Measurement of adsorption of a single component from the liquid phase : modelling investigation and sensitivity analysis

In this work, we consider an alternative approach for the measurement of adsorption from the liquid phase. Consider a mixture consisting of a non-adsorbed component (B) and an adsorbed component (A) present at some low concentration. Initially, a feed of component B only flows through a column packed with an adsorbent. Then, the feed is switched to the mixture of A and B. As soon as the mixture enters the column, there will be a reduction in the outlet flow rate as component A leaves the liquid phase and passes into the adsorbed phase. There are three stages to this work. The first is to develop overall and component balances to show how the amount adsorbed of component A can be determined from the variation in the column outlet flow rate. The second is to determine the actual variation in the column outlet flow rate for both plug flow and axial-dispersed plug flow. The final stage is to consider the suitability of a gravity-fed system to deliver the feed to the column. An analysis of the results shows that the experimental arrangement should be able to accurately monitor adsorption from the liquid phase where the mass fraction of the solute is of the order of 1%: the limiting experimental factor is how constant the volumetric flow rate of the liquid feed can be maintained

Keyword-Based Delegable Proofs of Storage

Cloud users (clients) with limited storage capacity at their end can outsource bulk data to the cloud storage server. A client can later access her data by downloading the required data files. However, a large fraction of the data files the client outsources to the server is often archival in nature that the client uses for backup purposes and accesses less frequently. An untrusted server can thus delete some of these archival data files in order to save some space (and allocate the same to other clients) without being detected by the client (data owner). Proofs of storage enable the client to audit her data files uploaded to the server in order to ensure the integrity of those files. In this work, we introduce one type of (selective) proofs of storage that we call keyword-based delegable proofs of storage, where the client wants to audit all her data files containing a specific keyword (e.g., "important"). Moreover, it satisfies the notion of public verifiability where the client can delegate the auditing task to a third-party auditor who audits the set of files corresponding to the keyword on behalf of the client. We formally define the security of a keyword-based delegable proof-of-storage protocol. We construct such a protocol based on an existing proof-of-storage scheme and analyze the security of our protocol. We argue that the techniques we use can be applied atop any existing publicly verifiable proof-of-storage scheme for static data. Finally, we discuss the efficiency of our construction.Comment: A preliminary version of this work has been published in International Conference on Information Security Practice and Experience (ISPEC 2018

Novel bicistronic lentiviral vectors correct beta-Hexosaminidase deficiency in neural and hematopoietic stem cells and progeny: implications for in vivo and ex vivo gene therapy of GM2 gangliosidosis

The favorable outcome of in vivo and ex vivo gene therapy approaches in several Lysosomal Storage Diseases suggests that these treatment strategies might equally benefit GM2 gangliosidosis. Tay-Sachs and Sandhoff disease (the main forms of GM2 gangliosidosis) result from mutations in either the HEXA or HERB genes encoding, respectively, the alpha- or beta-subunits of the lysosomal beta-Hexosaminidase enzyme. In physiological conditions, alpha- and beta-subunits combine to generate beta-Hexosaminidase A (HexA, alpha beta) and beta-Hexosaminidase B (HexB, 1313). A major impairment to establishing in vivo or ex vivo gene therapy for GM2 gangliosidosis is the need to synthesize the alpha- and beta-subunits at high levels and with the correct stoichiometric ratio, and to safely deliver the therapeutic products to all affected tissues/organs. Here, we report the generation and in vitro validation of novel bicistronic lentiviral vectors (LVs) encoding for both the murine and human codon optimized Hexa and Hex!) genes. We show that these LVs drive the safe and coordinate expression of the alpha- and beta-subunits, leading to supranormal levels of beta-Hexosaminidase activity with prevalent formation of a functional HexA in SD murine neurons and glia, murine bone marrow-derived hematopoietic stem/progenitor cells (HSPCs), and human SD fibroblasts. The restoration/overexpression of beta-Hexosaminidase leads to the reduction of intracellular GM2 ganglioside storage in transduced and in cross-corrected SD murine neural progeny, indicating that the transgenic enzyme is secreted and functional. Importantly, bicistronic LVs safely and efficiently transduce human neurons/glia and CD34 + HSPCs, which are target and effector cells, respectively, in prospective in vivo and ex vivo GT approaches. We anticipate that these bicistronic LVs may overcome the current requirement of two vectors co-delivering the alpha- or beta-subunits genes. Careful assessment of the safety and therapeutic potential of these bicistronic LVs in the SD murine model will pave the way to the clinical development of LV-based gene therapy for GM2 gangliosidosis

Gemcitabine plus vinorelbine in elderly or unfit patients with non-small cell lung cancer

Cisplatin-based combinations are efficacious in increasing the overall survival of patients with non-small cell lung cancer (NSCLC), but their toxicity makes them unsuitable for elderly and unfit patients. The primary objective of this non-randomized phase II study was to evaluate the feasibility and activity of the gemcitabine plus vinorelbine combination in previously untreated elderly and/or unfit patients with measurable stage III or IV NSCLC. Forty-three patients aged ≥ 65 years or with contraindications against cisplatin treatment (36 males and seven females: median age 66 years; range 48–75: PS 0 = 11, PS 1 = 19, PS 2 = 13) received intravenous (i.v.) gemcitabine 1000 mg m–2, followed by vinorelbine 25 mg m–2i.v. on day 1 and 8 every 21 days. Fifteen patients (34.9%) achieved partial remission (confidence interval: 27.6–42.2%) for a median duration of 6 months; the median survival of these patients has not yet been reached. A further 15 had stable disease for a median of 4 months and a median survival of 7 months. The 10 patients (23.2%) who experienced disease progression had a median survival of 4 months. Three patients are not evaluable. The 1-year actuarial survival rate is 31.1%. The treatment was well tolerated: only 35% of the patients had grade 3 or 4 granulocytopenia on day 14, none experienced episodes of neutropenic fever, and there was no evidence of severe haematological toxicity upon recycling. Only 9% of the patients suffered from gastrointestinal toxicity (grade 3); increased but reversible transaminase levels were observed in 11.6%. In conclusion, the results of this phase II study show that the combination of gemcitabine and vinorelbine is active and well tolerated in NSCLC, and thus encourage its use in elderly or unfit patients. © 2000 Cancer Research Campaig

Nivolumab combined with brentuximab vedotin for R/R primary mediastinal large B-cell lymphoma: a 3-year follow-up.

Patients with relapsed/refractory primary mediastinal large B-cell lymphoma (R/R PMBL) have poor responses to salvage therapy. Nivolumab and brentuximab vedotin (BV) showed promising early efficacy in patients with R/R PMBL in the phase 1/2 open-label, multicenter CheckMate 436 study; we report safety and efficacy findings from the 3-year follow-up. Patients who were eligible were aged ≥15 years with R/R PMBL previously treated with either high-dose chemotherapy plus autologous hematopoietic cell transplantation (HCT) or ≥2 prior multiagent chemotherapies, and had Eastern Cooperative Oncology Group performance status scores of 0 to 1 and CD30 expression of ≥1%. Patients were treated with nivolumab 240 mg and BV 1.8 mg/kg once every 3 weeks until disease progression or unacceptable toxicity. Primary end point was objective response rate (ORR); secondary end points included complete response rate, duration of response, progression-free survival (PFS), and overall survival (OS). Safety was monitored throughout. At final database lock (30 March 2022), 29 patients had received nivolumab plus BV; median follow-up was 39.6 months. Investigator-assessed ORR was 73.3%; median time to response was 1.3 months (range, 1.1-4.8). Median PFS was 26.0 months; median OS was not reached. PFS and OS rates at 24 months were 55.5% (95% confidence interval [CI], 32.0-73.8) and 75.5% (95% CI, 55.4-87.5), respectively. The most frequently occurring grade 3/4 treatment-related adverse event was neutropenia. Consolidative HCT was received by 12 patients, with a 100-day complete response rate of 100.0%. This 3-year follow-up showed long-term efficacy for nivolumab plus BV in R/R PMBL, with no new safety signals. This trial was registered at www.clinicaltrials.gov as #NCT02581631

Blood Chemistry, Acid- Base, Electrolyte, Blood Lactate Metabolism and Sleep at 3480 m in Mountain Marathon Runners

Altered blood chemistry, acid-base and electrolyte are suggested determinants of sleep disturbance, with frequent arousal at high altitude even in well and long-trained altitude marathon runners. In this sample of experienced altitude marathon runners with maximal aerobic power at sea level of 61.4 \ub1 2.7 ml/kg 121\u387min 121 we found that pO2 and percent of oxygen saturation (%SO2) were lower at 2050 m and 3480 m than at sea level; pO2 was higher after 38 - 41 hours than after 30 - 31 hours of acclimatization at 3480 m (P < 0.05). After ascent to 3480 m %SO2 decreased (P < 0.003). Compared to sea level values, pH increased at high altitude (P < 0.05) consistent with changes in pCO2 and [HCO3-] (P < 0.05). Nocturnal %SpaO2 at a sleeping altitude of 3480 m was lower (P < 0.05) than at sea level. At high altitude, the percent of wake (W) time and delay falling asleep (DFA) increased, whereas non-rapid eye movement sleep (N-REM), REM sleep and total sleep time (TST) decreased (P < 0.05). Simple regression analysis disclosed a significant correlation between the changes in TST and the percent of REM sleep and the changes in %SpaO2 recorded during sleep (P < 0.05). Simple regression analysis showed a positive correlation between the changes in pO2 at higher altitude and the percent of W and of TST (P < 0.05). The changes in pO2, tCO2 and [HCO3-] correlated negatively and significantly with the percent of REM sleep changes at high altitude (P < 0.05). The TST changes at high altitude correlated positively with the changes in pO2 and pH and correlated negatively with the changes in %SO2, pCO2, tCO2, and [HCO3-] (P < 0.05). The changes in the percent of W at high altitude correlated significantly and positively with the changes in bases excess [BE] at high altitude (P < 0.05). The changes in the percent of REM sleep correlated significantly and positively with the changes in [iCa++] and [BE] and negatively with the changes in buffered bases [BB] and [BEeffective] (P < 0.05). The change in the percent of NREM + REM sleep at high altitude correlated significantly and positively with the changes in [BE] and [BB] concentration (P < 0.05). The increase in DFA at high altitude correlated significantly and negatively with the changes in pCO2 and significantly and negatively with the changes in [K+] (P < 0.05). Simple regression analysis demonstrated that the changes in pH at high altitude correlated positively and significantly with the percent of W and the DFA and negatively with the percent of changes in NREM sleep, REM sleep, NREM + REM sleep (P < 0.05). The decrease in the TST at high altitude correlated significantly and negatively with the changes in pCO2, tCO2, [HCO3-]and [K+] (P < 0.05). Our data demonstrate that the arterialized ear lobe techniques we used for evaluating most of the changes in blood chemistry, acid-base, electrolyte and blood lactate metabolism are suitable for clinical and laboratory assessment and are important predictors of the quality and quantity of acclimatization and sleep at high altitude

A workflow for patient-specific fluid-structure interaction analysis of the mitral valve: A proof of concept on a mitral regurgitation case

The mechanics of the mitral valve (MV) are the result of the interaction of different anatomical structures complexly arranged within the left heart (LH), with the blood flow. MV structure abnormalities might cause valve regurgitation which in turn can lead to heart failure. Patient-specific computational models of the MV could provide a personalised understanding of MV mechanics, dysfunctions and possible interventions. In this study, we propose a semi-automatic pipeline for MV modelling based on the integration of state-of-the-art medical imaging, i.e. cardiac magnetic resonance (CMR) and 3D transoesophageal-echocardiogram (TOE) with fluid-structure interaction (FSI) simulations. An FSI model of a patient with MV regurgitation was implemented using the finite element (FE) method and smoothed particle hydrodynamics (SPH). Our study showed the feasibility of combining image information and computer simulations to reproduce patient-specific MV mechanics as seen on medical images, and the potential for efficient in-silico studies of MV disease, personalised treatments and device design

Adult cardiac stem cells are multipotent and robustly myogenic: c-kit expression is necessary but not sufficient for their identification

Multipotent adult resident cardiac stem cells (CSCs) were first identified by the expression of c-kit, the stem cell factor receptor. However, in the adult myocardium c-kit alone cannot distinguish CSCs from other c-kit-expressing (c-kitpos) cells. The adult heart indeed contains a heterogeneous mixture of c-kitpos cells, mainly composed of mast and endothelial/progenitor cells. This heterogeneity of cardiac c-kitpos cells has generated confusion and controversy about the existence and role of CSCs in the adult heart. Here, to unravel CSC identity within the heterogeneous c-kit-expressing cardiac cell population, c-kitpos cardiac cells were separated through CD45-positive or -negative sorting followed by c-kitpos sorting. The blood/endothelial lineage-committed (Lineagepos) CD45posc-kitpos cardiac cells were compared to CD45neg(Lineageneg/Linneg) c-kitpos cardiac cells for stemness and myogenic properties in vitro and in vivo. The majority (~90%) of the resident c-kitpos cardiac cells are blood/endothelial lineage-committed CD45posCD31posc-kitpos cells. In contrast, the LinnegCD45negc-kitpos cardiac cell cohort, which represents 10% of the total c-kitpos cells, contain all the cardiac cells with the properties of adult multipotent CSCs. These characteristics are absent from the c-kitneg and the blood/endothelial lineage-committed c-kitpos cardiac cells. Single Linnegc-kitpos cell-derived clones, which represent only 1–2% of total c-kitpos myocardial cells, when stimulated with TGF-β/Wnt molecules, acquire full transcriptome and protein expression, sarcomere organisation, spontaneous contraction and electrophysiological properties of differentiated cardiomyocytes (CMs). Genetically tagged cloned progeny of one Linnegc-kitpos cell when injected into the infarcted myocardium, results in significant regeneration of new CMs, arterioles and capillaries, derived from the injected cells. The CSC’s myogenic regenerative capacity is dependent on commitment to the CM lineage through activation of the SMAD2 pathway. Such regeneration was not apparent when blood/endothelial lineage-committed c-kitpos cardiac cells were injected. Thus, among the cardiac c-kitpos cell cohort only a very small fraction has the phenotype and the differentiation/regenerative potential characteristics of true multipotent CSCs