3,727 research outputs found
Influence of Nozzle Radiation on Solid Rocket Motors Tail-Off Thrust
No full textThe aims of this work are focused on the evaluation of the solid rocket motor residual thrust and
on the impact of thermal protection properties on such thrust. Indeed, tail-off thrust of solid rocket
motors upper stages can last tens of seconds after motor burn-out, affecting the performance of
the rocket on sequencing of stage separation. Hence, the knowledge of the tail-off thrust profile is
fundamental to properly design wait times and separation systems total impulse of a multi-stage
launcher. Therefore, although it has been shown in the past that pyrolysis gases responsible for the
residual thrust are mostly produced by alumina molten slag deposited next to the nozzle nose within
the combustion chamber, this study is aimed at suggesting that the portion of the nozzle within
the combustion chamber can act as the main radiative heat source leading to thermal protection
material ablation, and then to residual thrust production. An analysis of an actual solid rocket
motor has been performed in the direction of proving the effectiveness of the overall procedure. Then
a sensitivity analysis with respect to the quantities identifying the thermal protection properties has
been computed in order to evaluate the impact of such variations on the residual thrust profile
Mini Cooper 1961-2000
No full textFrom its launch on 20 September 1961 the Mini Cooper caused a sensation. The world’s first sports saloon, the diminutive Cooper combined the glamour and racing heritage of 1959 and 1960 Formula 1 champions the Cooper Car Company with the outstanding handling and downright practicability of the Austin Mini Seven and Morris Mini Minor. Alec Issigonis’s little people’s car had been launched by the manufacturer, the British Motor Corporation (BMC), two years earlier. A winner almost from the word go, the Mini Cooper not only ruled the racetracks and rally stages of the early and mid-1960s but proved to be a practical and fun sporting family saloon car. After over 100,000 examples were sold between 1961 and 1971, the Mini Cooper is still a practical sporting saloon in the guise of the BMW-owned MINI Cooper sixty years after the introduction of the original model.This remarkable product of the United Kingdom merits a fresh examination as it nears its sixtieth birthday. Based upon over fifty face-to-face interviews carried out by the author over more than a decade, this book quotes the Mini Cooper’s designers, developers, and professional race and rally drivers plus a host of contemporary owners. Here then in the words of its originators, is the story of the Mini Cooper
Supplementary_files – Supplemental material for Results from a meta-analysis of immune checkpoint inhibitors in first-line renal cancer patients: does PD-L1 matter?
No full textSupplemental material, Supplementary_files for Results from a meta-analysis of immune checkpoint inhibitors in first-line renal cancer patients: does PD-L1 matter? by Giandomenico Roviello, Silvia Paola Corona, Gabriella Nesi and Enrico Mini in Therapeutic Advances in Medical Oncology</p
An update on antibody–drug conjugates in urothelial carcinoma: state of the art strategies and what comes next
No full textIn recent years, considerable progress has been made in increasing the knowledge of tumour biology and drug resistance mechanisms in urothelial cancer. Therapeutic strategies have significantly advanced with the introduction of novel approaches such as immune checkpoint inhibitors and Fibroblast Growth Factor Receptor inhibitors. However, despite these novel agents, advanced urothelial cancer is often still progressive in spite of treatment and correlates with a poor prognosis. The introduction of antibody–drug conjugates consisting of a target-specific monoclonal antibody covalently linked to a payload (cytotoxic agent) is a novel and promising therapeutic strategy. In December 2019, the US Food and Drug Administration (FDA) granted accelerated approval to the nectin-4-targeting antibody–drug conjugate, enfortumab vedotin, for the treatment of advanced or metastatic urothelial carcinomas that are refractory to both immune checkpoint inhibitors and platinum-based treatment. Heavily pre-treated urothelial cancer patients reported a significant, 40% response to enfortumab vedotin while other antibody–drug conjugates are currently still under investigation in several clinical trials. We have comprehensively reviewed the available treatment strategies for advanced urothelial carcinoma and outlined the mechanism of action of antibody–drug conjugate agents, their clinical applications, resistance mechanisms and future strategies for urothelial cancer
Cyclodextrin Inclusion Complexes of Auranofin and Its Iodido Analog: A Chemical and Biological Study
No full textAuranofin (AF) and its iodido analog, i.e., Au(PEt3) I (AFI), were reported to exhibit very promising anticancer properties both in vitro and in vivo. However, both these gold compounds have a scarce aqueous solubility that hampers their pharmaceutical use. Here, we explore whether encapsulation of these metallodrugs inside hydroxypropyl-beta-cyclodextrin (HPβ-CD) may lead to an improved biopharmaceutical profile for the resulting adducts. Phase solubility studies, performed at 25 °C in an aqueous buffer, revealed, in both cases, the formation of a 1:1 drug to cyclodextrin complex; a far greater apparent stability constant (K1:1) was measured for AFI compared to AF (331 M-1 versus ca. 30 M-1). NMR studies conducted on the AFI/HPβ-CD system confirmed the formation of a stable 1:1 adduct. Then, binary systems of AF and AFI with HPβ-CD were prepared by colyophilization and characterized by DSC and PXRD. The results revealed the occurrence of drug complexation and/or amorphization for the AFI/HPβ-CD binary system. Afterwards, the antiproliferative properties of the two cyclodextrin adducts and of the corresponding free drugs were comparatively evaluated in vitro in three representative ovarian cancer cell lines, i.e., A2780, SKOV3, and IGROV-1. The results, in all cases, point out that CD complexation of the two gold drugs does not substantially affect their biological activity. The implications of these findings are discussed in the frame of the current knowledge of AF and its analogs
Trabectedin in combination with pegylated liposomal doxorubicin in patients with ovarian tumors
No full textThe majority of patients with ovarian cancer will experience relapse and thus require second-line therapy. While platinum-based therapies are the primary treatments for refractory disease other options are required, particularly for those with partially platinum-sensitive disease as their response rates are lower. Agents that can resensitize relapsed ovarian cancers to platinum, including trabectedin, are therefore of increasing interest. Trabectedin is a multitarget agent that has a complex, novel mechanism of action and has exhibited promising results in platinum-sensitive ovarian cancer when in combination with pegylated liposomal doxorubicin (PLD). The present study conducted retrospective analysis involving 11 cases (median age 60 years; range 45-75 years) of recurrent ovarian tumors and partial platinum sensitivity undergoing treatment with trabectedin + PLD. The cohort consisted of 7 serous carcinomas, 1 endometrial carcinoma, 2 undifferentiated carcinomas, and 1 mucinous carcinoma. Of the 11 patients, 4 exhibited a complete response, 3 achieved stable disease, and 4 had progression of disease. Mean overall survival was 32.42 months and median progression-free survival was 5.9 months. Trabectedin in combination with PLD was well tolerated in terms of gastrointestinal and hematological toxicity; Grade 3 cutaneous toxicity and grade 3 neutropenia were each observed in 18.2% of patients. There were no grade 4 events. Thus, the present study supports the use of trabectedin + PLD in patients with relapsed ovarian cancer and partial platinum sensitivity, with predictable and manageable toxicity
Theoretical Study on the Influence of Debondings on Solid Rocket Motor Performance
No full textIn solid rocket motors, propellant debondings are very dangerous since they could cause an increment of the burning surface area and anticipate the exposure of case-insulating thermal protection material. Therefore, when a debonding internal zone is discovered, it is of primary importance to guarantee that the solid rocket motor is still able to accomplish the mission within its operational requirements. From a numerical point of view, debondings cannot be evaluated in an analytical, closed form due to their variety of shapes. The present study is aimed at assessing the impact of debondings through the adoption of advanced computer graphic techniques like the offsetting of the solid rocket motor burning surface discretized as a dynamic three-dimensional triangular mesh. Mesh handling algorithms are discussed in detail. Numerical results are obtained through an in-house simulation software which has been developed based on the aforementioned methods
Structure-activity relationships in a series of auranofin analogues showing remarkable antiproliferative properties
No full textThe antiproliferative properties of a series of structurally-related gold(I) and silver(I) linear complexes inspired to the clinically established gold-based drug auranofin were investigated in A2780 ovarian cancer cells and in their auranofin (A2780/AF-R) and cisplatin (A2780/CDDP-R) resistant counterparts. In A2780 cells and in the cisplatin-resistant subline, gold-based analogues manifested a cytotoxicity profile comparable or superior to auranofin, while the silver-based analogues were less active; both gold and silver complexes overcame cisplatin resistance. Yet, a high degree of cross resistance toward gold analogues was noticed in A2780/AF-R cells. In the same cell line cross-resistance for silver analogues was also observed, though lower. All metal complexes were scrutinized for their ability to inhibit thioredoxin reductase (TrxR), the putative primary target for auranofin: overall, gold compounds were more potent TrxR inhibitors than the corresponding silver compounds, probably, as the consequence of the stronger binding of gold to the active site selenocysteine residue. These results highlight that the thiosugar ligand of auranofin is not essential for cytotoxicity while the nature of the metal center (gold/silver) plays a relevant role in its modulation. In addition, a rather clear correlation was found between cytotoxic potency of tested compounds and their ability to inhibit TrxR activity, being gold compounds more effective than silver analogues. However, the residual TrxR activity, measured in A2780 cells treated with the half-maximal inhibitory concentrations of various metal complexes, resulted far higher than expected. These results suggest that additional cytotoxic mechanisms must be operative. The implications of these results are discussed
Immune modulation of cancer: mechanisms and resistance
No full textThe development and clinical application of immune modulation represent one of the most extraordinary achievements in the treatment of cancer. Monoclonal antibodies against checkpoint inhibitors are actually used in clinical practice, but other antibodies that stimulate co-accessory molecules or kill regulatory cells are being studied. Interestingly, some conventional chemotherapeutics and tyrosine kinase inhibitors not only kill cancer cells but also modulate the immune response against tumors in that the induced immunogenic cell death can modulate tumor microenvironment (TME) cells. However, the tumor can hijack response to treatment and can be helped by the tolerogenic nature of the TME, resulting in an unexpected resistance that allows tumor progression in many patients.
In this review, after presenting how immune cells in TME are modulated by anticancer treatments, we analyze the mechanisms responsible for primary and secondary resistance to immunomodulatory drugs highlighting the urgent need to discover ways to overcome resistance. One such way is the association of drugs that modulate the activity of immune cells in the TME, particularly when they stimulate the immune system through different mechanisms.
Impact statement
The most promising approach to overcome drug resistance in cancer is the combination of treatments performed both in a biomarker-selected mode and as a first-line treatment
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