35 research outputs found
Physiological lentiviral vectors for the generation of improved CAR-T cells
Anti-CD19 chimeric antigen receptor (CAR)-T cells have achieved impressive outcomes for the treatment of relapsed and refractory B-lineage neoplasms. However, important limitations still remain due to severe adverse events (i.e., cytokine release syndrome and neuroinflammation) and relapse of 40%-50% of the treated patients. Most CAR-T cells are generated using retroviral vectors with strong promoters that lead to high CAR expression levels, tonic signaling, premature exhaustion, and overstimulation, reducing efficacy and increasing side effects. Here, we show that lentiviral vectors (LVs) expressing the transgene through a WAS gene promoter (AW-LVs) closely mimic the T cell receptor (TCR)/CD3 expression kinetic upon stimulation. These AW-LVs can generate improved CAR-T cells as a consequence of their moderate and TCR-like expression profile. Compared with CAR-T cells generated with human elongation factor alpha (EF1 alpha)-driven-LVs, AW-CAR-T cells exhibited lower tonic signaling, higher proportion of naive and stem cell memory T cells, less exhausted phenotype, and milder secretion of tumor necrosis factor alpha (TNF-alpha) and interferon (IFN)-gamma after efficient destruction of CD19(+) lymphoma cells, both in vitro and in vivo. Moreover, we also showed their improved efficiency using an in vitro CD19(+) pancreatic tumor model. We finally demonstrated the feasibility of large-scale manufacturing of AW-CAR-T cells in guanosine monophosphate (GMP)-like conditions. Based on these data, we propose the use of AWLVs for the generation of improved CAR-T products
Trends and outcome of neoadjuvant treatment for rectal cancer: A retrospective analysis and critical assessment of a 10-year prospective national registry on behalf of the Spanish Rectal Cancer Project
Introduction: Preoperative treatment and adequate surgery increase local control in rectal cancer. However, modalities and indications for neoadjuvant treatment may be controversial. Aim of this study was to assess the trends of preoperative treatment and outcomes in patients with rectal cancer included in the Rectal Cancer Registry of the Spanish Associations of Surgeons.
Method: This is a STROBE-compliant retrospective analysis of a prospective database. All patients operated on with curative intention included in the Rectal Cancer Registry were included. Analyses were performed to compare the use of neoadjuvant/adjuvant treatment in three timeframes: I)2006â2009; II)2010â2013; III)2014â2017. Survival analyses were run for 3-year survival in timeframes I-II.
Results: Out of 14, 391 patients, 8871 (61.6%) received neoadjuvant treatment. Long-course chemo/radiotherapy was the most used approach (79.9%), followed by short-course radiotherapy ± chemotherapy (7.6%). The use of neoadjuvant treatment for cancer of the upper third (15-11 cm) increased over time (31.5%vs 34.5%vs 38.6%, p = 0.0018). The complete regression rate slightly increased over time (15.6% vs 16% vs 18.5%; p = 0.0093); the proportion of patients with involved circumferential resection margins (CRM) went down from 8.2% to 7.3%and 5.5% (p = 0.0004). Neoadjuvant treatment significantly decreased positive CRM in lower third tumors (OR 0.71, 0.59â0.87, Cochrane-Mantel-Haenszel P = 0.0008). Most ypN0 patients also received adjuvant therapy. In MR-defined stage III patients, preoperative treatment was associated with significantly longer local-recurrence-free survival (p < 0.0001), and cancer-specific survival (p < 0.0001). The survival benefit was smaller in upper third cancers.
Conclusion: There was an increasing trend and a potential overuse of neoadjuvant treatment in cancer of the upper rectum. Most ypN0 patients received postoperative treatment. Involvement of CRM in lower third tumors was reduced after neoadjuvant treatment. Stage III and MRcN + benefited the most
Using Gene Editing Approaches to Fine-Tune the Immune System
Genome editing technologies not only provide unprecedented opportunities to study
basic cellular system functionality but also improve the outcomes of several clinical
applications. In this review, we analyze various gene editing techniques used to finetune
immune systems from a basic research and clinical perspective. We discuss
recent advances in the development of programmable nucleases, such as zinc-finger
nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and clustered
regularly interspaced short palindromic repeat (CRISPR)-Cas-associated nucleases. We
also discuss the use of programmable nucleases and their derivative reagents such
as base editing tools to engineer immune cells via gene disruption, insertion, and
rewriting of T cells and other immune components, such natural killers (NKs) and
hematopoietic stem and progenitor cells (HSPCs). In addition, with regard to chimeric
antigen receptors (CARs), we describe how different gene editing tools enable healthy
donor cells to be used in CAR T therapy instead of autologous cells without risking
graft-versus-host disease or rejection, leading to reduced adoptive cell therapy costs
and instant treatment availability for patients. We pay particular attention to the delivery
of therapeutic transgenes, such as CARs, to endogenous loci which prevents collateral
damage and increases therapeutic effectiveness. Finally, we review creative innovations,
including immune system repurposing, that facilitate safe and efficient genome surgery
within the framework of clinical cancer immunotherapies.Spanish ISCIII Health Research FundEuropean Union (EU)
PI12/01097
PI15/02015
PI18/00337
PI18/00330CECEyU and CSyF councils of the Junta de Andalucia FEDER/European Cohesion Fund (FSE)
2016000073391-TRA
2016000073332-TRA
PI-57069
PAIDI-Bio326
PI-0014-2016Nicolas Monardes regional Ministry of Health
0006/2018Spanish Government
FPU16/05467
FPU17/02268Industrial Doctorate Plan MCI
DIN2018-010180SMSI
PEJ-2018-001760-ALentiStem Biotec
Lidocaine, dexmedetomidine and their combination reduce isoflurane minimum alveolar concentration in dogs.
The effects of intravenous (i.v.) lidocaine, dexmedetomidine and their combination delivered as a bolus followed by a constant rate infusion (CRI) on the minimum alveolar concentration of isoflurane (MACISO) in dogs were evaluated. Seven healthy adult dogs were included. Anaesthesia was induced with propofol and maintained with isoflurane. For each dog, baseline MAC (MACISO/BASAL) was determined after a 90-minute equilibration period. Thereafter, each dog received one of the following treatments (loading dose, CRI): lidocaine 2 mg kg(-1), 100 ”g kg(-1) minute(-1); dexmedetomidine 2 ”g kg(-1), 2 ”g kg(-1) hour(-1); or their combination. MAC was then determined again after 45- minutes of treatment by CRI. At the doses administered, lidocaine, dexmedetomidine and their combination significantly reduced MACISO by 27.3% (range: 12.5-39.2%), 43.4% (33.3-53.3%) and 60.9% (46.1-78.1%), respectively, when compared to MACISO/BASAL. The combination resulted in a greater MACISO reduction than the two drugs alone. Their use, at the doses studied, provides a clinically important reduction in the concentration of ISO during anaesthesia in dogs
Lidocaine, dexmedetomidine and their combination reduce isoflurane minimum alveolar concentration in dogs.
The effects of intravenous (i.v.) lidocaine, dexmedetomidine and their combination delivered as a bolus followed by a constant rate infusion (CRI) on the minimum alveolar concentration of isoflurane (MACISO) in dogs were evaluated. Seven healthy adult dogs were included. Anaesthesia was induced with propofol and maintained with isoflurane. For each dog, baseline MAC (MACISO/BASAL) was determined after a 90-minute equilibration period. Thereafter, each dog received one of the following treatments (loading dose, CRI): lidocaine 2 mg kg(-1), 100 ”g kg(-1) minute(-1); dexmedetomidine 2 ”g kg(-1), 2 ”g kg(-1) hour(-1); or their combination. MAC was then determined again after 45- minutes of treatment by CRI. At the doses administered, lidocaine, dexmedetomidine and their combination significantly reduced MACISO by 27.3% (range: 12.5-39.2%), 43.4% (33.3-53.3%) and 60.9% (46.1-78.1%), respectively, when compared to MACISO/BASAL. The combination resulted in a greater MACISO reduction than the two drugs alone. Their use, at the doses studied, provides a clinically important reduction in the concentration of ISO during anaesthesia in dogs
Novel effects of strains in graphene and other two dimensional materials
The analysis of the electronic properties of strained or lattice deformed graphene combines ideas from classical condensed matter physics, soft matter, and geometrical aspects of quantum field theory (QFT) in curved spaces. Recent theoretical and experimental work shows the influence of strains in many properties of graphene not considered before, such as electronic transport, spin-orbit coupling, the formation of MoirĂ© patterns and optics. There is also significant evidence of anharmonic effects, which can modify the structural properties of graphene. These phenomena are not restricted to graphene, and they are being intensively studied in other two dimensional materials, such as the transition metal dichalcogenides. We review here recent developments related to the role of strains in the structural and electronic properties of graphene and other two dimensional compounds.We acknowledge the financial support of the following institutions: Fundação para a CiĂȘncia e a Tecnologia, Portugal, through Grant No. SFRH/BD/78987/2011 (BA); European Union through ESF funded-JAE doc program (AC); JAE-Pre (CSIC, Spain) (AGR); Juan de la Cierva Program (MINECO, Spain) and FCT-Portugal through Grant No. EXPL/FIS-NAN/1728/2013 (RR); ERC Advanced Grant 290846 (FG, VP); Spanish Ministry of Economy (MINECO) through Grant Nos. FIS2011-23713 (PSJ) and ` (RR); CONICET (PIP 0747) and ANPCyT (PICT 2012-1724) (MS); Spanish MECD grant PIB2010BZ-00512, and the European Union Seventh Framework Programme under Grant Agreement No. 604391 Graphene Flagship (MV, JS)
Identification of underlying and transfusion-related platelet qualitative alterations in the hemato-oncologic patient
Stemcel biology/Regenerative medicine (incl. bloodtransfusion
Mean ± SD of minimum alveolar concentration of isoflurane (MAC<sub>ISO</sub>) before (MAC<sub>ISO/BASAL</sub>) and after one of the following treatments (MAC<sub>ISO/T</sub>): lidocaine (LIDO), dexmedetomidine (DEX), or the combination LIDO-DEX in dogs (<i>n</i>â=â7).
<p>The percentage (%) change in MAC<sub>ISO</sub> after treatment was calculated from [(MAC<sub>ISO</sub> after treatment â MAC<sub>ISO/BASAL</sub>)/MAC<sub>ISO/BASAL</sub>] X 100.</p><p>*Statistically different from MAC<sub>ISO/BASAL</sub> (<i>p</i><0.05).</p>#<p>Statistically different from the rest of the treatments (<i>p</i><0.05).</p><p>Mean ± SD of minimum alveolar concentration of isoflurane (MAC<sub>ISO</sub>) before (MAC<sub>ISO/BASAL</sub>) and after one of the following treatments (MAC<sub>ISO/T</sub>): lidocaine (LIDO), dexmedetomidine (DEX), or the combination LIDO-DEX in dogs (<i>n</i>â=â7).</p
Mean ± SD of cardiovascular parameters and other variables measured immediately before the MAC determination of isoflurane (MAC<sub>ISO/BASAL</sub>) and immediately before the final MAC of isoflurane (MAC<sub>ISO/T</sub>) determination during constant rate infusion of lidocaine (LIDO), dexmedetomidine (DEX), or the combination LIDO-DEX.
#<p>Statistically different to baseline and to the rest of the treatments (<i>p</i><0.05).</p><p>Mean ± SD of cardiovascular parameters and other variables measured immediately before the MAC determination of isoflurane (MAC<sub>ISO/BASAL</sub>) and immediately before the final MAC of isoflurane (MAC<sub>ISO/T</sub>) determination during constant rate infusion of lidocaine (LIDO), dexmedetomidine (DEX), or the combination LIDO-DEX.</p