BACKGROUND Previous studies have suggested injury to the anterior talofibular ligament may be linked to altered kinematics and the development of osteoarthritis of the ankle joint. However, the effects of ATFL injury on the in vivo kinematics of the ankle joint are unclear. HYPOTHESIS Based on the orientation of the ATFL fibers, we hypothesized that ATFL deficiency would lead to increased anterior translation and increased internal rotation of the talus relative to the tibia. STUDY DESIGN Controlled laboratory study. METHODS The ankles of 9 patients with unilateral ATFL injuries were compared as they stepped onto a level surface. Kinematic measurements were made as a function of increasing load. Using magnetic resonance imaging and orthogonal fluoroscopy, the in vivo kinematics of the tibiotalar joint were measured in the ATFL deficient and intact ankles from the same individuals. RESULTS A statistically significant increase in internal rotation, anterior translation, and superior translation of the talus was measured in ATFL deficient ankles as compared to intact, contralateral controls. For example, at 100% body weight, ATFL deficient ankles demonstrated a statistically significant increase in anterior translation of 0.9 ± 0.5mm (p = 0.008). At 100% body weight, the ATFL deficient ankle was internally rotated relative to the intact ankle by 5.7 ± 3.6° (p = 0.008). There was a slight increase of 0.2 ± 0.2mm in the superior translation of the ATFL deficient ankle compared to the intact ankle at 100% body weight (p = 0.02). CONCLUSIONS ATFL deficiency increases anterior translation, internal rotation, and superior translation of the talus. CLINICAL RELEVANCE Altered kinematics may contribute to the degenerative changes observed with chronic lateral ankle instability. These findings might help to explain the degenerative changes frequently observed on the medial talus in patients with chronic ATFL insufficiency and provide a baseline for improving ankle ligament reconstructions aimed at restoring normal joint motion.

Cyclin-dependent kinase-like 5 (CDKL5) deficiency is a neurodevelopmental disorder characterized by epileptic seizures, severe intellectual disability, and autistic features. Mice lacking CDKL5 display multiple behavioral abnormalities reminiscent of the disorder, but the cellular origins of these phenotypes remain unclear. Here, we find that ablating CDKL5 expression specifically from forebrain glutamatergic neurons impairs hippocampal-dependent memory in male conditional knock-out mice. Hippocampal pyramidal neurons lacking CDKL5 show decreased dendritic complexity but a trend toward increased spine density. This morphological change is accompanied by an increase in the frequency of spontaneous miniature EPSCs and interestingly, miniature IPSCs. Using voltage-sensitive dye imaging to interrogate the evoked response of the CA1 microcircuit, we find that CA1 pyramidal neurons lacking CDKL5 show hyperexcitability in their dendritic domain that is constrained by elevated inhibition in a spatially and temporally distinct manner. These results suggest a novel role for CDKL5 in the regulation of synaptic function and uncover an intriguing microcircuit mechanism underlying impaired learning and memory.

Mammalian sirtuin 1 (SIRT1) has connected to an ever widening circle of activities that encompass cellular stress resistance, energy metabolism and tumorigenesis. However, underlying mechanisms leading to oncogenic SIRT1 overexpression are less understood. In this study, we identified SIRT1 regulatory microRNA (miRNA) and its function in hepatocellular carcinoma (HCC). Aberrant SIRT1 overexpression was demonstrated in a subset of human HCCs. SIRT1 knockdown suppressed HCC cell growth by transcriptional deregulation of cell cycle proteins. This led to hypophosphorylation of pRb, which inactivated E2F/DP1 target gene transcription, and thereby caused significant increase of HCC cells to remain in the G1/S phase. A comprehensive miRNA profiling analysis indentified five putative endogenous miRNAs that are significantly downregulated in HCC. Ectopic expression of miRNA mimics evidenced miR-29c to suppress SIRT1 in HCC cells. Notably, ectopic miR-29c expression repressed cancer cell growth and proliferation, and it recapitulated SIRT1 knockdown effects in HCC cells. In addition, miR-29c expression was downregulated in a large cohort of HCC patients, and low expression of miR-29c was significantly associated with poor prognosis of HCC patients. Taken together, we demonstrated that miR-29c suppresses oncogenic SIRT1 by way of binding to 3'-untranslated region of SIRT1 mRNA causing translational inhibition in liver cancer cells. The loss or suppression of miR-29c may cause aberrant SIRT1 overexpression and promotes liver tumorigenesis. Overall, we suggest that miR-29c functions as a tumor suppressor by regulating abnormal SIRT1 activity in liver.

Fas, a cell surface receptor and member of the tumour necrosis factor receptor superfamily, induces apoptosis upon oligomerization by its ligand (Fas ligand: FasL). Detailed studies have revealed that Fas is broadly expressed in normal human tissues, but relatively little is known about the range of cell types capable of expressing FasL. The aim of this study was to determine the in vivo patterns of expression of Fas and FasL in human skin tissues. Immunohistochemistry was performed using paraffin-embedded samples of normal and neoplastic skin tissues. In normal skin, FasL was expressed in the epidermis, sebaceous glands, sweat glands and outer root sheath of the hair. In squamous cell carcinomas (SCC), all cases analysed expressed FasL at high levels, whereas 60% of basal cell carcinomas (BCC) were positive for FasL. Expression of Fas in normal skin was observed in the basal and spinous layers of the epidermis, the outer root sheath of the hair, and the sebaceous glands. Expression of Fas was observed in all the SCC tested and none of the BCC tested. Expression of FasL by normal cells and tumour cells in skin tissue, demonstrated for the first time in the present study, may provide an important clue to understanding skin physiology, and immune evasion of skin tumours.

BackgroundObesity is associated with an increased risk of breast cancer recurrence and cancer death. Recurrent cancers arise from the pool of residual tumor cells, or minimal residual disease (MRD), that survives primary treatment and persists in the host. Whether the association of obesity with recurrence risk is causal is unknown, and the impact of obesity on MRD and breast cancer recurrence has not been reported in humans or in animal models.MethodsDoxycycline-inducible primary mammary tumors were generated in intact MMTV-rtTA;TetO-HER2/neu (MTB/TAN) mice or orthotopic recipients fed a high-fat diet (HFD; 60% kcal from fat) or a control low-fat diet (LFD; 10% kcal from fat). Following oncogene downregulation and tumor regression, mice were followed for clinical recurrence. Body weight was measured twice weekly and used to segregate HFD mice into obese (i.e., responders) and lean (i.e., nonresponders) study arms, and obesity was correlated with body fat percentage, glucose tolerance (measured using intraperitoneal glucose tolerance tests), serum biomarkers (measured by enzyme-linked immunosorbent assay), and tissue transcriptomics (assessed by RNA sequencing). MRD was quantified by droplet digital PCR.ResultsHFD-Obese mice weighed significantly more than HFD-Lean and LFD control mice (p < 0.001) and had increased body fat percentage (p < 0.001). Obese mice exhibited fasting hyperglycemia, hyperinsulinemia, and impaired glucose tolerance, as well as decreased serum levels of adiponectin and increased levels of leptin, resistin, and insulin-like growth factor 1. Tumor recurrence was accelerated in HFD-Obese mice compared with HFD-Lean and LFD control mice (median relapse-free survival 53.0 days vs. 87.0 days vs. 80.0 days, log-rank p < 0.001; HFD-Obese compared with HFD-Lean HR 2.52, 95% CI 1.52–4.16; HFD-Obese compared with LFD HR 2.27, 95% CI 1.42–3.63). HFD-Obese mice harbored a significantly greater number of residual tumor cells than HFD-Lean and LFD mice (12,550 ± 991 vs. 7339 ± 2182 vs. 4793 ± 1618 cells, p < 0.001).ConclusionThese studies provide a genetically engineered mouse model for study of the association of diet-induced obesity with breast cancer recurrence. They demonstrate that this model recapitulates physiological changes characteristic of obese patients, establish that the association between obesity and recurrence risk is causal in nature, and suggest that obesity is associated with the increased survival and persistence of residual tumor cells.Electronic supplementary materialThe online version of this article (10.1186/s13058-018-1087-7) contains supplementary material, which is available to authorized users.