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Physiologic activation of estrogen receptor [alpha] (ER[alpha]) is mediated by estradiol (E2) binding in the ligand- binding pocket of the receptor, repositioning helix 12 (H12) to facilitate binding of coactivator proteins in the unoccupied coactivator binding groove. In breast cancer, activation of ER[alpha] is often observed through point mutations that lead to the same H12 repositioning in the absence of E2. Through expanded genetic sequencing of breast cancer patients, we identified a collection of mutations located far from H12 but nonetheless capable of promoting E2-independent transcription and breast cancer cell growth. Using machine learning and computational structure analyses, this set of mutants was inferred to act distinctly from the H12-repositioning mutants and instead was associated with conformational changes across the ER[alpha] dimer interface. Through both in vitro and in-cell assays of full-length ER[alpha] protein and isolated ligand-binding domain, we found that these mutants promoted ER[alpha] dimerization, stability, and nuclear localization. Point mutations that selectively disrupted dimerization abrogated E2-independent transcriptional activity of these dimer-promoting mutants. The results reveal a distinct mechanism for activation of ER[alpha] function through enforced receptor dimerization and suggest dimer disruption as a potential therapeutic strategy to treat ER-dependent cancers., Introduction Estrogen receptor [alpha] (ER[alpha]; ESR1), a member of the steroid hormone receptor family, is a hormone-activated transcription factor that is essential for both physiologic mammary gland homeostasis and pathologic [...]

We find that foreign‐born CEOs are more inclined than domestic‐born ones to acquire across borders, and that this inclination is explained by their preference for targets in their birth country. This preference is motivated by foreign‐born CEOs' information advantage in their birth country and by these CEOs' desire to give back to the birth country. CEOs' desire to help their birth country also influences target location, increasing the likelihood of a target in countries that colonized the CEO birth country. The motives that drive acquisitions in acquirer CEOs' birth countries measurably affect the returns of acquirers' shareholders, target premium, and acquisition synergy. Both acquirers' returns and synergy but not target premium are abnormally positive when the motive for an acquisition is a CEO's information advantage in the birth country. Targets premiums but not acquirers' returns and synergy are abnormally positive when the motive for an acquisition is the desire to give back to the CEO's birth country. [ABSTRACT FROM AUTHOR]

PURPOSE: Electronic health records (EHRs) are valuable information repositories that offer insights for enhancing clinical research on breast cancer (BC) using real-world data. The objective of this study was to develop a natural language processing (NLP) model specifically designed to extract structured data from BC pathology reports written in natural language. METHODS: During the initial phase, the algorithm's development cohort comprised 193 pathology reports from 116 patients with BC from 2012 to 2016. A rule-based NLP algorithm was applied to extract 26 variables for analysis and was compared with the manual extraction of data performed by both a data entry specialist and an oncologist. Following the first approach, the data set was expanded to include 513 reports, and a Named Entity Recognition (NER)-NLP model was trained and evaluated using K-fold cross-validation. RESULTS: The first approach led to a concordance analysis, which revealed an 82.9% agreement between the algorithm and the oncologist, whereas the concordance between the data entry specialist and the oncologist was 90.8%. The second training approach introduced the definition of an NER-NLP model, in which the accuracy showed remarkable potential (97.8%). Notably, the model demonstrated remarkable performance, especially for parameters such as estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2, and Ki-67 (F1-score 1.0). CONCLUSION: The present study aligns with the rapidly evolving field of artificial intelligence (AI) applications in oncology, seeking to expedite the development of complex cancer databases and registries. The results of the model are currently undergoing postprocessing procedures to organize the data into tabular structures, facilitating their utilization in real-world clinical and research endeavors. A high-accuracy NLP model was developed to extract structured data from breast cancer pathology reports. [ABSTRACT FROM AUTHOR]

Background Uterine leiomyosarcoma (uLMS) represents one of the most common sarcoma histotypes, demonstrating an overall dismal prognosis. Previous studies reported uLMS to carry recurrent somatic BRCA2 homozygous deletions, related to significant clinical benefits from the use of PARP inhibitors. Methods To investigate the prevalence in uLMS of genomic alterations (alt) in BRCA2 and other homologous recombination (HR) and DNA damage response (DDR) genes, cBioPortal was accessed and data were retrieved from studies including pan-sarcoma histologies. HR-/DDR-genes included BRCA1 , BRCA2 , ATM , BARD1 , BRIP1 , CHEK1 , CHEK2 , FANCA , FANCB , FANCC , FANCD2 , FANCE , FANCF , FANCG , FANCI , FANCL , FANCM , NBN , PALB2 , RAD51C , RAD51D , RAD50 , and ATR. Only oncogenic/likely oncogenic alterations were included according to OncoKB. Clinical Report and Results We reported a clinical case of a patient affected by a highly pretreated uLMS discussed at the European Institute of Oncology Molecular Tumor Board. A targeted next-generation sequencing panel demonstrated a somatic BRCA2 homozygous deletion (homDel). Upon access to Niraparib, a remarkable response of 15 months was observed before experiencing disease progression. In the genomic query, among 2393 cases, uLMS (n  = 193) displayed 9 of all 31 BRCA2 alt observed, representing the only sarcoma histotype showing an enrichment in BRCA2 alt (4.66%; q  < 0.001). All of 9 BRCA2 alt were represented by homDel, which related to a high fraction of genome altered. Conclusion uLMS displays a significant frequency of somatic BRCA2 alt homDel. Considering their dismal prognosis, further investigation is warranted to test the use of PARPi in uLMS, and particularly in the setting of BRCA1/2 alterations. [ABSTRACT FROM AUTHOR]

Antibody–drug conjugates (ADCs) are anticancer agents with the capacity to selectively deliver their payloads to cancer cells. Antibody–drug conjugates consist of a monoclonal antibody backbone connected by a linker to cytotoxic payloads. Antibody–drug conjugate effect occurs either by directly targeting cancer cells via membrane antigen or through "bystander effect." Antibody–drug conjugates have demonstrated efficacy against various types of tumors, including breast cancer. Ado-trastuzumab emtansine is presently the only approved ADC for the treatment of breast cancer in the early setting, while several ADCs are now approved for metastatic breast cancer. Due to the transformative impact that several ADCs have reported in the setting of advanced breast cancer, researchers are now testing more of such compounds in the early setting, to portend benefits to patients through highly potent anticancer drugs. Ongoing trials hold the potential to transform treatment protocols for early breast cancer in the near future. These trials are aiming at evaluating different treatment modulation approaches, as informed by breast cancer risk of recurrence, including toward treatment de-escalation. Efforts are provided in ongoing clinical trials to identify the patients who will benefit most, to pursue paradigms of precision medicine with the novel ADCs. This review focuses on the potential role of ADCs in early breast cancer, providing an overview of the latest progress in their development and how they are implemented in ongoing clinical trials. [ABSTRACT FROM AUTHOR]

In the last decades, the development of high‐throughput molecular assays has revolutionised cancer diagnostics, paving the way for the concept of personalised cancer medicine. This progress has been driven by the introduction of such technologies through biomarker‐driven oncology trials. In this review, strengths and limitations of various state‐of‐the‐art sequencing technologies, including gene panel sequencing (DNA and RNA), whole‐exome/whole‐genome sequencing and whole‐transcriptome sequencing, are explored, focusing on their ability to identify clinically relevant biomarkers with diagnostic, prognostic and/or predictive impact. This includes the need to assess complex biomarkers, for example microsatellite instability, tumour mutation burden and homologous recombination deficiency, to identify patients suitable for specific therapies, including immunotherapy. Furthermore, the crucial role of biomarker analysis and multidisciplinary molecular tumour boards in selecting patients for trial inclusion is discussed in relation to various trial concepts, including drug repurposing. Recognising that today's exploratory techniques will evolve into tomorrow's routine diagnostics and clinical study inclusion assays, the importance of emerging technologies for multimodal diagnostics, such as proteomics and in vivo drug sensitivity testing, is also discussed. In addition, key regulatory aspects and the importance of patient engagement in all phases of a clinical trial are described. Finally, we propose a set of recommendations for consideration when planning a new precision cancer medicine trial. [ABSTRACT FROM AUTHOR]

Background Molecular-driven oncology allows oncologists to identify treatments that match a cancer's genomic profile. Clinical trials are promoted as an effective modality to deliver a molecularly matched treatment. We explore the role of geographical accessibility in Italy, and its impact on patient access to clinical trials. Material and Methods We retrospectively reviewed molecular data from a single-institutional case series of patients receiving next-generation sequencing testing between March 2019 and July 2020. Actionable alterations were defined as the ones with at least one matched treatment on Clinicaltrials.gov at the time of genomic report signature. We then calculated the hypothetical distance to travel to reach the nearest assigned clinical trial. Results We identified 159 patients eligible for analysis. One hundred and one could be potentially assigned to a clinical trial in Italy, and the median distance that patients needed to travel to reach the closest location with a suitable clinical trial was 76 km (interquartile range = 127.46 km). Geographical distribution of clinical trials in Italy found to be heterogeneous, with Milan and Naples being the areas with a higher concentration. We then found that the probability of having a clinical trial close to a patient's hometown increased over time, according to registered studies between 2015 and 2020. Conclusions The median distance to be travelled to the nearest trial was generally acceptable for patients, and trials availability is increasing. Nevertheless, many areas are still lacking trials, so efforts are required to increase and homogenize the possibilities to be enrolled in clinical trials for Italian patients with cancer. [ABSTRACT FROM AUTHOR]

Background Baseline tumor size (BTS) has been associated with outcomes in patients with cancer treated with immunotherapy. However, the prognostic impact of BTS on patients receiving targeted therapies (TTs) remains undetermined. Methods We reviewed data of patients with advanced solid tumors consecutively treated within early-phase clinical trials at our institution from 01/2014 to 04/2021. Treatments were categorized as immunotherapy-based or TT-based (biomarker-matched or not). BTS was calculated as the sum of RECIST1.1 baseline target lesions. Results A total of 444 patients were eligible; the median BTS was 69 mm (IQR 40-100). OS was significantly longer for patients with BTS lower versus higher than the median (16.6 vs. 8.2 months, P <.001), including among those receiving immunotherapy (12 vs. 7.5 months, P =.005). Among patients receiving TT, lower BTS was associated with longer PFS (4.7 vs. 3.1 months, P =.002) and OS (20.5 vs. 9.9 months, P <.001) as compared to high BTS. However, such association was only significant among patients receiving biomarker-matched TT, with longer PFS (6.2 vs. 3.3 months, P <.001) and OS (21.2 vs. 6.7 months, P <.001) in the low-BTS subgroup, despite a similar ORR (28% vs. 22%, P =.57). BTS was not prognostic among patients receiving unmatched TT, with similar PFS (3.7 vs. 4.4 months, P =.30), OS (19.3 vs. 11.8 months, P =.20), and ORR (33% vs. 28%, P =.78) in the 2 BTS groups. Multivariate analysis confirmed that BTS was independently associated with PFS (P =.03) and OS (P <.001) but not with ORR (P =.11). Conclusions Higher BTS is associated with worse survival outcomes among patients receiving biomarker-matched, but not biomarker-unmatched TT. [ABSTRACT FROM AUTHOR]

Background: Cyclin-Dependent Kinase 4/6 inhibitors (CDK4/6i) combined with Endocrine Therapy (ET) are the standard treatment for patients with Hormone Receptor-positive/HER2-negative advanced breast cancer (HR+/HER2− aBC). Objectives: While CDK4/6i are known to reduce several peripheral blood cells, such as neutrophils, lymphocytes and platelets, the impact of these modulations on clinical outcomes is unknown. Design: A multicenter, retrospective-prospective Italian study. Methods: We investigated the association between baseline peripheral blood cells, or their early modifications (i.e. 2 weeks after treatment initiation), and the progression-free survival (PFS) of HR+/HER2− aBC patients treated with ETs plus CDK4/6i. Random Forest models were used to select covariates associated with patient PFS among a large list of patient- and tumor-related variables. Results: We evaluated 638 HR+/HER2− aBC patients treated with ET plus CDK4/6i at six Italian Institutions between January 2017 and May 2021. High baseline lymphocyte counts were independently associated with longer PFS [median PFS (mPFS) 20.1 versus 13.2 months in high versus low lymphocyte patients, respectively; adjusted Hazard Ratio (aHR): 0.78; 95% confidence interval (CI): 0.66–0.92; p = 0.0144]. Moreover, patients experiencing a lower early reduction of lymphocyte counts had significantly longer PFS when compared to patients undergoing higher lymphocyte decrease (mPFS 18.1 versus 14.5 months; aHR: 0.82; 95% CI: 0.73–0.93; p = 0.0037). Patients with high baseline lymphocytes and undergoing a lower reduction, or even an increase, of lymphocyte counts during CDK4/6i therapy experienced the longest PFS, while patients with lower baseline lymphocytes and undergoing a higher decrease of lymphocytes had the lowest PFS (mPFS 21.4 versus 11 months, respectively). Conclusion: Baseline and on-treatment modifications of peripheral blood lymphocytes have independent prognostic value in HR+/HER2− aBC patients. This study supports the implementation of clinical strategies to boost antitumor immunity in patients with HR+/HER2− aBC treated with ETs plus CDK4/6i. [ABSTRACT FROM AUTHOR]

Antibody-drug conjugates (ADCs) represent a cornerstone in the treatment of many cancers nowadays. ADCs fulfill their function by binding a target on tumor cell membrane to deliver a cytotoxic payload; in addition, those moieties capable of crossing cancer cell membranes can achieve near-by cells that do not express the target antigen, exerting the so-called "bystander" cytotoxic effect. The presence of a specific target antigen expressed on cancer cells has been for long considered crucial for ADCs and commonly required for the inclusion of patients in clinical trials with ADCs. To date, only ado-trastuzumab-emtansine, fam-trastuzumab deruxtecan-nxki, and mirvetuximab soravtansine-gynx are approved according to the expression of a target antigen in solid tumors, while the clinical use of other ADCs (eg, sacituzumab govitecan) is not conditioned by the presence of a specific biomarker. Given the ever-growing number of approved ADCs and those under investigation, it is essential to find new biomarkers to guide their use, especially in those settings for which different ADCs are approved to establish the best therapeutic sequence based on robust biomarkers. Hence, this work addresses the role of target antigens in predicting response to ADCs, focusing on examples of antigens' targetability according to their expression on cancer cells' surface or to the presence of specific target aberrations (eg, mutation or over-expression). New methods for the assessment and quantification of targets' expression, like molecular imaging and in vitro assays, might be key tools to improve biomarker analysis and eventually deliver better outcomes by refined patient selection. This article provides an overview of biomarkers predicting response to antibody-drug conjugates. [ABSTRACT FROM AUTHOR]

Concentrating solar technology plays a role, albeit a niche role compared to commercial solar systems (photovoltaics and thermal collectors). Within the context of sustainable development and within the green transition phase, it could be a respectable player. The main purpose of this study is to create and validate a model that approximates the temperature trend of a receiver installed in a CSP (concentrated solar plant). A method to approximate optical and thermal performance is discussed. The paraboloid installed in the Energy Center (Turin, Italy) was taken as a reference, creating a model that could simulate real operating conditions. The Monte Carlo (MC) method for ray tracing was adopted developing two models. The first model sets the maximum reflectivity of the paraboloid and neglects the loss of "limb darkening," while the second one sets a reflectivity of 80%. Once the incident flux was obtained, the optical performance was analytically calculated and compared to the value provided by the manufacturer. The thermal performance was also studied, reproducing the dimensions of the receiver consisting of a sintered alumina tube placed at a focal distance from the paraboloid. Two configurations were analyzed: one neglecting the losses due to radiation and natural convection, the other one including the losses due to radiation and considering the atmospheric wind condition. Finally, the model was validated by comparing the obtained temperatures with those measured by thermocouples placed on the receiver. Analyzing two random days in the year 2020, an average error of 7% and 2% was obtained. [ABSTRACT FROM AUTHOR]

Summary: In this article we present an application of the Usage Control paradigm to a Smart Home infrastructure, based on a model extension and structured use of obligations. In the proposed extended model obligations are exploited to enforce two different access revocation time, namely revoke and suspend. This increases the policy expressiveness and enable to optimize the resource usage. Furthermore, obligations are exploited to send commands via IFTTT to different interconnected Smart Home devices, to impose safety‐relevant behaviors, or to act on policy attributes to implement a self‐healing paradigm for revoked sessions. The article is motivated by a parental control use case where deep learning is used in combination with Usage Control to regulate dynamically viewing rights of a smart‐TV and interactions with interconnected devices. Accuracy and performance experiments show the effectiveness and feasibility of the proposed work. [ABSTRACT FROM AUTHOR]

To authenticate to the full-text of this article, please visit this link: http://dx.doi.org/10.1111/j.1468-5957.2010.02218.x Byline: Aloke Ghosh (1), Antonio Marra (1), Doocheol Moon (1) Keywords: corporate boards; audit committees; earnings management; accounting accruals Abstract: Abstract: Primarily motivated by the claims that the recent regulatory initiatives empowering boards and audit committees restrain earnings management, we examine whether board characteristics (composition, size, and structure) and audit committee characteristics (composition, size, activity, expertise, ownership, and tenure) are associated with earnings management before and after Sarbanes-Oxley Act (SOX). Using absolute performance-adjusted discretionary accruals, special items, and deferred tax expense as alternative constructs for earnings management, we find that earnings management does not vary with board composition and structure, or with audit committee composition, expertise, and ownership. In contrast, board size and audit committee size, activity, and tenure are associated with earnings management. More important, the strength of this association is considerably weaker for the post-SOX years compared to the pre-SOX years. Finally, we find no evidence to suggest that the overall level of earnings management declined following SOX. Author Affiliation: (1)The authors are respectively from the Stan Ross Department of Accountancy, Baruch College, The City University of New York; the Department of Accounting, University of Bocconi; and the School of Business, Yonsei University. They thank Martin Walker (editor), an anonymous referee, John Bizjak, Rob Fisher, Larry Harris, Murgie Krishnan, Ying Li, Martien Lubberink, Ken Peasnell, Peter Pope, Steve Lustgarten, Steve Young and the participants of Baruch College and Office of Economic Analysis at the SEC workshops for their helpful comments and suggestions. The authors are especially grateful to Hangsoo Kyung for help in collecting some of the corporate governance data. Article History: (Paper received November 2007, revised version accepted July 2010) Article note: (*) Address for correspondence: Aloke Ghosh, Stan Ross Department of Accountancy, Baruch College, The City University of New York, Box B12-225, One Bernard Baruch Way, New York, NY 10010, USA., e-mail: Aloke.Ghosh@baruch.cuny.edu

Background: Gastroesophageal junction (GEJ) adenocarcinoma is a rare cancer associated with poor prognosis. The genetic factors conferring predisposition to GEJ adenocarcinoma have yet to be identified.Methods: We analyzed germline testing results from 23 381 cancer patients undergoing tumor-normal sequencing, of which 312 individuals had GEJ adenocarcinoma. Genomic profiles and clinico-pathologic features were analyzed for the GEJ adenocarcinomas. Silencing of ATM and ATR was performed using validated short-interfering RNA species in GEJ, esophageal, and gastric adenocarcinoma cell lines. All statistical tests were 2-sided.Results: Pathogenic or likely pathogenic ATM variants were identified in 18 of 312 patients (5.8%), and bi-allelic inactivation of ATM through loss of heterozygosity of the wild-type allele was detected in all (16 of 16) samples with sufficient tumor content. Germline ATM-mutated GEJ adenocarcinomas largely lacked somatic mutations in TP53, were more likely to harbor MDM2 amplification, and harbored statistically significantly fewer somatic single nucleotide variants (2.0 mutations/Mb vs 7.9 mutations/Mb; P < .001). A statistically significantly higher proportion of germline ATM-mutated than ATM-wild-type GEJ adenocarcinoma patients underwent a curative resection (10 [100%] vs 92 [86.8%], P = .04; Fisher's exact test.), A synthetic lethal interaction between short-interfering RNA silencing of ATM and ATR was observed in the models analyzed.Conclusions: Our results indicate that germline pathogenic variants in ATM drive oncogenesis in GEJ adenocarcinoma and might result in a distinct clinical phenotype. Given the high prevalence of germline ATM-mutated GEJ adenocarcinomas, genetic testing for individuals with GEJ adenocarcinomas may be considered to better inform prognostication, treatment decisions, and future cancer risk. [ABSTRACT FROM AUTHOR]

We investigate how connections to organized crime manifest on firms' financial statements and analyze the impact of these connections on firm performance outcomes. Using a unique dataset that identifies Italian firms connected to organized crime, we find that connected firms have lower profitability, even though they report higher sales and lower labor cost. Connected firms also have higher bank debt, report lower cash holdings, experience quicker operating cycles and are more likely to file for bankruptcy. Further, we find that connected firms are more tax aggressive and engage in downward earnings manipulation. To corroborate our results, we exploit an amendment to the Italian Anti-Money Laundering regulation as a shock to the extent to which criminal organizations could expropriate connected firms' resources through money laundering. Our collective evidence suggests that connections to organized crime can drain a firm's resources, possibly through money-laundering schemes, and jeopardize its existence, thereby harming its shareholders. Data Availability: Data are available from the public sources cited in the text. JEL Classifications: G31; G32; G38; K42; K49. [ABSTRACT FROM AUTHOR]

Purpose: Despite advances in adjuvant therapeutic strategies, many patients with hormone receptor (HR)-positive/HER2-negative early breast cancer (EBC) experience disease recurrence, even many years after primary surgery. The aim of this review is: (i) to point out the current clinical, pathological, and genomic features that contribute to define the risk of recurrence in HR-positive EBC, (ii) to explore the potential role of liquid biopsy-based assays for refining risk assessment, and (iii) to discuss future perspectives and innovative strategies to optimize risk stratification and select patients for treatment escalation. Methods: We searched PubMed, EMBASE and Scopus to review the current evidence about risk stratification in patients with HR-positive EBC, and to identify studies deemed to have the highest scientific value. Results: Risk stratification of HR-positive/HER2-negative relies on traditional clinicopathological features (age, menopausal status, tumor size, nodal status, tumor grading, HR expression level, and proliferation markers), along with newly developed genomic scores, which accurately predict risk of recurrence and survival. Multiparametric scores including both clinicopathological and genomic variables have the highest prognostication power, even if comparative studies have not defined which one should be preferred. In parallel, liquid biopsy-based showed to be a valuable tool to identify high risk patients. Conclusion: The most appropriate definition of "high" and "low" risk HR-positive EBC is still unclear. Accordingly, treatment escalation/de-escalation depending on recurrence risk remains challenging. Implementation of new tools for risk stratification, such as liquid biopsy-based assays, as well as development of novel treatment strategies are strongly warranted. [ABSTRACT FROM AUTHOR]