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Abstract We analyzed genomic data from the prostate cancer of African- and European American men to identify differences contributing to racial disparity of outcome. We also performed FISH-based studies of Chromodomain helicase DNA-binding protein 1 (CHD1) loss on prostate cancer tissue microarrays. We created CHD1-deficient prostate cancer cell lines for genomic, drug sensitivity and functional homologous recombination (HR) activity analysis. Subclonal deletion of CHD1 was nearly three times as frequent in prostate tumors of African American than in European American men and it associates with rapid disease progression. CHD1 deletion was not associated with HR deficiency associated mutational signatures or HR deficiency as detected by RAD51 foci formation. This was consistent with the moderate increase of olaparib and talazoparib sensitivity with several CHD1 deficient cell lines showing talazoparib sensitivity in the clinically relevant concentration range. CHD1 loss may contribute to worse disease outcome in African American men.

Introducción: las caídas son sucesos involuntarios que hacen perder el equilibrio y dar con el cuerpo en el suelo o en otra superficie firme que lo detenga. El análisis objetivo e instrumentado de la marcha y el equilibrio es una herramienta importante para estimar el riesgo de caídas de los pacientes. El objetivo fue describir la forma de ponderación de las alteraciones en el equilibrio que utilizan los kinesiólogos que residen en la Argentina en el marco de la neurorrehabilitación, rehabilitación vestibular y adultos mayores. Otro objetivo: identificar las barreras y facilitadores autopercibidos por los kinesiólogos que ificultan/facilitan la realización de la ponderación de las deficiencias en el equilibrio. Materiales y método: se realizó un estudio observacional, descriptivo, transversal de tipo encuesta. Se utilizaron las recomendaciones incluidas en la Checklist for Reporting of Survey Studies. La encuesta estuvo destinada a todos aquellos kinesiólogos de la Argentina que se dedican a neurorrehabilitación, rehabilitación vestibular y adultos mayores. Resultados: doscientos cuatro (204) kinesiólogos completaron la encuesta. El 78,79% de ellos respondieron que siempre ponderan a sus pacientes. Las limitaciones biomecánicas, las estrategias sensoriales, la ansiedad y el miedo a caer son los factores menos ponderados. La principal barrera fueron las características de los pacientes (36,76%) y, como principal facilitador, el entrenamiento (33,33%). El 93,63% indicó que le gustaría en el futuro ser entrenado en el área. Conclusión: prevalece, entre los kinesiólogos encuestados, ponderar a sus pacientes e identifican que sus características son una barrera al momento de realizarla, y que el entrenamiento es un facilitador. Registro: ClinicalTrials.gov: NCT05285150

Abstract Stromal antigen 2 (STAG2), a subunit of the cohesin complex, is recurrently mutated in various tumors. However, the role of STAG2 in DNA repair and its therapeutic implications are largely unknown. Here it is reported that knockout of STAG2 results in increased double‐stranded breaks (DSBs) and chromosomal aberrations by reducing homologous recombination (HR) repair, and confers hypersensitivity to inhibitors of ataxia telangiectasia mutated (ATMi), Poly ADP Ribose Polymerase (PARPi), or the combination of both. Of note, the impaired HR by STAG2‐deficiency is mainly attributed to the restored expression of KMT5A, which in turn methylates H4K20 (H4K20me0) to H4K20me1 and thereby decreases the recruitment of BRCA1‐BARD1 to chromatin. Importantly, STAG2 expression correlates with poor prognosis of cancer patients. STAG2 is identified as an important regulator of HR and a potential therapeutic strategy for STAG2‐mutant tumors is elucidated.

ABSTRACT Objective To investigate the effect of 12 weeks of rehearsals on cardiorespiratory parameters and body composition in Brazilian samba dancers belonging to a first-league samba school. Methods Twenty-six women were divided into a Samba Group (n=13) and a Control Group (n=13). Cardiorespiratory parameters (cardiopulmonary exercise test) and body composition (skinfold assessment) were assessed before and after the 12 weeks of rehearsals. The Samba Group rehearsed three times per week for 30–60 minutes, and the Control Group participated in no physical activity. A comparison test was performed within and between groups, with p

ABSTRACT Objective As the soccer culture in Brazil is more popular than schooling, this study reflected on the formal education levels of soccer (football) players through descriptive and quantitative analyses. Methods We evaluated 179 national soccer players playing various positions on different teams across six seasons (2012, 2013, 2014, 2015, 2016, and 2022). Data were collected using a questionnaire comprising the following variables: age, position in the pitch, age of professionalization, and education (years of study). The data were distributed according to the pitch position. Results The mean age, length of professional career, and professionalization age were 23±6 years, 7±5 years, and 17±2 years, respectively. In terms of education, 121 athletes (67%) completed high school, equivalent to 11 years of study. Only 5.5% completed higher education, with defensive players (goalkeepers and defenders) being the most educated at 37% (66/179). According to 2017 figures from the Pesquisa Nacional por Amostra de Domicílios Contínua of the Federal Government of Brazil, the schooling rate is 31.7%, wherein 46.1% of Brazilians aged 25 years or over have completed education. In this study of 179 athletes, 67% had completed high school. Thus, players outrank the Brazilian population in terms of achieving a high school education. There were marked disparities in the relative proportions of goalkeepers (85%), defensive players (68%), midfielders (63%), and forward players (64%) in terms of their education. Conclusion Our survey revealed that attending higher education remains a distant reality in Brazil.

Abstract Recently developed inhibitors of polymerase theta (POLθ) have demonstrated synthetic lethality in BRCA-deficient tumor models. To examine the contribution of the immune microenvironment to antitumor efficacy, we characterized the effects of POLθ inhibition in immunocompetent models of BRCA1-deficient triple-negative breast cancer (TNBC) or BRCA2-deficient pancreatic ductal adenocarcinoma (PDAC). We demonstrate that genetic POLQ depletion or pharmacological POLθ inhibition induces both innate and adaptive immune responses in these models. POLθ inhibition resulted in increased micronuclei, cGAS/STING pathway activation, type I interferon gene expression, CD8+ T cell infiltration and activation, local paracrine activation of dendritic cells and upregulation of PD-L1 expression. Depletion of CD8+ T cells compromised the efficacy of POLθ inhibition, whereas antitumor effects were augmented in combination with anti-PD-1 immunotherapy. Collectively, our findings demonstrate that POLθ inhibition induces immune responses in a cGAS/STING-dependent manner and provide a rationale for combining POLθ inhibition with immune checkpoint blockade for the treatment of HR-deficient cancers.

The use of components obtained through the additive manufacturing (AM) technique has become increasingly widespread in recent years, playing a central role in industrial production, and in particular in some fields such as automotive, biomedical, aerospace and electronics. Among all AM techniques, FDM (Fused Deposition Modelling) represents the most used printing technique to produce polymeric and composite components, thanks to the flexible printing process, the low cost and the diversity of the materials adopted. The aim of the present work concerns the comparison between the mechanical properties of three plastic materials printed with the FDM technique (polylactic acid PLA, polyethylene terephthalate glycol-modified PETG and Acrylonitrile-butadiene-styrene ABS) using an Original Prusa i3 MK3S, by varying the raster angle between 0�, 45� and 90� degrees. Infrared Thermography has been adopted to monitor the temperature evolution during static tensile tests and to assess stress level that can initiate damage within the material. Failure analysis was performed to correlate the mechanical behaviour with the microstructural characteristics of the materials

BCG is the most efficient adjuvant therapy for high-risk, non-muscle-invasive bladder cancer (NMIBC). Both innate and adaptive immune responses have been implicated in BCG-mediated effects. BCG vaccination can boost innate immune responses via trained immunity (TI), resulting in an increased resistance to respiratory viral infections. Here we evaluated for the first time whether intravesical application of BCG triggers increased immunity against SARS-CoV-2 in patients with high-risk NMIBC. Serum and peripheral blood mononuclear cells (PBMCs) from heparinized whole blood samples of 11 unvaccinated SARS-CoV-2-naïve high-risk NMIBC patients were collected at baseline and during BCG treatment in a pre-COVID-19 era. To examine B-cell or T cell-dependent adaptive immunity against SARS-CoV-2, sera were tested for the presence of SARS-CoV-2 neutralizing antibodies. Using a SARS-CoV-2 peptide pool, virus-specific T cells were quantified via IFNγ ELISpot assays. To analyze innate immune responses, mRNA and protein expression levels of pro- and anti-inflammatory cytokines were measured after a 24-hour stimulation of PBMCs with either BCG or SARS-CoV-2 wildtype. ATAC- sequencing was performed to identify a potential epigenetic reprogramming in immune cells. We neither identified SARS-CoV-2 neutralizing antibodies nor SARS-CoV-2- reactive T cells, indicating that intravesical BCG did not induce adaptive immunity against SARS-CoV-2. However, a significant increase in mRNA as well as protein expression of IL-1β, IL-6 and TNFα, which are key cytokines of trained immunity, could be observed after at least four intravesical BCG instillations. Genomic regions in the proximity of TI genes (TLR2, IGF1R, AKT1, MTOR, MAPK14, HSP90AA1) were more accessible during BCG compared to baseline. Although intravesical BCG did not induce adaptive immune responses, repetitive intravesical instillations of BCG induced circulating innate immune cells that produce TI cytokines also in response to SARS-CoV-2.

Fanconi Anemia (FA) clinical phenotypes are heterogenous and rely on a mutation in one of the 22 FANC genes (FANCA-W) involved in a common interstrand DNA crosslink-repair pathway. A critical step in the activation of FA pathway is the monoubiquitination of FANCD2 and its binding partner FANCI. To better address the clinical phenotype associated with FANCI and the epistatic relationship with FANCD2, we created the first conditional inactivation model for FANCI in mouse. Fanci -/- mice displayed typical FA features such as delayed development in utero, microphtalmia, cellular sensitivity to mitomycin C, occasional limb abnormalities and hematological deficiencies. Interestingly, the deletion of Fanci leads to a strong meiotic phenotype and severe hypogonadism. FANCI was localized in spermatocytes and spermatids and in the nucleus of oocytes. Both FANCI and FANCD2 proteins co-localized with RPA along meiotic chromosomes, albeit at different levels. Consistent with a role in meiotic recombination, FANCI interacted with RAD51 and stimulated D-loop formation, unlike FANCD2. The double knockout Fanci-/- Fancd2-/- also showed epistatic relationship for hematological defects while being not epistatic with respect to generating viable mice in crosses of double heterozygotes. Collectively, this study highlights common and distinct functions of FANCI and FANCD2 during mouse development, meiotic recombination and hematopoiesis.

Background: Standardized methods for reporting surgical quality have been described for all the major urological procedures apart from radical nephroureterectomy (RNU). Objective: To propose a tetrafecta criterion for assessing the quality of RNU based on a consensus panel within the Young Association of Urology (YAU) Urothelial Group, and to test the impact of this tetrafecta in a multicenter, large contemporary cohort of patients treated with RNU for upper tract urothelial carcinoma (UTUC). Design, setting, and participants: This was a retrospective analysis of 1765 patients with UTUC treated between 2000 and 2021. Outcome measurements and statistical analysis: We interviewed the YAU Urothelial Group to propose and score a list of items to be included in the “RNU-fecta.” A ranking was generated for the criteria with the highest sum score. These criteria were applied to a large multicenter cohort of patients. Kaplan-Meier curves were built to evaluate differences in overall survival (OS) rates between groups, and a multivariable logistic regression model was used to find the predictors of achieving the RNU tetrafecta. Results and limitations: The criteria with the highest score included three surgical items such as negative soft tissue surgical margins, bladder cuff excision, lymph node dissection according to guideline recommendations, and one oncological item defined by the absence of any recurrence in ≤12 mo. These items formed the RNU tetrafecta. Within a median follow-up of 30 mo, 52.6% of patients achieved the RNU tetrafecta. The 5-yr OS rates were significantly higher for patients achieving tetrafecta than for their counterparts (76% vs 51%). Younger age, lower body mass index, and robotic approach were found to be independent predictors of tetrafecta achievement. Conversely, a higher Eastern Cooperative Oncology Group score, higher clinical stage, and bladder cancer history were inversely associated with tetrafecta. Conclusions: Herein, we present a “tetrafecta” composite endpoint that may serve as a potential tool to assess the overall quality of the RNU procedure. Pending external validation, this tool could allow a comparison between surgical series and may be useful for assessing the learning curve of the procedure as well as for evaluating the impact of new technologies in the field. Patient summary: In this study, a tetrafecta criterion was developed for assessing the surgical quality of radical nephroureterectomy in patients with upper tract urothelial carcinoma. Patients who achieved tetrafecta had higher 5-yr overall survival rates than those who did not.

The tumour microenvironment has not been fully characterised in high-grade serous ovarian cancers (HGSOC). Here, the authors use highly multiplexed imaging to analyse the HGSOC immune microenvironment at spatial and single-cell resolution, with clinically relevant findings for BRCA1/2-mutated tumours.

Basal progenitors are enriched in gyrencephalic species like humans contributing to neuronal expansion. Here the authors show that LGALS3BP de novo variants are related to reduced cortical complexity and area in humans and that LGALS3BP regulates neural progenitor position in organoids, human fetal tissue and mice.

Overexpression of the TGFβ pathway impairs the proliferation of the hematopoietic stem and progenitor cells (HSPCs) pool in Fanconi anemia (FA). TGFβ promotes the expression of NHEJ genes, known to function in a low-fidelity DNA repair pathway, and pharmacological inhibition of TGFβ signaling rescues FA HSPCs. Here, we demonstrate that genetic disruption of Smad3, a transducer of the canonical TGFβ pathway, modifies the phenotype of FA mouse models deficient for Fancd2. We observed that the TGFβ and NHEJ pathway genes are overexpressed during the embryogenesis of Fancd2-/- mice and that the Fancd2-/-Smad3-/- double knockout (DKO) mice undergo high levels of embryonic lethality due to loss of the TGFβ-NHEJ axis. Fancd2-deficient embryos acquire extensive genomic instability during gestation which is not reversed by Smad3 inactivation. Strikingly, the few DKO survivors have activated the non-canonical TGFβ-ERK pathway, ensuring expression of NHEJ genes during embryogenesis and improved survival. Activation of the TGFβ-NHEJ axis was critical for the survival of the few Fancd2-/-Smad3-/- DKO newborn mice but had detrimental consequences for these surviving mice, such as enhanced genomic instability and ineffective hematopoiesis.

Summary: Hematological cancers such as leukemia, lymphoma, and multiple myeloma have traditionally been treated with chemo and radiotherapy approaches. Introduction of immunotherapies for treatment of these diseases has led to patient remissions that would not have been possible with traditional approaches. In this critical review we identify main disease characteristics, symptoms, and current treatment options. Five common immunotherapies, namely checkpoint inhibitors, vaccines, cell-based therapies, antibodies, and oncolytic viruses, are described, and their applications in hematological cancers are critically discussed.

A randomized phase 2 study recently showed that the addition of ATR inhibitor berzosertib to gemcitabine improved PFS compared to gemcitabine alone in patients with ovarian cancer. In this preplanned exploratory study, the authors demonstrate that a genomic biomarker of replication-stress is associated with outcome to gemcitabine alone and may predict which patients benefit from addition of the ATR inhibitor berzosertib.

Fournier’s gangrene is a rare form of necrotizing fasciitis that affects the genital area up to the perineal region and sometimes the abdominal wall.

A Phase I/II trial previously revealed variable anti-tumor efficacy of the PARP inhibitor niraparib in combination with the PD-1 inhibitor pembrolizumab in platinum-resistant ovarian cancer patients. Here, the authors perform an integrated genomic and immunomics analysis of tumor samples from the same patients and find potential predictive biomarkers of response to such combination therapy.

Uveal melanoma is the most common primary intraocular malignancy. The aim of this retrospective study was to report the results after ruthenium-106 (Ru-106) plaque brachytherapy for uveal melanoma in terms of tumor control, visual acuity, radiation-related complications, tumor recurrence, metastases, and patients’ survival rate during 4 years’ follow-up. A total of 355 eyes from 355 patients have been treated with Ru-106 plaque brachytherapy for uveal melanoma between February 2011 and March 2020. Five patients were lost to follow-up, and then 350 eyes of 350 patients (mean age 58 ± 11 years) were enrolled in this retrospective study. All patients underwent a complete ophthalmic examination including echography and spectral domain–optical coherence tomography. The mean follow-up was 4 years (3 months to 9 years). After treatment, the mean tumor thickness was reduced to 1.75 ± 0.21 mm. Radiation complications were found in 63% of patients: 38% showed radiation maculopathy, 11% had optic neuropathy, and 14% developed cataracts. Cancer-free survival was 99%, 97%, and 85%, respectively, at 5, 7, and 9 years. Ru-106 plaque brachytherapy represents a reliable treatment of uveal melanoma. This technique is valid and safe with a low rate of ocular complications during a long-term follow-up.

Summary: Hematopoietic stem and progenitor cells (HSPCs) reside in the bone marrow and supply blood cells. Efficient methods for isolation of HSPCs are required. Here, we present protocols for the isolation of human and murine HSPCs using manual and FACS-assisted techniques. Isolated HSPCs can be used for downstream applications, including colony forming unit assays and DNA damage and repair assays.For complete details on the use and execution of this protocol, please refer to Rodríguez et al. (2021a) and (2021b).

A leishmaniose visceral (LV) é uma doença zoonótica de grande importância em saúde pública e as ações realizadas pelos Serviços de Zoonoses (SZ) podem minimizar seu transtorno. O objetivo foi avaliar a situação dos Serviços de Zoonose dos municípios na região de saúde de Presidente Prudente/SP e compreender o papel que eles desempenham na vigilância em saúde para LV. Foi realizado tratamento cartográfico da informação sobre a situação epidemiológica da LV e o tipo de SZ ofertado nos municípios de estudo. Dos 45 municípios estudados, 62,2% possuem SZ totalmente estruturado; 1,35% não possuem estrutura física e funcionam parcialmente; 0,9% não funcionam e 5,4% não o possuem. Concluímos que é de grande relevância o papel que os SZs desempenham na vigilância em saúde e há uma elevada quantidade de municípios que não possuem SZ estruturado, fato que pode dificultar no controle da LV, favorecendo a disseminação na região.

A Leishmaniose Visceral (LV) possui interdependência com regiões de florestas remanescentes modificadas, e os espaços rurais tendem a armazenar vetores e reservatórios. Esse estudo objetivou dimensionar diferentes situações de risco epidemiológico conforme a classificação epidemiológica e o favorecimento da ocorrência de LV em municípios que abrigam assentamentos de reforma agrária, pertencentes à Região de Saúde de Presidente Prudente, São Paulo. As regiões de estudo foram classificadas segundo a estrutura do serviço de zoonoses e situação epidemiológica, aplicando-se análise espacial e tratamento cartográfico das informações. De 45 municípios, 19 (42,2%) abrigam um total de 121 assentamentos, enfrentando diferentes cenários. Houve estreita relação quanto à disponibilização e atuação da equipe de zoonoses e a situação da LV, especialmente nos municípios de estudo silenciosos (receptivos ou não) e em investigação. Os resultados contribuem para a vigilância em saúde, apoio a decisão em áreas prioritárias e fortalecimento do Sistema Único de Saúde (SUS).

The cohesin complex plays an essential role in chromosome maintenance and transcriptional regulation. Recurrent somatic mutations in the cohesin complex are frequent genetic drivers in cancer, including myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Here, using genetic dependency screens of stromal antigen 2–mutant (STAG2-mutant) AML, we identified DNA damage repair and replication as genetic dependencies in cohesin-mutant cells. We demonstrated increased levels of DNA damage and sensitivity of cohesin-mutant cells to poly(ADP-ribose) polymerase (PARP) inhibition. We developed a mouse model of MDS in which Stag2 mutations arose as clonal secondary lesions in the background of clonal hematopoiesis driven by tet methylcytosine dioxygenase 2 (Tet2) mutations and demonstrated selective depletion of cohesin-mutant cells with PARP inhibition in vivo. Finally, we demonstrated a shift from STAG2- to STAG1-containing cohesin complexes in cohesin-mutant cells, which was associated with longer DNA loop extrusion, more intermixing of chromatin compartments, and increased interaction with PARP and replication protein A complex. Our findings inform the biology and therapeutic opportunities for cohesin-mutant malignancies.