), a form of mutual support. Neither the intervention group (Z = -0.83, p = 0.40) nor the control group (Z = -0.86, p = 0.38) showed a significant increase in depression scores after childbirth. Although conflicts during the transition to parenthood declined and postnatal delegated dyadic coping strengthened, the study design does not allow to draw conclusion on group effects. Nevertheless, the promising results of this pilot intervention are a base for future studies.

Bidirectional Associations between Youth Adjustment and Mothers' and Fathers' Coparenting Conflict.

Research demonstrates significant associations between coparenting conflict and child adjustment problems. However, the implications of youth adjustment for coparenting, especially during youth's adolescence, remain poorly understood. Addressing several gaps in the literature, this study examines the longitudinal trajectory of mothers' and fathers' reported coparenting conflict from youth ages 10-17 and tests bidirectional associations between youth social anxiety, hostility, risk-taking behaviors, and mothers' and fathers' coparenting conflict. Participants include 757 mothers, fathers, and youth in two-parent families (M youth age = 11.28, SD = 0.49; 53% female) who participated in 5 waves of data collection when youth were in the 6th to 9th grades. Multilevel growth curve models revealed significant non-linear change in mothers' and fathers' coparenting conflict, such that coparenting conflict declined through youth's transition to adolescence, leveled off in early adolescence, and declined in the mid-late adolescent years. Cross-lagged models showed significant positive associations between youth social anxiety and hostility and coparenting conflict at the following time point, but coparenting conflict did not predict later youth adjustment problems in these domains. There were significant bidirectional associations between mother-reported coparenting conflict and youth risk-taking behaviors; the associations between coparenting conflict and risk-taking were not significant for fathers. The findings demonstrate that investigating longitudinal associations between youth adjustment and coparenting conflict may provide new insights into the role of child effects for mothers' and fathers' coparenting experiences.

Advancing Research and Measurement on Fathering and Child Development.

Fathers are more than social accidents. Research has demonstrated that fathers matter to children's development. Despite noted progress, challenges remain on how best to conceptualize and assess fathering and father-child relationships. The current monograph is the result of an SRCD-sponsored meeting of fatherhood scholars brought together to discuss these challenges and make recommendations for best practices for incorporating fathers in studies on parenting and children's development. The first aim of this monograph was to provide a brief update on the current state of research on fathering and to lay out a developmental ecological systems perspective as a conceptual framework for understanding the different spaces fathers inhabit in their children's lives. Because there is wide variability in fathers' roles, the ecological systems perspective situates fathers, mothers, children, and other caregivers within an evolving network of interrelated social relationships in which children and their parents change over time and space (e.g., residence). The second aim was to present examples of empirical studies conducted by members of the international working group that highlighted different methods, data collection, and statistical analyses used to capture the variability in father-child relationships. The monograph ends with a commentary that elaborates on the ecological systems framework with a discussion of the broader macrosystem and social-contextual influences that impinge on fathers and their children. The collection of articles contributes to research on father-child relationships by advancing theory and presenting varied methods and analysis strategies that assist in understanding the father-child relationship and its impact on child development.

Detection of Methylated SEPT9 in Korean Colorectal Cancer Patients: Comparison with Previous Studies.

BACKGROUND: This study aimed to investigate the detection of methylated Septin 9 (mSEPT9) in Korean patients with colorectal cancer (CRC) and compare the results with those of previous studies. METHODS: A total of 127 plasma samples (111 patients with untreated CRC, 5 patients with adenomas, and 11 CRC patients treated with concurrent chemoradiotherapy before surgery) were collected. mSEPT9 was measured qualitatively with the Abbott RealTime ms9 Colorectal Cancer Assay. RESULTS: mSEPT9 was detected in 44 of 111 (39.6%) cases of untreated CRC but was not detected in the adenoma cases. The difference in the sensitivity of mSEPT9 among patients with adenomas and those with each stage of untreated CRC was statistically significant (Dukes' staging, p = 0.002 and TNM staging, p = 0.008). The sensitivity of mSEPT9 for each of the stages (I - IV) of untreated CRC patients were 20.7%, 54.1%, 36.6%, and 75.0%, respectively. The positive mSEPT9 results in untreated CRC patients reverted to negative in 19 of 21 patients (90.5%) after treatment. CONCLUSIONS: Compared to previous studies, the overall sensitivity of mSEPT9 was lower, but similar patterns were found in the sensitivities for each stage. Additionally, mSEPT9 appeared to have potential as a monitoring tool for CRC.

BCPA {N,N'-1,4-Butanediylbis[3-(2-chlorophenyl)acrylamide]} Inhibits Osteoclast Differentiation through Increased Retention of Peptidyl-Prolyl cis-trans Isomerase Never in Mitosis A-Interacting 1.

Osteoporosis is caused by an imbalance of osteoclast and osteoblast activities and it is characterized by enhanced osteoclast formation and function. Peptidyl-prolyl cis-trans isomerase never in mitosis A (NIMA)-interacting 1 (Pin1) is a key mediator of osteoclast cell-cell fusion via suppression of the dendritic cell-specific transmembrane protein (DC-STAMP). We found that N,N'-1,4-butanediylbis[3-(2-chlorophenyl)acrylamide] (BCPA) inhibited receptor activator of nuclear factor kappa-B ligand (RANKL)-induced osteoclastogenesis in a dose-dependent manner without cytotoxicity. In addition, BCPA attenuated the reduction of Pin1 protein during osteoclast differentiation without changing Pin1 mRNA levels. BCPA repressed the expression of osteoclast-related genes, such as DC-STAMP and osteoclast-associated receptor (OSCAR), without altering the mRNA expression of nuclear factor of activated T cells (NFATc1) and cellular oncogene fos (c-Fos). Furthermore, Tartrate-resistant acid phosphatase (TRAP)-positive mononuclear cells were significantly decreased by BCPA treatment compared to treatment with the Pin1 inhibitor juglone. These data suggest that BCPA can inhibit osteoclastogenesis by regulating the expression of the DC-STAMP osteoclast fusion protein by attenuating Pin1 reduction. Therefore, BCPA may be used to treat osteoporosis.

DPIE [2-(1,2-diphenyl-1H-indol-3-yl)ethanamine] Augments Pro-Inflammatory Cytokine Production in IL-1ß-Stimulated Primary Human Oral Cells.

Interleukin-1β (IL-1β) is a prominent pro-inflammatory cytokine that is implicated in a variety of autoimmune diseases and plays an important role in host defense against infections. IL-1β activity increases with its increasing binding capacity to IL-1 receptors (IL-1Rs). Thus, numerous studies have targeted the discovery of molecules modulating the interactions between IL-1β and IL-1R1. We have conducted an IL-1R1 structure-based virtual screening to identify small molecules that could alter IL-1β activity, using in silico computational analysis. Sixty compounds from commercial libraries were predicted to bind to IL-1R1, and their influence on cytokine production in IL-1β-stimulated gingival fibroblasts (GFs) was determined. Of these, only (2-(1,2-diphenyl-1H-indol-3-yl)ethanamine (DPIE) showed a synergistic increase in inflammatory molecules and cytokine production (IL-6, IL-8, and COX-2) at both mRNA and protein levels in IL-1β-stimulated GFs. The enhancing activity of DPIE in IL-1β-induced cytokine production increased in a dose-dependent manner without cytotoxicity. This pattern was also observed in IL-1β-stimulated primary human periodontal ligament cells (PDLs). Furthermore, we measured the impact of DPIE on the IL-1β⁻IL-1R1 system using surface plasmon resonance and demonstrated that DPIE increased the binding affinity of IL-1β to IL-1R1. These data indicate that DPIE boosts IL-1β signaling by enhancing the binding of IL-1β to IL-1R1 in oral primary cells.

Cascade Polymerization via Controlled Tandem Olefin Metathesis/Metallotropic 1,3-Shift Reactions for the Synthesis of Fully Conjugated Polyenynes.

We demonstrate the first example of cascade polymerization by combining olefin metathesis and metallotropic 1,3-shift reactions to form unique conjugated polyenynes. Rational design of monomers enabled controlled polymerization, and kinetic investigation of the polymerization mechanism was conducted.

Piperlongumine downregulates the expression of HER family in breast cancer cells.

HER family receptors are frequently deregulated in breast cancer and the deregulation of these receptors is associated with poor prognosis. Thus, these receptors are considered therapeutic targets. In the present study, we found that piperlongumine (PL) downregulates the expression of HER family receptors HER1, HER2, and HER3 in breast cancer cells. Downregulation of these receptors by PL is mediated through the generation of reactive oxygen species (ROS), as N-acetyl-cysteine blocks it. Interestingly, the HER2-overexpressing cell lines BT474 and SkBr3 are somewhat more sensitive to PL than the low HER2-expressing cell line MCF7. In addition, the overexpression of HER2 increases the sensitivity of MCF7 cells to PL. Collectively, our data indicate the therapeutic potential of PL in the treatment of breast cancer.

Heat Shock Protein 90 Regulates Subcellular Localization of Smads in Mv1Lu Cells.

Heat shock protein 90 (HSP90) regulates the stability of various proteins and plays an essential role in cellular homeostasis. Many client proteins of HSP90 are involved in cell growth, survival, and migration; processes that are generally accepted as participants in tumorigenesis. HSP90 is also up-regulated in certain tumors. Indeed, the inhibition of HSP90 is known to be effective in cancer treatment. Recently, studies showed that HSP90 regulates transforming growth factor ß1 (TGF-ß1)-induced transcription by increasing the stability of the TGF-ß receptor. TGF-ß signaling also has been implicated in cancer, suggesting the possibility that TGF-ß1 and HSP90 function cooperatively during the cancer cell progression. Here in this paper, we investigated the role of HSP90 in TGF-ß1-stimulated Mv1Lu cells. Treatment of Mv1Lu cells with the HSP90 inhibitor, 17-allylamino-demethoxy-geldanamycin (17AAG), or transfection with truncated HSP90 (ΔHSP90) significantly reduced TGF-ß1-induced cell migration. Pretreatment with 17AAG or transfection with ΔHSP90 also reduced the levels of phosphorylated Smad2 and Smad3. In addition, the HSP90 inhibition interfered the nuclear localization of Smads induced by constitutively active Smad2 (S2EE) or Smad3 (S3EE). We also found that the HSP90 inhibition decreased the protein level of importin-ß1 which is known to regulate R-Smad nuclear translocation. These data clearly demonstrate a novel function of HSP90; HSP90 modulates TGF-ß signaling by regulating Smads localization. Overall, our data could provide a detailed mechanism linking HSP90 and TGF-ß signaling. The extension of our understanding of HSP90 would offer a better strategy for treating cancer.

Diversity-Oriented Polymerization: One-Shot Synthesis of Library of Graft and Dendronized Polymers by Cu-Catalyzed Multicomponent Polymerization.

Graft and dendronized polymers have attracted much attention in the polymer community, and there have been significant efforts to develop better synthetic methods. Herein, we report the highly efficient synthesis of graft and dendronized polymers by using Cu-catalyzed multicomponent polymerization (MCP). Based on diversity-oriented synthesis, we prepared a library of various graft and dendronized polymers from combinations of three types of monomers (mono-functionalized alkynes, bis-sulfonyl azides, and diamines/diols) that are bench stable and readily accessible. After reaction optimization, 54 samples of high-molecular-weight graft and dendronized polymers were prepared, the MCP method allowing simultaneous manipulation of the structures of both the main chains and the side chains. Moreover, because of the severe steric hindrance of the side chains, these polymers adopted extended conformations, as shown by the large shape parameter in solution. Also, the extended morphology of the single polymer chains was directly visualized by atomic force microscopy and transmission electron microscopy in the solid state. Most importantly, this diversity-oriented polymerization became possible because of highly step-economical and efficient one-step MCP, paving the way toward the easily tunable synthesis of graft and dendronized polymers.

Targeting HIF-1α is a prerequisite for cell sensitivity to dichloroacetate (DCA) and metformin.

Recently, targeting deregulated energy metabolism is an emerging strategy for cancer therapy. In the present study, combination of DCA and metformin markedly induced cell death, compared with each drug alone. Furthermore, the expression levels of glycolytic enzymes including HK2, LDHA and ENO1 were downregulated by two drugs. Interestingly, HIF-1α activation markedly suppressed DCA/metformin-induced cell death and recovered the expressions of glycolytic enzymes that were decreased by two drugs. Based on these findings, we propose that targeting HIF-1α is necessary for cancer metabolism targeted therapy.

TRAIL restores DCA/metformin-mediated cell death in hypoxia.

Previous studies have shown that hypoxia can reverse DCA/metformin-induced cell death in breast cancer cells. Therefore, targeting hypoxia is necessary for therapies targeting cancer metabolism. In the present study, we found that TRAIL can overcome the effect of hypoxia on the cell death induced by treatment of DCA and metformin in breast cancer cells. Unexpectedly, DR5 is upregulated in the cells treated with DCA/metformin, and sustained under hypoxia. Blocking DR5 by siRNA inhibited DCA/metformin/TRAIL-induced cell death, indicating that DR5 upregulation plays an important role in sensitizing cancer cells to TRAIL-induced cell death. Furthermore, we found that activation of JNK and c-Jun is responsible for upregulation of DR5 induced by DCA/metformin. These findings support the potential application of combining TRAIL and metabolism-targeting drugs in the treatment of cancers under hypoxia.