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.

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.

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.

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.

In vivo reprogramming leads to premature death linked to hepatic and intestinal failure.

The induction of cellular reprogramming via expression of the transcription factors Oct4, Sox2, Klf4 and c-Myc (OSKM) can drive dedifferentiation of somatic cells and ameliorate age-associated phenotypes in multiple tissues and organs. However, the benefits of long-term in vivo reprogramming are limited by detrimental side-effects. Here, using complementary genetic approaches, we demonstrated that continuous induction of the reprogramming factors in vivo leads to hepatic and intestinal dysfunction resulting in decreased body weight and contributing to premature death (within 1 week). By generating a transgenic reprogrammable mouse strain, avoiding OSKM expression in both liver and intestine, we reduced the early lethality and adverse effects associated with in vivo reprogramming and induced a decrease in organismal biological age. This reprogramming mouse strain, which allows longer-term continuous induction of OSKM with attenuated toxicity, can help better understand rejuvenation, regeneration and toxicity during in vivo reprogramming.

Neural tracking of social hierarchies in adolescents' real-world social networks.

In the current study, we combined sociometric nominations and neuroimaging techniques to examine adolescents' neural tracking of peers from their real-world social network that varied in social preferences and popularity. Adolescent participants from an entire school district (N = 873) completed peer sociometric nominations of their grade at school, and a subset of participants (N = 117, Mage = 13.59 years) completed a neuroimaging task in which they viewed peer faces from their social networks. We revealed two neural processes by which adolescents track social preference: (1) the fusiform face area, an important region for early visual perception and social categorization, simultaneously represented both peers high in social preference and low in social preference; (2) the dorsolateral prefrontal cortex (DLPFC), which was differentially engaged in tracking peers high and low in social preference. No regions specifically tracked peers high in popularity and only the inferior parietal lobe, temporoparietal junction, midcingulate cortex and insula were involved in tracking unpopular peers. This is the first study to examine the neural circuits that support adolescents' perception of peer-based social networks. These findings identify the neural processes that allow youths to spontaneously keep track of peers' social value within their social network.

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.

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.

Adolescents' neural sensitivity to high and low popularity: Longitudinal links to risk-taking and prosocial behavior.

Adolescents are particularly attuned to popularity within peer groups, which impacts behaviors such as risk-taking and prosocial behavior. Neurodevelopmental changes orient adolescents toward salient social cues in their environment. We examined whether neural regions that track popularity are associated with longitudinal changes in risk-taking and prosocial behavior. During an fMRI scan, adolescents (n = 109, Mage=13.59, SD=0.59) viewed pictures of their popular and unpopular classmates based on sociometric nominations from their social networks. Neural tracking of high popularity in the dorsomedial prefrontal cortex was associated with increases in risk-taking behavior, whereas tracking of low popularity in the right insula was associated with increases in prosocial behavior. Results suggest that individual differences in neural tracking of popularity relate to longitudinal changes in adolescents' social behaviors.

Germline ATM Mutations Detected by Somatic DNA Sequencing in Lethal Prostate Cancer.

Background: Germline mutations in the ataxia telangiectasia mutated (ATM) gene occur in 0.5-1% of the overall population and are associated with tumour predisposition. The clinical and pathological features of ATM-mutated prostate cancer (PC) are poorly defined but have been associated with lethal PC. Objective: To report on the clinical characteristics including family history and clinical outcomes of a cohort of patients with advanced metastatic castration-resistant PC (CRPC) who were found to have germline ATM mutations after mutation detection by initial tumour DNA sequencing. Design setting and participants: We acquired germline ATM mutation data by saliva next-generation sequencing from patients with ATM mutations in PC biopsies sequenced between January 2014 and January 2022. Demographics, family history, and clinical data were collected retrospectively. Outcome measurements and statistical analysis: Outcome endpoints were based on overall survival (OS) and time from diagnosis to CRPC. Data were analysed using R version 3.6.2 (R Foundation for Statistical Computing, Vienna, Austria). Results and limitations: Overall, seven patients (n = 7/1217; 0.6%) had germline ATM mutations detected, with five of them having a family history of malignancies, including breast, prostate, pancreas, and gastric cancer; leukaemia; and lymphoma. Two patients had concomitant somatic mutations in tumour biopsies in genes other than ATM, while two patients were found to carry more than one ATM pathogenic mutation. Five tumours in germline ATM variant carriers had loss of ATM by immunohistochemistry. The median OS from diagnosis was 7.1 yr (range 2.9-14 yr) and the median OS from CRPC was 5.3 yr (range 2.2-7.3 yr). When comparing these data with PC patients sequenced by The Cancer Genome Atlas, we found that the spatial localisation of mutations was similar, with distribution of alterations occurring on similar positions in the ATM gene. Interestingly, these include a mutation within the FRAP-ATM-TRRAP (FAT) domain, suggesting that this represents a mutational hotspot for ATM. Conclusions: Germline ATM mutations are rare in patients with lethal PC but occur at mutational hotspots; further research is warranted to better characterise the family histories of these men and PC clinical course. Patient summary: In this report, we studied the clinical and pathological features of advanced prostate cancers associated with germline mutations in the ATM gene. We found that most patients had a strong family history of cancer and that this mutation might predict the course of these prostate cancers, as well as response to specific treatments.

High-intensity interval training prevents muscle mass loss in overweight Chilean young adults during a hypocaloric-Mediterranean diet: a randomized trial.

The hypocaloric Mediterranean diet (MD) mainly reduces fat mass but inevitably causes a loss of skeletal muscle mass. High-intensity interval training (HIIT) seems to have advantages in preserving muscle mass during a hypocaloric regime. Our study compares body composition and metabolic changes in overweight and obese Chilean women and men after 3 months of weight loss treatment with a Mediterranean-type hypocaloric diet, HIIT, or a combination of both. The study included 83 overweight or obese women and men between the ages of 25 and 50. The subjects were randomly assigned to one of the three intervention groups: (1) MD, (2) EX, and (3) MD + EX. Baseline and post-intervention measurements included: (a) body composition by dual-beam densitometry, muscle, and fat measurements by thigh ultrasound and computed tomography; (b) handgrip and quadriceps muscle strength; (c) exercise performance by peak oxygen consumption, peak load, work efficiency, and exercise energy expenditure; and (d) metabolic parameters. Out of 83 participants, the retention rate was 49% due to low compliance with the interventions. As expected, the MD group resulted in significantly greater weight loss (MD -7%, EX -0.6% and MD + EX -5.3%) and appendicular fat mass loss (MD -11.1%, EX -2.9, MD + EX -10.2%) but was associated with significant lean tissue loss (2.8%), which was prevented by HIIT (EX -0.1 and MD + EX -0.6%). Metabolic and glycoxidative parameters remained unchanged, irrespective of changes in body composition. Hypocaloric diets remain the most effective means to lose weight and body fat. However, it induces a loss of lean body mass when not accompanied by exercise training. This study shows that HIIT prevents the loss of muscle mass caused by a hypocaloric Mediterranean diet.

Effects of Bipolar Radiofrequency on Collagen Synthesis from Patients with Brachial Ptosis.

Radiofrequency is frequently used for skin rejuvenation, localized fat elimination and cellulite treatment. It prompts the expression of thermal shock proteins that lead to dermal thickening as a result of collagen synthesis. The authors report a histological and clinical analysis of the arm subdermal changes before and after bipolar radiofrequency treatment plus liposuction to determine their benefits for arm contouring. Methods: Inclusion criteria included patients with stage 1, 2a, and 2b brachial ptosis (Duncan classification) and upper limb fat deposits who were considered candidates for third-generation ultrasound-assisted liposculpture plus radiofrequency-assisted lipolysis/skin tightening. Arm subdermal tissue samples (5 mm³) were analyzed before and after the intervention. We used 10% formaldehyde for tissue fixation and stained each sample with hematoxylin/eosin, Masson trichrome, and antibody markers against the cell cycle Ki-67 protein. Results: We analyzed a total of 12 biopsies from six patients who meet the inclusion/exclusion criteria. Histological findings with hematoxylin/eosin revealed hyperplastic and metaplastic changes with focal distribution within the papillary and reticular dermis. Masson trichrome staining showed an increase of the characteristic basophilia of thin type-I and type-III collagen fibers. In contrast, molecular analysis reported an increase in fibroblast activity mediated by the activation of the heat shock protein HSP47. Conclusion: Radiofrequency may be a great alternative to improve skin retraction in patients with mild to moderate brachial dermatochalasis through the activation of HSP47 heat shock protein and the production of type-I and type-III collagen.

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.

Diversity of immune responses in children highly exposed to SARS-CoV-2.

Background: Children are less susceptible than adults to symptomatic COVID-19 infection, but very few studies addressed their underlying cause. Moreover, very few studies analyzed why children highly exposed to the virus remain uninfected. Methods: We analyzed the serum levels of ACE2, angiotensin II, anti-spike and anti-N antibodies, cytokine profiles, and virus neutralization in a cohort of children at high risk of viral exposure, cohabiting with infected close relatives during the lockdown in Spain. Results: We analyzed 40 children who were highly exposed to the virus since they lived with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-infected relatives during the lockdown for several months without taking preventive measures. Of those, 26 reported mild or very mild symptoms. The induced immune response to the virus was analyzed 3 months after the household infection. Surprisingly, only 15 children had IgG anti-S (IgG+) determined by a sensitive method indicative of a past infection. The rest, negative for IgG anti-N or S in various tests, could be further subdivided, according to IgM antibodies, into those having IgM anti-S and IgM anti-N (IgG-IgMhigh) and those having only IgM anti-N (IgG-IgMlow). Interestingly, those two subgroups of children with IgM antibodies have strikingly different patterns of cytokines. The IgMhigh group had significantly higher IFN-α2 and IFN-γ levels as well as IL-10 and GM-CSF than the IgMlow group. In contrast, the IgMlow group had low levels of ACE2 in the serum. Both groups have a weaker but significant capacity to neutralize the virus in the serum than the IgG+ group. Two children were negative in all immunological antibody tests. Conclusions: A significant proportion of children highly exposed to SARS-CoV-2 did not develop a classical adaptive immune response, defined by the production of IgG, despite being in close contact with infected relatives. A large proportion of those children show immunological signs compatible with innate immune responses (as secretion of natural antibodies and cytokines), and others displayed very low levels of the viral receptor ACE2 that may have protected them from the virus spreading in the body despite high and constant viral exposure.

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.

B7-H3 as a Therapeutic Target in Advanced Prostate Cancer.

BACKGROUND: B7-H3 is a cell surface immunomodulatory glycoprotein overexpressed in prostate cancers (PCs). Understanding its longitudinal expression at emergence of castration resistance and association with tumour genomics are critical to the development of and patient selection for B7-H3 targeted therapies. OBJECTIVE: To characterise B7-H3 expression in same-patient hormone-sensitive (HSPC) and castration-resistant (CRPC) PC biopsies, associating this with PC genomics, and to evaluate the antitumour activity of an anti-B7-H3 antibody-drug conjugate (ADC) in human CRPC in vitro and in vivo. DESIGN, SETTING, AND PARTICIPANTS: We performed immunohistochemistry and next-generation sequencing on a cohort of 98 clinically annotated CRPC biopsies, including 72 patients who also had HSPC biopsies for analyses. We analysed two CRPC transcriptome and exome datasets, and PC scRNASeq datasets. PC organoids (patient-derived xenograft [PDX]-derived organoids [PDX-Os]) were derived from PDXs generated from human CRPC biopsies. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We evaluated B7-H3 mRNA expression in relation to a panel of 770 immune-related genes, compared B7-H3 protein expression between same-patient HSPC and CRPC biopsies, determined associations with PC genomic alterations, and evaluated the antitumour activity of DS-7300a, a topoisomerase-1 inhibitor payload anti-B7-H3 ADC, in human PC cell lines, organoids (PDX-Os), and xenografts (PDXs) of different histologies, B7-H3 expressions, and genomics. RESULTS AND LIMITATIONS: B7-H3 was among the most highly expressed immunomodulatory genes in CRPCs. Most CRPCs (93%) expressed B7-H3, and in patients who developed CRPC, B7-H3 expression was frequently expressed at the time of HSPC diagnosis (97%). Conversion from B7-H3 positive to negative, or vice versa, during progression from HSPC to CRPC was uncommon. CRPC with neuroendocrine features were more likely to be B7-H3 negative (28%) than adenocarcinomas. B7-H3 is overexpressed in tumours with defective DNA repair gene (ATM and BRCA2) alterations and is associated with ERG expression, androgen receptor (AR) expression, and AR activity signature. DS7300a had antitumour activity against B7-H3 expressing human PC models including cell lines, PDX-Os, and PDXs of adenocarcinoma and neuroendocrine histology. CONCLUSIONS: The frequent overexpression of B7-H3 in CRPC compared with normal tissue and other B7 family members implicates it as a highly relevant therapeutic target in these diseases. Mechanisms driving differences in B7-H3 expression across genomic subsets warrant investigation for understanding the role of B7-H3 in cancer growth and for the clinical development of B7-H3 targeted therapies. PATIENT SUMMARY: B7-H3, a protein expressed on the surface of the most lethal prostate cancers, in particular those with specific mutations, can be targeted using drugs that bind B7-H3. These findings are relevant for the development of such drugs and for deciding which patients to treat with these new drugs.

A paradigm shift in the quantification of wave energy attenuation due to saltmarshes based on their standing biomass.

Most existing analytical and numerical models to quantify wave energy attenuation attributed to saltmarshes are based on the definition of a drag coefficient that varies with vegetation and wave characteristics and requires calibration, i.e., a case-specific variable. With the aim of determining a new variable to estimate wave energy attenuation without the use of calibration coefficients, wave attenuation caused by different saltmarsh species and the relationship with the ecosystem standing biomass are experimentally studied. Samples of four real saltmarshes with contrasting morphological and biomechanical properties, namely, Spartina sp., Salicornia sp., Halimione sp. and Juncus sp., are collected in the field and placed in a wave flume for testing under different regular and random wave conditions. Two meadow densities are considered, in addition to zero-density cases. Thus, wave damping coefficients are obtained in vegetated cases, ß, and bare soil cases, ßB, and wave damping produced solely by the meadow standing biomass, ßSB, is determined. The obtained wave damping coefficients are related to a new variable, the hydraulic standing biomass (HSB), which is defined as a function of the meadow mean height and standing biomass and incident flow characteristics. Linear fitting relationships between the wave damping coefficient and HSB are obtained, allowing ß and ßSB estimation without the need for calibration. Therefore, the use of these new relationships facilitates direct quantification of wave energy attenuation due to saltmarshes based on incident wave conditions, mean plant height and meadow standing biomass, variables that can be obtained from aerial images or remote sensing data, extending the applicability of the approach. Another key aspect is that this approach does not depend on any calibration coefficient and can be directly applied with knowledge of the abovementioned characteristics. This may represent a paradigm shift in the estimation of wave energy attenuation attributed to saltmarshes.

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.