Emission lines due to ionizing radiation from a compact object in the remnant of Supernova 1987A.

The nearby Supernova 1987A was accompanied by a burst of neutrino emission, which indicates that a compact object (a neutron star or black hole) was formed in the explosion. There has been no direct observation of this compact object. In this work, we observe the supernova remnant with JWST spectroscopy, finding narrow infrared emission lines of argon and sulfur. The line emission is spatially unresolved and blueshifted in velocity relative to the supernova rest frame. We interpret the lines as gas illuminated by a source of ionizing photons located close to the center of the expanding ejecta. Photoionization models show that the line ratios are consistent with ionization by a cooling neutron star or a pulsar wind nebula. The velocity shift could be evidence for a neutron star natal kick.

A copper chaperone-mimetic polytherapy for SOD1-associated amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease in which motor neurons progressively and rapidly degenerate, eventually leading to death. The first protein found to contain ALS-associated mutations was copper/zinc superoxide dismutase 1 (SOD1), which is conformationally stable when it contains its metal ligands and has formed its native intramolecular disulfide. Mutations in SOD1 reduce protein folding stability via disruption of metal binding and/or disulfide formation, resulting in misfolding, aggregation, and ultimately cellular toxicity. A great deal of effort has focused on preventing the misfolding and aggregation of SOD1 as a potential therapy for ALS; however, the results have been mixed. Here, we utilize a small-molecule polytherapy of diacetylbis(N(4)-methylthiosemicarbazonato)copper(II) (CuATSM) and ebselen to mimic the metal delivery and disulfide bond promoting activity of the cellular chaperone of SOD1, the "copper chaperone for SOD1." Using microscopy with automated image analysis, we find that polytherapy using CuATSM and ebselen is highly effective and acts in synergy to reduce inclusion formation in a cell model of SOD1 aggregation for multiple ALS-associated mutants. Polytherapy reduces mutant SOD1-associated cell death, as measured by live-cell microscopy. Measuring dismutase activity via zymography and immunoblotting for disulfide formation showed that polytherapy promoted more effective maturation of transfected SOD1 variants beyond either compound alone. Our data suggest that a polytherapy of CuATSM and ebselen may merit more study as an effective method of treating SOD1-associated ALS.

Long-term efficacy and safety of addition of carboplatin with or without veliparib to standard neoadjuvant chemotherapy in triple-negative breast cancer: 4-year follow-up data from BrighTNess, a randomized phase III trial.

BACKGROUND: Primary analyses of the phase III BrighTNess trial showed addition of carboplatin with/without veliparib to neoadjuvant chemotherapy significantly improved pathological complete response (pCR) rates with manageable acute toxicity in patients with triple-negative breast cancer (TNBC). Here, we report 4.5-year follow-up data from the trial. PATIENTS AND METHODS: Women with untreated stage II-III TNBC were randomized (2 : 1 : 1) to paclitaxel (weekly for 12 doses) plus: (i) carboplatin (every 3 weeks for four cycles) plus veliparib (twice daily); (ii) carboplatin plus veliparib placebo; or (iii) carboplatin placebo plus veliparib placebo. All patients then received doxorubicin and cyclophosphamide every 2-3 weeks for four cycles. The primary endpoint was pCR. Secondary endpoints included event-free survival (EFS), overall survival (OS), and safety. Since the co-primary endpoint of increased pCR with carboplatin plus veliparib with paclitaxel versus carboplatin with paclitaxel was not met, secondary analyses are descriptive. RESULTS: Of 634 patients, 316 were randomized to carboplatin plus veliparib with paclitaxel, 160 to carboplatin with paclitaxel, and 158 to paclitaxel. With median follow-up of 4.5 years, the hazard ratio for EFS for carboplatin plus veliparib with paclitaxel versus paclitaxel was 0.63 [95% confidence interval (CI) 0.43-0.92, P = 0.02], but 1.12 (95% CI 0.72-1.72, P = 0.62) for carboplatin plus veliparib with paclitaxel versus carboplatin with paclitaxel. In post hoc analysis, the hazard ratio for EFS was 0.57 (95% CI 0.36-0.91, P = 0.02) for carboplatin with paclitaxel versus paclitaxel. OS did not differ significantly between treatment arms, nor did rates of myelodysplastic syndromes, acute myeloid leukemia, or other secondary malignancies. CONCLUSIONS: Improvement in pCR with the addition of carboplatin was associated with long-term EFS benefit with a manageable safety profile, and without increasing the risk of second malignancies, whereas adding veliparib did not impact EFS. These findings support the addition of carboplatin to weekly paclitaxel followed by doxorubicin and cyclophosphamide neoadjuvant chemotherapy for early-stage TNBC.

X-ray crystallography and computational docking for the detection and development of protein-ligand interactions.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterised by the selective dysfunction and death of the upper and lower motor neurons. Median survival rates are between 3 and 5 years after diagnosis. Mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1) have been linked to a subset of familial forms of ALS (fALS). Herein, we describe a fragment- based drug discovery (FBDD) approach for the investigation of small molecule binding sites in SOD1. X-ray crystallography has been used as the primary screening method and has been shown to directly detect protein-ligand interactions which cannot be unambiguously identified using other biophysical methods. The structural requirements for effective binding at Trp32 are detailed for a series of quinazoline-containing compounds. The investigation of an additional site that binds a range of catecholamines and the use of computational modelling to assist fragment evolution is discussed. This study also highlights the importance of ligand solubility for successful Xray crystallographic campaigns in lead compound design.

Early detection and prevention of lung cancer.

Lung cancer remains the leading cause of cancer death in the United States and is one of the world's leading causes of preventable death. Technologic advances have brought new modalities that may be useful for the early detection of lung cancer. However, because of the large number of persons at increased risk for lung cancer, screening is a formidable task. There are several risk factors that can be identified, including potential susceptibility factors, which may aid in pinpointing individuals who need to participate in regular screening programs. Aside from recognized environmental exposures including cigarette smoking, there are a number of genetic and metabolic susceptibility factors that have been examined. These include polymorphisms in the cytochrome p450 enzymes and the metabolizing capability of glutathione s-transferase or acetylation. Additionally, defects in DNA repair and in bleomycin sensitivity assays may also aid in identifying individuals who are at an increased risk for lung cancer. Additional work has been done in the area of characterizing the molecular alterations in the bronchial epithelium in high-risk smokers. This manuscript addresses only selected molecular alterations that have been examined in preneoplastic bronchial epithelium. In addition to mutations in the k-ras oncogene and the p53 gene, which are frequently seen in malignancy, alterations in the p16 gene, microsatellite instability and loss of heterozygocity are also promising potential markers of preneoplasia. The hnRNP A2/B1 gene also shows some promising increased expression in preneoplasia. Lung cancer prevention has made some strides. A number of trials with molecular and morphologic intermediate endpoints have been conducted and have suggested that some of the molecular alterations and morphologic alterations are reversible. However, the rate of spontaneous regression of these lesions is, as yet, uncharacterized. Two recent large studies, the beta-carotene and retinol efficacy trial (CARET) trial conducted in the United States and the Alpha-Tocopherol Beta Carotene (ATBC) trial conducted in Finland, both demonstrated an unexpected increased risk for lung cancer associated with beta-carotene supplementation. The EUROSCAN trial evaluation of vitamin A and N-acetylcystine also showed no benefit to supplementation in reducing risk for lung cancer. Results from the Intergroup study of 1 3-cis-retinoic acid are pending, and plans are underway for an Intergroup trial studying high selenium yeast to reduce lung cancer risk. Hopefully, the combination of identifying markers of increased risk among the numerous current and former smokers will identify high-risk populations to participate in future trials of promising agents that may lead to reduction in incidence and mortality of the leading cause of cancer death.

Comparative studies of pulsatile and nonpulsatile flow during cardiopulmonary bypass. II. The effects on adrenal secretion of cortisol.

Previous studies have indicated that a significant reduction in plasma cortisol levels occurs during nonpulsatile cardiopulmonary bypass as a result of adrenocorticol hypofunction. The Stöckert pulsatile pump system described in Part I has been employed in a comparative study of plasma cortisol levels in 20 patients subjected to pulsatile or nonpulsatile perfusion during open-heart surgery. The plasma cortisol response pattern in the nonpulsatile group was identical to the pattern previously described, with no significant rise in cortisol levels during the period of perfusion. In the pulsatile group, however, plasma cortisol levels rose significantly during perfusion, reaching a mean level at the end of perfusion which was highly significantly greater than that in the nonpulsatile group (p less than 0.001). Correction of the plasma cortisol values for the effect of hemodilution was performed and, again, corrected cortisol values indicated a highly significant increase in end-bypass levels in the pulsatile groups (p less than 0.001). These results clearly indicate that the reduction in cortisol secretion during nonpulsatile bypass may be prevented by the use of pulsatile perfusion.

Comparative studies of pulsatile and nonpulsatile flow during cardiopulmonary bypass. III. Response of anterior pituitary gland to thyrotropin-releasing hormone.

Previous studies have indicated that, during nonpulsatile cardiopulmonary bypass, the anterior pituitary gland fails to respond to the tropic stimulus of thyrotropin-releasing hormone (TRH). This is in contrast to the normal response seen during closed cardiac and general surgical procedures. The Stöckert pulsatile pump system described in Part I has been employed in a comparative study of TRH responses in 20 patients subjected to pulsatile or nonpulsatile perfusion during open-heart surgery. In the nonpulsatile group, a consistently subnormal response to TRH injection was again found. In the pulsatile group, however, the pituitary response to TRH was normal in nine patients out of 10. The quantitative difference between the groups was statistically highly significant (p less than 0.005). These results indicate that the subnormal pituitary function seen with nonpulsatile bypass may be prevented by the use of pulsatile perfusion.

Anterior pituitary response to thyrotrophin-releasing hormone during open-heart surgery.

The anterior pituitary response to thyrotrophin-releasing hormone has been studied in 20 patients submitted to elective open-heart surgical procedures, and in six control patients submitted to closed mitral valvotomy. Standard non-pulsatile normothermic perfusion was used in all the open-heart cases. 400 microgram thyrotropin-releasing hormone was administered by intravenous injection during bypass, at 30 min post-bypass, and at 60 min post-bypass. The same dose (400 microgram) was given during closed mitral valvotomy (Control Group). Thyrotrophin-releasing hormone administration during bypass failed to produce a normal response from the anterior pituitary, in contrast to the normal response pattern seen in the control group (P less than 0.01). Thyrotrophin-releasing hormone given after the period of bypass produced responses within the normal range in the majority of patients. These results suggest that anterior pituitary hypofunction may exist during the period of extracorporeal circulation using non-pulsatile perfusion and that recovery of pituitary function is evident within the first hour post-extracorporeal circulation.