Background & Objectives Chromatin structure is the single most important feature that distinguishes a cancer cell from a normal cell histologically. Chromatin remodeling proteins regulate chromatin structure and high mobility group A (HMGA1) proteins are among the most abundant, nonhistone chromatin remodeling proteins found in cancer cells. These proteins include HMGA1a/HMGA1b isoforms, which result from alternatively spliced mRNA. The HMGA1 gene is overexpressed in cancer and high levels portend a poor prognosis in diverse tumors. HMGA1 is also highly expressed during embryogenesis and postnatally in adult stem cells. Overexpression of HMGA1 drives neoplastic transformation in cultured cells, while inhibiting HMGA1 blocks oncogenic and cancer stem cell properties. Hmga1 transgenic mice succumb to aggressive tumors, demonstrating that dysregulated expression of HMGA1 causes cancer in vivo. HMGA1 is also required for reprogramming somatic cells into induced pluripotent stem cells. HMGA1 proteins function as ancillary transcription factors that bend chromatin and recruit other transcription factors to DNA. They induce oncogenic transformation by activating or repressing specific genes involved in this process and an HMGA1 “transcriptome” is emerging. Although prior studies reveal potent oncogenic properties of HMGA1, we are only beginning to understand the molecular mechanisms through which HMGA1 functions. In this review, we summarize the list of putative downstream transcriptional targets regulated by HMGA1. We also briefly discuss studies linking HMGA1 to Alzheimer’s disease and type-2 diabetes. Conclusion Further elucidation of HMGA1 function should lead to novel therapeutic strategies for cancer and possibly for other diseases associated with aberrant HMGA1 expression.

High mobility group A1 (HMGA1) chromatin remodeling proteins are enriched in aggressive cancers and stem cells, although their common function in these settings has remained elusive until now. Recent work in murine intestinal stem cells (ISC) revealed a novel role for Hmga1 in enhancing self-renewal by amplifying Wnt signaling, both by inducing genes expressing Wnt agonist receptors and Wnt effectors. Surprisingly, Hmga1 also "builds" a stem cell niche by upregulating , a factor required for differentiation to Paneth cells; these cells constitute an epithelial niche by secreting Wnt and other factors to support ISCs. is also highly upregulated in colon cancer compared with nonmalignant epithelium and becomes overexpressed during colon carcinogenesis. Intriguingly, is overexpressed in diverse cancers with poor outcomes, where it regulates developmental genes. Similarly, HMGA1 induces genes responsible for pluripotency and self-renewal in embryonic stem cells. These findings demonstrate that HMGA1 maintains Wnt and other developmental transcriptional networks and suggest that overexpression fosters carcinogenesis and tumor progression through dysregulation of these pathways. Studies are now needed to determine more precisely how HMGA1 modulates chromatin structure to amplify developmental genes and how to disrupt this process in cancer therapy..

Background Not all anterior cruciate ligament (ACL) injuries are preventable. While some ACL injuries are unavoidable such as those resulting from a tackle, others that occur in non-contact situations like twisting and turning in the absence of external contact might be more preventable. Because ACL injuries commonly occur in team ball-sports that involve jumping, landing and cutting manoeuvres, accurate information about the epidemiology of non-contact ACL injuries in these sports is needed to quantify their extent and burden to guide resource allocation for risk-reduction efforts. Objective To synthesize the evidence on the incidence and proportion of non-contact to total ACL injuries by sex, age, sport, participation level and exposure type in team ball-sports. Methods Six databases (MEDLINE, EMBASE, Web of Science, CINAHL, Scopus and SPORTDiscus) were searched from inception to July 2021. Cohort studies of team ball-sports reporting number of knee injuries as a function of exposure and injury mechanism were included. Results Forty-five studies covering 13 team ball-sports were included. The overall proportion of non-contact to total ACL injuries was 55% (95% CI 48–62, I2 = 82%; females: 63%, 95% CI 53–71, I2 = 84%; males: 50%, 95% CI 42–58, I2 = 86%). The overall incidence of non-contact ACL injuries was 0.07 per 1000 player-hours (95% CI 0.05–0.10, I2 = 77%), and 0.05 per 1000 player-exposures (95% CI 0.03–0.07, I2 = 97%). Injury incidence was higher in female athletes (0.14 per 1000 player-hours, 95% CI 0.10–0.19, I2 = 40%) than male athletes (0.05 per 1000 player-hours, 95% CI 0.03–0.07, I2 = 48%), and this difference was significant. Injury incidence during competition was higher (0.48 per 1000 player-hours, 95% CI 0.32–0.72, I2 = 77%; 0.32 per 1000 player-exposures, 95% CI 0.15–0.70, I2 = 96%) than during training (0.04 per 1000 player-hours, 95% CI 0.02–0.07, I2 = 63%; 0.02 per 1000 player-exposures, 95% CI 0.01–0.05, I2 = 86%) and these differences were significant. Heterogeneity across studies was generally high. Conclusion This study quantifies several key epidemiological findings for ACL injuries in team ball-sports. Non-contact ACL injuries represented over half of all ACL injuries sustained. The proportion of non-contact to total ACL injuries and injury incidence were higher in female than in male athletes. Injuries mostly occurred in competition settings.

A key hallmark of cancer, unlimited replication, requires cancer cells to evade both replicative senescence and potentially lethal chromosomal instability induced by telomere dysfunction. The majority of cancers overcome these critical barriers by upregulating telomerase, a telomere-specific reverse transcriptase. However, a subset of cancers maintains telomere lengths by the telomerase-independent Alternative Lengthening of Telomeres (ALT) pathway. The presence of ALT is strongly associated with recurrent cancer-specific somatic inactivating mutations in the ATRX-DAXX chromatin-remodeling complex. Here, we generate an ALT-positive adenocarcinoma cell line following functional inactivation of ATRX and telomerase in a telomerase-positive adenocarcinoma cell line. Inactivating mutations in ATRX were introduced using CRISPR-cas9 nickase into two prostate cancer cell lines, LAPC-4 (derived from a lymph node metastasis) and CWR22Rv1 (sourced from a xenograft established from a primary prostate cancer). In LAPC-4, but not CWR22Rv1, abolishing ATRX was sufficient to induce multiple ALT-associated hallmarks, including the presence of ALT-associated promyelocytic leukemia bodies (APB), extrachromosomal telomere C-circles, and dramatic telomere length heterogeneity. However, telomerase activity was still present in these ATRX KO cells. Telomerase activity was subsequently crippled in these LAPC-4 ATRX KO cells by introducing mutations in the TERC locus, the essential RNA component of telomerase. These LAPC-4 ATRX KO TERC mut cells continued to proliferate long-term and retained ALT-associated hallmarks, thereby demonstrating their reliance on the ALT mechanism for telomere maintenance.Implications: These prostate cancer cell line models provide a unique system to explore the distinct molecular alterations that occur upon induction of ALT, and may be useful tools to screen for ALT-specific therapies.