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Abstract Background Pathogenic BRCA1 or BRCA2 germline mutations contribute to hereditary breast, ovarian, prostate, and pancreatic cancer. Paradoxically, bi-allelic inactivation of BRCA1 or BRCA2 (bBRCA1/2) is embryonically lethal and decreases cellular proliferation. The compensatory mechanisms that facilitate oncogenesis in bBRCA1/2 tumors remain unclear. Methods We identified recurrent genetic alterations enriched in human bBRCA1/2 tumors and experimentally validated if these improved proliferation in cellular models. We analyzed mutations and copy number alterations (CNAs) in bBRCA1/2 breast and ovarian cancer from the TCGA and ICGC. We used Fisher’s exact test to identify CNAs enriched in bBRCA1/2 tumors compared to control tumors that lacked evidence of homologous recombination deficiency. Genes located in CNA regions enriched in bBRCA1/2 tumors were further screened by gene expression and their effects on proliferation in genome-wide CRISPR/Cas9 screens. A set of candidate genes was functionally validated with in vitro clonogenic survival and functional assays to validate their influence on proliferation in the setting of bBRCA1/2 mutations. Results We found that bBRCA1/2 tumors harbor recurrent large-scale genomic deletions significantly more frequently than histologically matched controls (n = 238 cytobands in breast and ovarian cancers). Within the deleted regions, we identified 277 BRCA1-related genes and 218 BRCA2-related genes that had reduced expression and increased proliferation in bBRCA1/2 but not in wild-type cells in genome-wide CRISPR screens. In vitro validation of 20 candidate genes with clonogenic proliferation assays validated 9 genes, including RIC8A and ATMIN (ATM-Interacting protein). We identified loss of RIC8A, which occurs frequently in both bBRCA1/2 tumors and is synthetically viable with loss of both BRCA1 and BRCA2. Furthermore, we found that metastatic homologous recombination deficient cancers acquire loss-of-function mutations in RIC8A. Lastly, we identified that RIC8A does not rescue homologous recombination deficiency but may influence mitosis in bBRCA1/2 tumors, potentially leading to increased micronuclei formation. Conclusions This study provides a means to solve the tumor suppressor paradox by identifying synthetic viability interactions and causal driver genes affected by large-scale CNAs in human cancers.

In the registration trials, follitropin delta was compared with a fixed dose of 150 UI of follitropin alpha/beta, finding higher chances to reach a target response of 8–14 oocytes compared to controls. For this reason, follitropin delta is marketed as particularly useful in expected hyper-responder patients. The main outcome of this study is to report if comparable results are reached in a real-life scenario with follitropin alpha/beta doses chosen by the physician, based on patients’ characteristics. This is a retrospective study performed in two public fertility centres. All first cycles from January 2020 to June 2022 with either follitropin delta (cases) or alpha/beta (controls) in patients with anti-Müllerian hormone >2.5 ng/mL were compared by an inverse probability weighting approach based on propensity score. The follitropin total dose was higher in controls (1179.06 ± 344.93 vs 1668.67 ± 555.22 IU, P < 0.001). The target response of 8–14 oocytes was reached by 40.2% of cases and 40.7% of controls (odds ratio (OR): 0.99, 95% confidence interval (CI): 0.65–1.53, P = 0.98). Fewer than 8 oocytes were collected in 24.1% of cases and 22% of controls (OR: 1.10, 95% CI: 0.71–1.69, P = 0.67); more than 14 oocytes in 35.7% of cases and 37.3% of controls (OR: 0.83, 95% CI: 0.54–1.28, P = 0.40). Our experience did not find worse results in term of proportion of patients who reached the target response with an algorithm-chosen dose of follitropin delta compared to a personalised starting dose of follitropin alpha/beta, with follitropin delta having the advantage of objectivity. However, larger numbers are needed to confirm these results.

Abstract Hematopoietic stem cell gene therapy (GT) using a γ-retroviral vector (γ-RV) is an effective treatment for Severe Combined Immunodeficiency due to Adenosine Deaminase deficiency. Here, we describe a case of GT-related T-cell acute lymphoblastic leukemia (T-ALL) that developed 4.7 years after treatment. The patient underwent chemotherapy and haploidentical transplantation and is currently in remission. Blast cells contain a single vector insertion activating the LIM-only protein 2 (LMO2) proto-oncogene, confirmed by physical interaction, and low Adenosine Deaminase (ADA) activity resulting from methylation of viral promoter. The insertion is detected years before T-ALL in multiple lineages, suggesting that further hits occurred in a thymic progenitor. Blast cells contain known and novel somatic mutations as well as germline mutations which may have contributed to transformation. Before T-ALL onset, the insertion profile is similar to those of other ADA-deficient patients. The limited incidence of vector-related adverse events in ADA-deficiency compared to other γ-RV GT trials could be explained by differences in transgenes, background disease and patient’s specific factors.

Summary: Mechanosensitive Piezo channels regulate cell division, cell extrusion, and cell death. However, systems-level functions of Piezo in regulating organogenesis remain poorly understood. Here, we demonstrate that Piezo controls epithelial cell topology to ensure precise organ growth by integrating live-imaging experiments with pharmacological and genetic perturbations and computational modeling. Notably, the knockout or knockdown of Piezo increases bilateral asymmetry in wing size. Piezo’s multifaceted functions can be deconstructed as either autonomous or non-autonomous based on a comparison between tissue-compartment-level perturbations or between genetic perturbation populations at the whole-tissue level. A computational model that posits cell proliferation and apoptosis regulation through modulation of the cutoff tension required for Piezo channel activation explains key cell and tissue phenotypes arising from perturbations of Piezo expression levels. Our findings demonstrate that Piezo promotes robustness in regulating epithelial topology and is necessary for precise organ size control.

Abstract CDH1 (E-cadherin) bi-allelic inactivation is the hallmark alteration of breast invasive lobular carcinoma (ILC), resulting in its discohesive phenotype. A subset of ILCs, however, lack CDH1 genetic/epigenetic inactivation, and their genetic underpinning is unknown. Through clinical targeted sequencing data reanalysis of 364 primary ILCs, we identified 25 ILCs lacking CDH1 bi-allelic genetic alterations. CDH1 promoter methylation was frequent (63%) in these cases. Targeted sequencing reanalysis revealed 3 ILCs harboring AXIN2 deleterious fusions (n = 2) or loss-of-function mutation (n = 1). Whole-genome sequencing of 3 cases lacking bi-allelic CDH1 genetic/epigenetic inactivation confirmed the AXIN2 mutation and no other cell-cell adhesion genetic alterations but revealed a new CTNND1 (p120) deleterious fusion. AXIN2 knock-out in MCF7 cells resulted in lobular-like features, including increased cellular migration and resistance to anoikis. Taken together, ILCs lacking CDH1 genetic/epigenetic alterations are driven by inactivating alterations in other cell adhesion genes (CTNND1 or AXIN2), endorsing a convergent phenotype in ILC.

Abstract The interactions between tumor and immune cells along the course of breast cancer progression remain largely unknown. Here, we extensively characterize multiple sequential and parallel multiregion tumor and blood specimens of an index patient and a cohort of metastatic triple-negative breast cancers. We demonstrate that a continuous increase in tumor genomic heterogeneity and distinct molecular clocks correlated with resistance to treatment, eventually allowing tumors to escape from immune control. TCR repertoire loses diversity over time, leading to convergent evolution as breast cancer progresses. Although mixed populations of effector memory and cytotoxic single T cells coexist in the peripheral blood, defects in the antigen presentation machinery coupled with subdued T cell recruitment into metastases are observed, indicating a potent immune avoidance microenvironment not compatible with an effective antitumor response in lethal metastatic disease. Our results demonstrate that the immune responses against cancer are not static, but rather follow dynamic processes that match cancer genomic progression, illustrating the complex nature of tumor and immune cell interactions.

PurposeLynch syndrome is defined by germline pathogenic mutations involving DNA mismatch repair (MMR) genes and linked with the development of MMR-deficient colon and endometrial cancers. Whether breast cancers developing in the context of Lynch syndrome are causally related to MMR deficiency (MMRd), remains controversial. Thus, we explored the morphologic and genomic characteristics of breast cancers occurring in Lynch syndrome individuals.Experimental designA retrospective analysis of 20,110 patients with cancer who underwent multigene panel genetic testing was performed to identify individuals with a likely pathogenic/pathogenic germline variant in MLH1, MSH2, MSH6, or PMS2 who developed breast cancers. The histologic characteristics and IHC assessment of breast cancers for MMR proteins and programmed death-ligand 1 (PD-L1) expression were assessed on cases with available materials. DNA samples from paired tumors and blood were sequenced with Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (≥468 key cancer genes). Microsatellite instability (MSI) status was assessed utilizing MSISensor. Mutational signatures were defined using SigMA.ResultsA total of 272 individuals with Lynch syndrome were identified, 13 (5%) of whom had primary breast cancers. The majority of breast cancers (92%) were hormone receptor-positive tumors. Five (42%) of 12 breast cancers displayed loss of MMR proteins by IHC. Four (36%) of 11 breast cancers subjected to tumor-normal sequencing showed dominant MSI mutational signatures, high tumor mutational burden, and indeterminate (27%) or high MSISensor scores (9%). One patient with metastatic MMRd breast cancer received anti-PD1 therapy and achieved a robust and durable response.ConclusionsA subset of breast cancers developing in individuals with Lynch syndrome are etiologically linked to MMRd and may benefit from anti-PD1/PD-L1 immunotherapy.

Abstract This study describes “lobular-like invasive mammary carcinomas” (LLIMCas), a group of low- to intermediate-grade invasive mammary carcinomas with discohesive, diffusely infiltrative cells showing retained circumferential membranous immunoreactivity for both E-cadherin and p120. We analyzed the clinical-pathologic features of 166 LLIMCas compared to 104 classical invasive lobular carcinomas (ILCs) and 100 grade 1 and 2 invasive ductal carcinomas (IDCs). Tumor size and pT stage of LLIMCas were intermediate between IDCs and ILCs, and yet often underestimated on imaging and showed frequent positive margins on the first resection. Despite histomorphologic similarities to classical ILC, the discohesion in LLIMCa was independent of E-cadherin/p120 immunophenotypic alteration. An exploratory, hypothesis-generating analysis of the genomic features of 14 randomly selected LLIMCas and classical ILCs (7 from each category) was performed utilizing an FDA-authorized targeted capture sequencing assay (MSK-IMPACT). None of the seven LLIMCas harbored CDH1 loss-of-function mutations, and none of the CDH1 alterations detected in two of the LLIMCas was pathogenic. In contrast, all seven ILCs harbored CDH1 loss-of-function mutations coupled with the loss of heterozygosity of the CDH1 wild-type allele. Four of the six evaluable LLIMCas were positive for CDH1 promoter methylation, which may partially explain the single-cell infiltrative morphology seen in LLIMCa. Further studies are warranted to better define the molecular basis of the discohesive cellular morphology in LLIMCa. Until more data becomes available, identifying LLIMCas and distinguishing them from typical IDCs and ILCs would be justified. In patients with LLIMCas, preoperative MRI should be entertained to guide surgical management.

El M&A de activos es una figura que presenta ciertas particularidades respecto de otros mecanismos de adquisición de negocios o empresas (especialmente respecto de la compraventa de acciones), como (i) la posibilidad de elegir los activos –y pasivos– que se desean adquirir; (ii) un proceso de due diligence acotado a la empresa o negocio en marcha que se adquiere (y no a toda la sociedad que los transfiere); (iii) un proceso de valorización acotado; (iv) un régimen de declaraciones y garantías enfocado fundamentalmente en la empresa o negocio que se adquiere; y (v) una plena identificación del titular de dicha empresa o negocio en marcha. En el Perú existen diversos problemas de índole legal que generan que el M&A de activos sea una transacción menos eficiente y más costosa. En este contexto, proponemos una regulación especial sobre el M&A de activos en Perú, que fomente su mayor uso.

The exploitation of marine molluscs during the Middle and Upper Palaeolithic is a topic that has been extensively investigated over the last few years, shedding light on human adaptation in coastal environments. However, such studies mainly focus on the role of marine molluscs in the subsistence practices of the hunter-fisher-gatherers of the Mediterranean Basin.Although small, non-dietary gastropods found in archaeological deposits have the potential to provide important clues regarding past human activities, their role is still little investigated. This research explores the question of whether taphonomy could be useful for the interpretation of these less conspicuous “incidental” shell remains found in archaeomalacological assemblages.In this paper we present the results of a taphonomic study carried out on a total of 314 Bittium shells recovered in the Mousterian and Protoaurignacian levels of Riparo Bombrini, a collapsed rockshelter in the Balzi Rossi Palaeolithic site complex (NW Italy). How did these small, non-dietary gastropods come to be deposited? Are they an unintentional by-product of certain harvesting techniques, or the result of a deliberate gathering? Or, could natural factors be responsible for their presence at the site? To answer these questions, different types of taphonomic processes were considered. Comparing the Bombrini archaeomalacological remains and modern shells accumulated on beaches leads us to propose that the most likely cause of their presence at the site is a correlation between Bittium shells and small sea pebbles, rather than the accidental transport of these shells with algae and seagrasses that could have been brought back to the site.

Traumatic injuries of the subclavian and axillary arteries are uncommon but have high morbidity and mortality. In contrast to penetrating injuries, which are often lethal, blunt injuries present a wide and heterogeneous spectrum of imaging findings. If a vessel tear or transsection is a life-threatening circumstance, minor injuries might be overlooked in an emergency setting but could cause or aggravate the functional loss of a limb. The aim of this pictorial essay is to acquaint radiologists with the spectrum of imaging findings that could be encountered during the radiological evaluation of the subclavian/axillary artery (SAA) in trauma patients and offer tips and tricks to improve the diagnostic workup of patients with suspected blunt SAA injuries.

Purpose: To assess whether mRNA and viral vector coronavirus disease 2019 (COVID-19) vaccines detrimentally affected semen parameters. Materials and Methods: In this prospective study, we enrolled 101 men vaccinated for COVID-19 (76% received mRNA vaccines, 20% viral vector vaccines, 2% a mixed formulation, and for 2 men no information about vaccine type was available) in 2021 and with a previous semen analysis. For each man we compared semen parameters before and after vaccination. Results: Post-vaccine samples were obtained at a median of 2.3±1.5 months after the second dose. After vaccination, the median sample volume significantly decreased (from 3.0 to 2.6 mL, p=0.036), whereas the median sperm concentration, the progressive motility, and total motile sperm count increased (from 25.0 to 43.0 million/mL, p

Reasoning is a process of inference from given premises to new conclusions. Deductive reasoning is truth-preserving and conclusions can only be either true or false. Probabilistic reasoning is based on degrees of belief and conclusions can be more or less likely. While deductive reasoning requires people to focus on the logical structure of the inference and ignore its content, probabilistic reasoning requires the retrieval of prior knowledge from memory. Recently, however, some researchers have denied that deductive reasoning is a faculty of the human mind. What looks like deductive inference might actually also be probabilistic inference, only with extreme probabilities. We tested this assumption in an fMRI experiment with two groups of participants: one group was instructed to reason deductively, the other received probabilistic instructions. They could freely choose between a binary and a graded response to each problem. The conditional probability and the logical validity of the inferences were systematically varied. Results show that prior knowledge was only used in the probabilistic reasoning group. These participants gave graded responses more often than those in the deductive reasoning group and their reasoning was accompanied by activations in the hippocampus. Participants in the deductive group mostly gave binary responses and their reasoning was accompanied by activations in the anterior cingulate cortex, inferior frontal cortex, and parietal regions. These findings show that (1) deductive and probabilistic reasoning rely on different neurocognitive processes, (2) people can suppress their prior knowledge to reason deductively, and (3) not all inferences can be reduced to probabilistic reasoning.

People often withdraw previously drawn conclusions in lightof new information. This defeasible reasoning is also im-portant for law, where judges often have to change their ver-dicts in light of new evidence. Here we investigate defeasibil-ity in the context of conflicting fundamental rights. When, forinstance, law to property conflicts with law to information,can one of these rights be “defeated” by the other? We em-bedded conflicting fundamental rights in inference tasks (Ex-periment 1) and in elaborated vignettes (Experiment 2). Re-sults show that people decide between two conflicting funda-mental rights in a rational way. Case by case, participants pro-tected that fundamental right whose violation evoked thehighest moral outrage (Experiment 1) or whose violation wasconsidered to be more serious (Experiment 2). We discuss theimplications of our findings for law theory and psychology.

Liver metastases that disappear after chemotherapy are called vanishing or disappearing liver metastases. These metastases represent a diagnostic and clinical challenge as their biological behaviour is hardly predictable and their treatment is not completely standardized. In this case report, we present an interesting solution to treat disappearing liver metastases using percutaneous microwave ablation and US/MRI fusion guidance employing pre-chemotherapy MRI as reference imaging.

Abstract Metaplastic breast cancers (MBCs) are characterized by complex genomes, which seem to vary according to their histologic subtype. TERT promoter hotspot mutations and gene amplification are rare in common forms of breast cancer, but present in a subset of phyllodes tumors. Here, we sought to determine the frequency of genetic alterations affecting TERT in a cohort of 60 MBCs with distinct predominant metaplastic components (squamous, 23%; spindle, 27%; osseous, 8%; chondroid, 42%), and to compare the repertoire of genetic alterations of MBCs according to the presence of TERT promoter hotspot mutations or gene amplification. Forty-four MBCs were subjected to: whole-exome sequencing (WES; n = 27) or targeted sequencing of 341-468 cancer-related genes (n = 17); 16 MBCs were subjected to Sanger sequencing of the TERT promoter, TP53 and selected exons of PIK3CA, HRAS, and BRAF. TERT promoter hotspot mutations (n = 9) and TERT gene amplification (n = 1) were found in 10 of the 60 MBCs analyzed, respectively. These TERT alterations were less frequently found in MBCs with predominant chondroid differentiation than in other MBC subtypes (p = 0.01, Fisher’s exact test) and were mutually exclusive with TP53 mutations (p