Secondary somatic mutations restoring RAD51C and RAD51D associated with acquired resistance to the PARP inhibitor rucaparib in high-grade ovarian carcinoma

High-grade epithelial ovarian carcinomas (OC) containing mutated BRCA1 or BRCA2 (BRCA1/2) homologous recombination (HR) genes are sensitive to platinum-based chemotherapy and poly(ADP-ribose) polymerase inhibitors (PARPi), while restoration of HR function due to secondary mutations in BRCA1/2 has been recognized as an important resistance mechanism. We sequenced core HR pathway genes in 12 pairs of pre-treatment and post-progression tumor biopsy samples collected from patients in ARIEL2 Part 1, a phase 2 study of the PARPi rucaparib as treatment for platinum-sensitive, relapsed OC. In six of 12 pre-treatment biopsies, a truncation mutation in BRCA1, RAD51C or RAD51D was identified. In five of six paired post-progression biopsies, one or more secondary mutations restored the open reading frame. Four distinct secondary mutations and spatial heterogeneity were observed for RAD51C. In vitro complementation assays and a patient-derived xenograft (PDX), as well as predictive molecular modeling, confirmed that resistance to rucaparib was associated with secondary mutations

Order-disorder transformations in Sm–Co and Sm–Co–ZrC systems with 2-17 stoichiometry

This work investigates the order-disorder transformations utilizing time-resolved x-ray diffraction at the Advanced Photon Source. The metastable phases that can form during the order-disorder transformations in the Sm–Co intermetallics have the potential to produce materials with enhanced permanent magnetic properties. The high-temperature experiments transformed the disordered alloys with the TbCu7-type structure obtained by rapid solidification into the mixture of the hexagonal and rhombohedral ordered structures at 1375 K. The ordering process and the role of the ZrC alloying on the phase formation and ordering transformations were examined. The results showed the formation of shoulders of the fundamental peaks and superlattice peak broadening prior to complete ordering. The lattice parameters expanded linearly up to the onset of ordering, after which an abrupt change of slope was observed. The change in slope suggests a nucleation and growth mechanism for the ordering transformation. The effect of ZrC alloying promoted the formation of the disordered structure in the as-solidified state and lowered the onset of the ordering temperature

Cooperative and noncooperative magnetization reversal in alnicos

It is investigated how magnetostatic interactions affect the coercivity of alnicotype magnets. Starting from exact micromagnetic relations, we analyze two limits, namely cooperative reversal processes operative on short lengths scales and noncooperative reversal processes on long length scales. In alnicos, intrawire interactions are predominantly cooperative, whereas interwire effects are typically noncooperative. However, the transition between the regimes depends on feature size and hysteresis-loop shape, and interwire cooperative effects are largest for nearly rectangular loops. Our analysis revises the common shape-anisotropy interpretation of alnicos

Hamstring muscle-tendon geometric adaptations to resistance training using the hip extension and Nordic hamstring exercises

Targeted resistance training stimulates hamstring muscle hypertrophy, but its effect on tendon-aponeurosis geometry is unknown. This study examined changes in hamstring muscle, free tendon, and aponeurosis geometry following a 10?week Nordic or hip extension exercise intervention. Thirty recreationally active males were randomly allocated (n?=?10 per group) to a Nordic, hip extension, or control group. Magnetic resonance imaging of both thighs was acquired pre- and post-intervention. Changes in free tendon and aponeurosis volume for each hamstring muscle, biceps femoris long head (BFlh) aponeurosis interface area and muscle volume-to-interface area ratio were compared between groups. Regional changes in muscle CSA were examined via statistical parametric mapping. The change in semimembranosus free tendon volume was greater for the Nordic than control group (mean difference?=?0.06?cm3, 95% CI?=?0.02?0.11?cm3). No significant between-group differences existed for other hamstring free tendons or aponeuroses. There were no between-group differences in change in BFlh interface area. Change in BFlh muscle volume-to-interface area ratio was greater in the hip extension than Nordic (mean difference?=?0.10, 95% CI?=?0.007?0.19, p?=?0.03) and control (mean difference?=?0.12, 95% CI?=?0.03?0.22, p?=?0.009) groups. Change in muscle CSA following training was greatest in the mid-portion of semitendinosus for both intervention groups, and the mid-portion of BFlh for the hip extension group. There was limited evidence for tendon-aponeurosis hypertrophy after 10?weeks of training with the Nordic or hip extension exercises. For the BFlh, neither intervention altered the interface area although hip extension training stimulated an increase in the muscle volume-to-interface area ratio, which may have implications for localized tissue strains. Alternative muscle-tendon loading strategies appear necessary to stimulate hamstring tendon adaptations

Texture development and coercivity enhancement in cast alnico 9 magnets

The effect of Y addition and magnetic field on texture and magnetic properties of arc-melted alnico 9 magnets has been investigated. Small additions of Y (1.5 wt.%) develop a (200) texture for the arc-melted alnico 9 magnet. Such a texture is hard to form in cast samples. To achieve this goal, we set up a high-field annealing system with a maximum operation temperature of 12500 C. This system enabled annealing in a field of 45 kOe with subsequent draw annealing for the solutionized buttons; we have been able to substantially increase remanence ratio and coercivity, from 0.70 and 1200 Oe for the Y-free alnico 0 to 0.90 and 1400 Oe for the Y-doped alnico 9, respectively. A high energy product of 7.3 MGOe has been achieved for the fully heat-treated Y-doped alnico 9. The enhancement of coercvity is believed to arise from the introduction of magnetocrystalline anisotropy from 80 nm Y2Co17- type grains, which are exchange-coupled to the main-phase alnico rods

Four consecutive yearly point-prevalence studies in Wales indicate lack of improvement in sepsis care on the wards

The ‘Sepsis Six’ bundle was promoted as a deliverable tool outside of the critical care settings, but there is very little data available on the progress and change of sepsis care outside the critical care environment in the UK. Our aim was to compare the yearly prevalence, outcome and the Sepsis Six bundle compliance in patients at risk of mortality from sepsis in non-intensive care environments. Patients with a National Early Warning Score (NEWS) of 3 or above and suspected or proven infection were enrolled into four yearly 24-h point prevalence studies, carried out in fourteen hospitals across Wales from 2016 to 2019. We followed up patients to 30 days between 2016–2019 and to 90 days between 2017 and 2019. Out of the 26,947 patients screened 1651 fulfilled inclusion criteria and were recruited. The full ‘Sepsis Six’ care bundle was completed on 223 (14.0%) occasions, with no significant difference between the years. On 190 (11.5%) occasions none of the bundle elements were completed. There was no significant correlation between bundle element compliance, NEWS or year of study. One hundred and seventy (10.7%) patients were seen by critical care outreach; the ‘Sepsis Six’ bundle was completed significantly more often in this group (54/170, 32.0%) than for patients who were not reviewed by critical care outreach (168/1385, 11.6%; p < 0.0001). Overall survival to 30 days was 81.7% (1349/1651), with a mean survival time of 26.5 days (95% CI 26.1–26.9) with no difference between each year of study. 90-day survival for years 2017–2019 was 74.7% (949/1271), with no difference between the years. In multivariate regression we identified older age, heart failure, recent chemotherapy, higher frailty score and do not attempt cardiopulmonary resuscitation orders as significantly associated with increased 30-day mortality. Our data suggests that despite efforts to increase sepsis awareness within the NHS, there is poor compliance with the sepsis care bundles and no change in the high mortality over the study period. Further research is needed to determine which time-sensitive ward-based interventions can reduce mortality in patients with sepsis and how can these results be embedded to routine clinical practice

Polycystic Kidney Disease with Hyperinsulinemic Hypoglycemia Caused by a Promoter Mutation in Phosphomannomutase 2

Hyperinsulinemic hypoglycemia (HI) and congenital polycystic kidney disease (PKD) are rare, genetically heterogeneous disorders. The co-occurrence of these disorders (HIPKD) in 17 children from 11 unrelated families suggested an unrecognized genetic disorder. Whole-genome linkage analysis in five informative families identified a single significant locus on chromosome 16p13.2 (logarithm of odds score 6.5). Sequencing of the coding regions of all linked genes failed to identify biallelic mutations. Instead, we found in all patients a promoter mutation (c.-167G&gt;T) in the phosphomannomutase 2 gene (PMM2), either homozygous or in trans with PMM2 coding mutations. PMM2 encodes a key enzyme in N-glycosylation. Abnormal glycosylation has been associated with PKD, and we found that deglycosylation in cultured pancreatic β cells altered insulin secretion. Recessive coding mutations in PMM2 cause congenital disorder of glycosylation type 1a (CDG1A), a devastating multisystem disorder with prominent neurologic involvement. Yet our patients did not exhibit the typical clinical or diagnostic features of CDG1A. In vitro, the PMM2 promoter mutation associated with decreased transcriptional activity in patient kidney cells and impaired binding of the transcription factor ZNF143. In silico analysis suggested an important role of ZNF143 for the formation of a chromatin loop including PMM2. We propose that the PMM2 promoter mutation alters tissue-specific chromatin loop formation, with consequent organ-specific deficiency of PMM2 leading to the restricted phenotype of HIPKD. Our findings extend the spectrum of genetic causes for both HI and PKD and provide insights into gene regulation and PMM2 pleiotropy.</p

Eccentric knee-flexor strength and risk of hamstring injuries in Rugby Union: A prospective study

BACKGROUND Hamstring strain injuries (HSIs) represent the most common cause of lost playing time in rugby union. Eccentric knee-flexor weakness and between-limb imbalance in eccentric knee-flexor strength are associated with a heightened risk of hamstring injury in other sports; however these variables have not been explored in rugby union. PURPOSE To determine if lower levels of eccentric knee-flexor strength or greater between-limb imbalance in this parameter during the Nordic hamstring exercise are risk-factors for hamstring strain injury in rugby union. STUDY DESIGN Cohort study; level of evidence, 3. METHODS This prospective study was conducted over the 2014 Super Rugby and Queensland Rugby Union seasons. In total, 178 rugby union players (age, 22.6 ± 3.8 years; height, 185 ± 6.8 cm; mass, 96.5 ± 13.1 kg) had their eccentric knee-flexor strength assessed using a custom-made device during the pre-season. Reports of previous hamstring, quadriceps, groin, calf and anterior cruciate ligament injury were also obtained. The main outcome measure was prospective occurrence of hamstring strain injury. RESULTS Twenty players suffered at least one hamstring strain during the study period. Players with a history of hamstring strain injury had 4.1 fold (RR = 4.1, 95% CI = 1.9 to 8.9, p = 0.001) greater risk of subsequent hamstring injury than players without such history. Between-limb imbalance in eccentric knee-flexor strength of ≥ 15% and ≥ 20% increased the risk of hamstring strain injury 2.4 fold (RR = 2.4, 95% CI = 1.1 to 5.5, p = 0.033) and 3.4 fold (RR = 3.4, 95% CI = 1.5 to 7.6, p = 0.003), respectively. Lower eccentric knee flexor strength and other prior injuries were not associated with increased risk of future hamstring strain. Multivariate logistic regression revealed that the risk of re-injury was augmented in players with strength imbalances. CONCLUSION Previous hamstring strain injury and between-limb imbalance in eccentric knee-flexor strength were associated with an increased risk of future hamstring strain injury in rugby union. These results support the rationale for reducing imbalance, particularly in players who have suffered a prior hamstring injury, to mitigate the risk of future injury