Transcription factor EB (TFEB) activity increases resistance of TNBC stem cells to metabolic stress.

Breast cancer stem cells (CSCs) are difficult to therapeutically target, but continued efforts are critical given their contribution to tumor heterogeneity and treatment resistance in triple-negative breast cancer. CSC properties are influenced by metabolic stress, but specific mechanisms are lacking for effective drug intervention. Our previous work on TFEB suggested a key function in CSC metabolism.

The Buddy Program: High school students inform the design of a school-based peer support program for concussion.

Prior research provides little guidance on how to support return to school post-concussion. Peer support may be one strategy to enable adolescents to return to school post-concussion. The purpose of this study was to explore what high school students preferred in a school-based peer support program post-concussion.

Are we asking the right questions? Female athletes' perspectives on the menstrual cycle in sport.

Background: Menstrual cycle (MC) research employing qualitative and quantitative methods has recently increased in athlete populations. A move towards a participant-centered approach to help formulate questions that align with practitioners' and stakeholders' priorities in the sport environment is needed. Therefore, our study aims were to 1) understand what athletes feel is important to consider regarding their MC in sport, and 2) provide practical recommendations for coaches and practitioners to support a positive sport culture around the MC.

Best practices for the dissemination and implementation of neuromuscular training injury prevention warm-ups in youth team sport: a systematic review.

Objective: To evaluate best practices for neuromuscular training (NMT) injury prevention warm-up programme dissemination and implementation (D&I) in youth team sports, including characteristics, contextual predictors and D&I strategy effectiveness.

Design: Systematic review.

Data Sources: Seven databases were searched.

Youth Injury Knowledge and Beliefs following Neuromuscular Training Warm-up Implementation in Schools.

Neuromuscular training warm-up programs can reduce injury rates in youth sports, but they often have poor uptake and adherence. Delivering such programs in school physical education classes may provide greater public health benefit, particularly if they promote improved injury knowledge and prevention beliefs amongst students. The purpose of this secondary analysis of a large cluster-randomized controlled trial was to understand how students' (age 11-15 years) knowledge and beliefs change after exposure to an evidence-informed neuromuscular training warm-up program.

Elucidating the direct effects of the novel HDAC inhibitor bocodepsin (OKI-179) on T cells to rationally design regimens for combining with immunotherapy.

Histone deacetylase inhibitors (HDACi) are currently being explored for the treatment of both solid and hematological malignancies. Although originally thought to exert cytotoxic responses through tumor-intrinsic mechanisms by increasing expression of tumor suppressor genes, several studies have demonstrated that therapeutic responses depend on an intact adaptive immune system: particularly CD8 T cells. It is therefore critical to understand how HDACi directly affects T cells in order to rationally design regimens for combining with immunotherapy.

High Sport Specialization Is Associated With More Musculoskeletal Injuries in Canadian High School Students.

Objective: To describe levels of sport specialization in Canadian high school students and investigate whether sport specialization and/or sport participation volume is associated with the history of musculoskeletal injury and/or concussion.

Design: Cross-sectional study.

Setting: High schools, Alberta, Canada.

Who Does Not Respond to Injury Prevention Warm-up Programs? A Secondary Analysis of Trial Data From Neuromuscular Training Programs in Youth Basketball, Soccer, and Physical Education.

To identify factors associated with nonresponse to neuromuscular training (NMT) warm-up programs among youth exposed to NMT warm-ups. This is a secondary analysis of youth (aged 11-18 years) in the intervention groups of 4 randomized controlled trials in high school basketball, youth community soccer, and junior high school physical education. Youth who were exposed to NMT and who sustained an injury during the study were considered .

Covalent JNK Inhibitor, JNK-IN-8, Suppresses Tumor Growth in Triple-Negative Breast Cancer by Activating TFEB- and TFE3-Mediated Lysosome Biogenesis and Autophagy.

The heterogeneity and aggressiveness of triple-negative breast cancer (TNBC) contribute to its early recurrence and metastasis. Despite substantial research to identify effective therapeutic targets, TNBC remains elusive in terms of improving patient outcomes. Here, we report that a covalent JNK inhibitor, JNK-IN-8, suppresses TNBC growth both in vitro and in vivo.

Sport Specialization, Physical Performance and Injury History in Canadian Junior High School Students.

Background: Youth sports participation is encouraged for proposed physical and psychological benefits. However early sport specialization and the potentially negative consequences may be a cause for concern.

Purpose: To describe sport specialization in Canadian youth and investigate associations with previous injury and physical performance.

Canadian High School Rugby Coaches Readiness for an Injury Prevention Strategy Implementation: Evaluating a Train-the-Coach Workshop.

Canadian rugby coach injury prevention beliefs and attitudes have not been studied, yet are key to informing injury prevention strategy implementation. Despite neuromuscular training (NMT) warm-up success in reducing injury, adoption of these programs is variable. Therefore, objectives of this study included (1) describing Canadian youth rugby coach injury prevention beliefs and attitudes and current warm-up practices and (2) evaluating intention to use a rugby-specific NMT warm-up.

BCDIN3D RNA methyltransferase stimulates Aldolase C expression and glycolysis through let-7 microRNA in breast cancer cells.

Type II diabetes (T2D) and specific cancers share many risk factors, however, the molecular mechanisms underlying these connections are often not well-understood. BCDIN3D is an RNA modifying enzyme that methylates specific precursor microRNAs and tRNA. In addition to breast cancer, BCDIN3D may also be linked to metabolism, as its gene locus is associated with obesity and T2D.

Warm-Ups and Coaches' Perceptions: Searching for Clues to Improve Injury Prevention in Youth Basketball.

Regular use of neuromuscular training (NMT) warm-up programs improves performance and prevents injuries. However, low level of adoption of these programs remains a problem. Understanding the current warm-ups in youth basketball and coaches' perceptions on injury prevention can guide the design of superior implementation strategies.

Facilitators and Barriers to the Implementation of iSPRINT: A Sport Injury Prevention Program in Junior High Schools.

Objectives: Sport injury is the leading cause of hospitalization in Canadian youth and represents a high burden to the health care system. This study aims to describe the facilitators and barriers to implementation of a sport injury prevention program in junior high school physical education (known as iSPRINT), previously shown to reduce the risk of sport-related injury in youth (age, 11-15 years).

Methods: Focus group data were mapped onto constructs from the Consolidated Framework for Implementation Research (CFIR).

Implementing a junior high school-based programme to reduce sports injuries through neuromuscular training (iSPRINT): a cluster randomised controlled trial (RCT).

Objective: To evaluate the effectiveness of a junior high school-based sports injury prevention programme to reduce injuries through neuromuscular training (NMT).

Methods: This was a cluster randomised controlled trial. Students were recruited from 12 Calgary junior high schools (2014-2017).

Single-cell RNA sequencing of lung adenocarcinoma reveals heterogeneity of immune response-related genes.

Immunotherapy has emerged as a promising approach to treat cancer. However, partial responses across multiple clinical trials support the significance of characterizing intertumor and intratumor heterogeneity to achieve better clinical results and as potential tools in selecting patients for different types of cancer immunotherapies. Yet, the type of heterogeneity that informs clinical outcome and patient selection has not been fully explored.

A c-Jun N-terminal kinase inhibitor, JNK-IN-8, sensitizes triple negative breast cancer cells to lapatinib.

Triple negative breast cancers (TNBC) have poor prognosis compared to other breast cancer subtypes and represent 15-20% of breast cancers diagnosed. Unique targets and new molecularly-targeted therapies are urgently needed for this subtype. Despite high expression of Epidermal Growth Factor Receptor, inhibitors such as lapatinib have not shown therapeutic efficacy in TNBC patients.

Serotonin Analogues as Inhibitors of Breast Cancer Cell Growth.

Serotonin (5-hydroxytryptamine, 5-HT) is a critical local regulator of epithelial homeostasis in the breast and exerts its actions through a number of receptors. Dysregulation of serotonin signaling is reported to contribute to breast cancer pathophysiology by enhancing cell proliferation and promoting resistance to apoptosis. Preliminary analyses indicated that the potent 5-HT1B/1D serotonin receptor agonist 5-nonyloxytryptamine (5-NT), a triptan-like molecule, induced cell death in breast cancer cell lines.

Extracellular Matrix Stiffening Induces a Malignant Phenotypic Transition in Breast Epithelial Cells.

Tumors are much stiffer than healthy tissue, and progressively stiffen as the cancer develops. Tumor stiffening is largely the result of extracellular matrix (ECM) remodeling, for example, deposition and crosslinking of collagen I. Well established models have demonstrated the influence of the microenvironment in regulating tissue homeostasis, with matrix stiffness being a particularly influential mediator.

ATM regulation of IL-8 links oxidative stress to cancer cell migration and invasion.

Ataxia-telangiectasia mutated (ATM) protein kinase regulates the DNA damage response (DDR) and is associated with cancer suppression. Here we report a cancer-promoting role for ATM. ATM depletion in metastatic cancer cells reduced cell migration and invasion.

c-Jun N-terminal kinase 2 prevents luminal cell commitment in normal mammary glands and tumors by inhibiting p53/Notch1 and breast cancer gene 1 expression.

Breast cancer is a heterogeneous disease with several subtypes carrying unique prognoses. Patients with differentiated luminal tumors experience better outcomes, while effective treatments are unavailable for poorly differentiated tumors, including the basal-like subtype. Mechanisms governing mammary tumor subtype generation could prove critical to developing better treatments.

c-Jun N-Terminal Kinases Mediate a Wide Range of Targets in the Metastatic Cascade.

Disseminated cancer cells rely on intricate interactions among diverse cell types in the tumor-associated stroma, vasculature, and immune system for survival and growth. Ubiquitous expression of c-Jun N-terminal kinase (jnk) genes in various cell types permits their control of metastasis. In early stages of metastasis, JNKs affect tumor-associated inflammation and angiogenesis as well as tumor cell migration and intravasation.

Strategies for optimizing the serum persistence of engineered human arginase I for cancer therapy.

Systemic L-arginine depletion following intravenous administration of l-arginine hydrolyzing enzymes has been shown to selectively impact tumors displaying urea cycle defects including a large fraction of hepatocellular carcinomas, metastatic melanomas and small cell lung carcinomas. However, the human arginases display poor serum stability (t(1/2)=4.8h) whereas a bacterial arginine deiminase evaluated in phase II clinical trials was reported to be immunogenic, eliciting strong neutralizing antibody responses.

c-Jun N-terminal Kinase 2 Regulates Multiple Receptor Tyrosine Kinase Pathways in Mouse Mammary Tumor Growth and Metastasis.

c-Jun N-terminal kinase 2 (JNK2) isoforms are transcribed from the jnk2 gene and are highly homologous with jnk1 and jnk3 transcriptional products. JNK proteins mediate cell proliferation, stress response, and migration when activated by a variety of stimuli, including receptor tyrosine kinases (RTKs), but their ability to influence tumor metastasis is ill defined. To evaluate JNK2 in this manner, we used the highly metastatic 4T1.

Development of JNK2-selective peptide inhibitors that inhibit breast cancer cell migration.

Despite their lack of selectivity toward c-Jun N-terminal kinase (JNK) isoforms, peptides derived from the JIP (JNK Interacting Protein) scaffolds linked to the cell-penetrating peptide TAT are widely used to investigate JNK-mediated signaling events. To engineer an isoform-selective peptide inhibitor, several JIP-based peptide sequences were designed and tested. A JIP sequence connected through a flexible linker to either the N-terminus of an inverted TAT sequence (JIP(10)-Δ-TAT(i)) or to a poly arginine sequence (JIP(10)-Δ-R(9)) enabled the potent inhibition of JNK2 (IC(50) ≈ 90 nM) and exhibited 10-fold selectivity for JNK2 over JNK1 and JNK3.