Evaluation of forces applied to tissues during robotic-assisted surgical tasks using a novel force feedback technology.

BACKGROUND: The absence of force feedback (FFB) is considered a technical limitation in robotic-assisted surgery (RAS). This pre-clinical study aims to evaluate the forces applied to tissues using a novel integrated FFB technology, which allows surgeons to sense forces exerted at the instrument tips. METHODS: Twenty-eight surgeons with varying experience levels employed FFB instruments to perform three robotic-assisted surgical tasks, including retraction, dissection, and suturing, on inanimate or ex-vivo models, while the instrument sensors recorded and conveyed the applied forces to the surgeon hand controllers of the robotic system. Generalized Estimating Equations (GEE) models were used to analyze the mean and maximal forces applied during each task with the FFB sensor at the "Off" setting compared to the "High" sensitivity setting for retraction and to the "Low", "Medium", and "High" sensitivity settings for dissection and suturing. Sub-analysis was also performed on surgeon experience levels. RESULTS: The use of FFB at any of the sensitivity settings resulted in a significant reduction in both the mean and maximal forces exerted on tissue during all three robotic-assisted surgical tasks (p < 0.0001). The maximal force exerted, potentially associated with tissue damage, was decreased by 36%, 41%, and 55% with the use of FFB at the "High" sensitivity setting while performing retraction, dissection, and interrupted suturing tasks, respectively. Further, the use of FFB resulted in substantial reductions in force variance during the performance of all three types of tasks. In general, reductions in mean and maximal forces were observed among surgeons at all experience levels. The degree of force reduction depends on the sensitivity setting selected and the types of surgical tasks evaluated. CONCLUSIONS: Our findings demonstrate that the utilization of FFB technology integrated in the robotic surgical system significantly reduced the forces exerted on tissue during the performance of surgical tasks at all surgeon experience levels. The reduction in the force applied and a consistency of force application achieved with FFB use, could result in decreases in tissue trauma and blood loss, potentially leading to better clinical outcomes in patients undergoing RAS. Future studies will be important to determine the impact of FFB instruments in a live clinical environment.

Clinical and Molecular Analysis of Longitudinal Rhinitis Phenotypes in an Urban Birth Cohort.

BACKGROUND: Chronic rhinitis symptoms cause significant health burden among children and can have a heterogeneous presentation. Defining phenotypes of childhood chronic rhinitis and associated pathobiology may lead to prevention or improved treatments. OBJECTIVES: To identify longitudinal patterns of rhinitis symptoms in childhood and determine their associations with early life risk factors, allergic comorbidities, and nasal epithelial cell gene expression. METHODS: Chronic rhinitis symptoms were evaluated from ages 1 through 11 years in 485 urban children at high risk for allergic disease in the Urban Environment and Childhood Asthma (URECA) birth cohort. We identified longitudinal rhinitis phenotypes and their relationships to early life exposures, atopic comorbidities, and patterns of nasal epithelial gene expression at age 11 years. RESULTS: Chronic rhinitis symptoms started early in many children and were a risk factor for developing aeroallergen sensitization. We identified four longitudinal rhinitis phenotypes: low/minimal disease, persistent, persistent decreasing, and late increasing. Persistent rhinitis was most closely linked to allergic sensitization and asthma. Risk factors for persistent rhinitis included frequent colds (p<0.001), antibiotic use (p<0.001), and reduced exposure to common indoor aeroallergens (p=0.003). Compared to low/minimal disease, rhinitis phenotypes were associated with increased expression of canonical Type 2 genes and decreased expression of immune response genes. CONCLUSIONS: In urban children, rhinitis symptoms often precede aeroallergen sensitization. Rhinitis phenotypes based on symptoms had distinct risk factors and nasal transcriptome. These results suggest that focusing on early life risk factors and distinct immune mechanisms may be a target to preventing chronic rhinitis in childhood.

Inflammation mediated by gut microbiome alterations promotes lung cancer development and an immunosuppressed tumor microenvironment.

Accumulating evidence indicates that the gut microbiome influences cancer progression and therapy. We recently showed that progressive changes in gut microbial diversity and composition are closely associated with tobacco-associated lung adenocarcinoma (LUAD) in a human-relevant mouse model. Furthermore, we demonstrated that the loss of the antimicrobial protein Lcn2 in these mice, exacerbates pro-tumor inflammatory phenotypes while further reducing microbial diversity. Yet, how gut microbiome alterations impinge on LUAD development remains poorly understood. Here, we investigated the role of gut microbiome changes in LUAD development using fecal microbiota transfer and delineated a pathway by which gut microbiome alterations incurred by loss of Lcn2 fostered the proliferation of pro-inflammatory bacteria of the genus Alistipes, triggering gut inflammation. This inflammation propagated systemically, exerting immunosuppression within the tumor microenvironment, augmenting tumor growth through an IL-6-dependent mechanism and dampening response to immunotherapy. Corroborating our preclinical findings, we found that patients with LUAD with a higher relative abundance of Alistipes species in the gut showed diminished response to neoadjuvant immunotherapy. These insights reveal the role of microbiome-induced inflammation in LUAD and present new potential targets for interception and therapy.

Optimizing outcomes in paraesophageal hernia repair: a novel critical view.

BACKGROUND: The recurrence rate of paraesophageal hernia repair (PEHR) is high with reported rates of recurrence varying between 25 and 42%. We present a novel approach to PEHR that involves the visualization of a critical view to decrease recurrence rate. Our study aims to investigate the outcomes of PEHR following the implementation of a critical view. METHODS: This is a single-center retrospective study that examines operative outcomes in patients who underwent PEHR with a critical view in comparison to patients who underwent standard repair. The critical view is defined as full dissection of the posterior mediastinum with complete mobilization of the esophagus to the level of the inferior pulmonary vein, visualization of the left crus of the diaphragm as well as the left gastric artery while the distal esophagus is retracted to expose the spleen in the background. Bivariate chi-squared analysis and multivariable logistic and linear regressions were used for statistical analysis. RESULTS: A total of 297 patients underwent PEHR between 2015 and 2023, including 207 with critical view and 90 with standard repair which represents the historic control. Type III hernias were most common (48%) followed by type I (36%), type IV (13%), and type II (2.0%). Robotic-assisted repair was most common (65%), followed by laparoscopic (22%) and open repair (14%). Fundoplications performed included Dor (59%), Nissen (14%), Belsey (5%), and Toupet (2%). Patients who underwent PEHR with critical view had lower hernia recurrence rates compared to standard (9.7% vs 20%, P < .01) and lower reoperation rates (0.5% vs 10%, P < .001). There were no differences in postoperative complications on unadjusted bivariate analysis; however, adjusted outcomes revealed a lower odds of postoperative complications in patients with critical view (AOR .13, 95% CI .05-.31, P < .001). CONCLUSION: We present dissection of a novel critical view during repair of all types of paraesophageal hernia that results in reproducible, consistent, and durable postoperative outcomes, including a significant reduction in recurrence and reoperation.

Drug Screening Using Normal Cell and Cancer Cell Mixture in an Automated 3D Cell Culture System.

Three-dimensional (3D) cell culture creates a more physiologically relevant environment for enhanced drug screening capabilities using microcarriers. An automated 3D system that integrates robotic manipulators, liquid handling systems, sensors, and environment control systems has the capacity to handle multiple samples in parallel, perform repetitive tasks, and provide real-time monitoring and analysis. This chapter describes a potential 3D cell culture drug screening model by combining renal proximal tubule cells as a representative normal cell line with cancer cell lines. This combination is subjected to drug screening to evaluate the drug's efficacy in suppressing cancer cells while minimizing impact on normal cells with the added benefit of having the ability to separate the two cell types by magnetic isolation for high content screens including mass spectrometry-based proteomics. This study presents advancements in 3D cell culture techniques, emphasizing the importance of automation and the potential of microcarriers in drug screening and disease modeling.

Decisional Conflict Among Patients Newly Diagnosed With Clinical T1 Renal Masses: A Prospective Study.

PURPOSE: Because multiple management options exist for clinical T1 renal masses, patients may experience a state of uncertainty about the course of action to pursue (ie, decisional conflict). To better support patients, we examined patient, clinical, and decision-making factors associated with decisional conflict among patients newly diagnosed with clinical T1 renal masses suspicious for kidney cancer. MATERIALS AND METHODS: From a prospective clinical trial, participants completed the Decisional Conflict Scale (DCS), scored 0 to 100 with < 25 associated with implementing decisions, at 2 time points during the initial decision-making period. The trial further characterized patient demographics, health status, tumor burden, and patient-centered communication, while a subcohort completed additional questionnaires on decision-making. Associations of patient, clinical, and decision-making factors with DCS scores were evaluated using generalized estimating equations to account for repeated measures per patient. RESULTS: Of 274 enrollees, 250 completed a DCS survey; 74% had masses ≤ 4 cm in size, while 11% had high-complexity tumors. Model-based estimated mean DCS score across both time points was 17.6 (95% CI 16.0-19.3), though 50% reported a DCS score ≥ 25 at least once. On multivariable analysis, DCS scores increased with age (+2.64, 95% CI 1.04-4.23), high- vs low-complexity tumors (+6.50, 95% CI 0.35-12.65), and cystic vs solid masses (+9.78, 95% CI 5.27-14.28). Among decision-making factors, DCS scores decreased with higher self-efficacy (-3.31, 95% CI -5.77 to -0.86]) and information-seeking behavior (-4.44, 95% CI -7.32 to -1.56). DCS scores decreased with higher patient-centered communication scores (-8.89, 95% CI -11.85 to -5.94). CONCLUSIONS: In addition to patient and clinical factors, decision-making factors and patient-centered communication relate with decisional conflict, highlighting potential avenues to better support patient decision-making for clinical T1 renal masses.

Preliminary evaluation of behavior technician burnout when working with boarded and traditional psychiatric inpatients diagnosed with developmental disabilities.

PROBLEM: The COVID-19 pandemic has led to a youth mental health crisis, with research demonstrating an increased prevalence of depression, anxiety, and disruptive behavior in youth compared to pre-pandemic years. Consequently, the insurgence of emergency psychiatric evaluations has increased the demands for extended inpatient stay (or patient boarding) at various licensed treatment facilities. Questions remain about the extent of burnout being experienced by behavior technicians who are caring for these patients. METHODS: The Shirom-Melamed Burnout Measure was used to evaluate symptoms of burnout of behavior technicians practicing at a specialized psychiatric inpatient unit. Comparisons were made for instances of caring for boarded (meeting criteria for discharge but unable to be discharged due to disposition) and traditional patients (short-term treatment). FINDINGS: Behavior technicians caring for boarded patients reported significantly higher scores in overall stress, physical exhaustion, cognitive fatigue, and emotional exhaustion than those managing patients getting traditional care. CONCLUSIONS: Extensive burnout can have adverse impacts at both the personal level (staff well-being, individual staff-patient interactions) and clinic level (daily operations and service, general quality of care). Efforts need to be made to address this issue to prevent staff turnover.

Association Between Anatomic and Clinical Indicators of Injury Severity After Moderate-Severe Traumatic Brain Injury: A Pilot Study Using Multiparametric Magnetic Resonance Imaging.

This study sought to identify whether an anatomical indicator of injury severity as measured by multiparametric magnetic resonance imaging (MRI) including magnetic resonance elastography (MRE), is predictive of a clinical measure of injury severity after moderate-severe traumatic brain injury (TBI). Nine individuals who were admitted to acute inpatient rehabilitation after moderate-to-severe TBI completed a comprehensive MRI protocol prior to discharge from rehabilitation, which included conventional MRI with diffusion tensor imaging (DTI). Of those, five of nine also underwent brain MRE to measure the brain parenchyma stiffness. Clinical severity of injury was measured by the length of post-traumatic amnesia (PTA). MRI-assessed non-hemorrhage contusion score and hemorrhage score, DTI-measured white matter fractional anisotropy, and MRE-measured lesion stiffness were all assessed. A higher hemorrhagic score was significantly associated with a longer length of PTA (p = 0.026). Participants with a longer PTA tended to have a higher non-hemorrhage contusion score and softer contusion lesions than the contralateral control side, although the small sample size did not allow for assessment of a significant association. To our knowledge, this is the first report applying MRI/MRE imaging protocol to quantitate altered brain anatomy after moderate-severe TBI and its association with PTA, a known clinical predictor of post-acute outcome. Future larger studies could lead to the development of prediction models that integrate clinical data with anatomical (MRI), structural (DTI), and mechanical (MRE) changes caused by TBI, to inform prognosis and care planning.

A cyclin D1 intrinsically disordered domain accesses modified histone motifs to govern gene transcription.

The essential G1-cyclin, CCND1, is frequently overexpressed in cancer, contributing to tumorigenesis by driving cell-cycle progression. D-type cyclins are rate-limiting regulators of G1-S progression in mammalian cells via their ability to bind and activate CDK4 and CDK6. In addition, cyclin D1 conveys kinase-independent transcriptional functions of cyclin D1. Here we report that cyclin D1 associates with H2BS14 via an intrinsically disordered domain (IDD). The same region of cyclin D1 was necessary for the induction of aneuploidy, induction of the DNA damage response, cyclin D1-mediated recruitment into chromatin, and CIN gene transcription. In response to DNA damage H2BS14 phosphorylation occurs, resulting in co-localization with γH2AX in DNA damage foci. Cyclin D1 ChIP seq and γH2AX ChIP seq revealed ~14% overlap. As the cyclin D1 IDD functioned independently of the CDK activity to drive CIN, the IDD domain may provide a rationale new target to complement CDK-extinction strategies.

Associations between paraspinal muscle characteristics and spinal curvature in conservatively treated adolescent idiopathic scoliosis: a systematic review.

BACKGROUND CONTEXT: Children with adolescent idiopathic scoliosis (AIS) may show asymmetrical paraspinal muscle characteristics. PURPOSE: To summarize the evidence regarding: (1) the associations between various paraspinal muscle characteristics and spinal curvature; (2) whether paraspinal muscle properties significantly differed between children with and without AIS; and (3) whether baseline paraspinal muscle characteristics predicted curve progression. STUDY DESIGN/SETTING: Systematic literature review. METHODS: Five databases (CINAHL, Academic Search Premier, MEDLINE, Scopus, and PubMed) were searched from inception to May 2022. This protocol was registered in the PROSPERO database of systematic reviews CRD 42020171263. The Critical appraisal skills program, the Appraisal Tool for Cross-Sectional Studies and Quality In Prognosis Studies tool were used to evaluate the risk of bias of the included studies. The strength of evidence of each identified association was determined by the Grading of Recommendations Assessment, Development, and Evaluation System (GRADE). RESULTS: Of 1,530 identified citations, four cohort, 17 cross-sectional, and 23 case-control studies including 31 with low, nine with moderate and four with high risk of bias were included. Low to very low-strength evidence supported that the convex side of the curve had more type I muscle fibers, higher muscle volume and paraspinal muscle activity, while the concavity had more intramuscular fatty infiltration. Very low-strength evidence substantiated greater side-to-side surface electromyography signals during left trunk bending in prone lying, standing, and standing with perturbation between people with and without AIS. Also, low to very low-strength evidence supported that a larger side-to-side surface electromyography ratio at the lower end vertebra predicted curve progression. CONCLUSIONS: Our review highlights that paraspinal muscles on the concavity of the curve demonstrate consistent changes (ie, altered muscle-related gene expression, muscle atrophy, increased fatty infiltration, reduced type I fibers, and reduced muscle activity), which may be the cause or consequence.

Antimicrobial photocatalysis using bio-hydrothermally synthesized Zinc oxide nanoparticles in the management of periodontitis: a prospective split-mouth, double-blind, randomized, controlled clinical trial.

BACKGROUND: The antimicrobial activity of metallic nanoparticles (NPs) has been confirmed to fight a broad spectrum of microorganisms, through antimicrobial effects that are amplified when these particles are irradiated with light of the proper wavelength. This is the first study to use phytoconjugated Zinc oxide (ZnO) NPs containing traces of active biomolecules derived from Emblica officinalis (E. officinalis) plant extract in antimicrobial photocatalysis (PCT) during non-surgical periodontal therapy. OBJECTIVES: This study aimed to evaluate the effects of repeated PCT application in the treatment of periodontitis, using a gel containing bio-hydrothermally synthesized ZnO NPs and visible light as an adjunct to scaling and root planing (SRP). METHODOLOGY: In total, 16 systemically healthy volunteers with stage 3 grade B generalized periodontitis were recruited for this prospective double blind, randomized placebo-controlled trial. After receiving SRP, the subjects received the following interventions in a split-mouth design at baseline, 1 week and 1 month: Group 1 - Placebo gel + Sham PCT; Group 2 - Nano ZnO gel + Sham PCT; Group 3 - Placebo gel + PCT; and Group 4 - Nano ZnO gel + PCT. The site-specific profile of Porphyromonas gingivalis in the subgingival plaque and clinical parameters (Plaque Index, Gingival Index, Gingival Bleeding Index, Probing pocket Depth and Clinical Attachment Level) were assessed at baseline, 1 month and 3 months. RESULTS: All interventions tested caused participants' clinical and microbiological parameters to generally improve after 3 months. Subjects who received the Nano ZnO gel + PCT combination showed a sustained and progressive improvement in their treatment outcomes, a result that presented statistically significant differences from the outcomes obtained through the remaining interventions, at all time points during the study period. CONCLUSIONS: The repeated application of PCT using bio-hydrothermally synthesized ZnO NPs can effectively complement SRP in the non-surgical treatment of Periodontitis.

Two cases of Rapunzel syndrome in adult males.

Trichobezoar are foreign bodies formed from undigested hairs that accumulate in the gastrointestinal tract and cause obstruction. Trichobezoar are usually found in the stomach but when the tail of the bezoar extends into the small intestine it is referred to as Rapunzel syndrome. Patients are usually females and have a history of psychiatric illness. However, in this study, we present two cases of Rapunzel syndrome in adult male patients that were managed with surgery. Trichobezoar should be considered in all patients with a history of psychiatric illness presenting with abdominal symptoms regardless of gender.

Associations Between Parenting Behaviors and Behavioral Problems in Young Children With Developmental Delays.

Children with developmental delays (DD) are at heightened risk for developing behavior problems, which contribute to parenting stress and caregiving burden. There is an established relation between parenting behaviors and child developmental outcomes with less known about parent-child interactions in young children with DD. The present study examined the associations between parenting behaviors and child behavior in a sample of 180 families with preschool-aged children with DD. Results indicated that caregivers' harsh and coercive behaviors were associated with observed challenging behavior in children. Child age, as well as the number of commands issued by caregivers were associated with noncompliance in children. The significance and limitations of these findings are discussed, as well as recommendations for interventions and future research.

Social Determinants of Health and Parenting Self-Efficacy Among Mothers of Preterm Infants.

Objective: To explore the relationships between social and environmental factors and parenting self-efficacy (PSE) among mothers of preterm infants hospitalized in neonatal intensive care units (NICUs) using a social determinants of health (SDoH) framework. Method: We analyzed data from a prospective cohort study that included 187 mother-infant dyads admitted to four NICUs in the Mountain West region between June 2017 and December 2019. We used multivariable linear regression models to assess the independent associations between maternal and infant characteristics and PSE. Results: Our final multiple linear regression model predicting the efficacy score including maternal race/ethnicity, age, insurance, employment status before giving birth, gestational age, depression, and having other children was significant (F(12,160) = 3.17, p = .0004, adjusted R¬2 = .131). Significant predictors of PSE were race/ethnicity (ß= 3.3, p = .022), having another child/children (ß= 4.2, p = .005), and depression (ß= -4.2, p = .004). Conclusions: Findings suggest that social workers and medical practitioners should consider SDoH, such as insurance type, household income, and employment, along with traditional clinical indicators when assessing families' infant care needs. Social workers, medical practitioners, and researchers should be mindful of how implicit bias may influence the allocation of care and parental supports.

Deterioration free discharge comparison of andexanet-alfa and prothrombin complex concentrates (PCC) for reversal of factor Xa inhibitor associated bleeds.

Given the paucity of comparative efficacy data and the difference in cost between andexanet-alfa and prothrombin complex concentrates (PCC), debates continue regarding optimal cost-effective therapy for patients who present with major bleeding associated with oral factor Xa inhibitors. Available literature comparing the cost-effectiveness of the reversal agents is limited, and the large difference in price between therapy options has led many health systems to exclude andexanet-alfa from their formularies. To evaluate the clinical outcomes and cost of PCC compared to andexanet-alfa for patients with factor Xa inhibitor associated bleeds. We performed a quasi-experimental, single health system study of patients treated with PCC or andexanet-alfa from March 2014 to April 2021. Deterioration-free discharge, thrombotic events, length of stay, discharge disposition, and cost were reported. 170 patients were included in the PCC group and 170 patients were included in the andexanet-alfa group. Deterioration-free discharge was achieved in 66.5% of PCC-treated patients compared to 69.4% in the andexanet alfa-treated patients. 31.8% of PCC-treated patients were discharged home compared to 30.6% in the andexanet alfa-treated patients. The cost per deterioration-free discharge was $20,773.62 versus $5230.32 in the andexanet alfa and 4 F-PCC group, respectively. Among patients that experienced a bleed while taking a factor Xa inhibitor, there was no difference in clinical outcomes for patients treated with andexanet-alfa compared to PCC. Although there was no difference in the clinical outcomes, there was a significant difference in cost with andexanet-alfa costing approximately four times as much as PCC per deterioration-free discharge.

Per- and polyfluoroalkyl substances (PFAS) in United States tapwater: Comparison of underserved private-well and public-supply exposures and associated health implications.

Drinking-water quality is a rising concern in the United States (US), emphasizing the need to broadly assess exposures and potential health effects at the point-of-use. Drinking-water exposures to per- and poly-fluoroalkyl substances (PFAS) are a national concern, however, there is limited information on PFAS in residential tapwater at the point-of-use, especially from private-wells. We conducted a national reconnaissance to compare human PFAS exposures in unregulated private-well and regulated public-supply tapwater. Tapwater from 716 locations (269 private-wells; 447 public supply) across the US was collected during 2016-2021 including three locations where temporal sampling was conducted. Concentrations of PFAS were assessed by three laboratories and compared with land-use and potential-source metrics to explore drivers of contamination. The number of individual PFAS observed ranged from 1 to 9 (median: 2) with corresponding cumulative concentrations (sum of detected PFAS) ranging from 0.348 to 346 ng/L. Seventeen PFAS were observed at least once with PFBS, PFHxS and PFOA observed most frequently in approximately 15% of the samples. Across the US, PFAS profiles and estimated median cumulative concentrations were similar among private wells and public-supply tapwater. We estimate that at least one PFAS could be detected in about 45% of US drinking-water samples. These detection probabilities varied spatially with limited temporal variation in concentrations/numbers of PFAS detected. Benchmark screening approaches indicated potential human exposure risk was dominated by PFOA and PFOS, when detected. Potential source and land-use information was related to cumulative PFAS concentrations, and the number of PFAS detected; however, corresponding relations with specific PFAS were limited likely due to low detection frequencies and higher detection limits. Information generated supports the need for further assessments of cumulative health risks of PFAS as a class and in combination with other co-occurring contaminants, particularly in unmonitored private-wells where information is limited or not available.

Environmental and molecular regulation of asexual reproduction in the sea anemone Nematostella vectensis.

Cnidarians exhibit incredible reproductive diversity, with most capable of sexual and asexual reproduction. Here, we investigate factors that influence asexual reproduction in the burrowing sea anemone Nematostella vectensis, which can propagate asexually by transverse fission of the body column. By altering culture conditions, we demonstrate that the presence of a burrowing substrate strongly promotes transverse fission. In addition, we show that animal size does not affect fission rates, and that the plane of fission is fixed along the oral-aboral axis of the polyp. Homeobox transcription factors and components of the TGFß, Notch, and FGF signalling pathways are differentially expressed in polyps undergoing physal pinching suggesting they are important regulators of transverse fission. Gene ontology analyses further suggest that during transverse fission the cell cycle is suppressed, and that cell adhesion and patterning mechanisms are downregulated to promote separation of the body column. Finally, we demonstrate that the rate of asexual reproduction is sensitive to population density. Collectively, these experiments provide a foundation for mechanistic studies of asexual reproduction in Nematostella, with implications for understanding the reproductive and regenerative biology of other cnidarian species.

The DACH1 gene is frequently deleted in prostate cancer, restrains prostatic intraepithelial neoplasia, decreases DNA damage repair, and predicts therapy responses.

Prostate cancer (PCa), the second leading cause of death in American men, includes distinct genetic subtypes with distinct therapeutic vulnerabilities. The DACH1 gene encodes a winged helix/Forkhead DNA-binding protein that competes for binding to FOXM1 sites. Herein, DACH1 gene deletion within the 13q21.31-q21.33 region occurs in up to 18% of human PCa and was associated with increased AR activity and poor prognosis. In prostate OncoMice, prostate-specific deletion of the Dach1 gene enhanced prostatic intraepithelial neoplasia (PIN), and was associated with increased TGFß activity and DNA damage. Reduced Dach1 increased DNA damage in response to genotoxic stresses. DACH1 was recruited to sites of DNA damage, augmenting recruitment of Ku70/Ku80. Reduced Dach1 expression was associated with increased homology directed repair and resistance to PARP inhibitors and TGFß kinase inhibitors. Reduced Dach1 expression may define a subclass of PCa that warrants specific therapies.