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We aimed to determine whether the anatomical location (intramuscular tendon or T-Junction) of hamstring muscle injuries in professional men's rugby union associates with a prolonged time to return to full training and a higher rate of re-injury/subsequent injury. We reviewed the medical records of an Irish professional rugby union club to identify hamstring muscle injuries incurred across five seasons. Clinicians and players were not blinded to MRI results at the time of rehabilitation. A blinded musculoskeletal radiologist re-classified all included injuries (n = 91) according to the British Athletics Muscle Injury Classification framework. Players who sustained an injury with intramuscular tendon involvement required a longer time to return to full training compared to players who sustained an injury without intramuscular tendon involvement (78 days vs. 24 days). Players who sustained a biceps femoris injury with T-junction involvement did not require a longer time to return to full training compared to players who sustained a biceps femoris injury without T-junction involvement (29 days vs. 27 days). Injuries with either intramuscular tendon or T-junction involvement were not associated with an increased rate of re-injury/subsequent injury to the same limb (intramuscular tendon involvement - odds ratio = 0.96, T-junction involvement - odds ratio = 1.03). When a hamstring muscle injury involves the intramuscular tendon, the injured player and stakeholders should be made aware that a longer time to return to full training is likely required. T-junction involvement does not alter the expected clinical course of biceps femoris injuries.

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Hamstring strain injuries (HSI) are one of the most common sport-related injuries. They have a high injury burden and a high recurrence rate. The development of novel muscle injury grading systems has provided new insights into the possible impact of injury location on the time to return to play (TTRTP) and re-injury following HSI. In particular, injuries to the intramuscular tendon (IMT) may be present in up to 41% of all HSI and have been described as a 'serious thigh muscle strain'. Re-injury rates as high as 60% have been described in elite track and field athletes, as well as prolonged TTRTP. A systematic search was carried out using appropriate keywords to identify articles reporting on HSI involving the IMT in athletes. The primary aim was to determine whether IMT injuries warrant being classified as a distinct clinical entity with different expected outcomes to other hamstring muscle injuries. This narrative review summarises the existing evidence on: (1) the anatomy of the IMT and its response to injury; (2) the role of MRI and novel grading scales in IMT injury management (3) clinical assessment of IMT injuries, (4) TTRTP and re-injury rates across sports following IMT, (5) conservative rehabilitation and the role of specific 'IMT-oriented' strategies, and (6) indications for and approaches to surgery. The review found that important clinical outcomes such as re-injury rates and TTRTP vary across populations, cohorts and sports which suggest that outcomes are specific to the sporting context. Bespoke rehabilitation, tailored to IMT injury, has been shown to significantly reduce re-injuries in elite track and field athletes, without compromising TTRTP. Continued prospective studies across other sports and cohorts, are warranted to further establish relevant clinical findings, indications for surgical intervention and outcomes across other sporting cohorts.

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Fragment-based drug discovery (FBDD) has come of age in the last decade with the FDA approval of four fragment-derived drugs. Biophysical methods are at the heart of hit discovery and validation in FBDD campaigns. The three most commonly used methods, thermal shift, surface plasmon resonance, and nuclear magnetic resonance, can be daunting for the novice user. We aim here to provide the nonexpert user of these methods with a summary of problems and challenges that might be faced, but also highlight the potential gains that each method can contribute to an FBDD project. While our view on FBDD is slightly biased toward enabling structure-guided drug discovery, most of the points we address in this review are also valid for non-structure-focused FBDD.

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Proteins of the NSD family are histone-methyl transferases with critical functions in the regulation of chromatin structure and function. NSD1 and NSD2 are homologous proteins that function as epigenetic regulators of transcription through their abilities to catalyse histone methylation. Misregulation of NSD1 and NSD2 expression or mutations in their genes are linked to a number of human diseases such as Sotos syndrome, and cancers including acute myeloid leukemia, multiple myeloma, and lung cancer. The catalytic domain of both proteins contains a conserved SET domain which is involved in histone methylation. Here we report the backbone resonance assignments and secondary structure information of the catalytic domains of human NSD1 and NSD2.

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Harvey Ras (H-Ras) is a membrane-associated GTPase with critical functions in cell proliferation and differentiation. The G12V mutant of H-Ras is one of the most commonly encountered oncoproteins in human cancer. This mutation disrupts the GTPase activity of H-Ras, leading to constitutive activation and aberrant downstream signalling. Here we report the backbone resonance assignments of human H-Ras mutant G12V lacking the C-terminal membrane attachment domain.

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BACKGROUND: Despite limitations of routine methods, Clinical Practice Guidelines support the assessment of bone mineral density (BMD) and vascular calcification in renal transplant recipients. Changes in fat mass also occur post-transplantation, although they are traditionally difficult to measure accurately. We report the feasibility, convenience and accuracy of measuring the above 3 parameters using a novel CT protocol. METHODS: We conducted a cross-sectional study of 64 first renal allograft recipients (eGFR > 30 ml/min/1.73 m(2)). Quantitative CT (QCT) BMD analysis was conducted using CT lumbar spine (GE Medical Systems Lightspeed VCT & Mindways QCT Pro Bone Mineral Densitometry System Version 4.2.3) to calculate spinal volumetric BMD and compared with standard DXA calculated areal BMD at the spine, hip and distal forearm. Abdominal aortic calcification was assessed by semi-quantitative Aortic Calcification Index (ACI) method and compared with lateral lumbar x-ray Kappuila score and pulse wave velocity (PWV). Visceral and subcutaneous adipose tissue volume (Osirix 16 Ver 3.7.1) was compared with BMI. RESULTS: Participants were 61 % male, had a mean age of 47 years, median ESKD duration of 5.4 years and a mean eGFR of 54 ml/min. iDXA median T-score at proximal femur was -1.2 and at lumbar spine was -0.2. Median QCT Trabecular T-score at lumbar spine was -1.2. The percent of subjects with a T-score of < 2.5 by site and method was DXA Proximal Femur: 7 %, DXA distal radius: 17 %, DXA spine: 9 %, QCT (American College of Radiology cutoffs): 9 %. CT derived ACI correlated with PWV (r = 0.29, p = 0.02), pulse wave pressure (r = 0.51, p < 0.001), QCT Trabecular (-0.31, p = 0.01) and cortical volumetric BMD and history of cardiovascular events (Mann-Whitney U, p = 0.02). Both visceral and subcutaneous adipose tissue correlated with BMI (r = 0.63 & 0.64, p < 0.001). CONCLUSIONS: Single CT scan triple assessment of BMD, vascular calcification and body composition is an efficient, accurate and convenient method of risk factor monitoring post renal transplantation.

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BACKGROUND: Low back pain is one of the most prevalent musculoskeletal conditions in the world. Many exercise treatment options exist but few interventions have utilised free-weight resistance training. To investigate the effects of a free-weight-based resistance training intervention on pain and lumbar fat infiltration in those with chronic low back pain. METHODS: Thirty participants entered the study, 11 females (age=39.6±12.4 years, height=164 cm±5.3 cm, body mass=70.9±8.2 kg,) and 19 males (age=39.7±9.7 years, height=179±5.9 cm, body mass=86.6±15.9 kg). A 16-week, progressive, free-weight-based resistance training intervention was used. Participants completed three training sessions per week. Participants completed a Visual Analogue Pain Scale, Oswestry Disability Index and Euro-Qol V2 quality of life measure at baseline and every 4 weeks throughout the study. Three-dimensional kinematic and kinetic measures were used for biomechanical analysis of a bodyweight squat movement. Maximum strength was measured using an isometric mid-thigh pull, and lumbar paraspinal endurance was measured using a Biering-Sorensen test. Lumbar paraspinal fat infiltration was measured preintervention and postintervention using MRIs. RESULTS: Postintervention pain, disability and quality of life were all significantly improved. In addition, there was a significant reduction in fat infiltration at the L3L4 and L4L5 levels and increase in lumbar extension time to exhaustion of 18%. CONCLUSIONS: A free-weight-based resistance training intervention can be successfully utilised to improve pain, disability and quality of life in those with low back pain.

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OBJECTIVE: To quantify cumulative exposure to ionizing radiation in patients with end stage kidney disease (ESKD). To investigate factors which may be independently associated with risk of high cumulative effective dose (CED). MATERIALS AND METHODS: The study had local institutional review board ethical approval. We conducted a retrospective study of 394 period prevalent ESKD patients attending a single tertiary referral centre between 2004 and 2009. Patient demographics were obtained from case records. Details of radiological investigations were obtained from the institutional radiology computerized database. CED was calculated using standard procedure specific radiation levels. High exposure was defined as CED > 50 mSv, an exposure which has been reported to increase cancer mortality by 5%. Data were compared using Pearson χ(2) and Mann-Whitney U test or Kruskal-Wallis tests. RESULTS: 394 patients were followed for a median of 4 years (1518 patient years follow-up). Of these 63% were male. Seventeen percent of patients had a CED of >50 mSv. Computed tomography (CT) accounted for 9% of total radiological studies/procedures while contributing 61.4% of total study dose. Median cumulative dose and median dose per patient year were significantly higher in the hemodialysis (HD) group (15.13 and 5.79 mSv, respectively) compared to the post-transplant group (2.9 and 0.52 mSv, respectively) (P < 0.001). CONCLUSION: ESKD patients are at risk of cumulative exposure to significant levels of diagnostic radiation. The majority of this exposure is imparted as a result of CT examinations to patients in the HD group.

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A ubiquitously expressed chaperone, heat shock protein 90 (HSP90) is of considerable interest as an oncology target because tumor cells and oncogenic proteins are acutely dependent on its activity. AT13387 (2,4-dihydroxy-5-isopropyl-phenyl)-[5-(4-methyl-piperazin-1-ylmethyl)-1,3-dihydro-isoindol-2-yl] methanone, l-lactic acid salt) a novel, high-affinity HSP90 inhibitor, which is currently being clinically tested, has shown activity against a wide array of tumor cell lines, including lung cancer cell lines. This inhibitor has induced the degradation of specific HSP90 client proteins for up to 7 days in tumor cell lines in vitro. The primary driver of cell growth (mutant epidermal growth factor receptors) was particularly sensitive to HSP90 inhibition. The long duration of client protein knockdown and suppression of phospho-signaling seen in vitro after treatment with AT13387 was also apparent in vivo, with client proteins and phospho-signaling suppressed for up to 72 h in xenograft tumors after treatment with a single dose of AT13387. Pharmacokinetic analyses indicated that while AT13387 was rapidly cleared from blood, its retention in tumor xenografts was markedly extended, and it was efficacious in a range of xenograft models. AT13387's long duration of action enabled, in particular, its efficacious once weekly administration in human lung carcinoma xenografts. The use of longer-acting HSP90 inhibitors, such as AT13387, on less frequent dosing regimens has the potential to maintain antitumor efficacy as well as minimize systemic exposure and unwanted effects on normal tissues.

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Hemodialysis is associated with an increased risk of neoplasms which may result, at least in part, from exposure to ionizing radiation associated with frequent radiographic procedures. In order to estimate the average radiation exposure of those on hemodialysis, we conducted a retrospective study of 100 patients in a university-based dialysis unit followed for a median of 3.4 years. The number and type of radiological procedures were obtained from a central radiology database, and the cumulative effective radiation dose was calculated using standardized, procedure-specific radiation levels. The median annual radiation dose was 6.9 millisieverts (mSv) per patient-year. However, 14 patients had an annual cumulative effective radiation dose over 20 mSv, the upper averaged annual limit for occupational exposure. The median total cumulative effective radiation dose per patient over the study period was 21.7 mSv, in which 13 patients had a total cumulative effective radiation dose over 75 mSv, a value reported to be associated with a 7% increased risk of cancer-related mortality. Two-thirds of the total cumulative effective radiation dose was due to CT scanning. The average radiation exposure was significantly associated with the cause of end-stage renal disease, history of ischemic heart disease, transplant waitlist status, number of in-patient hospital days over follow-up, and death during the study period. These results highlight the substantial exposure to ionizing radiation in hemodialysis patients.

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INTRODUCTION: Residual appendicitis involving the stump of the appendix has been well described in the literature in the past. CASE REPORT: We report the case of a 43 year old male with acute onset of abdominal pain who had undergone an appendicectomy ten years previously. Ultrasound revealed the presence of an inflamed tubular structure. Subsequent laparotomy and histology confirmed that this structure was an inflamed residual appendiceal tip. CONCLUSION: Residual tip appendicitis has not been reported in the literature previously and should be considered in the differential diagnosis of localised peritonitis in a patient with a history of a previous open appendicectomy.

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The cyclin D1-cyclin-dependent kinase 4 (CDK4) complex is a key regulator of the transition through the G(1) phase of the cell cycle. Among the cyclin/CDKs, CDK4 and cyclin D1 are the most frequently activated by somatic genetic alterations in multiple tumor types. Thus, aberrant regulation of the CDK4/cyclin D1 pathway plays an essential role in oncogenesis; hence, CDK4 is a genetically validated therapeutic target. Although X-ray crystallographic structures have been determined for various CDK/cyclin complexes, CDK4/cyclin D1 has remained highly refractory to structure determination. Here, we report the crystal structure of CDK4 in complex with cyclin D1 at a resolution of 2.3 A. Although CDK4 is bound to cyclin D1 and has a phosphorylated T-loop, CDK4 is in an inactive conformation and the conformation of the heterodimer diverges from the previously known CDK/cyclin binary complexes, which suggests a unique mechanism for the process of CDK4 regulation and activation.

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