Targeting myeloid chemotaxis to reverse prostate cancer therapy resistance.

Inflammation is a hallmark of cancer1. In patients with cancer, peripheral blood myeloid expansion, indicated by a high neutrophil-to-lymphocyte ratio, associates with shorter survival and treatment resistance across malignancies and therapeutic modalities2-5. Whether myeloid inflammation drives progression of prostate cancer in humans remain unclear. Here we show that inhibition of myeloid chemotaxis can reduce tumour-elicited myeloid inflammation and reverse therapy resistance in a subset of patients with metastatic castration-resistant prostate cancer (CRPC). We show that a higher blood neutrophil-to-lymphocyte ratio reflects tumour myeloid infiltration and tumour expression of senescence-associated mRNA species, including those that encode myeloid-chemoattracting CXCR2 ligands. To determine whether myeloid cells fuel resistance to androgen receptor signalling inhibitors, and whether inhibiting CXCR2 to block myeloid chemotaxis reverses this, we conducted an investigator-initiated, proof-of-concept clinical trial of a CXCR2 inhibitor (AZD5069) plus enzalutamide in patients with metastatic CRPC that is resistant to androgen receptor signalling inhibitors. This combination was well tolerated without dose-limiting toxicity and it decreased circulating neutrophil levels, reduced intratumour CD11b+HLA-DRloCD15+CD14- myeloid cell infiltration and imparted durable clinical benefit with biochemical and radiological responses in a subset of patients with metastatic CRPC. This study provides clinical evidence that senescence-associated myeloid inflammation can fuel metastatic CRPC progression and resistance to androgen receptor blockade. Targeting myeloid chemotaxis merits broader evaluation in other cancers.

A New Old Target: Androgen Receptor Signaling and Advanced Prostate Cancer.

Owing to the development of multiple novel therapies, there has been major progress in the treatment of advanced prostate cancer over the last two decades; however, the disease remains invariably fatal. Androgens and the androgen receptor (AR) play a critical role in prostate carcinogenesis, and targeting the AR signaling axis with abiraterone, enzalutamide, darolutamide, and apalutamide has improved outcomes for men with this lethal disease. Targeting the AR and elucidating mechanisms of resistance to these agents remain central to drug development efforts. This review provides an overview of the evolution and current approaches for targeting the AR in advanced prostate cancer. It describes the biology of AR signaling, explores AR-targeting resistance mechanisms, and discusses future perspectives and promising novel therapeutic strategies.

Development and Validation of a New BAG-1L-Specific Antibody to Quantify BAG-1L Protein Expression in Advanced Prostate Cancer.

BCL-2-associated athanogene-1L (BAG-1L) is a critical co-regulator that binds to and enhances the transactivation function of the androgen receptor, leading to prostate cancer development and progression. Studies investigating the clinical importance of BAG-1L protein expression in advanced prostate cancer have been limited by the paucity of antibodies that specifically recognize the long isoform. In this study, we developed and validated a new BAG-1L-specific antibody using multiple orthogonal methods across several cell lines with and without genomic manipulation of BAG-1L and all BAG-1 isoforms. Following this, we performed exploratory immunohistochemistry to determine BAG-1L protein expression in normal human, matched castration-sensitive prostate cancer (CSPC) and castration-resistant prostate cancer (CRPC), unmatched primary and metastatic CRPC, and early breast cancer tissues. We demonstrated higher BAG-1L protein expression in CRPC metastases than in unmatched, untreated, castration-sensitive prostatectomies from men who remained recurrence-free for 5 years. In contrast, BAG-1L protein expression did not change between matched, same patient, CSPC and CRPC biopsies, suggesting that BAG-1L protein expression may be associated with more aggressive biology and the development of castration resistance. Finally, in a cohort of patients who universally developed CRPC, there was no association between BAG-1L protein expression at diagnosis and time to CRPC or overall survival, and no association between BAG-1L protein expression at CRPC biopsy and clinical outcome from androgen receptor targeting therapies or docetaxel chemotherapy. The limitations of this study include the requirement to validate the reproducibility of the assay developed, the potential influence of pre-analytical factors, timing of CRPC biopsies, relatively small patient numbers, and heterogenous therapies on BAG-1L protein expression, and the clinical outcome analyses performed. We describe a new BAG-1L-specific antibody that the research community can further develop to elucidate the biological and clinical significance of BAG-1L protein expression in malignant and nonmalignant diseases.

An open-access accelerated adult equivalent of the ABCD Study neuroimaging dataset (a-ABCD).

As public access to longitudinal developmental datasets like the Adolescent Brain Cognitive Development StudySM (ABCD Study®) increases, so too does the need for resources to benchmark time-dependent effects. Scan-to-scan changes observed with repeated imaging may reflect development but may also reflect practice effects, day-to-day variability in psychological states, and/or measurement noise. Resources that allow disentangling these time-dependent effects will be useful in quantifying actual developmental change. We present an accelerated adult equivalent of the ABCD Study dataset (a-ABCD) using an identical imaging protocol to acquire magnetic resonance imaging (MRI) structural, diffusion-weighted, resting-state and task-based data from eight adults scanned five times over five weeks. We report on the task-based imaging data (n = 7). In-scanner stop-signal (SST), monetary incentive delay (MID), and emotional n-back (EN-back) task behavioral performance did not change across sessions. Post-scan recognition memory for emotional n-back stimuli, however, did improve as participants became more familiar with the stimuli. Functional MRI analyses revealed that patterns of task-based activation reflecting inhibitory control in the SST, reward success in the MID task, and working memory in the EN-back task were more similar within individuals across repeated scan sessions than between individuals. Within-subject, activity was more consistent across sessions during the EN-back task than in the SST and MID task, demonstrating differences in fMRI data reliability as a function of task. The a-ABCD dataset provides a unique testbed for characterizing the reliability of brain function, structure, and behavior across imaging modalities in adulthood and benchmarking neurodevelopmental change observed in the open-access ABCD Study.

Optimising CT-guided biopsies of sclerotic bone lesions in cancer patients.

OBJECTIVES: Investigate the laboratory, imaging and procedural factors that are associated with a tumour-positive and/or NGS-feasible CT-guided sclerotic bone lesion biopsy result in cancer patients. METHODS: In total, 113 CT-guided bone biopsies performed in cancer patients by an interventional radiologist in one institution were retrospectively reviewed. Sixty-five sclerotic bone biopsies were eventually included and routine blood parameters and tumour marker levels were recorded. Non-contrast (NC) biopsy CTs (65), contrast-enhanced CTs (24), and PET/CTs (22) performed within four weeks of biopsy were reviewed; lesion location, diameter, lesion-to-cortex distance, and NC-CT appearance (dense-sclerosis versus mild-sclerosis) were noted. Mean NC-CT, CE-CT HU, and PET SUVmax were derived from biopsy tract and lesion segmentations. Needle diameter, tract length, and number of samples were noted. Comparisons between tumour-positive/negative and next-generation sequencing (NGS)-feasible/non-feasible biopsies determined significant (p < 0.05) laboratory, imaging, and procedural parameter differences. RESULTS: Seventy-four percent of biopsies were tumour-positive. NGS was feasible in 22/30 prostate cancer patients (73%). Neither laboratory blood parameters, PET/CT availability, size, nor lesion-to-cortex distance affected diagnostic yield or NGS feasibility (p > 0.298). Eighty-seven percent of mildly sclerotic bone (mean 244 HU) biopsies were positive compared with 56% in dense sclerosis (622 HU, p = 0.005) and NC-CT lesion HU was significantly lower in positive biopsies (p = 0.003). A 610 HU threshold yielded 89% PPV for tumour-positive biopsies and a 370 HU threshold 94% PPV for NGS-feasible biopsies. FDG-PET and procedural parameters were non-significant factors (each p > 0.055). CONCLUSION: In cancer patients with sclerotic bone disease, targeting areas of predominantly mild sclerosis in lower CT-attenuation lesions can improve tumour tissue yield and NGS feasibility. KEY POINTS: • Areas of predominantly mild sclerosis should be preferred to areas of predominantly dense sclerosis for CT-guided bone biopsies in cancer patients. • Among sclerotic bone lesions in prostate cancer patients, lesions with a mean HU below 370 should be preferred as biopsy targets to improve NGS feasibility. • Laboratory parameters and procedure related factors may have little implications for CT-guided sclerotic bone biopsy success.

Multiparametric bone MRI can improve CT-guided bone biopsy target selection in cancer patients and increase diagnostic yield and feasibility of next-generation tumour sequencing.

OBJECTIVES: To evaluate whether multiparametric bone MRI (mpBMRI) utilising a combination of DWI signal, ADC and relative fat-fraction (rFF) can identify bone metastases, which provide high diagnostic biopsy yield and next-generation genomic sequencing (NGS) feasibility. METHODS: A total of 150 CT-guided bone biopsies performed by interventional radiologists (3/2013 to 2/2021) at our centre were reviewed. In 43 patients, contemporaneous DWI and rFF images, calculated from 2-point T1w Dixon MRI, were available. For each biopsied lesion, a region of interest (ROI) was delineated on ADC and rFF images and the following MRI parameters were recorded: visual classification of DWI signal intensity (SI), mean, median, 10th and 90th centile ADC and rFF values. Non-parametric tests were used to compare values between tumour positive/negative biopsies and feasible/non-feasible NGS, with p-values < 0.05 deemed significant. RESULTS: The mpBMRI combination high DWI signal, mean ADC < 1100 µm2/s and mean rFF < 20% identified tumour-positive biopsies with 82% sensitivity, 80% specificity, a positive predictive value (PPV) of 93% (p = 0.001) and NGS feasibility with 91% sensitivity, 78% specificity and 91% PPV (p < 0.001). The single MRI parameters DWI signal, ADC and rFF failed to distinguish between tumour-positive and tumour-negative biopsies (each p > 0.082). In NGS feasible biopsies, mean and 90th centile rFF were significantly smaller (each p < 0.041). Single ADC parameters did not show significant difference regarding NGS feasibility (each p > 0.292). CONCLUSIONS: MpBMRI utilising the combination of DWI signal, ADC and rFF can identify active bone metastases, which provide biopsy tissue with high diagnostic yield and NGS feasibility. KEY POINTS: • Multiparametric bone MRI with diffusion-weighted and relative fat-fraction images helps to identify active bone metastases suitable for CT-guided biopsy. • Target lesions for CT-guided bone biopsies in cancer patients can be chosen with greater confidence. • CT-guided bone biopsy success rates, especially yielding sufficient viable tissue for advanced molecular tissue analyses, can be improved.

Targeting defective DNA repair in prostate cancer.

PURPOSE OF REVIEW: Prostate cancer is the second leading cause of cancer death in men. Characterization of the genomic landscape of prostate cancer has demonstrated frequent aberrations in DNA repair pathways, identifiable in up to 25% patients with metastatic disease, which may sensitize to novel therapies, including PARP inhibitors and immunotherapy. Here, we summarize the current clinical landscape and future horizons for targeting defective DNA repair pathways in PC. RECENT FINDINGS: Several clinical trials have demonstrated efficacy of different PARP inhibitors in metastatic castration-resistant prostate cancer (mCRPC), most pronounced in those with BRCA mutations. The PROfound trial is the first positive phase 3 biomarker-selected trial to demonstrate improved outcomes with a targeted treatment, Olaparib, in mCRPC. Whilst the Keynote-199 trial failed to demonstrate efficacy of immune-checkpoint inhibitor pembrolizumab in unselected mCRPC patients, there was evidence of response in those harbouring DNA repair defects. SUMMARY: These landmark trials represent a significant advance towards personalization of PC therapy. However, resistance remains inevitable and there is a lack of reliable predictive biomarkers to select patients for treatment. Characterization of resistance mechanisms, and validation of novel biomarkers is critical to maximize clinical benefit and inform novel treatment combinations to improve outcomes.

Association between activity energy expenditure and peak oxygen consumption with sarcopenia.

BACKGROUND: Sedentariness may be an important risk factor for sarcopenia. The aim of this work was to assess the association between muscle mass and strength and markers of usual physical activity such as activity energy expenditure and peak oxygen uptake. METHODS: Young and old participants were assessed measuring body composition by DEXA (double beam X ray absorptiometry), handgrip strength, peak oxygen consumption and workload during an exercise calorimetry in a braked cycle ergometer and a 72 h activity energy expenditure using Actiheart actigraphs. A heart rate/energy expenditure curve derived from the exercise calorimetry was used to calibrate each actigraph. Sarcopenia was defined as having an appendicular fat free mass index below 7.5 kg/m2 and 5.6 kg/m2 in men and women respectively, or a handgrip strength z score below 1, using local normal data or having both parameters below the cutoff points. RESULTS: We analyzed data from 192 assessments performed in participants aged 22 to 88 years (106 women). Sarcopenic participants (as determined by muscle mass, strength or both) had a significantly lower peak oxygen uptake and work load and a significantly lower activity energy expenditure. When analyzing lean mass and strength as continuous variables, peak oxygen consumption was a significant predictor of fat free mass in men. Among women, the association was observed only when percentage of muscle mass was expressed as a z score. CONCLUSIONS: Activity energy expenditure and peak oxygen consumption are associated with a lower muscle mass and the presence of sarcopenia and should be considered as risk factors for this condition.

Effects of Two Training Modalities on Body Fat and Insulin Resistance in Postmenopausal Women.

Henríquez, S, Monsalves-Alvarez, M, Jimenez, T, Barrera, G, Hirsch, S, de la Maza, MP, Leiva, L, Rodriguez, JM, Silva, C, and Bunout, D. Effects of two training modalities on body fat and insulin resistance in postmenopausal women. J Strength Cond Res 31(11): 2955-2964, 2017-Our objective was to compare the effects of a low-load circuit resistance training protocol and usual aerobic training in postmenopausal women. Postmenopausal women with at least 1 feature of the metabolic syndrome were randomly allocated to a low-load circuit resistance training protocol or traditional aerobic training in a braked cycle ergometer. The intervention consisted in supervised sessions lasting 40 minutes, 3 times per week, during 6 months. At baseline and at the end of the intervention, fasting serum lipid levels, serum interleukin 6, C-reactive protein, 8 isoprostanes, and insulin resistance (assessed through QUICKI and HOMA-IR) were measured. Body fat was measured by double-beam X-ray absorptiometry and by computed tomography densitometric quantification at lumbar 3 vertebral level. Twenty-one women aged 58 (54-59) years were allocated to aerobic training and 21 women aged 55 (52-61) years were allocated to the low-load circuit resistance training protocol. Eighteen and 16 women in each group completed the 6 months training period. Women in both groups experienced significant reductions in blood pressure, total body, subcutaneous, and intraabdominal body fat. Reductions in total cholesterol and triacylglycerol levels were also observed. No changes in insulin resistance indexes, 8 isoprostanes, C-reactive protein, or interleukin 6 were observed in either group. No significant differences between treatment groups were observed in any of the measured parameters. We conclude that low-load circuit resistance training and aerobic training resulted in the same reductions in body fat and serum lipid levels.

Associations between socioeconomic status, aging and functionality among older women.

To assess if there is an association between socioeconomic status and quality of life, functional status and markers of aging, we studied 86 women aged 73 ± 7 years, who answered the WHO Qol Bref quality of life survey. Mini mental state examination, timed up and go test, 12 minutes' walk, hand grip and quadriceps strength, dual X-ray absorptiometry (DEXA), carotid intima-media thickness and telomere length in peripheral leukocytes were measured. Successful aging was defined as a walking speed, handgrip strength, appendicular lean body mass, timed up and go and minimental values above cutoff points for disability. Participants with successful aging had a higher quality of life score and were more likely to live in rich municipalities. There was a positive correlation between telomere length, right handgrip strength and total fat free mass. Therefore, there is an association between socioeconomic status, successful aging and quality of life.

Folates Induce Colorectal Carcinoma HT29 Cell Line Proliferation Through Notch1 Signaling.

Folic acid (FA) consumption at high levels has been associated with colon cancer risk. Several mechanisms have been proposed to explain this association. The Notch signal pathway has been implicated in the regulation of cellular proliferation. Our aim was to demonstrate that high concentrations of FA or its reduced form, 5-methyltetrahydrofolic acid (5-MTHF), increase colorectal carcinoma HT29 cell proliferation through an increase of Notch1 activation and to prove if the inhibition of Notch1 activation by gamma secretase inhibitor, reduce the effect of folic acid. HT29 cells were cultured in high (400 nM), low (20 nM), or 0 nM FA or 5-MTHF concentrations during 96 h with or without DAPT (gamma secretase inhibitor). Cell proliferation was determined by the methylthiazole tetrazolium method, and Notch1-intracellular domain (NICD) was analyzed by flow cytometry. HT29 cells exposed to 400 nM FA or 5-MTHF showed higher proliferation rate than those exposed to 20 nM of FA or 5-MTHF (P < 0.01) during 96 h. NICD expression increased at higher FA or 5-MTHF concentrations compared with lower concentrations (P < 0.01). This effect on proliferation was partially reversible when we blocked Notch1 activation with the inhibitor of γ-secretase (P < 0.05).These data suggest that high concentration of FA and 5-MTHF induce HT29 cell proliferation activating Notch1 pathway.

[Evaluation of a program for management of metabolic syndrome in adults with overweight and obesity]. / Evaluación de un programa ministerial para manejo del síndrome metabólico en adultos con sobrepeso y obesidad.

BACKGROUND: The Chilean Ministry of Health developed a healthy lifestyles intervention directed to adults with overweight and cardiovascular risk factors, called "Program on Healthy Eating and Physical Activity" (PASAF). AIM: To evaluate the impact of PASAF on nutritional status and metabolic parameters. PATIENTS AND METHODS: We analyzed databases from three primary care centers belonging to a municipality of Metropolitan Santiago. We selected adults enrolled in the PASAF during three years (2007-2009). The program lasted four months and included an assessment of anthropometric and metabolic parameters at baseline and at the end, eight workshops with a nutritionist, seven with a psychologist and 32 sessions of physical activity. RESULT: We evaluated 526 subjects aged ≥18 years (93% females), of whom 85.6% attended the last appointment for assessment. Analyzing available data, attendance to workshops was <50% of the scheduled sessions. Weight, body mass index and waist circumference decreased significantly (median: -1.4 kg, -0.6 kg/m² and -3 cm, respectively). The median weight loss was 1.8% of initial weight and 17.1% of participants experienced a decrease ≥5% of their initial weight. There were significant improvements in lipid levels and blood pressure among participants with lower initial excess weight. A reduction in fasting blood glucose was observed only among subjects who lost ≥5% of their initial weight. CONCLUSIONS: The PASAF modestly reduced nutritional parameters. Correction of metabolic parameters was especially effective in less obese subjects. The attendance to workshops was low.

[Nutritional status and postoperative complications in patients with digestive cancer]. / Relación entre estado nutricional y evolución postoperatoria, en cirugía oncológica digestiva.

BACKGROUND: Risk of malnutrition is elevated among oncologic patients, and this increases postoperative morbidity and mortality. AIM: To study the association between nutritional status and postoperative outcomes in a group of patients with gastrointestinal cancers. PATIENTS AND METHODS: We studied 129 patients with diagnosis of digestive cancer, previous to potentially curative surgery. Nutritional status was evaluated through anthropometric measures, Subjective Global Assessment (SGA), dietary intake recalls and routine biochemical parameters. Functional performance was assessed by the Karnofsky index (KI). Cancer stage was classified according to TNM4. During the postoperative period, complications, length of stay at the critical care ward and duration of hospitalization were registered. Thirty days after discharge, patients were contacted, and the appearance of new complications was listed. RESULTS: According to SGA 14.7% of patients were classified as well nourished (A), 57.3% as moderately undernourished or at risk of malnutrition (B) and 27.9% as severely malnourished (C). The incidence of total complications was 25.5%. Nutritional status was not associated with cancer stage. The frequency of complications among patients classified as A, B and C were 5.5, 25.3 and 37.1% respectively (p = 0.03). CONCLUSIONS: We detected a high frequency of malnutrition in this group of patients. Overall the frequency of postoperative complications was low, however malnourished patients exhibited a higher rate of surgical complications.

Neurobiological sensitivity to popular peers moderates daily links between social media use and affect.

Social media behaviors increase during adolescence, and quantifiable feedback metrics (e.g., likes, followers) may amplify the value of social status for teens. Social media's impact on adolescents' daily affect may be exacerbated given the neurodevelopmental changes that increase youths' sensitivity to socio-emotional information. This study examines whether neurobiological sensitivity to popularity moderates daily links between social media use and affect. Adolescents (N = 91, Mage=13.6 years, SDage=0.6 years) completed an fMRI task in which they viewed faces of their high (>1 SD above the mean) and low (<1 SD below the mean) popular peers based on peer-nominated sociometric ratings from their school social networks. Two years later, adolescents reported their time spent on social media and affect daily for two weeks. Neural tracking of popularity in the ventromedial and dorsomedial prefrontal cortex moderated the association between time on social media and affect. Specifically, adolescents who tracked high popular peers in the vmPFC reported more positive affect on days when they used social media more. Adolescents who tracked low popular peers in the vmPFC and dmPFC reported more negative affect on days when they used social media more. Results suggest that links between social media and affect depend on individual differences in neural sensitivity to popularity.

First-line Management of Metastatic Urothelial Cancer: Current and Future Perspectives After the EV-302 and CheckMate-901 Studies.

The standard of care for the first-line management of metastatic urothelial carcinoma has been recently challenged, with the combination of pembrolizumab and enfortumab vedotin (P-EV) strongly arising as a practice-changing option from classical platinum-based chemotherapies. With this paradigm shift on the horizon new questions, including the most suitable second line of treatment for these patients, and the role that the molecular characterization of these tumours will have when selecting these therapies will inevitably arise. Furthermore, after the negative results of the Keynote 361 and IMvigor 130 trials, the combination of nivolumab with platinum-based chemotherapy followed by nivolumab maintenance (Nivo GC-Nivo) has also shown positive results when compared with chemotherapy alone. Translational studies at a molecular, cellular, and functional level will be key to better explain these discordant results. In this Current Perspective, we discuss the potential impact of these results in clinical practice and propose specific guidance for prospective translational research.

Loss of H3K9 trimethylation leads to premature aging.

Aging is the major risk factor for most human diseases and represents a major socio-economical challenge for modern societies. Despite its importance, the process of aging remains poorly understood. Epigenetic dysregulation has been proposed as a key driver of the aging process. Modifications in transcriptional networks and chromatin structure might be central to age-related functional decline. A prevalent feature described during aging is the overall reduction in heterochromatin, specifically marked by the loss of repressive histone modification, Histone 3 lysine 9 trimethylation (H3K9me3). However, the role of H3K9me3 in aging, especially in mammals, remains unclear. Here we show using a novel mouse strain, (TKOc), carrying a triple knockout of three methyltransferases responsible for H3K9me3 deposition, that the inducible loss of H3K9me3 in adulthood results in premature aging. TKOc mice exhibit reduced lifespan, lower body weight, increased frailty index, multi-organ degeneration, transcriptional changes with significant upregulation of transposable elements, and accelerated epigenetic age. Our data strongly supports the concept that the loss of epigenetic information directly drives the aging process. These findings reveal the importance of epigenetic regulation in aging and suggest that interventions targeting epigenetic modifications could potentially slow down or reverse age-related decline. Understanding the molecular mechanisms underlying the process of aging will be crucial for developing novel therapeutic strategies that can delay the onset of age-associated diseases and preserve human health at old age specially in rapidly aging societies.

Discovery of circulating miRNAs as biomarkers of chronic Chagas heart disease via a small RNA-Seq approach.

Chagas disease affects approximately 7 million people worldwide in Latin America and is a neglected tropical disease. Twenty to thirty percent of chronically infected patients develop chronic Chagas cardiomyopathy decades after acute infection. Identifying biomarkers of Chagas disease progression is necessary to develop better therapeutic and preventive strategies. Circulating microRNAs are increasingly reliable biomarkers of disease and therapeutic targets. To identify new circulating microRNAs for Chagas disease, we performed exploratory small RNA sequencing from the plasma of patients and performed de novo miRNA prediction, identifying potential new microRNAs. The levels of the new microRNAs temporarily named miR-Contig-1519 and miR-Contig-3244 and microRNAs that are biomarkers for nonchagasic cardiomyopathies, such as miR-148a-3p and miR-224-5p, were validated by quantitative reverse transcription. We found a specific circulating microRNA signature defined by low miR-Contig-3244, miR-Contig-1519, and miR-148a-3 levels but high miR-224-5p levels for patients with chronic Chagas disease. Finally, we predicted in silico that these altered circulating microRNAs could affect the expression of target genes involved in different cellular pathways and biological processes, which we will explore in the future.

RNASEH2B loss and PARP inhibition in advanced prostate cancer.

BACKGROUND: Clinical trials have suggested antitumor activity from PARP inhibition beyond homologous recombination deficiency (HRD). RNASEH2B loss is unrelated to HRD and preclinically sensitizes to PARP inhibition. The current study reports on RNASEH2B protein loss in advanced prostate cancer and its association with RB1 protein loss, clinical outcome and clonal dynamics during treatment with PARP inhibition in a prospective clinical trial. METHODS: Whole tumor biopsies from multiple cohorts of patients with advanced prostate cancer were interrogated using whole-exome sequencing (WES), RNA sequencing (bulk and single nucleus) and immunohistochemistry (IHC) for RNASEH2B and RB1. Biopsies from patients treated with olaparib in the TOPARP-A and TOPARP-B clinical trials were used to evaluate RNASEH2B clonal selection during olaparib treatment. RESULTS: Shallow co-deletion of RNASEH2B and adjacent RB1, co-located at chromosome 13q14, was common, deep co-deletion infrequent, and gene loss associated with lower mRNA expression. In castration-resistant PC (CRPC) biopsies, RNASEH2B and RB1 mRNA expression correlated, but single nucleus RNA sequencing indicated discordant loss of expression. IHC studies showed that loss of the two proteins often occurred independently, arguably due to stochastic second allele loss. Pre- and post-treatment metastatic CRPC (mCRPC) biopsy studies from BRCA1/2 wildtype tumors, treated on the TOPARP phase II trial, indicated that olaparib eradicates RNASEH2B-loss tumor subclones. CONCLUSION: PARP inhibition may benefit men suffering from mCRPC by eradicating tumor subclones with RNASEH2B loss. CLINICALTRIALS: gov NCT01682772FUNDING. AstraZeneca; Cancer Research UK; Medical Research Council; Cancer Research UK; Prostate Cancer UK; Movember Foundation; Prostate Cancer Foundation.

Cascading bidirectional influences of digital media use and mental health in adolescence.

A substantial portion of critical adolescent development is occurring within digital environments. However, certain individual differences may lead adolescents to use digital media in diverse ways. In this chapter we suggest that the way teens use digital media influences how digital media affects their mental health. Further, we propose a model in which these influences, in the context of ongoing development, may have feedback effects on how digital media is subsequently used, thus resulting in a self-perpetuating cycle. Our model suggests that certain developmental risk/protective factors and maladaptive/adaptive digital media behaviors likely perpetuate each other in a cyclical manner each serving to maintain and/or escalate the other. We discuss existing evidence of these processes in psychosocial, identity, incentive processing, and physical health development. Future research focusing on individual differences and self-reinforcing digital media behaviors that manifest these feedback loops may portray a more complete picture of cascading digital media influences across adolescent development.

Association of Habitual Checking Behaviors on Social Media With Longitudinal Functional Brain Development.

Importance: Social media platforms provide adolescents with unprecedented opportunities for social interactions during a critical developmental period when the brain is especially sensitive to social feedback. Objective: To explore how adolescents' frequency of checking behaviors on social media platforms is associated with longitudinal changes in functional brain development across adolescence. Design, Setting, and Participants: A 3-year longitudinal cohort study of functional magnetic resonance imaging (fMRI) among sixth- and seventh-grade students recruited from 3 public middle schools in rural North Carolina. Exposures: At wave 1, participants reported the frequency at which they checked Facebook, Instagram, and Snapchat. Main Outcome or Measure: Neural responses to the Social Incentive Delay task when anticipating receiving social feedback, measured annually using fMRI for 3 years. Participants saw a cue that indicated whether the social feedback (adolescent faces with emotional expressions) would be a reward, punishment, or neutral; after a delay, a target appeared and students responded by pressing a button as quickly as possible; a display of social feedback depended on trial type and reaction time. Results: Of 178 participants recruited at age 12 years, 169 participants (mean [SD] age, 12.89 [0.58] years; range, 11.93-14.52 years; 91 [53.8%] female; 38 [22.5%] Black, 60 [35.5%] Latinx, 50 [29.6%] White, 15 [8.9%] multiracial) met the inclusion criteria. Participants with habitual social media checking behaviors showed lower neural sensitivity to social anticipation at age 12 years compared with those with nonhabitual checking behaviors in the left amygdala, posterior insula (PI), and ventral striatum (VS; ß, -0.22; 95% CI, -0.33 to -0.11), right amygdala (ß, -0.19; 95% CI, -0.30 to -0.08), right anterior insula (AI; ß, -0.23; 95% CI, -0.37 to -0.09), and left dorsolateral prefrontal cortex (DLPFC; ß, -0.29; 95% CI, -0.44 to -0.14). Among those with habitual checking behaviors, there were longitudinal increases in the left amygdala/PI/VS (ß, 0.11; 95% CI, 0.04 to 0.18), right amygdala (ß, 0.09; 95% CI, 0.02 to 0.16), right AI (ß, 0.15; 95% CI, 0.02 to 0.20), and left DLPFC (ß, 0.19; 95% CI, 0.05 to 0.25) during social anticipation, whereas among those with nonhabitual checking behaviors, longitudinal decreases were seen in the left amygdala/PI/VS (ß, -0.12; 95% CI, -0.19 to -0.06), right amygdala (ß, -0.10; 95% CI, -0.17 to -0.03), right AI (ß, -0.13; 95% CI, -0.22 to -0.04), and left DLPFC (ß, -0.10, 95% CI, -0.22 to -0.03). Conclusions and Relevance: The results of this cohort study suggest that social media checking behaviors in early adolescence may be associated with changes in the brain's sensitivity to social rewards and punishments. Further research examining long-term associations between social media use, adolescent neural development, and psychological adjustment is needed to understand the effects of a ubiquitous influence on development for today's adolescents.