Regulated induced proximity targeting chimeras-RIPTACs-A heterobifunctional small molecule strategy for cancer selective therapies.

We describe a protein proximity inducing therapeutic modality called Regulated Induced Proximity Targeting Chimeras or RIPTACs: heterobifunctional small molecules that elicit a stable ternary complex between a target protein (TP) selectively expressed in tumor cells and a pan-expressed protein essential for cell survival. The resulting co-operative protein-protein interaction (PPI) abrogates the function of the essential protein, thus leading to death selectively in cells expressing the TP. This approach leverages differentially expressed intracellular proteins as novel cancer targets, with the advantage of not requiring the target to be a disease driver. In this chemical biology study, we design RIPTACs that incorporate a ligand against a model TP connected via a linker to effector ligands such as JQ1 (BRD4) or BI2536 (PLK1) or CDK inhibitors such as TMX3013 or dinaciclib. RIPTACs accumulate selectively in cells expressing the HaloTag-FKBP target, form co-operative intracellular ternary complexes, and induce an anti-proliferative response in target-expressing cells.

A Pilot Randomized Controlled Trial of Text Messages to Improve Well-Child Visit Attendance After No-Show.

OBJECTIVE: Evaluate the effectiveness of text messages to systematically engage parents/guardians ("caregivers") to reschedule a well-child visit (WCV) that was missed ("no-show") and attend that rescheduled WCV visits. METHODS: Patients <18 years in one of five pediatrics or family medicine clinics, in one health system in the Southeast US, were eligible. Patients without a rescheduled WCV after a no-show were randomized into intervention (text messages) or care-as-usual comparison, stratified by language (English/Spanish). Enrollment occurred May-July 2022. Up to three text messages were sent to caregivers one week apart via REDCap and Twilio, advising how to reschedule the missed appointment by phone or health portal. Primary outcomes were 1) rescheduling a WCV within 6 weeks of no-show and 2) completing a rescheduled WCV within 6 weeks. Risk differences (RD) and odds ratios (OR) were used to evaluate the effect of text messages. RESULTS: Seven hundred and twenty patients were randomized and analyzed (texts: 361, comparison: 359). The proportion rescheduling WCV after text versus usual care was English: 18.85% versus 15.02%, respectively, and Spanish: 5.94% versus 8.14%, with overall RD+ 1.98% (95% CI: -1.85, 5.81) and OR 1.21 (95% CI: 0.79, 1.84; P-value .38). Completed WCV rates in text or usual care were English: 13.08% versus 6.59%, and Spanish: 5.81% versus 5.94% with texts associated with RD+ 2.83% (95% CI: 1.66, 4.00) and OR 1.86 (95% CI: 1.09, 3.19). CONCLUSION: Text message follow-up after a no-show WCV may positively impact attendance at WCVs rescheduled in the subsequent 6 weeks. TRIAL REGISTRATION: ClinicalTrials.gov NCT05086237.

Considerations from employed African-American and white prostate cancer survivors on prostate cancer treatment and survivorship: a qualitative analysis.

OBJECTIVE: To solicit information/suggestions from prostate cancer survivors to improve survivorship experiences specific to work/workability. DESIGN: The study employed a qualitative/phenomenological approach. Black/African-American and white prostate cancer survivors who: (1) had prostatectomy or radiation therapy 6-36 months prior, (2) were working for pay within 30 days before having treatment, and (3) expected to be working for pay 6 months later (n = 45) were eligible for this study. Survivors were engaged in 60-to-90-minute structured interviews. Content analysis was used to ascertain prominent themes. RESULTS: Participants had the following recommendations for survivors: ask about research on treatment options and side effects; speak with other survivors about cancer diagnosis; and inform family/friends and employers about needed accommodations. Considerations for family/friends emphasized the significance of instrumental (e.g. help finding information) and emotional support (e.g. encouragement). Employer/co-worker considerations most often related to work-related accommodations/support and avoiding stigmatization of the survivor. Considerations for healthcare providers commonly included the provision of unbiased, plain-language communication about treatment options and side effects. No major differences existed by race. CONCLUSIONS: Needs of employed PrCA survivors, regardless of their race or treatment type, are commonly related to their desire for informational, instrumental, and/or emotional support from family/friends, employers/co-workers, and healthcare providers. The requested supports are most often related to the side effects of prostate cancer treatment.

Stereospecific Furanosylations Catalyzed by Bis-thiourea Hydrogen-Bond Donors.

We report a new method for stereoselective O-furanosylation reactions promoted by a precisely tailored bis-thiourea hydrogen-bond-donor catalyst. Furanosyl donors outfitted with an anomeric dialkylphosphate leaving group undergo substitution with high anomeric selectivity, providing access to the challenging 1,2-cis substitution pattern with a range of alcohol acceptors. A variety of stereochemically distinct, benzyl-protected glycosyl donors were engaged successfully as substrates. Mechanistic studies support a stereospecific mechanism in which rate-determining substitution occurs from a catalyst-donor resting-state complex.

Suicide attempts in a longitudinal sample of adolescents followed through adulthood: Evidence of escalation.

OBJECTIVES: This study was designed to examine escalation in repeat suicide attempts from adolescence through adulthood, as predicted by sensitization models (and reflected in increasing intent and lethality with repeat attempts, decreasing amount of time between attempts, and decreasing stress to trigger attempts). METHOD: In a prospective study of 180 adolescents followed through adulthood after a psychiatric hospitalization, suicide attempts, and antecedent life events were repeatedly assessed (M = 12.6 assessments, SD = 5.1) over an average of 13 years 6 months (SD = 4 years 5 months). Multivariate logistic, multiple linear, and negative binomial regression models were used to examine patterns over time. RESULTS: After age 17-18, the majority of suicide attempts were repeat attempts (i.e., made by individuals with prior suicidal behavior). Intent increased both with increasing age, and with number of prior attempts. Medical lethality increased as a function of age but not recurrent attempts. The time between successive suicide attempts decreased as a function of number of attempts. The amount of precipitating life stress was not related to attempts. CONCLUSIONS: Adolescents and young adults show evidence of escalation of recurrent suicidal behavior, with increasing suicidal intent and decreasing time between successive attempts. However, evidence that sensitization processes account for this escalation was inconclusive. Effective prevention programs that reduce the likelihood of individuals attempting suicide for the first time (and entering this cycle of escalation), and relapse prevention interventions that interrupt the cycle of escalating suicidal behavior among individuals who already have made attempts are critically needed. (PsycINFO Database Record

Evaluating the predictive validity of suicidal intent and medical lethality in youth.

OBJECTIVES: To examine whether suicidal intent and medical lethality of past suicide attempts are predictive of future attempts, the association between intent and lethality, and the consistency of these characteristics across repeated attempts among youth. METHOD: Suicide attempts in a 15-year prospective study of 180 formerly psychiatrically hospitalized adolescents (M(age at hospitalization) = 14.83; 51% female; 80% Caucasian) were characterized with the Subjective Intent Rating Scale and Lethality of Attempt Rating Scale. Anderson-Gill recurrent events survival models and generalized estimating equations were used to assess predictive validity. Generalized linear models were used to examine stability of characteristics across attempts. RESULTS: Neither intent nor lethality from the most recent attempt predicted future attempts. The highest level of intent and most severe lethality of attempts during the follow-up predicted subsequent attempts, but the degree to which highest intent and most severe lethality contributed to prediction after considering methods of suicide attempts, past number of attempts, or psychiatric diagnoses was mixed. Across successive attempts, there was little consistency in reported characteristics. Intent and lethality were related to each other only for attempts occurring in early adulthood. CONCLUSIONS: Highest intent and lethality were better predictors of future attempts than intent and lethality of the most recent attempt. However, these characteristics should be considered as predictors only within the context of other factors. For youth, clinicians should not infer true intent from the lethality of attempts, nor assume that characteristics of future suicide attempts will be similar to those of previous attempts.

Psychiatric diagnoses as contemporaneous risk factors for suicide attempts among adolescents and young adults: developmental changes.

The purpose of this prospective, naturalistic study was to examine the relationships between suicide attempts and contemporaneous psychiatric disorders, and developmental changes in these relationships from adolescence to young adulthood. The sample consisted of 180 adolescents, 12-19 years of age at hospitalization, repeatedly assessed for up to 13 years (n = 1,825 assessments). Semistructured psychiatric diagnostic instruments were administered at repeated assessments to assess psychiatric disorders and suicide attempts. After controlling for demographic variables and prehospitalization suicide attempts, most contemporaneous psychiatric disorders (major depressive disorder [MDD], dysthymic disorder, generalized anxiety disorder [GAD], panic disorder, attention-deficit/hyperactivity disorder [AD/HD], conduct disorder, and substance use disorder [SUD]) were related to increased risk of attempts. The relationship between suicide attempts and MDD, GAD, AD/HD, and SUD strengthened as participants got older. MDD, dysthymic disorder, GAD, and panic disorder were more commonly associated with repeat than 1st-time suicide attempts. In sum, most major psychiatric disorders are associated with increased risk for suicide attempts, but the strength of the relationships between these disorders and attempts changes over the course of development.

Trait anger, anger expression, and suicide attempts among adolescents and young adults: a prospective study.

Previous studies of the relationship between anger, anger expression, and suicidal behavior have been largely cross-sectional and have yielded mixed findings. In a prospective, naturalistic study, we examined how trait anger and anger expression influenced the likelihood of suicide attempts among 180 adolescents followed for up to 13.3 years after discharge from an inpatient psychiatry unit. Results showed that higher trait anger and anger expressed outwardly over the follow-up was related to increased likelihood of suicide attempts among boys. For girls, trait anger and both the inward and outward expression of anger moderated the risk for suicide attempts associated with major depression. These results are interpreted in light of theory regarding behavioral activation and behavioral inhibition systems.