Targeting EMT using low-dose Teniposide by downregulating ZEB2-driven activation of RNA polymerase I in breast cancer.

Metastatic dissemination from the primary tumor is a complex process that requires crosstalk between tumor cells and the surrounding milieu and involves the interplay between numerous cellular-signaling programs. Epithelial-mesenchymal transition (EMT) remains at the forefront of orchestrating a shift in numerous cellular programs, such as stemness, drug resistance, and apoptosis that allow for successful metastasis. Till date, there is limited success in therapeutically targeting EMT. Utilizing a high throughput screen of FDA-approved compounds, we uncovered a novel role of the topoisomerase inhibitor, Teniposide, in reversing EMT. Here, we demonstrate Teniposide as a potent modulator of the EMT program, specifically through an IRF7-NMI mediated response. Furthermore, Teniposide significantly reduces the expression of the key EMT transcriptional regulator, Zinc Finger E-Box Binding Homeobox 2 (ZEB2). ZEB2 downregulation by Teniposide inhibited RNA polymerase I (Pol I) activity and rRNA biogenesis. Importantly, Teniposide treatment markedly reduced pulmonary colonization of breast cancer cells. We have uncovered a novel role of Teniposide, which when used at a very low concentration, mitigates mesenchymal-like invasive phenotype. Overall, its ability to target EMT and rRNA biogenesis makes Teniposide a viable candidate to be repurposed as a therapeutic option to restrict breast cancer metastases.

A high-throughput response to the SARS-CoV-2 pandemic.

Four years after the beginning of the COVID-19 pandemic, it is important to reflect on the events that have occurred during that time and the knowledge that has been gained. The response to the pandemic was rapid and highly resourced; it was also built upon a foundation of decades of federally funded basic and applied research. Laboratories in government, pharmaceutical, academic, and non-profit institutions all played roles in advancing pre-2020 discoveries to produce clinical treatments. This perspective provides a summary of how the development of high-throughput screening methods in a biosafety level 3 (BSL-3) environment at Southern Research Institute (SR) contributed to pandemic response efforts. The challenges encountered are described, including those of a technical nature as well as those of working under the pressures of an unpredictable virus and pandemic.

The occurrence of mental health symptoms in isotretinoin-treated adolescents.

BACKGROUND: Isotretinoin treatment for acne can reduce adverse psychiatric outcomes in adults, but there has been little investigation of the incidence of psychiatric outcomes in treated adolescents. METHODS: This retrospective cohort study using the Rochester Epidemiology Project identified 606 patients aged 12-18 prescribed isotretinoin over a 10-year period between January 1, 2008 and December 31, 2017. Medical records were reviewed to identify psychiatric diagnoses before and during isotretinoin therapy, as well as psychiatric symptoms not captured by formal diagnoses and changes to isotretinoin dosing because of psychiatric diagnoses or symptoms. RESULTS: One hundred seventy-seven (29.2%) had a psychiatric diagnosis prior to isotretinoin initiation, but 98 (16.2%) had a new psychiatric diagnosis or psychiatric symptom while taking isotretinoin. Patients with a psychiatric history were no more likely than those without to receive a new psychiatric diagnosis during treatment (4.5% vs. 3.7%; p = .650), but did experience more psychiatric symptoms, primarily low mood and mood swings (23.7% vs. 7.7%; p < .001). Only 25.5% of the 98 with a new psychiatric diagnosis or psychiatric symptom had a subsequent dose change. A dose change was more likely if patients received a new psychiatric diagnosis (41.7% vs. 20.3%; p = .037) or patients did not have a psychosocial explanation for psychiatric symptoms (34.4% vs. 10.8%; p = .009). CONCLUSIONS: A substantial proportion of adolescent patients prescribed isotretinoin had a prior psychiatric diagnosis. This predicts more psychiatric symptoms during isotretinoin treatment. Adolescents with a psychiatric history who have worsening symptoms and those with new-onset psychiatric symptoms would benefit from close monitoring while taking isotretinoin.

Development of small-molecule Tau-SH3 interaction inhibitors that prevent amyloid-ß toxicity and network hyperexcitability.

Alzheimer's disease (AD) is the leading cause of dementia and lacks highly effective treatments. Tau-based therapies hold promise. Tau reduction prevents amyloid-ß-induced dysfunction in preclinical models of AD and also prevents amyloid-ß-independent dysfunction in diverse disease models, especially those with network hyperexcitability, suggesting that strategies exploiting the mechanisms underlying Tau reduction may extend beyond AD. Tau binds several SH3 domain-containing proteins implicated in AD via its central proline-rich domain. We previously used a peptide inhibitor to demonstrate that blocking Tau interactions with SH3 domain-containing proteins ameliorates amyloid-ß-induced dysfunction. Here, we identify a top hit from high-throughput screening for small molecules that inhibit Tau-FynSH3 interactions and describe its optimization with medicinal chemistry. The resulting lead compound is a potent cell-permeable Tau-SH3 interaction inhibitor that binds Tau and prevents amyloid-ß-induced dysfunction, including network hyperexcitability. These data support the potential of using small molecule Tau-SH3 interaction inhibitors as a novel therapeutic approach to AD.

Factors associated with suicide attempts in the antecedent illness trajectory of bipolar disorder and schizophrenia.

BACKGROUND: Factors associated with suicide attempts during the antecedent illness trajectory of bipolar disorder (BD) and schizophrenia (SZ) are poorly understood. METHODS: Utilizing the Rochester Epidemiology Project, individuals born after 1985 in Olmsted County, MN, presented with first episode mania (FEM) or psychosis (FEP), subsequently diagnosed with BD or SZ were identified. Patient demographics, suicidal ideation with plan, self-harm, suicide attempts, psychiatric hospitalizations, substance use, and childhood adversities were quantified using the electronic health record. Analyses pooled BD and SZ groups with a transdiagnostic approach given the two diseases were not yet differentiated. Factors associated with suicide attempts were examined using bivariate methods and multivariable logistic regression modeling. RESULTS: A total of 205 individuals with FEM or FEP (BD = 74, SZ = 131) were included. Suicide attempts were identified in 39 (19%) patients. Those with suicide attempts during antecedent illness trajectory were more likely to be female, victims of domestic violence or bullying behavior, and have higher rates of psychiatric hospitalizations, suicidal ideation with plan and/or self-harm, as well as alcohol, drug, and nicotine use before FEM/FEP onset. Based on multivariable logistic regression, three factors remained independently associated with suicidal attempts: psychiatric hospitalization (OR = 5.84, 95% CI 2.09-16.33, p < 0.001), self-harm (OR = 3.46, 95% CI 1.29-9.30, p = 0.014), and nicotine use (OR = 3.02, 95% CI 1.17-7.76, p = 0.022). CONCLUSION: Suicidal attempts were prevalent during the antecedents of BD and SZ and were associated with several risk factors before FEM/FEP. Their clinical recognition could contribute to improve early prediction and prevention of suicide during the antecedent illness trajectory of BD and SZ.

Racial differences in pathways to care preceding first episode mania or psychosis: a historical cohort prodromal study.

Background: There is evidence suggesting racial disparities in diagnosis and treatment in bipolar disorder (BD) and schizophrenia (SZ). The purpose of this study is to compare psychiatric diagnoses and psychotropic use preceding a first episode of mania (FEM) or psychosis (FEP) in racially diverse patients. Methods: Using a comprehensive medical records linkage system (Rochester Epidemiology Project, REP), we retrospectively identified individuals diagnosed with BD or SZ and a documented first episode of mania or psychosis. Illness trajectory before FEP/FEM were characterized as the time from first visit for a mental health complaint to incident case. Pathways to care and clinical events preceding FEP/FEM were compared based on subsequent incident case diagnosis (BD or SZ) and self-reported race (White vs. non-White). Results: A total of 205 (FEM = 74; FEP = 131) incident cases were identified in the REP. Duration of psychiatric antecedents was significantly shorter in non-White patients, compared to White patients (2.2 ± 4.3 vs. 7.4 ± 6.6 years; p < 0.001) with an older age at time of first visit for a mental health complaint (15.7 ± 6.3 vs. 11.1 ± 6.0 years; p = 0.005). There were no significant differences by race in FEM pathway to care or age of first seeking mental health. Overall non-White patients had lower rates of psychotropic use. Conclusion: These data are unable to ascertain reasons for shorter duration of psychiatric antecedents and later age of seeking care, and more broadly first age of initial symptom presentation. If symptoms are confirmed to be earlier than first time seeking care in both groups, it would be important to identify barriers that racial minorities face to access timely psychiatric care and optimize early intervention strategies.

Antecedents to first episode psychosis and mania: Comparing the initial prodromes of schizophrenia and bipolar disorder in a retrospective population cohort.

OBJECTIVE: We aim to compare the psychiatric antecedents of schizophrenia (SZ) and bipolar disorder (BD). METHODS: Using the Rochester Epidemiology Project, we searched for residents of Olmsted County that had a diagnosis of SZ or BD. We confirmed each case using DSM-5 criteria and obtained the psychiatric antecedents. RESULTS: We identified 205 cases with first episode psychosis or mania (SZ = 131; BD = 74). The mean age at first visit for mental health reasons was 12.3 ± 6.3 years for SZ and 13.9 ± 5.6 years for BD. The duration of the initial prodrome (time from first mental health visit to first episode) was similar for both groups (SZ 8.3 ± 6.2 years vs BD 7.3 ± 5.9 years). We found that SZ and BD have overlapping antecedents, but SZ was more common in males and in foreign born and had more learning deficits before the first episode. BD was more common in white population and had higher rates of depressive and adjustment disorders prior to first episode. BD also had more affective symptoms, nightmares, and panic attacks before the first episode. Both groups had similarly high rates of substance use (SZ 74 % vs BD 74.3 %), prescription of antidepressants (SZ 46.6 % vs BD 55.4 %) and stimulants (SZ 30.5 % vs BD 22.9 %). CONCLUSIONS: The psychiatric antecedents of SZ and BD usually start during adolescence, overlap, and present in unspecific ways. The initial prodromes are more alike than distinct. Further studies are encouraged to continue looking for specific factors that distinguish the antecedents of these two disorders.

Systematic Review of Interventions to Reduce Suicide Risk in Transgender and Gender Diverse Youth.

Transgender youth experience high rates of suicidal ideation and suicide attempts. This systematic review sought to examine interventions for suicide prevention in transgender children and adolescents. Literature related to suicide in the transgender population was systematically collected in accordance with PRISMA criteria. Searches identified studies with at least one suicide prevention method for participants ages 24 years or younger with gender identity and sex clearly defined. Primary outcomes include suicide-related thoughts and behaviors. A total of 1558 citations were identified with 17 articles meeting inclusion criteria. Interventions with potential effectiveness included a gender-affirming crisis hotline, medical care via interdisciplinary gender clinics, online media-based outreach, safety and connectedness in schools, and family system-based interventions. In the included studies, the overall quality of evidence was low and the risk of bias high. Further high-quality studies are needed.

To treat or not to treat? High-potency benzodiazepine use in a case of comorbid hallucinogen persisting perception disorder and alcohol use disorder.

Hallucinogen persisting perception disorder (HPPD) is characterized by visual disturbances that resemble psychedelic intoxication and linger after use has ceased. The most common substances precipitating HPPD, lysergic acid diethylamide (LSD) and psilocybin, are posited to do so via damage to serotonergic neurons involved in vision. Mr. N is a 37-year-old with a history of alcohol, cannabis, LSD, cocaine, and nicotine use disorders who described visual distortions that resolved when he drank heavily or received benzodiazepines for withdrawal. He did not appear psychotic. Over 20 years after his last LSD use, he continued to experience illusions of halos around objects, moving walls, and figures appearing cartoonish. He understood that his perceptual disturbances were not reality based. During hospitalization for suicidal ideation, laboratory tests, head computed tomography (CT), and electroencephalogram (EEG) studies offered no explanation for his visual disturbances other than HPPD. The visual distortions remitted with scheduled clonazepam treatment, although chemical dependency treatment programs were hesitant to accept him while on a benzodiazepine. This case emphasizes the importance of diagnostic clarification when patients present with perceptual disturbances that do not fit typical psychotic presentations. Our discussion will distinguish misperceptions from hallucinations and review the pathophysiology of HPPD. Last, we will discuss management strategies for patients with co-occurring HPPD and substance use disorders. It is necessary to discern the correct cause of visual disturbances in order to provide proper treatment. The risks and benefits of long-term benzodiazepine use must be weighed when deciding whether to prescribe them for patients with comorbid HPPD and alcohol use disorder. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Oscillations of Drops with Mobile Contact Lines on the International Space Station: Elucidation of Terrestrial Inertial Droplet Spreading.

We analyze shape oscillations of sessile water drops with fully mobile contact lines (CL) aboard the International Space Station. The unique microgravity environment enables the study of centimeter-sized droplets with associated inertial-capillary motions. Plane-normal substrate vibrations induce resonance behaviors quantified by frequency scans from which the natural frequencies and mode shapes are identified for nine different hydrophobic surfaces. Experimental observations agree well with, and validate, a recent spectral prediction of mobile CL sessile drop oscillations. The experimental findings help elucidate terrestrial droplet inertial spreading, a poorly understood phenomenon pervasive in many processes.

The Effect of Abuse and Mistreatment on Healthcare Providers (TEAM): A Survey Assessing the Prevalence of Aggression From Patients and Their Families and Its Impact.

OBJECTIVE: Aggression from patients and families on health care providers (HCP) is common yet understudied. We measured its prevalence and impact on HCPs in inpatient and outpatient settings. METHODS: Four thousand six hundred seven HCPs employed by a community teaching hospital received an anonymous survey with results analyzed. RESULTS: Of 1609 HCPs (35%) completing the survey, 88% of inpatient staff reported experiencing different types of aggression compared to 82% in outpatient setting. Almost half did not report it to their supervisor. Younger staff were more likely to report abuse. Negative impacts on productivity and patient care were reported. A third of all responders' indicated negative effects on mental health. CONCLUSIONS: Despite negative impacts on staff wellbeing and productivity, patient/family aggression toward HCPs is highly prevalent and underreported. Our healthcare system needs measures to address staff security and wellness.

Model of spontaneous droplet transport on a soft viscoelastic substrate with nonuniform thickness.

Dynamic wetting of droplets on soft solids has many industrial and biological applications which require an understanding of the underlying fluid transport mechanism. Here we study the case of a droplet on a viscoelastic substrate of variable thickness which is known to give rise to a spontaneous droplet transport. This phenomenon is known as droplet durotaxis and has been observed experimentally. Here we develop a model assuming a small linear gradient in substrate thickness to reveal the physical mechanism behind this transport phenomena. We show the variable thickness causes an asymmetric deformation along the drop contact line, which causes a variation in the contact angle. This generates a net driving force on the drop, causing it to move in the direction of higher thickness. The resulting drop velocity is determined by balancing the work done by the moving drop with the viscoelastic dissipation of the substrate (viscoelastic braking) and computed from a self-consistent model. We find our results to be in qualitative agreement to previously reported experimental findings.

Surgical Scrubbing and Attire in the Operating Room and ICU: A Multicultural Guide.

In response to the challenges faced as diverse students when first encountering the intricacies of scrubbing into the operating room (OR), we have prepared a rudimentary surgical skills guide to supplement the knowledge of students and educators alike. In keeping with the need to adapt standard protocols to accommodate religious and cultural practices, this guide focuses on hijab, natural hair, dastar, protective styles, and beard protocol in the OR. It addresses some of the personal protective equipment needs of Muslims, Orthodox Jews, Sikhs, and groups maintaining beards as a part of cultural or religious practices. We intend this guide to serve as a foundation on which the medical field can update its educational practices in line with the increased diversity of the medical professions, while also continuing to ensure the safety of OR and ICU patients. This guide also highlights COVID-19-specific changes in personal protective equipment and seeks to open up a conversation about the necessity of currently held surgical practices.

Clinical Characteristics, Outcomes, Disposition, and Acute Care of Children and Adolescents Treated for Acetaminophen Toxicity.

OBJECTIVE: Acetaminophen is a common cause of intentional and inadvertent overdoses among children and adolescents worldwide. Little is known about characteristics and clinical outcomes of these youths. The primary goal of this naturalistic study was to describe the psychiatric characteristics, medical management, outcomes, and dispositions of children and adolescents evaluated for excessive acetaminophen exposure. METHODS: The Rochester Epidemiology Project database was searched for all patients ages 0-18 treated for excessive acetaminophen exposure in Olmsted County, Minnesota, during a 7-year period (2004-2010). Demographic factors, overdose intentionality, medical and psychiatric treatment, mental health and addiction history, and disposition from the emergency department (ED) were documented. RESULTS: Of 110 cases of acetaminophen overdose (89 female patients and 21 male patients), 97 (88%) were intentional and 13 (12%) were unintentional. Fifteen patients (14%) were discharged from the ED, and 69 (63%) required admission to a medical unit. Sixty-four (59%) received N-acetylcysteine. Ninety-eight (89%) were evaluated by psychiatry, and 80 (73%) were admitted for psychiatric hospitalization. Most had at least one psychiatric diagnosis, most commonly depression (55%); 22 (20%) had a prior suicide attempt. Substance use was common, notably alcohol dependence (N=16, 15%), alcohol abuse (N=18, 16%), and cannabis abuse (N=18, 16%). All survived and recovered without liver transplant. CONCLUSIONS: Among pediatric patients with acetaminophen overdoses, psychiatric comorbidities and substance use were common. Most received both inpatient medical and psychiatric treatment. Interventions that restrict acetaminophen access are needed for this population, as are suicide risk reduction interventions for delivery in emergency settings.

Correction: Plateau-Rayleigh instability in a soft viscoelastic material.

Correction for 'Plateau-Rayleigh instability in a soft viscoelastic material' by S. I. Tamim et al., Soft Matter, 2021, DOI: .