X-ray characterization of oriented β-tantalum films

Includes bibliographical references (pages 408-409).Tantalum (Ta) metal films (10-70 nm) were deposited on a Si(100) substrate with a 500 nm silicon dioxide (SiO2) interlayer by ion-beam assisted sputtering. The as-deposited films have been characterized by X-ray diffraction (XRD) and X-ray reflectivity (XRR) techniques. XRD measurements showed the presence of films of the tetragonal phase of tantalum (β-Ta) oriented along the (00l) plane. XRR measurements indicated the presence of graded Ta films, with a thin interface layer between the 500 nm SiO2 layer and the Ta films. The thickness and density of this interface layer was estimated to be 1.9±0.2 nm and 10.5±0.5 g/cm3, respectively. X-ray photoelectron spectroscopy (XPS) was used to probe the chemical composition of this interface layer. XPS investigative studies indicated that the interface was likely composed of tantalum silicide (TaSi2) and tantalum silicate (TaSiOx). However, the TaSiOx layer was reduced during Ar ion sputter depth profile analysis

Perspectives in melanoma: meeting report from the Melanoma Bridge (December 5th-7th, 2019, Naples, Italy).

The melanoma treatment landscape changed in 2011 with the approval of the first anti-cytotoxic T-lymphocyte-associated protein (CTLA)-4 checkpoint inhibitor and of the first BRAF-targeted monoclonal antibody, both of which significantly improved overall survival (OS). Since then, improved understanding of the tumor microenvironment (TME) and tumor immune-evasion mechanisms has resulted in new approaches to targeting and harnessing the host immune response. The approval of new immune and targeted therapies has further improved outcomes for patients with advanced melanoma and other combination modalities are also being explored such as chemotherapy, radiotherapy, electrochemotherapy and surgery. In addition, different strategies of drugs administration including sequential or combination treatment are being tested. Approaches to overcome resistance and to potentiate the immune response are being developed. Increasing evidence emerges that tissue and blood-based biomarkers can predict the response to a therapy. The latest findings in melanoma research, including insights into the tumor microenvironment and new biomarkers, improved understanding of tumor immune response and resistance, novel approaches for combination strategies and the role of neoadjuvant and adjuvant therapy, were the focus of discussions at the Melanoma Bridge meeting (5-7 December, 2019, Naples, Italy), which are summarized in this report

Long-Term Outcomes With Nivolumab Plus Ipilimumab or Nivolumab Alone Versus Ipilimumab in Patients With Advanced Melanoma

PURPOSE In the phase III CheckMate 067 trial, durable clinical benefit was demonstrated previously with nivolumab plus ipilimumab and nivolumab alone versus ipilimumab. Here, we report 6.5-year efficacy and safety outcomes. PATIENTS AND METHODS Patients with previously untreated unresectable stage III or stage IV melanoma were randomly assigned 1:1:1 to receive nivolumab 1 mg/kg plus ipilimumab 3 mg/kg once every 3 weeks (four doses) followed by nivolumab 3 mg/kg once every 2 weeks (n = 314), nivolumab 3 mg/kg once every 2 weeks (n = 316), or ipilimumab 3 mg/kg once every 3 weeks (four doses; n = 315). Coprimary end points were progression-free survival and overall survival (OS) with nivolumab plus ipilimumab or nivolumab versus ipilimumab. Secondary end points included objective response rate, descriptive efficacy assessments of nivolumab plus ipilimumab versus nivolumab alone, and safety. Melanoma-specific survival (MSS; descriptive analysis), which excludes deaths unrelated to melanoma, was also evaluated. RESULTS Median OS (minimum follow-up, 6.5 years) was 72.1, 36.9, and 19.9 months in the combination, nivolumab, and ipilimumab groups, respectively. Median MSS was not reached, 58.7, and 21.9 months, respectively; 6.5-year OS rates were 57%, 43%, and 25% in patients with BRAF-mutant tumors and 46%, 42%, and 22% in those with BRAF–wild-type tumors, respectively. In patients who discontinued treatment, the median treatment-free interval was 27.6, 2.3, and 1.9 months, respectively. Since the 5-year analysis, no new safety signals were observed. CONCLUSION These 6.5-year CheckMate 067 results, which include the longest median OS in a phase III melanoma trial reported to date and the first report of MSS, showed durable, improved clinical outcomes with nivolumab plus ipilimumab or nivolumab versus ipilimumab in patients with advanced melanoma and, in descriptive analyses, with the combination over nivolumab monotherapy

Five-Year Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma

945 patients with inoperable stage III or stage IV melanoma were randomised to ipilimumab plus nivolumab (ipi/nivo)(314), nivolumab (nivo) (316) or ipilimumab (Ipilimumab) (315). The minimum follow up from randomisation of the last patient was 60 months. Objective responses were seen in 58% of Ipilimumab/nivo, 45% of nivo and 19% of Ipilimumab patients. Complete responses were seen in 22% (Ipilimumab/nivo), 19% (nivo) and 6% (Ipi) patients. Overall survival (OS) at five years was 52% (Ipilimumab/nivo), 44% (nivo) and 26% (Ipi). In patients with and without bras mutations the OS at five years was 60 & 48% (Ipilimumab/nivo), 46 & 43% (nivo) and 30 & 25% (Ipi) respectively. OS curves were flat beyond three years indicating that these treatments lead to sustained long term survival of these patients

Transgenic expression of human APOL1 risk variants in podocytes induces kidney disease in mice

African Americans have a heightened risk of developing chronic and end-stage kidney disease, an association that is largely attributed to two common genetic variants, termed G1 and G2, in the APOL1 gene. Direct evidence demonstrating that these APOL1 risk alleles are pathogenic is still lacking because the APOL1 gene is present in only some primates and humans; thus it has been challenging to demonstrate experimental proof of causality of these risk alleles for renal disease. Here we generated mice with podocyte-specific inducible expression of the APOL1 reference allele (termed G0) or each of the risk-conferring alleles (G1 or G2). We show that mice with podocyte-specific expression of either APOL1 risk allele, but not of the G0 allele, develop functional (albuminuria and azotemia), structural (foot-process effacement and glomerulosclerosis) and molecular (gene-expression) changes that closely resemble human kidney disease. Disease development was cell-type specific and likely reversible, and the severity correlated with the level of expression of the risk allele. We further found that expression of the risk-variant APOL1 alleles interferes with endosomal trafficking and blocks autophagic flux, which ultimately leads to inflammatory-mediated podocyte death and glomerular scarring. In summary, this is the first demonstration that the expression of APOL1 risk alleles is causal for altered podocyte function and glomerular disease in vivo

APOL1 toxin, innate immunity, and kidney injury

The discovery that two common APOL1 alleles were strongly associated with non-diabetic kidney diseases in African descent populations led to hope for improved diagnosis and treatment. Unfortunately, we still do not have a clear understanding of the biological function played by APOL1 in podocytes or other kidney cells, nor how the renal risk alleles initiate the development of nephropathies. Important clues for APOL1 function may be gleaned from the natural defense mechanism of APOL1 against trypanosome infections and from similar proteins (e.g. diphtheria toxin, mammalian Bcl-2 family members). This review provides an update on the biological functions for circulating (trypanosome resistance) and intracellular (emerging role for autophagy) APOL1. Further, we introduce a multimer model for APOL1 in kidney cells that reconciles the gain-of-function variants with the recessive inheritance pattern of APOL1 renal risk alleles