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Background Evidence-based parenting programs effectively prevent the onset and escalation of child and adolescent behavioral health problems. When programs have been taken to scale, declines in the quality of implementation diminish intervention effects. Gold-standard methods of implementation monitoring are cost-prohibitive and impractical in resource-scarce delivery systems. Technological developments using computational linguistics and machine learning offer an opportunity to assess fidelity in a low burden, timely, and comprehensive manner. Methods In this study, we test two natural language processing (NLP) methods [i.e., Term Frequency-Inverse Document Frequency (TF-IDF) and Bidirectional Encoder Representations from Transformers (BERT)] to assess the delivery of the Family Check-Up 4 Health (FCU4Health) program in a type 2 hybrid effectiveness-implementation trial conducted in primary care settings that serve primarily Latino families. We trained and evaluated models using 116 English and 81 Spanish-language transcripts from the 113 families who initiated FCU4Health services. We evaluated the concurrent validity of the TF-IDF and BERT models using observer ratings of program sessions using the COACH measure of competent adherence. Following the Implementation Cascade model, we assessed predictive validity using multiple indicators of parent engagement, which have been demonstrated to predict improvements in parenting and child outcomes. Results Both TF-IDF and BERT ratings were significantly associated with observer ratings and engagement outcomes. Using mean squared error, results demonstrated improvement over baseline for observer ratings from a range of 0.83–1.02 to 0.62–0.76, resulting in an average improvement of 24%. Similarly, results demonstrated improvement over baseline for parent engagement indicators from a range of 0.81–27.3 to 0.62–19.50, resulting in an approximate average improvement of 18%. Conclusions These results demonstrate the potential for NLP methods to assess implementation in evidence-based parenting programs delivered at scale. Future directions are presented. Trial registration NCT03013309 ClinicalTrials.gov.

Supporting the reading comprehension and content knowledge acquisition of English language learners (ELs) requires instructional practices that continue beyond developing the foundational skills of reading. In particular, the challenges ELs face highlight the importance of teaching reading comprehension practices in the middle grades through content acquisition. We conducted a randomized control trial to examine the efficacy of a content acquisition and reading comprehension intervention implemented in eighth-grade social studies classrooms with English language learners. Using a within-teacher design, in which 18 eighth-grade teachers' social studies classes were randomly assigned to treatment or comparison conditions. Teachers taught the same instructional content to treatment and comparison classes, but the treatment classes used instructional practices that included comprehension canopy, essential words, knowledge acquisition, and team-based learning. Students in the treatment group (n = 845) outperformed students in the comparison group (n = 784) on measures of content knowledge acquisition and content reading comprehension but not general reading comprehension. Both ELs and non-ELs who received the treatment outperformed those assigned to the BAU comparison condition on measures of content knowledge acquisition (ES = 0.40) and content-related reading comprehension (ES = 0.20). In addition, the proportion of English language learners in classes moderated outcomes for content knowledge acquisition.

Abstract Cardiovascular diseases and cancer continue to be the two leading causes of death in the United States. While innovations in artificial intelligence, digital health, and telemedicine may revolutionize cardio-oncology clinical practice, barriers to widespread adoption continue to exist. The most effective way to advance these technologies is through a broad range of stakeholders sharing a common vision. Additionally, as we enter the digital era in healthcare, we must help lead this charge for the benefit of our cardiology and oncology patients. Bolstering collaborations in cardiology and oncology is key, in partnership with technology firms, industry, academia, and private practice, with an emphasis on various forms of innovation. The ultimate goal is to connect our patients and their health to informatics-based opportunities to advance cardiovascular disease prevention in cancer patients. We have established the Cardiology Oncology Innovation Network in accordance with this vision, to develop new care delivery options through the use of innovative technological strategies. Our tripartite mission – innovation, collaboration, and education – aims to increase access to and expertise in digital transformation to prevent cardiovascular diseases in cancer patients. Here we describe network initiatives, early accomplishments, and future milestones.

The encapsulated fungus Cryptococcus neoformans is the most common cause of fungal meningitis, with the highest rate of disease in patients with AIDS or immunosuppression. This microbe enters the human body via inhalation of infectious particles. C. neoformans capsular polysaccharide, in which the major component is glucuronoxylomannan (GXM), extensively accumulates in tissues and compromises host immune responses. C. neoformans travels from the lungs to the bloodstream and crosses to the brain via transcytosis, paracytosis, or inside of phagocytes using a "Trojan horse" mechanism. The fungus causes life-threatening meningoencephalitis with high mortality rates. Hence, we investigated the impact of intranasal exogenous GXM administration on C. neoformans infection in C57BL/6 mice. GXM enhances cryptococcal pulmonary infection and facilitates fungal systemic dissemination and brain invasion. Pre-challenge of GXM results in detection of the polysaccharide in lungs, serum, and surprisingly brain, the latter likely reached through the nasal cavity. GXM significantly alters endothelial cell tight junction protein expression in vivo, suggesting significant implications for the C. neoformans mechanisms of brain invasion. Using a microtiter transwell system, we showed that GXM disrupts the trans-endothelial electrical resistance, weakening human brain endothelial cell monolayers co-cultured with pericytes, supportive cells of blood vessels/capillaries found in the blood-brain barrier (BBB) to promote C. neoformans BBB penetration. Our findings should be considered in the development of therapeutics to combat the devastating complications of cryptococcosis that results in an estimated ~200,000 deaths worldwide each year.

Angiotensin-converting enzyme 2 (ACE2), part of the renin-angiotensin system (RAS), serves as an entry point for SARS-CoV-2, leading to viral proliferation in permissive cell types. Using mouse lines in which the Ace2 locus has been humanized by syntenic replacement, we show that regulation of basal and interferon induced ACE2 expression, relative expression levels of different ACE2 transcripts, and sexual dimorphism in ACE2 expression are unique to each species, differ between tissues, and are determined by both intragenic and upstream promoter elements. Our results indicate that the higher levels of expression of ACE2 observed in the lungs of mice relative to humans may reflect the fact that the mouse promoter drives expression of ACE2 in populous airway club cells while the human promoter drives expression in alveolar type 2 (AT2) cells. In contrast to transgenic mice in which human ACE2 is expressed in ciliated cells under the control of the human FOXJ1 promoter, mice expressing ACE2 in club cells under the control of the endogenous Ace2 promoter show a robust immune response after infection with SARS-CoV-2, leading to rapid clearance of the virus. This supports a model in which differential expression of ACE2 determines which cell types in the lung are infected, and this in turn modulates the host response and outcome of COVID-19.

Background/purpose: The use of fluoride is known to reduce the risk of dental caries. There is limited information on the relationship between Streptococcus mutans (S. mutans) and fluoride exposure. This study investigated the association between the count of S. mutans on supragingival biofilm and fluoride exposure of scholar children. Materials and methods: In this cross-sectional study, 56 children from 9 to 11 years of age were selected. Fluoride concentration in drinking water, urine and saliva of each participant were assessed. The count of S. mutans was estimated by calculating the DNA copy number through a quantitative real time polymerase chain reaction (qPCR) assay. Also, sociodemographic data, oral and general health information and variables related to caries risk were evaluated. A stepwise multiple linear regression was performed in all caries related predictor variables with the count of S. mutans as the dependent variable. Results: The multiple linear regression analysis showed that the concentration of fluoride in saliva (β = −3.029, p

Abstract We consider the Lorentz-violating extended QED involving all nonminimal dimension-5 additive CPT-odd terms. For this theory, we investigate the generation of the Carroll–Field–Jackiw (CFJ) term and its higher-derivative counterparts of the first order in any of these nonminimal couplings. The CFJ term is demonstrated to vanish in the dimensional regularization scheme. We also study the question of higher-derivative divergent contributions and demonstrate that they can be eliminated by considering a given proportionality between the coefficients.

Infection of the Central Nervous System (CNS) by the encapsulated fungus Cryptococcus neoformans can lead to high mortality meningitis, most commonly in immunocompromised patients. While the mechanisms by which the fungus crosses the blood-brain barrier to initiate infection in the CNS are well recognized, there are still substantial unanswered questions about the disease progression once the fungus is established in the brain. C. neoformans is characterized by a glucuronoxylomannan (GXM)-rich polysaccharide capsule which has been implicated in immune evasion, but its role during the host CNS infection needs further elucidation. Therefore, the present study aims to examine these key questions about the mechanisms underlying cryptococcal meningitis progression and the impact of fungal GXM release by using an intracerebral rodent infection model via stereotaxic surgery. After developing brain infection, we analyzed distinct brain regions and found that while fungal load and brain weight were comparable one-week post-infection, there were region-specific histopathological (with and without brain parenchyma involvement) and disease manifestations. Moreover, we also observed a region-specific correlation between GXM accumulation and glial cell recruitment. Furthermore, mortality was associated with the presence of subarachnoid hemorrhaging and GXM deposition in the meningeal blood vessels and meninges in all regions infected. Our results show that using the present infection model can facilitate clinical and neuropathological observations during the progression of neurocryptococcosis. Importantly, this mouse model can be used to further investigate disease progression as it develops in humans.

The applications of smart structures with integrated piezoelectric elements have been expanding in the last few decades due to the abilities of such structures to withstand mechanical loads and operate as sensors or actuators using their electromechanical coupling. The available manufacturing techniques can result in uncertainties in the structure's geometric parameters, which, coupled with uncertainties in material properties, can lead to unexpected failures or unreliable performance. This paper presents a reliability analysis of a smart laminated composite plate made of a graphite/epoxy cross-ply substrate with a piezoelectric fiber-reinforced composite (PFRC) actuator layer under static electrical and mechanical loads. A coupled finite element (FE) model was developed in COMSOL Multiphysics, from which nondimensional stresses and displacements were calculated. To investigate the effects of randomness in the material and geometric properties, an artificial neural network (ANN) model was developed and trained using generated FE data. Monte Carlo Simulation (MCS) and First- and Second-Order Reliability Methods (FORM/SORM) were then used to shed light on the significance of considering randomness in the various material and geometric parameters and the effect of such uncertainty on the resulting nondimensional stresses and displacements. A coefficient of variation (CV) study identified the piezoelectric stress coefficient as the most significant contributing factor to the variation of all nondimensional parameters. Variation in the nondimensional parameters also increases under the application of an electric load. ANN-based FORM, SORM, and MCS all indicate a pattern of low probability of failure until a threshold value of about 3% of input parameter variation is reached, beyond which there is a rapid nonlinear increase in failure probability with increasing input parameter variation.

P23H rats express a variant of rhodopsin with a mutation that leads to loss of visual function with similar properties as human autosomal dominant retinitis pigmentosa (RP). The advances made in different therapeutic strategies to recover visual system functionality reveal the need to know whether progressive retina degeneration affects the visual cortex structure. Here we are interested in detecting cortical alterations in young rats with moderate retinal degeneration, and in adulthood when degeneration is severer. For this purpose, we studied the synaptic architecture of the primary visual cortex (V1) by analyzing a series of pre- and postsynaptic elements related to excitatory glutamatergic transmission. Visual cortices from control Sprague Dawley (SD) and P23H rats at postnatal days 30 (P30) and P230 were used to evaluate the distribution of vesicular glutamate transporters VGLUT1 and VGLUT2 by immunofluorescence, and to analyze the expression of postsynaptic density protein-95 (PSD-95) by Western blot. The amount and dendritic spine distribution along the apical shafts of the layer V pyramidal neurons, stained by the Golgi-Cox method, were also studied. We observed that at P30, RP does not significantly affect any of the studied markers and structures, which suggests in young P23H rats that visual cortex connectivity seems preserved. However, in adult rats, although VGLUT1 immunoreactivity and PSD-95 expression were similar between both groups, a narrower and stronger VGLUT2-immunoreactive band in layer IV was observed in the P23H rats. Furthermore, RP significantly decreased the density of dendritic spines and altered their distribution along the apical shafts of pyramidal neurons, which remained in a more immature state compared to the P230 SD rats. Our results indicate that the most notable changes in the visual cortex structure take place after a prolonged retinal degeneration period that affected the presynaptic thalamocortical VGLUT2-immunoreactive terminals and postsynaptic dendritic spines from layer V pyramidal cells. Although plasticity is more limited at these ages, future studies will determine how reversible these changes are and to what extent they can affect the visual system’s functionality.

Objective: Articular cartilage injury is central for the development of post-traumatic osteoarthritis (PTOA). With few disease-modifying therapies successful at offsetting progressive osteoarthritis (OA), our goal is to use a high throughput screening platform of cartilage injury to identify novel chondroprotective compounds. Targeting articular cartilage damage immediately after injury remains a promising therapeutic strategy to overcome irreversible tissue damage. Method: We constructed a single impact-cartilage screening method using a multi-platen system that simultaneously impacts 48 samples and makes use of engineered cartilage tissue analogs (known as CTAs). Drug libraries were screened and assessed for their ability to alter two crucial biological responses to impact injuries, namely matrix degradation and cell stress. Results: Over 500 small molecules were screened for their ability to alter proteoglycan loss, matrix metalloproteinase activity, and cell stress or death. Fifty-five compounds passed through secondary screening and were from commercial libraries of natural and redox, stem cell related compounds, as well as protease, kinase and phosphatase inhibitors. Through secondary screening, 16 promising candidates exhibited activity on one or more critical function of chondrocytes. While many are mechanistically known compounds, their function in joint diseases is not known. Conclusion: This platform was validated for screening drug activity against a tissue engineered model of PTOA. Multiple compounds identified in this manner have potential application as early protective therapy for treating PTOA, and require further study. We propose this screening platform can identify novel molecules that act on early chondrocyte responses to injury and provide an invaluable tool for therapeutic development.

Summary: The emergence of SARS-CoV-2 variants of concern (VOCs) requires the development of next-generation biologics with high neutralization breadth. Here, we characterized a human VH domain, F6, which we generated by sequentially panning large phage-displayed VH libraries against receptor binding domains (RBDs) containing VOC mutations. Cryo-EM analyses reveal that F6 has a unique binding mode that spans a broad surface of the RBD and involves the antibody framework region. Attachment of an Fc region to a fusion of F6 and ab8, a previously characterized VH domain, resulted in a construct (F6-ab8-Fc) that broadly and potently neutralized VOCs including Omicron. Additionally, prophylactic treatment using F6-ab8-Fc reduced live Beta (B.1.351) variant viral titers in the lungs of a mouse model. Our results provide a new potential therapeutic against SARS-CoV-2 variants including Omicron and highlight a vulnerable epitope within the spike that may be exploited to achieve broad protection against circulating variants.

ABSTRACT Infectious diseases have shaped the human population genetic structure, and genetic variation influences the susceptibility to many viral diseases. However, a variety of challenges have made the implementation of traditional human Genome-wide Association Studies (GWAS) approaches to study these infectious outcomes challenging. In contrast, mouse models of infectious diseases provide an experimental control and precision, which facilitates analyses and mechanistic studies of the role of genetic variation on infection. Here we use a genetic mapping cross between two distinct Collaborative Cross mouse strains with respect to severe acute respiratory syndrome coronavirus (SARS-CoV) disease outcomes. We find several loci control differential disease outcome for a variety of traits in the context of SARS-CoV infection. Importantly, we identify a locus on mouse chromosome 9 that shows conserved synteny with a human GWAS locus for SARS-CoV-2 severe disease. We follow-up and confirm a role for this locus, and identify two candidate genes, CCR9 and CXCR6, that both play a key role in regulating the severity of SARS-CoV, SARS-CoV-2, and a distantly related bat sarbecovirus disease outcomes. As such we provide a template for using experimental mouse crosses to identify and characterize multitrait loci that regulate pathogenic infectious outcomes across species. IMPORTANCE Host genetic variation is an important determinant that predicts disease outcomes following infection. In the setting of highly pathogenic coronavirus infections genetic determinants underlying host susceptibility and mortality remain unclear. To elucidate the role of host genetic variation on sarbecovirus pathogenesis and disease outcomes, we utilized the Collaborative Cross (CC) mouse genetic reference population as a model to identify susceptibility alleles to SARS-CoV and SARS-CoV-2 infections. Our findings reveal that a multitrait loci found in chromosome 9 is an important regulator of sarbecovirus pathogenesis in mice. Within this locus, we identified and validated CCR9 and CXCR6 as important regulators of host disease outcomes. Specifically, both CCR9 and CXCR6 are protective against severe SARS-CoV, SARS-CoV-2, and SARS-related HKU3 virus disease in mice. This chromosome 9 multitrait locus may be important to help identify genes that regulate coronavirus disease outcomes in humans.

Study objective: Cancer and heart disease are leading causes of mortality, and cardio-oncology is emerging as a new field addressing the cardiovascular toxicities related to cancer and cancer therapy. Interdisciplinary research platforms that incorporate digital health to optimize cardiovascular health and wellness in cancer survivors are therefore needed as we advance in the digital era. Our goal was to develop the Connected Health Innovation Research Program (C.H.I.R.P.) to serve as a foundation for future integration and assessments of adoption and clinical efficacy of digital health tools for cardiovascular health and wellness in the general population and in oncology patients. Design/setting/participants: Partner companies were identified through the American Medical Association innovation platform, as well as LinkedIn and direct contact by our team. Company leaders met with our team to discuss features of their technology or software. Non-disclosure agreements were signed and data were discussed and obtained for descriptive or statistical analysis. Results: A suite of companies with technologies focused on wellness, biometrics tracking, audio companions, oxygen saturation, weight trends, sleep patterns, heart rate variability, electrocardiogram patterns, blood pressure patterns, real-time metabolism tracking, instructional video modules, or integration of these technologies into electronic health records was collated. We formed an interdisciplinary research team and established an academia-industry collaborative foundation for connecting patients with wellness digital health technologies. Conclusions: A suite of software and device technologies accessible to the cardiology and oncology population has been established and will facilitate retrospective, prospective, and case research studies assessing adoption and clinical efficacy of digital health tools in cardiology/oncology.

Abstract Background Advances in genetics and sequencing technologies are enabling the identification of more individuals with inherited cancer susceptibility who could benefit from tailored screening and prevention recommendations. While cancer family history information is used in primary care settings to identify unaffected patients who could benefit from a cancer genetics evaluation, this information is underutilized. System-level population health management strategies are needed to assist health care systems in identifying patients who may benefit from genetic services. In addition, because of the limited number of trained genetics specialists and increasing patient volume, the development of innovative and sustainable approaches to delivering cancer genetic services is essential. Methods We are conducting a randomized controlled trial, entitled Broadening the Reach, Impact, and Delivery of Genetic Services (BRIDGE), to address these needs. The trial is comparing uptake of genetic counseling, uptake of genetic testing, and patient adherence to management recommendations for automated, patient-directed versus enhanced standard of care cancer genetics services delivery models. An algorithm-based system that utilizes structured cancer family history data available in the electronic health record (EHR) is used to identify unaffected patients who receive primary care at the study sites and meet current guidelines for cancer genetic testing. We are enrolling eligible patients at two healthcare systems (University of Utah Health and New York University Langone Health) through outreach to a randomly selected sample of 2780 eligible patients in the two sites, with 1:1 randomization to the genetic services delivery arms within sites. Study outcomes are assessed through genetics clinic records, EHR, and two follow-up questionnaires at 4 weeks and 12 months after last genetic counseling contactpre-test genetic counseling. Discussion BRIDGE is being conducted in two healthcare systems with different clinical structures and patient populations. Innovative aspects of the trial include a randomized comparison of a chatbot-based genetic services delivery model to standard of care, as well as identification of at-risk individuals through a sustainable EHR-based system. The findings from the BRIDGE trial will advance the state of the science in identification of unaffected patients with inherited cancer susceptibility and delivery of genetic services to those patients. Trial registration BRIDGE is registered as NCT03985852 . The trial was registered on June 6, 2019 at clinicaltrials.gov .

Abstract Machine learning (ML) models have demonstrated the power of utilizing clinical instruments to provide tools for domain experts in gaining additional insights toward complex clinical diagnoses. In this context these tools desire two additional properties: interpretability, being able to audit and understand the decision function, and robustness, being able to assign the correct label in spite of missing or noisy inputs. This work formulates diagnostic classification as a decision-making process and utilizes Q-learning to build classifiers that meet the aforementioned desired criteria. As an exemplary task, we simulate the process of differentiating Autism Spectrum Disorder from Attention Deficit-Hyperactivity Disorder in verbal school aged children. This application highlights how reinforcement learning frameworks can be utilized to train more robust classifiers by jointly learning to maximize diagnostic accuracy while minimizing the amount of information required.

Abstract Methamphetamine (METH) is a strong addictive central nervous system stimulant. METH abuse can alter biological processes and immune functions necessary for host defense. The acquisition and transmission of HIV, hepatitis, and other communicable diseases are possible serious infectious consequences of METH use. METH also accumulates extensively in major organs. Despite METH being a major public health and safety problem globally, there are limited studies addressing the impact of this popular recreational psychostimulant on tissue adaptive immune responses after exposure to T cell dependent [ovalbumin (OVA)] and independent [lipopolysaccharide (LPS)] antigens. We hypothesized that METH administration causes pulmonary and splenic tissue alterations and reduces T cell responses to OVA and LPS in vivo, suggesting the increased susceptibility of users to infection. Using a murine model of METH administration, we showed that METH causes tissue injury, apoptosis, and alters helper and cytotoxic T cell recruitment in antigen challenged mice. METH also reduces the expression and distribution of CD3 and CD28 molecules on the surface of human Jurkat T cells. In addition, METH decreases the production of IL-2 in these T-like cells, suggesting a negative impact on T lymphocyte activation and proliferation. Our findings demonstrate the pleotropic effects of METH on cell-mediated immunity. These alterations have notable implications on tissue homeostasis and the capacity of the host to respond to infection.

Abstract Background Craniospinal irradiation (CSI) is part of the treatment of central nervous system (CNS) tumors and is associated with cardiovascular disease in adults. Global myocardial strain analysis including longitudinal peak systolic strain (GLS), circumferential peak systolic strain (GCS), and radial peak systolic strain (GRS) can reveal subclinical cardiac dysfunction. Methods Retrospective, single-center study in patients managed with CSI vs. age-matched controls. Clinical data and echocardiography, including myocardial strain analysis, were collected at early (

Patient‐derived samples present an advantage over current cell line models of high‐grade serous ovarian cancer (HGSOC) that are not always reliable and phenotypically faithful models of in vivo HGSOC. To improve upon cell line models of HGSOC, we set out to characterize a panel of patient‐derived cells and determine their epithelial and mesenchymal characteristics. We analyzed RNA and protein expression levels in patient‐derived xenograft (PDX) models of HGSOC, and functionally characterized these models using flow cytometry, wound healing assays, invasion assays, and spheroid cultures. Besides in vitro work, we also evaluated the growth characteristics of PDX in vivo (orthotopic PDX). We found that all samples had hybrid characteristics, covering a spectrum from an epithelial‐to‐mesenchymal state. Samples with a stronger epithelial phenotype were more active in self‐renewal assays and more tumorigenic in orthotopic xenograft models as compared to samples with a stronger mesenchymal phenotype, which were more migratory and invasive. Additionally, we observed an inverse association between microRNA let‐7 (lethal‐7) expression and stemness, consistent with the loss of let‐7 being an important component of the cancer stem cell phenotype. We observed that lower let‐7 levels were associated with the epithelial state and a lower epithelial mesenchymal transition (EMT) score, more efficient spheroid and tumor formation, and increased sensitivity to platinum‐based chemotherapy. Surprisingly, in these HGSOC cells, stemness could be dissociated from invasiveness: Cells with lower let‐7 levels were more tumorigenic, but less migratory, and with a lower EMT score, than those with higher let‐7 levels. We conclude that let‐7 expression and epithelial/mesenchymal state are valuable predictors of HGSOC proliferation, in vitro self‐renewal, and tumor burden in vivo.

Abstract We study dark matter (DM) abundance in the framework of the extension of the Standard Model (SM) with an additional $$U(1)_X$$ U(1)X gauge symmetry. One complex singlet is included to break the $$U(1)_X$$ U(1)X gauge symmetry, meanwhile one of the doublets is considered inert to introduce a DM candidate. The stability of the DM candidate is analyzed with a continuous $$U(1)_X$$ U(1)X gauge symmetry as well as discrete $$Z_2$$ Z2 symmetry. We find allowed regions for the free model parameters which are in agreement with the most up-to-date experimental results reported by CMS and ATLAS Collaborations, the upper limit on WIMP-nucleon cross section imposed by XENON1T Collaboration and the upper limit on the production cross-section of a $$Z^{\prime }$$ Z′ gauge boson times the branching ratio of the $$Z^{\prime }$$ Z′ boson decaying into $$\ell ^-\ell ^+$$ ℓ-ℓ+ . We also obtain allowed regions for the DM candidate mass from the relic density reported by the PLANCK Collaboration including light, intermediate and heavy masses; depending mainly on two parameters of the scalar potential, $$\lambda _{2x}$$ λ2x and $$\lambda _{345}=\lambda _3+\lambda _4+2\lambda _5$$ λ345=λ3+λ4+2λ5 . We find that trough $$pp\rightarrow \chi \chi \gamma $$ pp→χχγ production, it may only be possible for a future hadron–hadron circular collider (FCC-hh) to be able to detect a DM candidate within the range of masses 10–60 GeV.

PurposesMost molecular-based published studies on breast cancer do not adequately represent the unique and diverse genetic admixture of the Latin American population. Searching for similarities and differences in molecular pathways associated with these tumors and evaluating its impact on prognosis may help to select better therapeutic approaches.Patients and MethodsWe collected clinical, pathological, and transcriptomic data of a multi-country Latin American cohort of 1,071 stage II-III breast cancer patients of the Molecular Profile of Breast Cancer Study (MPBCS) cohort. The 5-year prognostic ability of intrinsic (transcriptomic-based) PAM50 and immunohistochemical classifications, both at the cancer-specific (OSC) and disease-free survival (DFS) stages, was compared. Pathway analyses (GSEA, GSVA and MetaCore) were performed to explore differences among intrinsic subtypes.ResultsPAM50 classification of the MPBCS cohort defined 42·6% of tumors as LumA, 21·3% as LumB, 13·3% as HER2E and 16·6% as Basal. Both OSC and DFS for LumA tumors were significantly better than for other subtypes, while Basal tumors had the worst prognosis. While the prognostic power of traditional subtypes calculated with hormone receptors (HR), HER2 and Ki67 determinations showed an acceptable performance, PAM50-derived risk of recurrence best discriminated low, intermediate and high-risk groups. Transcriptomic pathway analysis showed high proliferation (i.e. cell cycle control and DNA damage repair) associated with LumB, HER2E and Basal tumors, and a strong dependency on the estrogen pathway for LumA. Terms related to both innate and adaptive immune responses were seen predominantly upregulated in Basal tumors, and, to a lesser extent, in HER2E, with respect to LumA and B tumors.ConclusionsThis is the first study that assesses molecular features at the transcriptomic level in a multicountry Latin American breast cancer patient cohort. Hormone-related and proliferation pathways that predominate in PAM50 and other breast cancer molecular classifications are also the main tumor-driving mechanisms in this cohort and have prognostic power. The immune-related features seen in the most aggressive subtypes may pave the way for therapeutic approaches not yet disseminated in Latin America.Clinical Trial RegistrationClinicalTrials.gov (Identifier: NCT02326857).

Molecular profile of breast cancer in Latin-American women was studied in five countries: Argentina, Brazil, Chile, Mexico, and Uruguay. Data about socioeconomic characteristics, risk factors, prognostic factors, and molecular subtypes were described, and the 60-month overall cumulative survival probabilities (OS) were estimated. From 2011 to 2013, 1,300 eligible Latin-American women 18 years or older, with a diagnosis of breast cancer in clinical stage II or III, and performance status ≦̸1 were invited to participate in a prospective cohort study. Face-to-face interviews were conducted, and clinical and outcome data, including death, were extracted from medical records. Unadjusted associations were evaluated by Chi-squared and Fisher’s exact tests and the OS by Kaplan–Meier method. Log-rank test was used to determine differences between cumulative probability curves. Multivariable adjustment was carried out by entering potential confounders in the Cox regression model. The OS at 60 months was 83.9%. Multivariable-adjusted death hazard differences were found for women living in Argentina (2.27), Chile (1.95), and Uruguay (2.42) compared with Mexican women, for older (≥60 years) (1.84) compared with younger (≤40 years) women, for basal-like subtype (5.8), luminal B (2.43), and HER2-enriched (2.52) compared with luminal A subtype, and for tumor clinical stages IIB (1.91), IIIA (3.54), and IIIB (3.94) compared with stage IIA women. OS was associated with country of residence, PAM50 intrinsic subtype, age, and tumor stage at diagnosis. While the latter is known to be influenced by access to care, including cancer screening, timely diagnosis and treatment, including access to more effective treatment protocols, it may also influence epigenetic changes that, potentially, impact molecular subtypes. Data derived from heretofore understudied populations with unique geographic ancestry and sociocultural experiences are critical to furthering our understanding of this complexity.