Multi-Material Processing By Lens

During the past few years, solid freeform fabrication has evolved into direct fabrication of metallic components using computer aided design (CAD) solid models. [1-4] Laser Engineered Net Shaping (LENS™) is one such technique [5-7] being developed at Sandia to fabricate high strength, near net shape metallic components. In the past two years a variety of components have been fabricated using LENS™ for applications ranging from prototype parts to injection mold tooling. [8] To advance direct fabrication capabilities, a process must be able to accommodate a wide range ofmaterials, including alloys and composites. This is important for tailoring certain physical properties critical to component performance. Examples include graded deposition for matching coefficient ofthermal expansion between dissimilar materials, layered fabrication for novel mechanical properties, and new alloy design where elemental constituents and/or alloys are blended to create new materials. In this paper, we will discuss the development ofprecise powder feeding capabilities for the LENSTM process to fabricate graded or layered material parts. We also present preliminary results from chemical and microstructural analysis.Mechanical Engineerin

Thermal Behavior in the Lens Process

Direct laser metal deposition processing is a promising manufacturing technology which could significantly impact the length oftime between initial concept and finished part. For adoption ofthis technology in the manufacturing environment, further understanding is required to ensure robust components with appropriate properties are routinelyfabricated. This requires a complete understanding ofthe thermal history.during part fabrication and control ofthis behavior. This paper will describe our research to understand the thermal behavior for the Laser Engineered Net Shaping (LENS) process!, where a component is fabricated by focusing a laser beam onto a substrate to create a molten pool in which powder particles are simultaneously injected to build each layer. The substrate is moved beneath the l~ser beam to deposit a thin cross section, thereby creating the desired geometry for each layer. After deposition of each layer, the powder delivery nozzle and focusing lens assembly is incremented in the positive Z-direction, thereby building a three dimensional component layer additively. It is important to control the thermal behavior to reproducibly fabricate parts. The ultimate intent is to monitor the thermal signatures and to incorporate sensors and feedback algorithms to control part fabrication. With appropriate control, the geometric properties (accuracy, surface finish, low warpage) as well as the materials' properties (e.g. strength, ductility) of a component can be dialed into the part through the fabrication parameters. Thermal monitoring techniques will be described, and their particular benefits highlighted. Preliminary details in correlating thermal behavior with processing results will be discussed.Mechanical Engineerin

Individuals with presumably hereditary uveal melanoma do not harbour germline mutations in the coding regions of either the P16INK4A, P14ARF or cdk4 genes

In familial cutaneous malignant melanoma (CMM), disruption of the retinoblastoma (pRB) pathway frequently occurs through inactivating mutations in the p16 (p16INK4A/CDKN2A/MTS1) gene or activating mutations in the G1-specific cyclin dependent kinase 4 gene (CDK4). Uveal malignant melanoma (UMM) also occurs in a familial setting, or sometimes in association with familial or sporadic CMM. Molecular studies of sporadic UMM have revealed somatic deletions covering the INK4A-ARF locus (encoding P16INK4Aand P14ARF) in a large proportion of tumours. We hypothesized that germline mutations in the p16INK4A, p14ARFor CDK4 genes might contribute to some cases of familial UMM, or to some cases of UMM associated with another melanoma. Out of 155 patients treated at the Institut Curie for UMM between 1994 and 1997, and interviewed about their personal and familial history of melanoma, we identified seven patients with a relative affected with UMM (n = 6) or CMM (n = 1), and two patients who have had, in addition to UMM, a personal history of second melanoma, UMM (n = 1), or CMM (n = 1). We screened by polymerase chain reaction single-strand conformation polymorphism the entire coding sequence of the INK4A-ARF locus (exon 1α from p16INK4A, exon 1β from p14ARF, and exons 2 and 3, common to both genes), as well as the exons 2, 5 and 8 of the CDK4 gene, coding for the functional domains involved in p16 and/or cyclin D1 binding. A previously reported polymorphism in exon 3 of the INK4A-ARF locus was found in one patient affected with bilateral UMM, but no germline mutations were detected, either in the p16INK4A, p14ARFor CDK4 genes. Our data support the involvement of other genes in predisposition to uveal melanoma. © 2000 Cancer Research Campaig

Incidence of angioedema after initiation of angiotensin-converting enzyme inhibitors in adults with heart failure

Background: Angioedema, a potentially life-threatening adverse event associated with angiotensin-converting enzyme inhibitor (ACEI) use, occurs more often among Black patients than non-Black patients. Specific angioedema incidence rates (IRs) among heart failure (HF) patients initiating an ACEI are limited. Objectives: To provide estimates of angioedema incidence among HF patients initiating an ACEI, particularly among Black patients. Methods: We conducted a retrospective cohort study among adult (≥18 years) patients with HF who initiated ACEI use at 5 health care delivery systems within the Cardiovascular Research Network between July 2015 and May 2019. We required patients to have ≥12 months of continuous medical and prescription drug coverage and no ACEI dispensings in the 1 year before treatment initiation. Our primary outcome was serious angioedema, defined as a primary or secondary diagnosis of ICD-9 code 995.1 (‘Angioneurotic edema not elsewhere classified’) or ICD-10 codes in the T78.3 series (‘Angioneurotic edema’) during hospitalization. Our secondary out-come was ‘any angioedema’, which included serious angioedema and non-serious angioedema that was diagnosed in the outpatient setting. We followed patients from ACEI initiation until first angioedema diagnosis or a censoring event (treatment discontinuation, initiation of another renin-angiotensin-aldosterone system blocking agent, disenrollment, death, or end of 365-day follow-up or study). We calculated crude IRs and exact 95% confidence intervals (CI) for angioedema among HF patients initiating an ACEI. Results: We identified 14 ,241 ACEI users, of which 6,156 (43 .2%)were women and 2,105 (15%) were self-reported Black. Mean age was 70 ± 14 years. We observed 6 serious angioedema events overall (IR: 0.8/1,000 person-years (PYs), 95% CI: 0.3-1.7), with 2 events occurring among Black patients (IR: 1.8/1,000 PYs, 95%CI: 0.2-6.5) and 4 events among non-Black patients (IR: 0.6/1,000PYs, 95% CI: 0.2-1.5). We observed 43 angioedema events overall (IR: 5.4/1,000 PYs, 95% CI: 3.9-7.3), with 21 events occurring among Black patients (IR: 19/1,000 PYs, 95% CI: 11.8-29.1) and 22 events among non-Black patients (IR: 3.2/1,000 PYs, 95%CI: 2.0-4.9). Conclusions: Our estimate of angioedema incidence among HF patients who initiated an ACEI (5.4 events/1,000 PYs) is slightly higher than a previously published estimate (3.3/1,000 PYs) among a similarly-defined population identified through administrative claims data. Similar to prior reports, we found a higher incidence of angioedema, both serious and non-serious, among Black ACEI users than among non-black ACEI users

Second malignant neoplasms after a first cancer in childhood: temporal pattern of risk according to type of treatment

The variation in the risk of solid second malignant neoplasms (SMN) with time since first cancer during childhood has been previously reported. However, no study has been performed that controls for the distribution of radiation dose and the aggressiveness of past chemotherapy, which could be responsible for the observed temporal variation of the risk. The purpose of this study was to investigate the influence of the treatment on the long-term pattern of the incidence of solid SMN after a first cancer in childhood. We studied a cohort of 4400 patients from eight centres in France and the UK. Patients had to be alive 3 years or more after a first cancer treated before the age of 17 years and before the end of 1985. For each patient in the cohort, the complete clinical, chemotherapy and radiotherapy history was recorded. For each patient who had received external radiotherapy, the dose of radiation received by 151 sites of the body were estimated. After a mean follow-up of 15 years, 113 children developed a solid SMN, compared to 12.3 expected from general population rates. A similar distribution pattern was observed among the 1045 patients treated with radiotherapy alone and the 2064 patients treated with radiotherapy plus chemotherapy; the relative risk, but not the excess absolute risk, of solid SMN decreased with time after first treatment; the excess absolute risk increased during a period of at least 30 years after the first cancer. This pattern remained after controlling for chemotherapy and for the average dose of radiation to the major sites of SMN. It also remained when excluding patients with a first cancer type or an associated syndrome known to predispose to SMN. When compared with radiotherapy alone, the addition of chemotherapy increases the risk of solid SMN after a first cancer in childhood, but does not significantly modify the variation of this risk during the time after the first cancer. © 1999 Cancer Research Campaig

Ovarian cancer

Ovarian cancer is not a single disease and can be subdivided into at least five different histological subtypes that have different identifiable risk factors, cells of origin, molecular compositions, clinical features and treatments. Ovarian cancer is a global problem, is typically diagnosed at a late stage and has no effective screening strategy. Standard treatments for newly diagnosed cancer consist of cytoreductive surgery and platinum-based chemotherapy. In recurrent cancer, chemotherapy, anti-angiogenic agents and poly(ADP-ribose) polymerase inhibitors are used, and immunological therapies are currently being tested. High-grade serous carcinoma (HGSC) is the most commonly diagnosed form of ovarian cancer and at diagnosis is typically very responsive to platinum-based chemotherapy. However, in addition to the other histologies, HGSCs frequently relapse and become increasingly resistant to chemotherapy. Consequently, understanding the mechanisms underlying platinum resistance and finding ways to overcome them are active areas of study in ovarian cancer. Substantial progress has been made in identifying genes that are associated with a high risk of ovarian cancer (such as BRCA1 and BRCA2), as well as a precursor lesion of HGSC called serous tubal intraepithelial carcinoma, which holds promise for identifying individuals at high risk of developing the disease and for developing prevention strategies

Atorvastatin Improves Survival in Septic Rats: Effect on Tissue Inflammatory Pathway and on Insulin Signaling

The aim of the present study was to investigate whether the survival-improving effect of atorvastatin in sepsis is accompanied by a reduction in tissue activation of inflammatory pathways and, in parallel, an improvement in tissue insulin signaling in rats. Diffuse sepsis was induced by cecal ligation and puncture surgery (CLP) in male Wistar rats. Serum glucose and inflammatory cytokines levels were assessed 24 h after CLP. The effect of atorvastatin on survival of septic animals was investigated in parallel with insulin signaling and its modulators in liver, muscle and adipose tissue. Atorvastatin improves survival in septic rats and this improvement is accompanied by a marked improvement in insulin sensitivity, characterized by an increase in glucose disappearance rate during the insulin tolerance test. Sepsis induced an increase in the expression/activation of TLR4 and its downstream signaling JNK and IKK/NF-κB activation, and blunted insulin-induced insulin signaling in liver, muscle and adipose tissue; atorvastatin reversed all these alterations in parallel with a decrease in circulating levels of TNF-α and IL-6. In summary, this study demonstrates that atorvastatin treatment increased survival, with a significant effect upon insulin sensitivity, improving insulin signaling in peripheral tissues of rats during peritoneal-induced sepsis. The effect of atorvastatin on the suppression of the TLR-dependent inflammatory pathway may play a central role in regulation of insulin signaling and survival in sepsis insult