No effective pharmacotherapy for acute respiratory distress syndrome (ARDS) exists, and mortality remains high. Preclinical studies support the efficacy of mesenchymal stem (stromal) cells (MSCs) in ...the treatment of lung injury. We aimed to test the safety of a single dose of allogeneic bone marrow-derived MSCs in patients with moderate-to-severe ARDS.
The STem cells for ARDS Treatment (START) trial was a multicentre, open-label, dose-escalation, phase 1 clinical trial. Patients were enrolled in the intensive care units at University of California, San Francisco, CA, USA, Stanford University, Stanford, CA, USA, and Massachusetts General Hospital, Boston, MA, USA, between July 8, 2013, and Jan 13, 2014. Patients were included if they had moderate-to-severe ARDS as defined by the acute onset of the need for positive pressure ventilation by an endotracheal or tracheal tube, a PaO2:FiO2 less than 200 mm Hg with at least 8 cm H2O positive end-expiratory airway pressure (PEEP), and bilateral infiltrates consistent with pulmonary oedema on frontal chest radiograph. The first three patients were treated with low dose MSCs (1 million cells/kg predicted bodyweight PBW), the next three patients received intermediate dose MSCs (5 million cells/kg PBW), and the final three patients received high dose MSCs (10 million cells/kg PBW). Primary outcomes included the incidence of prespecified infusion-associated events and serious adverse events. The trial is registered with ClinicalTrials.gov, number NCT01775774.
No prespecified infusion-associated events or treatment-related adverse events were reported in any of the nine patients. Serious adverse events were subsequently noted in three patients during the weeks after the infusion: one patient died on study day 9, one patient died on study day 31, and one patient was discovered to have multiple embolic infarcts of the spleen, kidneys, and brain that were age-indeterminate, but thought to have occurred before the MSC infusion based on MRI results. None of these severe adverse events were thought to be MSC-related.
A single intravenous infusion of allogeneic, bone marrow-derived human MSCs was well tolerated in nine patients with moderate to severe ARDS. Based on this phase 1 experience, we have proceeded to phase 2 testing of MSCs for moderate to severe ARDS with a primary focus on safety and secondary outcomes including respiratory, systemic, and biological endpoints.
The National Heart, Lung, and Blood Institute.
Background
Despite advances in supportive care, moderate-severe acute respiratory distress syndrome (ARDS) is associated with high mortality rates, and novel therapies to treat this condition are ...needed. Compelling pre-clinical data from mouse, rat, sheep and ex vivo perfused human lung models support the use of human mesenchymal stem (stromal) cells (MSCs) as a novel intravenous therapy for the early treatment of ARDS.
Methods
This article describes the study design and challenges encountered during the implementation and phase 1 component of the START (STem cells for ARDS Treatment) trial, a phase 1/2 trial of bone marrow-derived human MSCs for moderate-severe ARDS. A trial enrolling 69 subjects is planned (9 subjects in phase 1, 60 subjects in phase 2 treated with MSCs or placebo in a 2:1 ratio).
Results
This report describes study design features that are unique to a phase 1 trial in critically ill subjects and the specific challenges of implementation of a cell-based therapy trial in the ICU.
Conclusions
Experience gained during the design and implementation of the START study will be useful to investigators planning future phase 1 clinical trials based in the ICU, as well as trials of cell-based therapy for other acute illnesses.
Trial registration
Clinical Trials Registration:
NCT01775774
and
NCT02097641
.
Treatment with bone-marrow-derived mesenchymal stromal cells (MSCs) has shown benefits in preclinical models of acute respiratory distress syndrome (ARDS). Safety has not been established for ...administration of MSCs in critically ill patients with ARDS. We did a phase 2a trial to assess safety after administration of MSCs to patients with moderate to severe ARDS.
We did a prospective, double-blind, multicentre, randomised trial to assess treatment with one intravenous dose of MSCs compared with placebo. We recruited ventilated patients with moderate to severe ARDS (ratio of partial pressure of oxygen to fractional inspired oxygen <27 kPa and positive end-expiratory pressure PEEP ≥8 cm H
O) in five university medical centres in the USA. Patients were randomly assigned 2:1 to receive either 10 × 10
/kg predicted bodyweight MSCs or placebo, according to a computer-generated schedule with a variable block design and stratified by site. We excluded patients younger than 18 years, those with trauma or moderate to severe liver disease, and those who had received cancer treatment in the previous 2 years. The primary endpoint was safety and all analyses were done by intention to treat. We also measured biomarkers in plasma. MSC viability was tested in a post-hoc analysis. This trial is registered with ClinicalTrials.gov, number NCT02097641.
From March 24, 2014, to Feb 9, 2017 we screened 1038 patients, of whom 60 were eligible for and received treatment. No patient experienced any of the predefined MSC-related haemodynamic or respiratory adverse events. One patient in the MSC group died within 24 h of MSC infusion, but death was judged to be probably unrelated. 28-day mortality did not differ between the groups (30% in the MSC group vs 15% in the placebo group, odds ratio 2·4, 95% CI 0·5-15·1). At baseline, the MSC group had numerically higher mean scores than the placebo group for Acute Physiology and Chronic Health Evaluation III (APACHE III; 104 SD 31 vs 89 33), minute ventilation (11·1 3·2 vs 9·6 2·4 L/min), and PEEP (12·4 3·7 vs 10·8 2·6 cm H
O). After adjustment for APACHE III score, the hazard ratio for mortality at 28 days was 1·43 (95% CI 0·40-5·12, p=0·58). Viability of MSCs ranged from 36% to 85%.
One dose of intravenous MSCs was safe in patients with moderate to severe ARDS. Larger trials are needed to assess efficacy, and the viability of MSCs must be improved.
National Heart, Lung, and Blood Institute.
Abstract Objectives Current therapies for ovarian cancer (OC) patients have a modest impact on long-term survival justifying the need for novel treatment strategies. We developed in vitro and in vivo ...systems to test the effects of cytokines in combination with peripheral blood mononuclear cells (PBMC) on OC cells. Methods Two OC cell-lines were transfected with a plasmid encoding Red Fluorescent Protein (SKOV3-RFP and CAR3-RFP). Proliferation of these lines in the presence of cytokines alone and in combination was assayed. Cytotoxicity of SKOV3-RFP cells mediated by PBMC and cytokines was determined by lactate dehydrogenase release. Mice were injected intraperitoneally (IP) with SKOV3-RFP cells; solid tumor and ascitic fluid were collected, analyzed, and cell lines were established. Tumor-derived cell lines were re-injected to produce a more tumorigenic line. Results IFNα-2b showed an inhibitory effect on OC cell proliferation. The remaining cytokines, either alone or in combination, showed no significant effect. PBMC in combination with IL-2 showed clear dose-dependent cytotoxicity against SKOV3-RFP. IFNα-2b had a synergistic effect with IL-2 and PBMC increasing the cytotoxicity by an average of 20%. Using an animal model, SKOV3-RFP cells continue to express RFP when harvested from the peritoneum and are more tumorigenic when re-injected into mice. Conclusion These observations justify the use of IL-2, IFNα-2b, and PBMC in a xenograph animal model of OC to determine if combination cytokine and cellular therapy has an anti-tumor effect in vivo . This approach may prove useful as an in vivo system of IP cytokines administered in combination with cellular therapy.
Aberrant methylation of promoter regions of tumor suppressor genes (TSG) has recently become recognized as an important epigenetic event in cancer and tumor progression including multiple myeloma. ...Interleukin-6 (IL-6), which is known to play a significant role in the pathophysiology of myeloma, regulates DNA methylation by inducing expression of FLI-1, a transcription factor of DNA methyltransferase-1 (DNMT-1), resulting in over-expression of DNMT-1 and thus hypermethylation of TSG. Despite this understanding, attempts to bring IL-6 blockade to the clinic have had limited success. We hypothesize that IL-6 regulation of epigenetic events (hypermethylation) may be an important pathway that could eventually allow rational chemotherapeutic/anit-IL-6 combinations. We have studied the correlation of IL-6 expression and dependence in myeloma cell lines and correlated that to the methylation profile of TSG, DcR1 and CDH1. Using three well-established multiple myeloma cell lines: U266B1 (U266), RPMI 8226 (RPMI), and KAS6/1 (KAS), we have confirmed that KAS is IL-6-dependent (exogenous IL-6 is needed) whereas the U266 and RPMI are IL-6 independent. To determine if blockade of the IL-6 pathway would inhibit the growth of the myeloma cell lines, these cells were grown in the presence of an anti-IL-6 antibody (B-E8; Cell Sciences, Canton, MA) that is known to block IL-6 signaling in the cells. We found that blocking IL-6 (by B-E8, 200 ng/ml) inhibited the growth of U266 (36% inhibition; n≥3, p<0.01) and KAS (68% inhibition; n≥3, p<0.001) cells, but not RPMI cells. We examined IL-6 expression in these three cell lines by RT-PCR and found that U266 expresses IL-6 mRNA, but RPMI and KAS cells do not. This IL-6 mRNA expression pattern correlates well with the anti-IL-6 cellular proliferation findings. Since RPMI is not dependent on the addition of exogenous IL-6 and blocking the IL-6 pathway had no effect on cell growth; therefore, we would not expect the cells to express IL-6. The U266 cells are not dependent on exogenous IL-6 but cellular proliferation can be blocked with an anti-IL-6 antibody; therefore, we expected that the cells would endogenously express IL-6. Furthermore, KAS cells are dependent on exogenous IL-6 and cell growth can be inhibited by anti-IL-6 antibody; therefore, we would not expect the cells to express IL-6. To determine if IL-6 sensitivity correlated with hypermethylation of TSG, we investigated the methylation status of the DcR1(tumor necrosis factor-related apoptosis inducing ligand decoy receptor 1) and CDH1 (Cadherin 1) loci. We have shown that CDH1 is methylated in U266 cells and un-methylated in RPMI cells. Experiments are underway to determine the methylation status in KAS cells and gene expression in all cell-lines for CDH1. Finally, we found that the RPMI and KAS cells are un-methylated and U266 cells are methylated at the DcR1 locus. We have found that in the RPMI and U266 cell lines that methylation of target TSG correlates with anti-IL-6 sensitivity. These data support our hypothesis that an IL-6-dependent pathway may regulate hypermethylation of important TSG in multiple myeloma. Newer chemotherapeutic agents that may affect methylation pathways are being studied in combination with IL-6 blockade.
Current therapies for ovarian cancer (OC) patients have a modest impact on long-term survival justifying the need for novel treatment strategies. We developed in vitro and in vivo systems to test the ...effects of cytokines in combination with peripheral blood mononuclear cells (PBMC) on OC cells.
Two OC cell-lines were transfected with a plasmid encoding Red Fluorescent Protein (SKOV3-RFP and CAR3-RFP). Proliferation of these lines in the presence of cytokines alone and in combination was assayed. Cytotoxicity of SKOV3-RFP cells mediated by PBMC and cytokines was determined by lactate dehydrogenase release. Mice were injected intraperitoneally (IP) with SKOV3-RFP cells; solid tumor and ascitic fluid were collected, analyzed, and cell lines were established. Tumor-derived cell lines were re-injected to produce a more tumorigenic line.
IFNalpha-2b showed an inhibitory effect on OC cell proliferation. The remaining cytokines, either alone or in combination, showed no significant effect. PBMC in combination with IL-2 showed clear dose-dependent cytotoxicity against SKOV3-RFP. IFNalpha-2b had a synergistic effect with IL-2 and PBMC increasing the cytotoxicity by an average of 20%. Using an animal model, SKOV3-RFP cells continue to express RFP when harvested from the peritoneum and are more tumorigenic when re-injected into mice.
These observations justify the use of IL-2, IFNalpha-2b, and PBMC in a xenograph animal model of OC to determine if combination cytokine and cellular therapy has an anti-tumor effect in vivo. This approach may prove useful as an in vivo system of IP cytokines administered in combination with cellular therapy.
El Perú es un país megadiverso favorecido por su ubicación y condiciones climáticas; cuenta con una alta variedad de especies, tanto de flora como de fauna, ocupando las primeras posiciones en el ...mundo en aves y mariposas, y en otros grupos como mamíferos, anfibios, peces e insectos; de igual manera se ubica entre los primeros lugares del mundo en recursos genéticos y diversidad en productos de alcance y necesidad global, como son la papa, arroz, trigo y maíz. El Perú posee ecosistemas estratégicos, como bosques tropicales y secos, ricos ecosistemas marinos y abundantes pastizales naturales. Además cuenta con generosas reservas minerales y de hidrocarburos a lo largo de su cordillera. Las peculiaridades de su territorio le brindan además grandes oportunidades para aprovechar energías alternativas de gran potencial (eólica, solar y geotérmica). El Perú es además uno de los principales países en reservas de agua, y paisajes naturales, propicios para desarrollar actividades sostenibles.A lo largo de su historia, los Recursos Naturales peruanos se han venido explotando sin una gestión estratégica que persiga una senda crecimiento del país, por el contrario su explotación se relaciona más con visiones cortoplacistas enmarcadas en procesos y lineamientos poco eficientes que no están generando efectos multiplicadores en el aparato productivo, los están llevando al agatonamiento, y que no están forjando un desarrollo equitativo en todas las partes involucradas. El contexto actual requiere una visión integral que vincule la importancia de los Recusrsos Naturales con las necesidades y retos que afronta el Perú, enfocando sus acciones en una explotación sostenible y eficiente, de tal manera que pueda distribuir rentas equitativamente y a la vez sean el soporte del desarrollo de su industria, minimizando los impactos ambientales y sociales, de manera que no se comprometa el bienestar y el desarrollo de las generaciones futuras.
El Perú es un país megadiverso favorecido por su ubicación y condiciones climáticas;;
cuenta con una alta variedad de especies, tanto de flora como de fauna, ocupando las primeras;
posiciones en el ...mundo en aves y mariposas, y en otros grupos como mamíferos, anfibios,;
peces e insectos; de igual manera se ubica entre los primeros lugares del mundo en recursos;
genéticos y diversidad en productos de alcance y necesidad global, como son la papa, arroz,;
trigo y maíz. El Perú posee ecosistemas estratégicos, como bosques tropicales y secos, ricos;
ecosistemas marinos y abundantes pastizales naturales. Además cuenta con generosas reservas;
minerales y de hidrocarburos a lo largo de su cordillera. Las peculiaridades de su territorio le;
brindan además grandes oportunidades para aprovechar energías alternativas de gran potencial;
(eólica, solar y geotérmica). El Perú es además uno de los principales países en reservas de;
agua, y paisajes naturales, propicios para desarrollar actividades sostenibles.;
A lo largo de su historia, los Recursos Naturales peruanos se han venido explotando sin;
una gestión estratégica que persiga una senda crecimiento del país, por el contrario su;
explotación se relaciona más con visiones cortoplacistas enmarcadas en procesos y;
lineamientos poco eficientes que no están generando efectos multiplicadores en el aparato;
productivo, los están llevando al agatonamiento, y que no están forjando un desarrollo;
equitativo en todas las partes involucradas.;
El contexto actual requiere una visión integral que vincule la importancia de los;
Recusrsos Naturales con las necesidades y retos que afronta el Perú, enfocando sus acciones;
en una explotación sostenible y eficiente, de tal manera que pueda distribuir rentas;
equitativamente y a la vez sean el soporte del desarrollo de su industria, minimizando los;
impactos ambientales y sociales, de manera que no se comprometa el bienestar y el desarrollo;
de las generaciones futuras.
Peru is a megadiverse country favored by its location and climatic conditions; it has a;
high variety of species, of both flora and fauna, occupying the top positions in the world for;
birds and butterflies, and other groups such as mammals, amphibians, fish and insects;;
likewise, it is positioned among the first places in the world in genetic resources and;
biodiversity in product range and global needs, such as potatoes, rice, wheat and corn.;
Similarly, Peru has strategic ecosystems such as tropical and dry forests, rich marine;
ecosystems and abundant natural grasslands. It also has generous mineral and hydrocarbon;
reserves deposited along its mountain chain. The peculiarities of its territory also provides;
great opportunity to leverage great potential alternative energy (wind, solar and geothermal).;
Peru is also one of the leading countries in water reserves, and natural activities conducive to;
developing sustainable landscapes.;
Throughout its history, the Peruvian natural resources have been exploited without;
any kind of strategic management which could lead to a growth path for the country, on the;
contrary, their exploitation is more related to short-term visions framed in inefficient;
processes and guidelines that are not generating any multiplier effects in the productive;
apparatus, which are leading to exhaustion, and are not forging equal development in all;
parties.;
The current situation requires a holistic vision which links the importance of Natural;
Resources with the needs and challenges facing Peru, focusing actions in a sustainable and;
efficient operation, so income can be evenly distributed and at the same time being the;
support for the development of the industry, minimizing environmental and social impacts, so;
that the welfare and development of future generations is not compromised.
Digital supply chain model in Industry 4.0 Garay-Rondero, Claudia Lizette; Martinez-Flores, Jose Luis; Smith, Neale R ...
Journal of manufacturing technology management,
11/2020, Letnik:
31, Številka:
5
Journal Article
Recenzirano
Odprti dostop
PurposeThe purpose of this paper is to present a conceptual model that defines the essential components shaping the new Digital Supply Chains (DSCs) through the implementation and acceleration of ...Industry 4.0.Design/methodology/approachThe scope of the present work exposes a conceptual approach and review of the key literature from 1989 to 2019, concerning the evolution and transformation of the actors and constructs in logistics and Supply Chain Management (SCM) by means of examining different conceptual models and a state-of-the-art review of Industry 4.0’s concepts and elements, with a focus on digitization in supply chain (SC) processes. A detailed study of the constructs and components of SCM, as defined by their authors, resulted in the development of a referential and systematic model that fuses the inherent concepts and roles of SCM, with the new technological trends directed toward digitization, automation, and the increasing use of information and communication technologies across logistics global value chains.FindingsHaving achieved an exploration of the different conceptual frameworks, there is no compelling evidence of the existence of a conceptual SCM that incorporates the basic theoretical constructs and the new roles and elements of Industry 4.0. Therefore, the main components of Industry 4.0 and their impact on DSC Management are described, driving the proposal for a new conceptual model which addresses and accelerates a vision of the future of the interconnectivity between different DSCs, grouped in clusters in order to add value, through new forms of cooperation and digital integration.Originality/valueThis research explores the gap in the current SCM models leading into Industry 4.0. The proposed model provides a novel and comprehensive overview of the new concepts and components driving the nascent and current DSCs. This conceptual framework will further aid researchers in the exploration of knowledge regarding the variables and components presented, as well as the verification of the newly revealed roles and constructs to understand the new forms of cooperation and implementation of Industry 4.0 in digitalized SCs.
Mexico is the third Latin American country with the most children and adolescents living with human immunodeficiency virus (ALHIV). There is a lack of information on the characteristics of this ...population. We aimed to describe the social and mental health characteristics of Mexican ALHIV. A census was conducted of all adolescent patients with HIV at a pediatric hospital (n = 47; mean age 14.39, S.D. = 3.65) and their caregivers. We collected data on socio-demographic characteristics, family, intelligence, mental health, adverse life events, substance use, treatment, knowledge of Antiretroviral Treatment (ART) and HIV, and biomarkers. Most cases were transmitted vertically and self-reported ART adherence was above 90%. Some obstacles to adherence were medicine discomfort, believing that they did not need it, and forgetfulness. The vulnerabilities were intellectual disability, adverse life events, possible mental health problems, and little knowledge of their illness and treatment. These findings suggest the importance of interventions to improve the perception and knowledge of HIV and ART to increase ART adherence.
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