Adjuvant Pertuzumab and Trastuzumab in Early Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer in the APHINITY Trial: Third Interim Overall Survival Analysis With Efficacy Update.

JCO The APHINITY trial (ClinicalTrials.gov identifier: NCT01358877) previously demonstrated that pertuzumab added to adjuvant trastuzumab and chemotherapy improved invasive disease-free survival (iDFS) for patients with early human epidermal growth factor receptor 2-positive (HER2+) breast cancer (BC). Here, we report the preplanned third interim analysis of overall survival (OS) and a descriptive updated iDFS analysis with 8.

An analysis of the association between breast density and body mass index with breast cancer molecular subtypes in early breast cancer: data from a Spanish population.

Purpose: Breast cancer is an important health problem, like obesity and dyslipidemia, with a strong association between body mass index (BMI) and breast cancer incidence and mortality. The risk of breast cancer is also high in women with high mammographic breast density (MBD). The purpose of this study was to analyze the association between BMI and MBD according to breast cancer molecular subtypes.

In vivo screening characterizes chromatin factor functions during normal and malignant hematopoiesis.

Cellular differentiation requires extensive alterations in chromatin structure and function, which is elicited by the coordinated action of chromatin and transcription factors. By contrast with transcription factors, the roles of chromatin factors in differentiation have not been systematically characterized. Here, we combine bulk ex vivo and single-cell in vivo CRISPR screens to characterize the role of chromatin factor families in hematopoiesis.

The bone marrow niche regulates redox and energy balance in MLL::AF9 leukemia stem cells.

Eradicating leukemia requires a deep understanding of the interaction between leukemic cells and their protective microenvironment. The CXCL12/CXCR4 axis has been postulated as a critical pathway dictating leukemia stem cell (LSC) chemoresistance in AML due to its role in controlling cellular egress from the marrow. Nevertheless, the cellular source of CXCL12 in the acute myeloid leukemia (AML) microenvironment and the mechanism by which CXCL12 exerts its protective role in vivo remain unresolved.

Deconvolution of the hematopoietic stem cell microenvironment reveals a high degree of specialization and conservation.

Understanding the regulation of normal and malignant human hematopoiesis requires comprehensive cell atlas of the hematopoietic stem cell (HSC) regulatory microenvironment. Here, we develop a tailored bioinformatic pipeline to integrate public and proprietary single-cell RNA sequencing (scRNA-seq) datasets. As a result, we robustly identify for the first time 14 intermediate cell states and 11 stages of differentiation in the endothelial and mesenchymal BM compartments, respectively.

Functional Mapping of AKT Signaling and Biomarkers of Response from the FAIRLANE Trial of Neoadjuvant Ipatasertib plus Paclitaxel for Triple-Negative Breast Cancer.

Purpose: Despite extensive genomic and transcriptomic profiling, it remains unknown how signaling pathways are differentially activated and how tumors are differentially sensitized to certain perturbations. Here, we aim to characterize AKT signaling activity and its association with other genomic or IHC-based PI3K/AKT pathway biomarkers as well as the clinical activity of ipatasertib (AKT inhibitor) in the FAIRLANE trial.

Experimental Design: In FAIRLANE, 151 patients with early triple-negative breast cancer (TNBC) were randomized 1:1 to receive paclitaxel with ipatasertib or placebo for 12 weeks prior to surgery.

The fission yeast FLCN/FNIP complex augments TORC1 repression or activation in response to amino acid (AA) availability.

The target of Rapamycin complex1 (TORC1) senses and integrates several environmental signals, including amino acid (AA) availability, to regulate cell growth. Folliculin (FLCN) is a tumor suppressor (TS) protein in renal cell carcinoma, which paradoxically activates TORC1 in response to AA supplementation. Few tractable systems for modeling FLCN as a TS are available.

Operationalisation of quality of life for students with intellectual and developmental disabilities to improve their inclusion.

Background: Quality of life (QoL) is regarded as a framework to enhance inclusive education outcomes in different domains for all students, especially for those with intellectual and developmental disabilities (IDD). Assessment tools are needed to implement this framework. Although there is a long trajectory of QoL assessment in people with IDD, we identify a lack of instruments for students with IDD who attend to general education contexts.

Obesity and Breast Cancer: A Paradoxical and Controversial Relationship Influenced by Menopausal Status.

Breast cancer is the most common tumor in women worldwide, and an increasing public health concern. Knowledge of both protective and negative risk factors is essential for a better understanding of this heterogenous disease. We undertook a review of the recent literature and evaluated the relationship between obesity mediators and breast cancer development depending on menopausal status.

Predictive Role of Leptin Receptor (Ob-R) Overexpression in Patients with Early Breast Cancer Receiving Neoadjuvant Systemic Treatment.

The primary aim of this retrospective study was to investigate the correlation between the immunohistochemical expression of Ob-R (leptin receptor) with pCR (pathological complete response) in early breast cancer patients receiving neoadjuvant systemic treatment (NST). A total of 100 women with breast cancer receiving NST (2017-2020) followed by surgical resection were retrospectively obtained. Demographic parameters and clinicopathological factors (e.

Molecular and Cellular Mechanisms of Delayed Fracture Healing in Mmp10 (Stromelysin 2) Knockout Mice.

The remodeling of the extracellular matrix is a central function in endochondral ossification and bone homeostasis. During secondary fracture healing, vascular invasion and bone growth requires the removal of the cartilage intermediate and the coordinate action of the collagenase matrix metalloproteinase (MMP)-13, produced by hypertrophic chondrocytes, and the gelatinase MMP-9, produced by cells of hematopoietic lineage. Interfering with these MMP activities results in impaired fracture healing characterized by cartilage accumulation and delayed vascularization.

Shelter from the cytokine storm: Healthy living is a vital preventative strategy in the COVID-19 era.

Coronavirus disease 2019 (COVID-19) continues to have a devastating effect on a global scale. COVID-19 variants continue to arise and counteract vaccination efficacy. As such, preventative health measures, such as social distancing and stay at home mandates, will continue for the foreseeable future.

MED15 prion-like domain forms a coiled-coil responsible for its amyloid conversion and propagation.

A disordered to β-sheet transition was thought to drive the functional switch of Q/N-rich prions, similar to pathogenic amyloids. However, recent evidence indicates a critical role for coiled-coil (CC) regions within yeast prion domains in amyloid formation. We show that many human prion-like domains (PrLDs) contain CC regions that overlap with polyQ tracts.

Dissection of two routes to naïve pluripotency using different kinase inhibitors.

Embryonic stem cells (ESCs) can be maintained in the naïve state through inhibition of Mek1/2 and Gsk3 (2i). A relevant effect of 2i is the inhibition of Cdk8/19, which are negative regulators of the Mediator complex, responsible for the activity of enhancers. Inhibition of Cdk8/19 (Cdk8/19i) stimulates enhancers and, similar to 2i, stabilizes ESCs in the naïve state.

Nutrition in medical education in Latin America: Results of a cross-sectional survey.

Rationale: The gap between the nutrition education provided to medical students and the nutrition competences and attitudes needed for doctors to provide effective nutrition care is a global concern. The goal of this study was to investigate the curricular content on nutrition education in Latin American medical schools and to evaluate the self-perceived knowledge, attitudes, and barriers to nutrition practice of final-year medical students.

Methods: Eighty-five public and private medical schools from 17 Latin American countries were invited to participate in the study.

Notch3 Deficiency Attenuates Pulmonary Fibrosis and Impedes Lung-Function Decline.

Fibroblast activation includes differentiation to myofibroblasts and is a key feature of organ fibrosis. The Notch pathway has been involved in myofibroblast differentiation in several tissues, including the lung. Here, we identify a subset of collagen-expressing cells in the lung that exhibit Notch3 activity at homeostasis.

Global hyperactivation of enhancers stabilizes human and mouse naive pluripotency through inhibition of CDK8/19 Mediator kinases.

Pluripotent stem cells (PSCs) transition between cell states in vitro, reflecting developmental changes in the early embryo. PSCs can be stabilized in the naive state by blocking extracellular differentiation stimuli, particularly FGF-MEK signalling. Here, we report that multiple features of the naive state in human and mouse PSCs can be recapitulated without affecting FGF-MEK signalling or global DNA methylation.

Engineering a Humanised Niche to Support Human Haematopoiesis in Mice: Novel Opportunities in Modelling Cancer.

Despite the bone marrow microenvironment being widely recognised as a key player in cancer research, the current animal models that represent a human haematopoietic system lack the contribution of the humanised marrow microenvironment. Here we describe a murine model that relies on the combination of an orthotopic humanised tissue-engineered bone construct (ohTEBC) with patient-specific bone marrow (BM) cells to create a humanised bone marrow (hBM) niche capable of supporting the engraftment of human haematopoietic cells. Results showed that this model supports the engraftment of human CD34 cells from a healthy BM with human haematopoietic cells migrating into the mouse BM, human BM compartment, spleen and peripheral blood.

Manipulating the Mediator complex to induce naïve pluripotency.

Human naïve pluripotent stem cells (PSCs) represent an optimal homogenous starting point for molecular interventions and differentiation strategies. This is in contrast to the standard primed PSCs which fluctuate in identity and are transcriptionally heterogeneous. However, despite many efforts, the maintenance and expansion of human naïve PSCs remains a challenge.

Concomitant Medications and Risk of Chemotherapy-Induced Peripheral Neuropathy.

Background: Peripheral neuropathy is the dose-limiting toxicity of many oncology drugs, including paclitaxel. There is large interindividual variability in the neuropathy, and several risk factors have been proposed; however, many have not been replicated. Here we present a comprehensive study aimed at identifying treatment and physiopathology-related paclitaxel-induced neuropathy risk factors in a large cohort of well-characterized patients.

Late Administration of Trastuzumab Emtansine Might Lead to Loss of Chance for Better Outcome in Patients with HER2-Positive Metastatic Breast Cancer.

The optimal sequence of anti-human epidermal growth factor receptor 2 (HER2) therapies in metastatic breast cancer (MBC) is still undetermined. Physicians must therefore make decisions based on clinical trials and their own experience for the best treatment sequence in these patients. The objective of this review is to summarize the efficacy and safety data for trastuzumab emtansine (T-DM1) in patients with MBC.

The RNA Polymerase II Factor RPAP1 Is Critical for Mediator-Driven Transcription and Cell Identity.

The RNA polymerase II-associated protein 1 (RPAP1) is conserved across metazoa and required for stem cell differentiation in plants; however, very little is known about its mechanism of action or its role in mammalian cells. Here, we report that RPAP1 is essential for the expression of cell identity genes and for cell viability. Depletion of RPAP1 triggers cell de-differentiation, facilitates reprogramming toward pluripotency, and impairs differentiation.