Overcoming Resistance to Anti-Nectin-4 Antibody-Drug Conjugate.

Antibody-drug conjugates (ADC) represent a fast-growing drug class in oncology. However, ADCs are associated with resistance, and therapies able to overcome it are of utmost importance. Recently, enfortumab vedotin-ejfv (EV) was approved in nectin-4+ metastatic urothelial cancer. We previously described PVRL4/nectin-4 as a new therapeutic target in breast cancer and produced an efficient EV-like ADC comprising a human anti-nectin-4 mAb conjugated to monomethyl auristatin-E (MMAE) named N41mab-vcMMAE. To study the consequence of the long-term treatment with this ADC, we developed a preclinical breast cancer model in mice, and report a mechanism of resistance to N41mab-vcMMAE after 9-month treatment and a way to reverse it. RNA-sequencing pointed to an upregulation in resistant tumors of ABCB1 expression, encoding the multidrug resistance protein MDR-1/P-glycoprotein (P-gp), associated with focal gene amplification and high protein expression. Sensitivity to N41mab-vcMMAE of the resistant model was restored in vitro by P-gp pharmacologic inhibitors, like tariquidar. P-gp is expressed in a variety of normal tissues. By delivering the drug to the tumor more specifically than classical chemotherapy, we hypothesized that the combined use of ADC with P-gp inhibitors might reverse resistance in vivo without toxicity. Indeed, we showed that the tariquidar/N41mab-vcMMAE combination was well tolerated and induced a rapid regression of ADC-resistant tumors in mice. In contrast, the tariquidar/docetaxel combination was toxic and poorly efficient. These results show that ABC transporter inhibitors can be safely used with ADC to reverse ADC-induced resistance and open new opportunities in the fight against multidrug resistance.

BMI1 nuclear location is critical for RAD51-dependent response to replication stress and drives chemoresistance in breast cancer stem cells.

Replication stress (RS) has a pivotal role in tumor initiation, progression, or therapeutic resistance. In this study, we depicted the mechanism of breast cancer stem cells' (bCSCs) response to RS and its clinical implication. We demonstrated that bCSCs present a limited level of RS compared with non-bCSCs in patient samples. We described for the first time that the spatial nuclear location of BMI1 protein triggers RS response in breast cancers. Hence, in bCSCs, BMI1 is rapidly located to stalled replication forks to recruit RAD51 and activate homologous-recombination machinery, whereas in non-bCSCs BMI1 is trapped on demethylated 1q12 megasatellites precluding effective RS response. We further demonstrated that BMI1/RAD51 axis activation is necessary to prevent cisplatin-induced DNA damage and that treatment of patient-derived xenografts with a RAD51 inhibitor sensitizes tumor-initiating cells to cisplatin. The comprehensive view of replicative-stress response in bCSC has profound implications for understanding and improving therapeutic resistance.

Asian in the Time of COVID-19: Creating a Social Work Agenda for Asian American and Pacific Islander Communities.

The health of Asian American and Pacific Islander (AAPI) communities remains an understudied area of racial/ethnic minority research in the United States, and even more so in the field of social work. The COVID-19 pandemic has highlighted how AAPI health and social welfare issues have not received adequate attention in social policy, social work practice, and research. Contrary to model minority myths, AAPIs are subject to racialized attitudes and discrimination, which have been associated with adverse physical and mental health outcomes, including increased anxiety, depression, and suicidality. Drawing from the theoretical framework of AsianCrit, which is grounded in critical race theory, authors analyze health disparities among AAPI communities as reflected in COVID-19 hospitalizations and fatalities, as well as increases in acts of anti-Asian racism and xenophobia. Better understanding health disparities of AAPI communities needs to be a key research issue for social workers in future years. The authors conclude by offering a short set of recommendations to improve social policy, social work practice, and research to more aptly address contemporary social issues impacting AAPI communities.

Anxiety, Depression, and Trauma Among Immigrant Mexican Women up to Two-Years Post-partum.

Anxiety has significant consequences for maternal and infant health, and Mexican immigrant mothers are at significantly high-risk. This study examined whether maternal depressive symptoms and trauma are related to anxiety symptoms in perinatal Mexican immigrants. Data were collected from 103 Mexican women residing in the Midwestern United States who were pregnant or up to two years postpartum. Half were aged 30-34. The majority had two or more children and low socio-economic status. Linear regression analyses predicted current anxiety symptoms from current maternal depression symptoms, trauma history, and socio-demographics. Anxiety symptoms were significantly related to depressive symptoms (B = 0.87, 95% CI 0.73, 1.01) and trauma. Compared to women with no trauma history, women who experienced more than ten traumas had increased anxiety symptoms (B = 7.15, 95% CI 0.34, 13.96). Perinatal Mexican women with higher depression symptoms and trauma have increased anxiety symptoms, increasing the need for more comprehensive screening.

EFA6B regulates a stop signal for collective invasion in breast cancer.

Cancer is initiated by somatic mutations in oncogenes or tumor suppressor genes. However, additional alterations provide selective advantages to the tumor cells to resist treatment and develop metastases. Their identification is of paramount importance. Reduced expression of EFA6B (Exchange Factor for ARF6, B) is associated with breast cancer of poor prognosis. Here, we report that loss of EFA6B triggers a transcriptional reprogramming of the cell-to-ECM interaction machinery and unleashes CDC42-dependent collective invasion in collagen. In xenograft experiments, MCF10 DCIS.com cells, a DCIS-to-IDC transition model, invades faster when knocked-out for EFA6B. In addition, invasive and metastatic tumors isolated from patients have lower expression of EFA6B and display gene ontology signatures identical to those of EFA6B knock-out cells. Thus, we reveal an EFA6B-regulated molecular mechanism that controls the invasive potential of mammary cells; this finding opens up avenues for the treatment of invasive breast cancer.

Molecular modifications of dermal and epidermal biomarkers following UVA exposures on reconstructed full-thickness human skin.

Ultraviolet A (UVA) radiation adversely affects skin health and appearance via multiple molecular pathways. Biologically relevant UVA damage are classified as short-term effects (e.g. formation of reactive oxygen species [ROS], inflammation, photo-oxidation, DNA damage, immunosuppression, photoallergy and cell-mediated contact hypersensitivity) or long-term effects (elastosis, photoageing and photocarcinogenesis). Single and chronic experimental exposure to UVA are limited in humans by ethical concerns, and furthermore it is impossible to quantify long-term endpoints such as photoageing over the life-span of a human volunteer. The aim of the present study was to investigate the biological relevance of the Phenion FT skin model for use in photobiological studies. Biological responses to acute and repeated UVA exposures were investigated by monitoring the kinetics of gene expression during the post-irradiation period. By using a dynamic approach, we were able to define early and stable markers of UVA-induced effects that could be predictive of UVA damage in vivo. The transcriptomic approach applied to 3D human tissues appears to be an encouraging method for gaining a deeper understanding of the UVA effects on skin and for studying the dermal response with non-invasive techniques.

Intergenerational Trauma among Families in El Salvador: an Exploratory Study.

Adverse childhood events have been shown to impact individuals through adulthood, particularly the impact on relationships. This study aimed to examine intergenerational trauma exposure among a sample of parents living in a semi-urban Salvadoran community and the relationship between child trauma exposure with maternal perceived discrimination, internal strengths and external support. Survey data was collected from 49 mothers residing in El Salvador. Bivariate analyses and multivariate linear regression analyses were used to examine the relationship between children's exposure to adverse childhood events and parents' exposure to adverse childhood events, while controlling for discrimination. The results of the regression analysis indicate that the maternal number of adverse childhood events and experience of discrimination as an adult explained 52.9% of the variance (R 2 = 0.59, F(6, 43) = 10.18, p < .0001). The number of adverse childhood events was significantly predicted by maternal number of adverse events (B = 0.32, 95% CI = 0.17-0.48, p < .0001) and experience of discrimination as adults (B = 5.79, 95% CI = 3.51-8.07, p < .0001). Results suggest that parent exposure to adverse childhood events and parent experience with discrimination are related to the exposure to adverse childhood events of their children. Further research in this area is warranted to better understand the experiences of parents who have been exposed to childhood trauma and the day-to-day parenting challenges. Greater understanding of the impact of childhood trauma also encourages service providers to explore intergenerational interventions.

Nidogen-1 Contributes to the Interaction Network Involved in Pro-B Cell Retention in the Peri-sinusoidal Hematopoietic Stem Cell Niche.

In the bone marrow, CXCL12 and IL-7 are essential for B cell differentiation, whereas hematopoietic stem cell (HSC) maintenance requires SCF and CXCL12. Peri-sinusoidal stromal (PSS) cells are the main source of IL-7, but their characterization as a pro-B cell niche remains limited. Here, we characterize pro-B cell supporting stromal cells and decipher the interaction network allowing pro-B cell retention. Preferential contacts are found between pro-B cells and PSS cells, which homogeneously express HSC and B cell niche genes. Furthermore, pro-B cells are frequently located in the vicinity of HSCs in the same niche. Using an interactome bioinformatics pipeline, we identify Nidogen-1 as essential for pro-B cell retention in the peri-sinusoidal niche as confirmed in Nidogen-1-/- mice. Finally, human pro-B cells and hematopoietic progenitors are observed close to similar IL-7+ stromal cells. Thus, a multispecific niche exists in mouse and human supporting both early progenitors and committed hematopoietic lineages.

Childhood Trauma and Psychopathic Features Among Juvenile Offenders.

Despite growing interest in psychopathic personality features in juvenile offenders, few studies have examined the relationship between childhood trauma and psychopathy. The present study utilized two datasets: 253 adolescents in a residential facility for juvenile offenders in Pennsylvania and 723 institutionalized delinquents in Missouri. Zero-order correlations and linear regression techniques were employed for boys and girls to examine the relationships between trauma, assessed using the Massachusetts Youth Screening Instrument Version 2 (MAYSI-2) Traumatic Experiences Scale and the Childhood Trauma Questionnaire (CTQ), and psychopathy as measured by the Youth Psychopathic Traits Inventory (YPI) and the Psychopathic Personality Inventory-Short Form (PPI-SF). Results indicate that psychopathy is significantly correlated with childhood trauma. For the Missouri data, trauma significantly predicted psychopathy scores for both boys and girls. These results suggest that nuanced understanding of traumatic history of these adolescents may not only be a pathway to psychopathy but also a critical part of their overall assessment and treatment plan.

Complete and irreversible unilateral vestibular loss: A novel rat model of vestibular pathology.

BACKGROUND: Both basic and applied studies on the pathophysiology of vestibular disorders are currently impaired by the lack of animal models of controlled vestibular damages. NEW METHODS: In the present study, we describe the procedure to achieve a surgical unilateral vestibular neurectomy (UVN) in the rat and evaluate its functional consequences. This procedure is suitable for reproducing a unilateral, sudden and definitive vestibular areflexia. RESULTS: Proper induction of a UVN induces a severe vestibular syndrome, which mimics vestibular disorders encountered in humans. This model is also used clinically in the surgical treatment of pharmacological intractable Meniere's disease. Comparison with existing methods unilateral vestibular neurectomy has been essentially used in other species such as cats, monkeys and humans. The current study describes this technique in rats. CONCLUSION: This experimental model is particularly adapted to study the restoration kinetics of vestibular function after removal of peripheral inputs. It is also suitable for determining the neurochemical and molecular mechanisms underlying central compensation processes, as well as to check for the efficacy of drugs with potent antivertigo properties. Finally, UVN is an acknowledged model of postlesional plasticity involving original processes such as reactive neurogenesis in the vestibular nuclei.

Post-transcriptional regulation of cadherin-11 expression by GSK-3 and beta-catenin in prostate and breast cancer cells.

BACKGROUND: The cell-cell adhesion molecule cadherin-11 is important in embryogenesis and bone morphogenesis, invasion of cancer cells, lymphangiogenesis, homing of cancer cells to bone, and rheumatoid arthritis. However, very little is known about the regulation of cadherin-11 expression. METHODOLOGY/PRINCIPAL FINDINGS: Here we show that cell density and GSK-3beta regulate cadherin-11 levels in cancer cells. Inactivation of GSK3beta with lithium chloride or the GSK3 inhibitor BIO and GSK3beta knockdown with siRNA repressed cadherin-11 mRNA and protein levels. RNA Polymerase II chromatin immunoprecipitation experiments showed that inhibition of GSK3 does not affect cadherin-11 gene transcription. Although the cadherin-11 3'UTR contains putative microRNA target sites and is regulated by Dicer, its stability is not regulated by GSK3 inhibition or density. Our data show that GSK3beta regulates cadherin-11 expression in two ways: first a beta-catenin-independent regulation of cadherin-11 steady state mRNA levels, and second a beta-catenin-dependent effect on cadherin-11 3'UTR stability and protein translation. CONCLUSIONS: Cadherin-11 mRNA and protein levels are regulated by the activity of GSK3beta and a significant degree of this regulation is exerted by the GSK3 target, beta-catenin, at the level of the cadherin-11 3'UTR.