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Many prostate cancer patients also suffer from depression, which can decrease their life satisfaction and also impede recovery from their cancer. This study described the network structure of depressive symptomatology in prostate cancer patients, with a view to providing suggestions for clinical interventions for depressed patients.Using a cross-sectional design, 555 prostate cancer patients completed the Patient Health Questionnaire-9 (PHQ-9).Network analysis and multidimensional scaling indicated that anhedonia was the most central symptom for these men, and that several sets of depression symptoms were closely associated with each other. These included anhedonia-depressed mood; sleeping problems-fatigue/lethargy; and suicidal ideation-low self-worth-depressed mood. Other depression symptoms such as appetite problems, concentration problems, and motor problems, were less well-related with the remainder of the network. Patients receiving treatment for reocurring prostate cancer (PCa) had significantly higher PHQ9 scores than patients undergoing their initial treatment, but no major differences in their network structures. Implications for clinical practice were derived from the relationships between individual depression symptoms and the overall depression network by examining node predictability.The use of total depression scores on an inventory does not reflect the underlying network structure of depression in PCa patients. Identification and treatment of the central symptom of anhedonia in PCa patients suggests the need to adopt specific therapies that are focussed upon this symptom.

Optimizing the Diels-Alder (DA) reaction for aqueous coupling has resulted in practical methods to link molecules such as drugs and diagnostic agents to proteins. Both normal electron demand (NED) and inverse electron demand (IED) DA coupling schemes have been employed, but neither mechanism entails a common multipurpose reactive group. This report focuses on expanding the bioconjugation toolbox for cyclopentadiene through the identification of reactive groups that couple through NED or IED mechanisms in aqueous solution. Dienophiles and tetrazine derivatives were screened for reactivity and selectivity toward antibodies bearing cyclopentadiene amino acids to yield bioconjugates. Twelve NED dienophiles and four tetrazine-based IED substrates were identified as capable of practical biocoupling. Furthermore, tetrazine ligation to cyclopentadiene occurred at a rate of 3.3 ± 0.5 Msup-1/supssup-1/supand was capable of bioorthogonal transformations, as evidenced by the selective protein labeling in serum. Finally, an antibody-drug conjugate (ADC)-bearing monomethyl auristatin E was prepared via tetrazine conjugation to cyclopentadiene. The resulting ADC was stable and demonstrated potent activityiin vitro/i. These findings expand the utility of cyclopentadiene as a tool to couple entities to proteins via dual DA addition mechanisms.

Supplementary Figure S1. Analytical characterization of INT016-ADCs; Supplementary Figure S2. Validation of B7-H4 antibodies for use in IHC; Supplementary Figure S3. Relationship between B7-H4 expression level and heterogeneity in the studied human triple-negative cohort; Supplementary Figure S4. Binding of antibody INT016 to HEK 293 cells stably expressing human, mouse, or cynomolgus monkey B7-H4; Supplementary Figure S5. Binding of antibody INT016 to human breast cancer cell lines and to HT29 cells stably expressing human B7-H4; Supplementary Figure S6. Internalization and lysosomal trafficking of INT016; Supplementary Figure S7. In vitro stability of INT016-ADCs in mouse and cynomolgus monkey serum; Supplementary Figure S8. In vitro cytotoxicity of INT016-ADCs in HT29 and HT29-huB7-H4 isogenic cell lines; Supplementary Figure S9. In vivo efficacy of INT016-ADCs in the MX-1 xenograft model; Supplementary Figure S10. Growth rate analysis of MX-1 in vivo efficacy study comparing INT016-ADCs from days 14–40.

Surface plasmon resonance; In vitro cytotoxicity assays; In vitro proliferation assays; Internalization assays; Subcellular localization microscopy; Immunoblotting; Statistical analysis

Supplementary Table S1. Primary antibodies used for immunoblotting; Supplementary Table S2. Characterization of ADCs evaluated in this study; Supplementary Table S3. B7-H4 expression in human normal tissue; Supplementary Table S4. Binding affinity of anti-B7-H4 antibody INT016 Fab to human, cynomolgus monkey, and mouse B7-H4, measured by surface plasmon resonance.

Purpose:We evaluated the activity of AZD8205, a B7-H4–directed antibody–drug conjugate (ADC) bearing a novel topoisomerase I inhibitor (TOP1i) payload, alone and in combination with the PARP1-selective inhibitor AZD5305, in preclinical models.Experimental Design:IHC and deep-learning–based image analysis algorithms were used to assess prevalence and intratumoral heterogeneity of B7-H4 expression in human tumors. Several TOP1i-ADCs, prepared with Val-Ala or Gly–Gly–Phe–Gly peptide linkers, with or without a PEG8 spacer, were compared in biophysical, in vivo efficacy, and rat toxicology studies. AZD8205 mechanism of action and efficacy studies were conducted in human cancer cell line and patient-derived xenograft (PDX) models.Results:Evaluation of IHC-staining density on a per-cell basis revealed a range of heterogeneous B7-H4 expression across patient tumors. This informed selection of bystander-capable Val-Ala–PEG8–TOP1i payload AZ14170133 and development of AZD8205, which demonstrated improved stability, efficacy, and safety compared with other linker–payload ADCs. In a study of 26 PDX tumors, single administration of 3.5 mg/kg AZD8205 provided a 69% overall response rate, according to modified RECIST criteria, which correlated with homologous recombination repair (HRR) deficiency (HRD) and elevated levels of B7-H4 in HRR-proficient models. Addition of AZD5305 sensitized very low B7-H4–expressing tumors to AZD8205 treatment, independent of HRD status and in models representing clinically relevant mechanisms of PARPi resistance.Conclusions:These data provide evidence for the potential utility of AZD8205 for treatment of B7-H4–expressing tumors and support the rationale for an ongoing phase 1 clinical study (NCT05123482).See related commentary by Pommier and Thomas, p. 991

The management of Hodgkin Lymphoma (HL) has undergone significant changes in recent years. Due to the predilection of HL to affect younger patients, balancing cure and treatment related morbidity is a constant source of concern, for physicians and patients alike. PET adapted therapy has been developed for both early and advanced stage HL to try and improve the outcome of treatment, whilst minimising toxicities. The aim of this review is to digest the plethora of studies recently conducted and provide some clear, evidence-based practice statements to simplify the management HL. This article is protected by copyright. All rights reserved.

Introduction:. Prostate-specific antigen (PSA) kinetic patterns during neoadjuvant androgen deprivation therapy have been shown to predict unfavorable long-term outcomes. Objective:. To investigate the effect of testosterone escape (TE) on these kinetic patterns, as this had not been previously reported. Methods:. There were 50 consecutive prostate cancer patients who received 6 months of triptorelin prior to definitive radiotherapy (RT). Testosterone and PSA levels were measured at baseline and every 6 weeks. Clinical factors were tested for their ability to predict for TE and unfavorable PSA kinetic patterns. The effects of TE, at both 1.7 and 0.7 nmol/L levels, were analyzed. Results:. TE occurred in at least one reading for 14% and 34% of the patients at the 1.7 and 0.7 nmol/L levels, respectively. No baseline factors predicted TE. The median PSA halving time was 25 days and the median pre-RT PSA level was 0.55 ng/mL. The only factor significantly associated with a higher pre-RT PSA level was a higher baseline PSA level. The only factor that significantly predicted a longer PSA halving time was TE at the 1.7 nmol/L level. Conclusions:. TE and higher baseline PSA levels may adversely affect PSA kinetics and other outcomes for patients undergoing neoadjuvant hormone therapy prior to radiotherapy. Studies investigating the tailoring of neoadjuvant therapy by extending the duration in those patients with a higher baseline PSA level or by the addition of anti-androgens in those demonstrating TE, should be considered.

Objective To test the 'buffering' effect of psychological resilience (PR) upon depression in prostate cancer patients and to also investigate any effects that past or current treatment may have had upon patients' PR as a test of the 'steeling' hypothesis of past adversity upon future resilience. Methods A total of 576 volunteer prostate cancer patients completed questionnaires about their demographic and treatment variables, and their psychological resilience and depression. Factor analysis was used to identify the underlying components of the resilience measure. Results PR was confirmed as an inverse correlate of depression in these men. Additionally, some past and current treatments were found to be significantly associated with patients' psychological resilience in a way suggestive of 'steeling' effects. Conclusion These data provide support for the model of PR as being influenced by past experiences of adversity and demonstrate that association for prostate cancer patients.

Many patients with prostate cancer experience severe levels of depression, which can negatively affect their treatment and disease course. Some prostate cancer treatments can increase the severity of a patient’s depression, for example, by increasing anhedonia and erectile dysfunction. Depression is often thought of as a unitary phenomenon, but multiple subtypes can be distinguished. This variety of manifestations challenges the successful application of universal antidepressant treatment options and argues for a multi-symptom assessment process that considers a patient’s disease burden and their particular form of depression. Inclusion of screening and detailed diagnosis of depression can be argued to be part of good practice, and clinicians are urged to consider when and how this might be accomplished within their urological practice. Sharpley et al. describe the prevalence and effects of depression in men with prostate cancer and explore the causes and factors contributing to depression. They discuss depression definitions applicable to this patient population, how depression can be identified in the clinical setting and treatment considerations.

Aims Perineural invasion (PNI) by prostatic adenocarcinoma is debated as a prognostic parameter. This study investigates the prognostic predictive value of PNI in a series of patients with locally advanced prostate cancer treated with radiotherapy and androgen deprivation using 10 years outcome data from the TROG 03.04 RADAR trial. Methods Diagnostic prostate biopsies from 976 patients were reviewed and the presence of PNI noted. Patients were followed for 10 years according to the trial protocol or until death. The primary endpoint for the study was time to bone metastasis. Secondary endpoints included time to soft tissue metastasis, transition to castration resistance, prostate cancer-specific mortality and all-cause mortality. Results PNI was detected in 449 cases (46%), with 234 cases (24%) having PNI in more than one core. The presence of PNI was significantly associated with higher ISUP grade, clinical T staging category, National Comprehensive Cancer Network risk group, and percent positive biopsy cores. The cumulative probability of bone metastases according to PNI status was significant over the 10 years follow-up interval of the study (log-rank testP < 0.0001). PNI was associated with all endpoints on univariable analysis. After adjusting for baseline clinicopathological and treatment factors, bone metastasis was the only endpoint in which PNI retained its prognostic significance (hazard ratio 1.42, 95% confidence interval 1.05-1.92,P = 0.021). Conclusions The association between PNI and the development of bone metastases supports the inclusion of this parameter as a component of the routine histology report. Further this association suggests that evaluation of PNI may assist in selecting those patients who should be monitored more closely during follow-up.

While alpha-blockers are commonly used to reduce lower urinary tract symptoms in prostate cancer patients receiving radiotherapy, their impact on response to radiotherapy remains unknown. Therefore, this pilot study aimed to retrospectively determine if alpha-blockers use, influenced response to radiotherapy for localised prostate cancer. In total, 303 prostate cancer patients were included, consisting of 84 control (alpha-blocker naïve), 72 tamsulosin and 147 prazosin patients. The main outcomes measured were relapse rates (%), time to biochemical relapse (months) and PSA velocity (ng/mL/year). Recurrence free survival was calculated using Kaplan-Meier analysis. Prazosin significantly reduced biochemical relapse at both two and five-years (2.72%, 8.84%) compared to control (22.61%, 34.52%). Recurrence free survival was also significantly higher in the prazosin group. This remained after multivariable analysis (HR: 0.09, 95% CI: 0.04–0.26, p

In 2016, during a visit to the Chemical Heritage Foundation in Philadelphia (now the Science History Institute), I and Carin Berkowitz, then director of the Beckman Center for the History of Chemis...

To clarify the relative effects of duration of androgen suppression (AS) and radiation dose escalation (RDE) on distant progression (DP) in men with locally advanced prostate cancer.Participants with locally advanced prostate cancer in the TROG 03.04 RADAR trial were randomized to 6 or 18 months AS ± 18 months zoledronic acid (Z). The trial incorporated a RDE program by stratification at randomization and dosing options were 66, 70, or 74 Gy external beam radiation therapy (EBRT), or 46 Gy EBRT plus high-dose-rate brachytherapy boost (HDRB). The primary endpoint for this study was distant progression (DP). Secondary endpoints included local progression, bone progression, prostate cancer-specific mortality and all-cause mortality. Effect estimates for AS duration and RDE were derived using Fine and Gray competing risk models adjusting for use of Z, age, tumor stage, Gleason grade group, prostate-specific antigen, and treatment center. Cumulative incidence at 10 years was estimated for each RDE group.A total of 1051 out of 1071 randomized subjects were eligible for inclusion in this analysis. Compared with 6 months AS, 18 months AS significantly reduced DP independently of radiation dose (subhazard ratio 0.70; 95% confidence interval [CI], 0.56-0.87; P = .002). No statistically significant interaction between effect of AS duration and RT dose was observed (Wald test P = .76). In subgroup analyses, DP was significantly reduced by the longer duration of AS in the 70 Gy and HDRB groups but not in the 66 Gy and 74 Gy. Compared with 70 Gy, HDRB significantly reduced DP (subhazard ratio 0.68 [95% CI, 0.57-0.80]; P.0001) independently of AS duration. At 10 years, adjusted cumulative incidences were 26.1% (95% CI, 18.9%-33.2%), 26.7% (22.9%-30.6%), 24.9% (20.0%-29.8%) and 19.7% (15.5%-23.8%) for DPs in the respective radiation dose groups.Compared with 6 months AS, 18 months AS reduced DP independently of radiation dose. Men treated with HDRB gained a significant benefit from a longer duration of AS. Evidence of improved oncologic outcomes for HDRB compared with dose-escalated EBRT needs to be confirmed in a randomized trial.

The normal electron-demand Diels-Alder (DA) cycloaddition is a classic transformation routinely used in synthesis; however, applications in biological systems are limited. Here, we report a spiro[2.4]hepta-4,6-diene-containing noncanonical amino acid (SCpHK) capable of efficient incorporation into antibodies and subsequent coupling with maleimide via a DA reaction. SCpHK was stable throughout protein expression in mammalian cells and enabled covalent attachment of maleimide drug-linkers yielding DA antibody-drug conjugates (DA-ADCs) with nearly quantitative conversion in a one-step process. The uncatalyzed DA reaction between SCpHK and maleimide in aqueous buffer was rapid (1.8-5.4 M-1 s-1), and the antibody-drug adduct was stable in rat serum for at least 1 week at 37 °C. Anti-EphA2 DA-ADCs containing AZ1508 or SG3249 maleimide drug-linkers were potent inhibitors of tumor growth in PC3 tumor models in vivo. The DA bioconjugation strategy described here represents a simple method to produce site-specific and stable ADCs with maleimide drug-linkers.

Objective: There are many important clinical scenarios in which estimates of the volume of the prostate gland can have an influence on clinical decisions. The digital rectal examination is the simplest and most readily available method for measuring it. It is commonly performed numerous times every day by practising urologists and radiation oncologists. The prostate gland volume is the most studied parameter arising from it. Although reported in many heterogeneous studies, the accuracy of the digital rectal examination in measuring the volume has never been reviewed. Our aim was to conduct the world’s first systematic review. Methods: Articles from the literature were included if they compared the digital rectal examination with more accurate measures including fluid displacement after radical prostatectomy and transrectal ultrasound measurements. Results: Nineteen articles describing 7891 patients were reviewed and summarised. Wide variations were noted but most studies provided correlation coefficients that lay between 0.3 and 0.7. For those studies that did not involve special training in volume estimation or were not conducted by a urologist with a special interest in the correlation, the coefficients were below 0.6. For eight studies that analysed the estimated volume as a categorical variable, concordance was described using a variety of statistical tests but was generally high. Conclusions: The reported correlations were weak to moderate strength indicating that the digital rectal examination may not be accurate enough when quantitative measurements are required. However, enlargement of the prostate was detectable with high levels of concordance, indicating that the digital rectal examination is effective for that purpose. Level of evidence: Not applicable for this multicentre audit.

Prior to human arrival in the 13th century, two large birds of prey were the top predators in New Zealand. In the absence of non-volant mammals, the extinct Haast's eagle (Hieraaetus moorei), the largest eagle in the world, and the extinct Eyles' harrier (Circus teauteensis) the largest harrier in the world, had filled ecological niches that are on other landmasses occupied by animals such as large cats or canines. The evolutionary and biogeographic history of these island giants has long been a mystery. Here we reconstruct the origin and evolution of New Zealand’s giant raptors using complete mitochondrial genome data. We show that both Eyles’ harrier and Haast’s eagle diverged from much smaller, open land adapted Australasian relatives in the late Pliocene to early Pleistocene. These events coincided with the development of open habitat in the previously densely forested islands of New Zealand. Our study provides evidence of rapid evolution of island gigantism in New Zealand’s extinct birds of prey. Early Pleistocene climate and environmental changes were likely to have triggered the establishment of Australian raptors into New Zealand. Our results shed light on the evolution of two of the most impressive cases of island gigantism in the world.

BACKGROUND: Exome sequencing is emerging as a first-line diagnostic method in some clinical disciplines, but its usefulness has yet to be examined for most constitutional disorders in adults, including chronic kidney disease, which affects more than 1 in 10 persons globally. METHODS: We conducted exome sequencing and diagnostic analysis in two cohorts totaling 3315 patients with chronic kidney disease. We assessed the diagnostic yield and, among the patients for whom detailed clinical data were available, the clinical implications of diagnostic and other medically relevant findings. RESULTS: In all, 3037 patients (91.6%) were over 21 years of age, and 1179 (35.6%) were of self-identified non-European ancestry. We detected diagnostic variants in 307 of the 3315 patients (9.3%), encompassing 66 different monogenic disorders. Of the disorders detected, 39 (59%) were found in only a single patient. Diagnostic variants were detected across all clinically defined categories, including congenital or cystic renal disease (127 of 531 patients [23.9%]) and nephropathy of unknown origin (48 of 281 patients [17.1%]). Of the 2187 patients assessed, 34 (1.6%) had genetic findings for medically actionable disorders that, although unrelated to their nephropathy, would also lead to subspecialty referral and inform renal management. CONCLUSIONS: Exome sequencing in a combined cohort of more than 3000 patients with chronic kidney disease yielded a genetic diagnosis in just under 10% of cases. (Funded by the National Institutes of Health and others.)

The cell-surface glycoprotein B7-H4 is overexpressed in a range of solid tumors including breast cancer, ovarian serous carcinoma, endometrial carcinoma, and cholangiocarcinoma, yet has limited expression in normal tissue, making it an attractive target for an antibody-drug conjugate (ADC). This presentation describes for the first time the development of AZD8205, a B7-H4 targeted ADC incorporating a novel topoisomerase 1 inhibitor (TOP1i) linker-warhead, AZ’0133 which was designed to exploit the full potential of B7-H4 as an ADC target. Initially, we investigated a series of more than 35 TOP1i compounds as warheads and achieved activity in a clinically relevant nM range. We further optimized the conjugation site and chemistry to reduce the potential for aggregation while maintaining potency, overcoming major synthetic challenges to deliver a robust synthetic route amenable to scale-up. Finally, with a series of optimized linker-warheads, we explored the impact of linker-warhead design on ADC hydrophobicity, stability, efficacy, pharmacokinetics and tolerability culminating in the development of AZD8205. The primary mechanism of action of AZD8205 is intracellular delivery of the TOP1i warhead to B7-H4 positive cells, leading to DNA damage and apoptotic cell death. AZD8205 drove bystander killing of target negative cells in mixed cultures in vitro, which is further supported by robust antitumor activity observed in in vivo studies with patient-derived xenograft (PDX) tumors with heterogeneous target expression, representing multiple tumor indications. In a study of 26 human TNBC PDX tumors, a single IV administration of 3.5 mg/kg AZD8205 provided an overall response rate of 69% (tumor regression of 30% or greater from baseline) and complete responses observed in 9/26 (36%) of models. To understand the biology underlying antitumor response, we conducted a multiparametric analysis including genomics, proteomics and computational pathology and found that deeper antitumor activity was observed in models with elevated B7-H4 expression as well as in models with defects in DNA damage repair (DDR). To further exploit the DNA damage elicited by the TOP1i warhead, we examined combinations of AZD8205 with small molecules, including a novel PARP1 selective inhibitor, in a BRCA wild type MDA-MB-468 model. These data suggest that AZD8205 is a promising therapeutic candidate for the treatment of B7-H4 positive solid tumors. A first in human phase 1 study in patients with advanced solid tumors is currently ongoing (NCT05123482). Citation Format: Krista Kinneer, Niall J. Dickinson, Luke Masterson, Thais Cailleau, Ian Hutchinson, Balakumar Vijayakrishnan, Nazzareno Dimasi, R. James Christie, Mary McFarlane, Kathryn Ball, Arthur Lewis, Sofia Koch, Lee Brown, Yue Huang, Anton I. Rosenbaum, Jiaqi Yuan, Si Mou, Noel R. Monks, Jon Chesebrough, Ravinder Tammali, Judith Anderton, Darrin Sabol, Frances Anne Tosto, Philipp Wortmann, Zachary A. Cooper, Pauline Ryan, John Hood, Carlos Fernandez Teruel, Carlos Serra Traynor, Andy Pike, Michael Davies, Elisabetta Leo, Kimberly Cook, Nadia Luheshi, Philip W. Howard, Puja Sapra. Discovery and first disclosure of AZD8205, a B7-H4-targeted antibody-drug conjugate utilizing a novel topoisomerase I linker-warhead [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1765.

Background Biliary atresia (BA), a fibrosing disorder of the developing biliary tract leading to liver failure in infancy, has an elevated incidence in indigenous New Zealand (NZ) Māori. We investigated a high rate of BA in a group of children (n = 12) belonging to a single Māori iwi (or ‘tribe’, related through a remote ancestor). Methods Population and geographical data was used to estimate the rate of BA in Māori sub-groups, and a pedigree linking most of the affected children was constructed from oral and documented history. Array genotyping was used to examine hypotheses about the inheritance of a possible genetic risk factor, and the history of the affected population, and Exome Sequencing to search for candidate genes. Results Most of these affected children (n = 7) link to a self-reported pedigree and carry a 50-fold increase in BA risk over unrelated Māori (χ2 = 296P 0.63). Genome-wide quantitation of intervals of contiguous, homozygous-by-state markers reached a similar conclusion (F (2,399) = 1.99, P = 0.138). Principal component analysis and investigation with STRUCTURE found no evidence of increased allele frequency of either a recessive variant, or additive, low-risk variants due to reproductive isolation. To identify candidate causal factors, Exome Sequencing datasets were scrutinised for shared rare coding variants across 8 affected individuals. No rare, non-synonymous, phylogenetically conserved variants were common to 6 or more affected children. Conclusion The substantially elevated risk for development of BA in this subgroup could be mediated by genetic factors, but the iwi exhibits no properties indicative of recent or remote reproductive isolation. Resolution of any risk loci may rely on extensive genomic sequencing studies in this iwi or investigation of other mechnaisms such as copy number variation. Electronic supplementary material The online version of this article (10.1186/s12920-018-0440-0) contains supplementary material, which is available to authorized users.

Men who suffer from prostate cancer (PCa) need to make important decisions regarding their treatment options. There is some evidence that these men may suffer from sleep difficulties due to their cancer or its diagnosis and treatment. Although sleep difficulties have been associated with cognitive depression in other samples of men, they have not been examined in PCa patients, despite the importance of decision-making for these men. This study was designed to investigate the association between sleep difficulties and cognitive depression in PCa patients. A sample of 96 PCa patients completed a background questionnaire, the Zung Self-Rating Depression Scale, and the Insomnia Severity Index. Comparison was made between sleep difficulty scores from before the patients received their diagnosis of PCa to the time of survey, allowing use of a “retrospective pretest” methodology. Just over 61% of the sample reported a deterioration in sleep quality, and this was significantly associated with cognitive depression ( r = .346, p = .007). At the specific symptom level, having a clear mind significantly contributed to the variance in difficulty falling asleep (R2 change = .140, F for change = 9.298, p = .003). Sleeping difficulties, particularly falling asleep, are common and associated with depression-related to ability to think clearly in PCa patients. This has potentially adverse effects upon the ability of men with PCa to understand their treatment options and make decisions about them.

IntroductionAsthma risk is a complex interplay between genetic susceptibility and environment. Despite many significantly-associated common variants, the contribution of rarer variants with potentially greater effect sizes has not been as extensively studied. We present an exome-based study adopting 24,576 cases and 120,530 controls to assess the contribution of rare protein-coding variants to the risk of early-onset or all-comer asthma.MethodsWe performed case-control analyses on three genetic units: variant-, gene- and pathway-level, using sequence data from the Scandinavian Asthma Genetic Study and UK Biobank participants with asthma. Cases were defined as all-comer asthma (n=24,576) and early-onset asthma (n=5,962). Controls were 120,530 UK Biobank participants without reported history of respiratory illness.ResultsVariant-level analyses identified statistically significant variants at moderate-to-common allele frequency, including protein-truncating variants in FLG and IL33. Asthma risk was significantly increased not only by individual, common FLG protein-truncating variants, but also among the collection of rare-to-private FLG protein-truncating variants (p=6.8×10−7). This signal was driven by early-onset asthma and did not correlate with circulating eosinophil levels. In contrast, a single splice variant in IL33 was significantly protective (p=8.0×10−10), while the collection of remaining IL33 protein-truncating variants showed no class effect (p=0.54). A pathway-based analysis identified that protein-truncating variants in loss-of-function intolerant genes were significantly enriched among individuals with asthma.ConclusionsAccess to the full allele frequency spectrum of protein-coding variants provides additional clarity about the potential mechanisms of action for FLG and IL33. Beyond these two significant drivers, we detected a significant enrichment of protein-truncating variants in loss-of-function intolerant genes.

In recent decades, feminism has resurfaced as a considerable and widespread political movement throughout the world, devoted to obtaining equal rights and status for women in the economic and political spheres. Put more generally, feminism seeks a world where the biological, sexual difference between female and male does not entail an economic, social and political inequality between the lives of the two genders, feminine and masculine. In theoretical, scholarly terms, the focus of feminism is upon the term gender, the socially and culturally-produced difference of identities attributed to biologically female and male persons. Around these different gender identities is organised the phenomenon known as patriarchy, the system which embodies and assures the inequitable distribution of power between women and men, to the continuing advantage of men. Patriarchy, then, is the structure of social relations which ensures that men tend to have better access to career, salary, status and power in any given set of economic, social and political circumstances. It further ensures that in situations usually thought of as ‘private’ or ‘personal’, men also tend to occupy the most powerful position. The point of concentrating upon gender is therefore to discover, understand, criticise and overthrow the means by which feminine and masculine identities are made; are socially-constructed artefacts which support and produce a fundamental, systematic and arguably universal condition of inequality which holds across boundaries of class, culture and race.

Synthetic gene delivery systems employ multiple functions to enable safe and effective transport of DNA to target cells. Here, we describe metabolite-based poly(l-lysine) (PLL) modifiers that improve transfection by imparting both pH buffering and nanoparticle stabilization functions within a single molecular unit. PLL modifiers were based on morpholine (M), morpholine and niacin (MN), or thiomorpholine (TM). PLL modification with (MN) or (TM) imparted buffering function over the pH range of 5-7 both in solution and live cells and enhanced the stability of PLL DNA nanoparticles, which exhibited higher resistance to polyanion exchange and prolonged blood circulation. These properties translated into increased transfection efficiency in vitro coupled with reduced toxicity compared to unmodified PLL and PLL(M). Furthermore, PEG-PLL(MN) DNA nanoparticles transfected muscle tissue in vivo for >45 days following intramuscular injection. These polymer modifiers demonstrate the successful design of multifunctional units that improve transfection of synthetic gene delivery systems while maintaining biocompatibility.

The tumour volume of a cancer within the prostate gland is commonly measured with multiparametric MRI. The measurement has a role in many clinical scenarios including focal therapy, but the accuracy of it has never been systematically reviewed. We included articles if they compared tumour volume measurements obtained by mpMRI with a reference volume measurement obtained after radical prostatectomy. Correlation and concordance statistics were summarised. A simple accuracy score was derived by dividing the given mean or median mpMRI volume by the histopathological reference volume. Factors affecting the accuracy were noted. Scores for potential bias and quality were calculated for each article. A total of 18 articles describing 1438 patients were identified. Nine articles gave Pearson's correlation scores, with a median value of 0.75 but the range was wide (0.42-0.97). A total of 11 articles reported mean values for volume while 9 reported median values. For all 18 articles, the mean or median values for MRI volumes were lower than the corresponding reference values suggesting consistent underestimation. For articles reporting mean and median values for volume, the median accuracy scores were 0.83 and 0.80, respectively. The accuracy was higher for tumours of greater volume, higher grade and when an endorectal coil was used. Accuracy did not seem to improve over time, with a 3 Tesla magnet or by applying a shrinkage factor to the reference measurement. Most studies showed evidence of at least moderate bias, and their quality was highly variable, but neither of these appeared to affect accuracy.

Successful gene therapies rely on methods that safely introduce DNA into target cells and enable subsequent expression of proteins. To that end, peptides are an attractive materials platform for DNA delivery, facilitating condensation into nanoparticles, delivery into cells, and subcellular release to enable protein expression. Peptides are programmable materials that can be designed to address biocompatibility, stability, and subcellular barriers that limit efficiency of non-viral gene delivery systems. This review focuses on fundamental structure-function relationships regarding peptide design and their impact on nanoparticle physical properties, biologic activity, and biocompatibility. Recent peptide technologies utilize multi-dimensional structures, non-natural chemistries, and combinations of peptides with lipids to achieve desired properties and efficient transfection. Advances in DNA cargo design are also presented to highlight further opportunities for peptide-based gene delivery. Modern DNA designs enable prolonged expression compared to traditional plasmids, providing an additional component that can be synergized with peptide carriers for improved transfection. Peptide transfection systems are poised to become a flexible and efficient platform incorporating new chemistries, functionalities, and improved DNA cargos to usher in a new era of gene therapy.

Purpose Follicular lymphoma (FL) is curable by involved-field radiotherapy (IFRT) in < 50% of patients with stage I to II disease. We hypothesized that adding systemic therapy to IFRT would improve long-term progression-free survival (PFS). Patients and Methods A multicenter randomized controlled trial enrolled patients with stage I to II low-grade FL after staging computed tomography scans and bone marrow biopsies. 18F-labeled fluorodeoxyglucose–positron emission tomography (PET) was not mandatory. Patients were randomly assigned to either arm A (30 Gy IFRT alone) or arm B (IFRT plus six cycles of cyclophosphamide, vincristine, and prednisolone [CVP]). From 2006, rituximab was added to arm B (R-CVP). Results Between 2000 and 2012, 150 patients were enrolled, 75 per arm. In arm B, 44 patients were allocated to receive CVP and 31 were allocated to receive R-CVP. At randomization, 75% had stage I, the median age was 57 years, 52% were male, and 48% were PET staged. With a median follow-up of 9.6 years (range, 3.1 to 15.8 years), PFS was superior in arm B (hazard ratio, 0.57; 95% CI, 0.34 to 0.95; P = .033). Ten-year PFS rates were 59% (95% CI, 46% to 74%) and 41% (95% CI, 30% to 57%) for arms B and A, respectively. Patients in arm B who received R-CVP had markedly superior PFS compared with contemporaneous patients in arm A (hazard ratio, 0.26; 95% CI, 0.07 to 0.97; P = .045). Fewer involved regions ( P = .047) and PET staging ( P = .056) were associated with better PFS. Histologic transformation occurred in four and 10 patients in arms B and A, respectively ( P = .1). Ten deaths occurred in arm A versus five in arm B, but overall survival was not significantly different ( P = .40; 87% and 95% at 10 years, respectively). Conclusion Systemic therapy with R-CVP after IFRT reduced relapse outside radiation fields and significantly improved PFS. IFRT followed by immunochemotherapy is more effective than IFRT in early-stage FL.

Despite recent advances in treatment, breast cancer remains the second-most common cause of cancer death among American women. A greater understanding of the molecular characteristics of breast tumors could ultimately lead to improved tumor-targeted treatment options, particularly for subsets of breast cancer patients with unmet needs. Using an unbiased genomics approach to uncover membrane-localized tumor-associated antigens (TAAs), we have identified glial cell line derived neurotrophic factor (GDNF) family receptor α 1 (GFRA1) as a breast cancer TAA. Immunohistochemistry (IHC) revealed that GFRA1 displays a limited normal tissue expression profile coupled with overexpression in specific breast cancer subsets. The cell surface localization as determined by fluorescence-activated cell sorting (FACS) and the rapid internalization kinetics of GFRA1 makes it an ideal target for therapeutic exploitation as an antibody-drug conjugate (ADC). Here, we describe the development of a pyrrolobenzodiazepine (PBD)-armed, GFRA1-targeted ADC that demonstrates cytotoxicity in GFRA1-positive cell lines and patient-derived xenograft (PDX) models. The safety profile of the rat cross-reactive GFRA1-PBD was assessed in a rat toxicology study to find transient cellularity reductions in the bone marrow and peripheral blood, consistent with known off-target effects of PBD ADC's. These studies reveal no evidence of on-target toxicity and support further evaluation of GFRA1-PBD in GFRA1-positive tumors.

Some prostate cancer (PCa) patients become clinically anxious or depressed after diagnosis and treatment. Some also show the physiological signs of chronic stress. However, there are currently no data describing how these particular patients might be identified at intake. This study tested the individual and combined predictive power of a psychological factor and a genetic factor as potential predictors of anxiety, depression, and chronic stress in a sample of PCa patients. Ninety-five PCa patients completed psychological inventories for anxiety, depression, and psychological resilience (PR) and also gave a saliva sample for cortisol and a mouthwash sample for genetic testing for the presence of the BDNF Val66Met polymorphism. High PR patients had significantly lower anxiety and depression than low PR patients, but showed no significant differences in their salivary cortisol. Carriers of the Met allele of the BDNF Val66Met polymorphism had significantly higher salivary cortisol concentrations than patients who did not carry this allele. Each of these two factors may provide valuable information regarding the vulnerability of PCa patients to anxiety, depression, or chronic stress. Suggestions are made for their inclusion in clinical settings.

To determine incidence and outcome of biliary atresia (BA) between ethnic groups in New Zealand (NZ), a retrospective review was undertaken of children with BA born between 2002 and 2014. Prioritized ethnicity was used to determine ethnicity and was compared to population data. Uni- and multivariate analyses were undertaken to determine demographic and biochemical factors associated with outcome. Overall incidence was 1 in 9181 (Māori 1 in 5285; European 1 in 16,228; P < 0.0001). Overall and transplant-free survival rates at 1, 2, and 5 years were 92%, 86%, 82% and 70%, 49%, 30% respectively with Māori having improved transplant-free survival (P < 0.05) despite European children undergoing Kasai earlier (49 vs 63 days). BA is more common in NZ than Europe and North America, which is attributable to a higher incidence in Māori but overall outcome is poorer. Māori have improved transplant-free survival compared to NZ European children but the reason is unknown.

Classification, phylogeography and the testing of evolutionary hypotheses rely on correct estimation of species phylogeny. Early molecular phylogenies often relied on mtDNA alone, which acts as a single linkage group with one history. Over the last decade, the use of multiple nuclear sequences has often revealed conflict among gene trees. This observation can be attributed to hybridization, lineage sorting, paralogy or selection. Here, we use 54 groups of fishes from 48 studies to estimate the degree of concordance between mitochondrial and nuclear gene trees in two ecological grades of fishes: marine and freshwater. We test the hypothesis that freshwater fish phylogenies should, on average, show more discordance because of their higher propensity for hybridization in the past. In keeping with this idea, concordance between mitochondrial and nuclear gene trees (as measured by proportion of components shared) is on average 50% higher in marine fishes. We discuss why this difference almost certainly results from introgression caused by greater historical hybridization among lineages in freshwater groups, and further emphasize the need to use multiple nuclear genes, and identify conflict among them, in estimation of species phylogeny.