Publications by authors named "María de Miguel"

103 Publications

Prognostic impact of cardiac surgery in left-sided infective endocarditis according to risk profile.

Heart 2021 Sep 11. Epub 2021 Sep 11.

Department of Cardiology, Instituto de Ciencias del Corazón (ICICOR), Hospital Clínico Universitario Valladolid, Valladolid, Spain.

Objective: To evaluate the prognostic impact of urgent cardiac surgery on the prognosis of left-sided infective endocarditis (LSIE) and its relationship to the basal risk of the patient and to the surgical indication.

Methods: 605 patients with LSIE and formal surgical indication were consecutively recruited between 2000 and 2020 among three tertiary centres: 405 underwent surgery during the active phase of the disease and 200 did not despite having indication. The prognostic impact of urgent surgery was evaluated by multivariable analysis and propensity score analysis. We studied the benefit of surgery according to baseline mortality risk defined by the ENDOVAL score and according to surgical indication.

Results: Surgery is an independent predictor of survival in LSIE with surgical indication both by multivariable analysis (OR 0.260, 95% CI 0.162 to 0.416) and propensity score (mortality 40% vs 66%, p<0.001). Its greatest prognostic benefit is seen in patients at highest risk (predicted mortality 80%-100%: OR 0.08, 95% CI 0.021 to 0.299). The benefit of surgery is especially remarkable for uncontrolled infection indication (OR 0.385, 95% CI 0.194 to 0.765), even in combination with heart failure (OR 0.220, 95% CI 0.077 to 0.632).

Conclusions: Surgery during active LSIE seems to significantly reduce in-hospital mortality. The higher the risk, the higher the improvement in outcome.
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http://dx.doi.org/10.1136/heartjnl-2021-319661DOI Listing
September 2021

Safety and antitumor activity of α-PD-L1 antibody as monotherapy or in combination with α-TIM-3 antibody in patients with microsatellite instability-high/mismatch repair-deficient tumors.

Clin Cancer Res 2021 Aug 31. Epub 2021 Aug 31.

Department of Internal Medicine, Seoul National University College of Medicine.

Purpose: Immune checkpoint inhibitors show high response rates and durable clinical benefit in microsatellite instability-high/mismatch repair-deficient (MSI‑H/dMMR) tumors. However, 50 to 60% do not respond to single-agent anti-PD‑1/PD-L1 antibodies, and approximately 50% of responders relapse within 6 to12 months. This phase 1b trial evaluated safety and antitumor activity of anti-PD-L1 antibody LY3300054 monotherapy or in combination with anti-TIM-3 antibody LY3321367 in patients with MSI‑H/dMMR advanced solid tumors.

Experimental Design: Eligible patients {greater than or equal to}18 years without prior anti-PD‑1/PD‑L1 therapy received LY3300054 monotherapy (=40) or combination (=20); patients with PD-1/PD-L1 inhibitor-resistant/refractory tumors received the combination (=22). LY3300054 (700 mg) and anti-TIM-3 antibody (Cycles 1-2: 1200mg, Cycle 3 onwards: 600mg) were administered intravenously every 2 weeks. Primary endpoints were safety and tolerability.

Results: Eighty-two patients were enrolled. Most had colorectal (=39, 47.6%) or endometrial (=14, 17.1%) tumors. >70% of patients in the PD‑1/PD-L1 inhibitor-resistant/refractory combination cohort had received {greater than or equal to}3 treatment lines. Treatment-related adverse events (TRAEs) occurred in 22 patients (55.0%) receiving monotherapy, 13 (65.0%) in the PD‑1/PD-L1 inhibitor-naïve combination cohort, and 6 (27.3%) in the PD‑1/PD-L1 inhibitor-resistant/refractory combination cohort. 2 patients (5.0%) receiving monotherapy and 3 (7.1%) receiving the combination experienced grade {greater than or equal to}3 TRAEs. Objective responses occurred in 13 patients (32.5%) with monotherapy, 9 (45.0%) in the PD‑1/PD-L1 inhibitor-naive combination cohort, and 1 patient (4.5%) in the PD-1/PD-L1 inhibitor-resistant/refractory combination cohort.

Conclusions: LY3300054 monotherapy and combined LY3300054/anti-TIM-3 had manageable safety profiles. Both regimens showed promising clinical activity against PD-1/PD-L1 inhibitor-naïve MSI-H/dMMR tumors. The combination had limited clinical benefit in patients with PD-1/PD-L1 inhibitor-resistant/refractory MSI‑H/dMMR tumors.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-0261DOI Listing
August 2021

The Phospholipid -Methyltransferase and Phosphatidylcholine Synthase Pathways and the ChoXWV Choline Uptake System Involved in Phosphatidylcholine Synthesis Are Widely Conserved in Most, but Not All Species.

Front Microbiol 2021 4;12:614243. Epub 2021 Aug 4.

Dpto. de Microbiología y Parasitología, Instituto de Salud Tropical (ISTUN), Instituto de Investigación Sanitaria de Navarra, Universidad de Navarra, Pamplona, Spain.

The brucellae are facultative intracellular bacteria with a cell envelope rich in phosphatidylcholine (PC). PC is abundant in eukaryotes but rare in prokaryotes, and it has been proposed that uses PC to mimic eukaryotic-like features and avoid innate immune responses in the host. Two PC synthesis pathways are known in prokaryotes: the PmtA-catalyzed trimethylation of phosphatidylethanolamine and the direct linkage of choline to CDP-diacylglycerol catalyzed by the PC synthase Pcs. Previous studies have reported that and possess non-functional PmtAs and that PC is synthesized exclusively Pcs in these strains. A putative choline transporter ChoXWV has also been linked to PC synthesis in . Here, we report that Pcs and Pmt pathways are active in biovar 2 and that a bioinformatics analysis of genomes suggests that PmtA is only inactivated in and strains. We also show that ChoXWV is active in biovar 2 and conserved in all brucellae except and Unexpectedly, the experimentally verified ChoXWV dysfunction in did not abrogate PC synthesis in a PmtA-deficient mutant, which suggests the presence of an unknown mechanism for obtaining choline for the Pcs pathway in . We also found that ChoXWV dysfunction did not cause attenuation in biovar 2. The results of these studies are discussed with respect to the proposed role of PC in virulence and how differential use of the Pmt and Pcs pathways may influence the interactions of these bacteria with their mammalian hosts.
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http://dx.doi.org/10.3389/fmicb.2021.614243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8371380PMC
August 2021

Safety, pharmacokinetics, and efficacy of budigalimab with rovalpituzumab tesirine in patients with small cell lung cancer.

Cancer Treat Res Commun 2021 25;28:100405. Epub 2021 May 25.

Cancer Care Center, Blacktown Hospital, Sydney, NSW, Australia. Electronic address:

Background: Agents targeting programmed cell death protein 1 (PD-1) have been approved as monotherapy for patients with small cell lung cancer (SCLC). In preclinical models, the combined targeting of PD-1 and delta-like protein 3 resulted in enhanced antitumor activity. Herein, we report results from the expansion arm of study NCT03000257 evaluating the combination of the anti-PD-1 antibody budigalimab and the targeted antibody-drug conjugate rovalpituzumab tesirine (Rova-T) in patients with previously treated SCLC.

Materials And Methods: This expansion arm of a multicenter, open-label, multi-arm, first-in-human phase 1 clinical trial enrolled adult patients with progressive SCLC. The primary objective was to assess safety and tolerability. Patients received budigalimab 375 mg via intravenous infusion every 3 weeks, and Rova-T was administered as a dose of 0.3 mg/kg intravenously, on day 1 of the first and third 3-week cycle.

Results: As of October 2019, 31 patients with SCLC were enrolled and treated with budigalimab plus Rova-T. The combination was tolerated, with the most common treatment-emergent adverse events (in >30%) being pleural effusion, fatigue, and cough. The overall response rate was 24.1%, with one confirmed complete response and six confirmed partial responses. The overall response rate in patients with high delta-like protein 3 expression was similar (21.1%). The median progression-free survival was 3.48 months.

Conclusion: Combination therapy with budigalimab and Rova-T had promising efficacy and appeared to be tolerated in patients with SCLC. Although Rova-T development has been discontinued, development of budigalimab combined with other anticancer agents is ongoing.

Clinical Trial Registration Number: NCT03000257 Statement on originality of the work The manuscript represents original work and has not been submitted for publication elsewhere nor previously published. Statement of prior presentation Data from this study were previously presented at the European Society for Medical Oncology (ESMO) Congress 2019.
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http://dx.doi.org/10.1016/j.ctarc.2021.100405DOI Listing
May 2021

Toxicity and antitumor activity of novel agents in elderly patients with cancer included in phase 1 studies.

Invest New Drugs 2021 Jul 21. Epub 2021 Jul 21.

START Madrid-HM CIOCC, Centro Integral Oncológico Clara Campal, Hospital Universitario HM Sanchinarro, Calle Oña, 10. 28050, Madrid, Spain.

Introduction The number of cancer cases among the elderly continue to increase as the worldwide population ages. This patient subset is underrepresented in clinical trials, partly because of unresolved uncertainties about age-associated tolerabilities and antitumor activities. We reviewed phase 1 trial data to study tolerance and efficacy of novel agents used for treatment of elderly patients with cancer. Methods Data from 773 consecutive evaluable patients in 85 phase 1 clinical trials (2008-2016) at START Madrid-CIOCC were analyzed according to age, with respect to objective response, survival, and toxicity. Results The mean age was 58.7 (range: 18-87) years; 260 (33.6%) patients were >65 y (elderly group). One hundred thirty-seven (17.8%) patients received immunotherapy drugs, 308 (39.8%) received targeted agents, and 328 (42.4%) received chemotherapy. No statistically significant differences in overall survival, objective response, or severe toxicity rates were found according to treatment type. Similar toxicities and clinical activities were found between the two age subgroups; 18.8% of the elderly and 20.7% of the younger patients experienced severe hematological toxicity (p=0.5), and 30.2% and 32.7%, respectively, experienced severe non-hematological toxicity (p=0.4). Regarding antitumor activity, 12.4% of the elderly and 15% of the younger patients achieved objective responses (p=0.41). There were no significant between-group differences in overall survival (9.7 versus 11.5 months, respectively, p=0.1) or progression-free survival (2.3 versus 2.2 months, respectively, p=0.7). Conclusions This retrospective study found that elderly and younger populations had comparable antitumor activities and toxicity profiles. These results support including elderly patients with cancer in early-phase trials.
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http://dx.doi.org/10.1007/s10637-021-01150-1DOI Listing
July 2021

Adoptive cell therapy for solid tumors: Chimeric antigen receptor T cells and beyond.

Curr Opin Pharmacol 2021 08 19;59:70-84. Epub 2021 Jun 19.

START Madrid-CIOCC: Centro Integral Oncológico Clara Campal, Madrid, Spain.

Adoptive cell therapy with chimeric antigen receptor T cells has caused a significant revolution in the treatment of hematological malignancies. Unfortunately, for solid tumors, this treatment modality has been proven insufficient to achieve significant antitumor activity. The use of modified T cell receptors towards tumor-associated antigens (NY-ESO, MAGE-A4) has recently shown antitumor activity in synovial sarcoma. Also, treatment with tumor-infiltrating lymphocytes shows clinical activity in metastatic cervical cancer and melanoma resistant to checkpoint inhibitors. Strategies to improve results and broaden the applicability of therapeutic lymphocytes for solid tumors include local delivery, fourth generation chimeric antigen receptor T cells, off-the-shelf T lymphocytes and private neoantigen-directed cells, among others. In this review, we summarize the status of adoptive cell therapy using T cells for solid tumors and the investigational strategies being tested in this field.
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http://dx.doi.org/10.1016/j.coph.2021.05.004DOI Listing
August 2021

Priming human adipose-derived mesenchymal stem cells for corneal surface regeneration.

J Cell Mol Med 2021 06 5;25(11):5124-5137. Epub 2021 May 5.

CellTec-UB, Department of Cell Biology, University of Barcelona, Barcelona, Spain.

Limbal stem cells (LSC) maintain the transparency of the corneal epithelium. Chemical burns lead the loss of LSC inducing an up-regulation of pro-inflammatory and pro-angiogenic factors, triggering corneal neovascularization and blindness. Adipose tissue-derived mesenchymal stem cells (AT-MSC) have shown promise in animal models to treat LSC deficiency (LSCD), but there are not studies showing their efficacy when primed with different media before transplantation. We cultured AT-MSC with standard medium and media used to culture LSC for clinical application. We demonstrated that different media changed the AT-MSC paracrine secretion showing different paracrine effector functions in an in vivo model of chemical burn and in response to a novel in vitro model of corneal inflammation by alkali induction. Treatment of LSCD with AT-MSC changed the angiogenic and inflammatory cytokine profile of mice corneas. AT-MSC cultured with the medium that improved their cytokine secretion, enhanced the anti-angiogenic and anti-inflammatory profile of the treated corneas. Those corneas also presented better outcome in terms of corneal transparency, neovascularization and histologic reconstruction. Priming human AT-MSC with LSC specific medium can potentiate their ability to improve corneal wound healing, decrease neovascularization and inflammation modulating paracrine effector functions in an in vivo optimized rat model of LSCD.
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http://dx.doi.org/10.1111/jcmm.16501DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8178265PMC
June 2021

Inhibition of PKCε induces primordial germ cell reprogramming into pluripotency by HIF1&2 upregulation and histone acetylation.

Am J Stem Cells 2021 15;10(1):1-17. Epub 2021 Feb 15.

Cell Engineering Laboratory, La Paz University Hospital Health Research Institute IDiPAZ, Madrid, Spain.

Historically, primordial germ cells (PGCs) have been a good model to study pluripotency. Despite their low numbers and limited accessibility in the mouse embryo, they can be easily and rapidly reprogrammed at high efficiency with external physicochemical factors and do not require transcription factor transfection. Employing this model to deepen our understanding of cell reprogramming, we specifically aimed to determine the relevance of Ca signal transduction pathway components in the reprogramming process. Our results showed that PGC reprogramming requires a normal extracellular [Ca] range, in contrast to neoplastic or transformed cells, which can continue to proliferate in Ca-deficient media, differentiating normal reprogramming from neoplastic transformation. Our results also showed that a spike in extracellular [Ca] of 1-3 mM can directly reprogram PGC. Intracellular manipulation of Ca signal transduction pathway components revealed that inhibition of classical Ca and diacylglycerol (DAG)-dependent PKCs, or intriguingly, of only the novel DAG-dependent PKC, PKCε, were able to induce reprogramming. PKCε inhibition changed the metabolism of PGCs toward glycolysis, increasing the proportion of inactive mitochondria. This metabolic switch from oxidative phosphorylation to glycolysis is mediated by hypoxia-inducible factors (HIFs), given we found upregulation of both HIF1α and HIF2α in the first 48 hours of culturing. PKCε inhibition did not change the classical pluripotency gene expression of PGCs, Oct4, or Nanog. PKCε inhibition changed the histone acetylation of PGCs, with histones H2B, H3, and H4 becoming acetylated in PKCε-inhibited cultures (markers were H2BacK20, H3acK9, and H4acK5K8, K12, K16), suggesting that reprogramming by PKCε inhibition is mediated by histone acetylation.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8012778PMC
February 2021

A Predictive Score of Antitumour Activity of Novel Agents in Cancer Patients Treated in Early Phase Studies.

Oncology 2021 30;99(7):454-463. Epub 2021 Mar 30.

START Madrid-CIOCC Early Clinical Drug Development Program, Hospital Universitario HM Sanchinarro, Madrid, Spain.

Introduction: Phase I trials aim to determine the maximum-tolerated dose of a particular drug while minimizing the number of patients exposed to either sub-therapeutic doses or severe toxicity. Thus, patient selection for phase I trials is a key component of any clinical trial design. Though several studies have been made to address this issue, patient selection still represents a major clinical challenge that needs further investigation.

Methods: Twenty-nine baseline clinical and analytical characteristics of 773 consecutive patients treated in phase I trials between 2008 and 2016 in START Madrid-CIOCC were analysed and correlated to objective response (OR), progression-free survival, median overall survival, toxicity, and treatment type. The ones associated to OR in the univariate analysis were included in the stepwise logistic regression multivariate and Cox analysis. The statistically significant ones were included in a predictive score (named here as the Madrid score) of antitumour activity.

Results: Body mass index (BMI) >25 (p = 0.027), two or less previous lines of treatment (p = 0.007), and normal levels of alkaline phosphatase (ALP) (p = 0.007) were found to positively correlate to radiological response. A Madrid score was generated using these three factors as predictive parameters: compared to a score of 2-3 (where 2 or 3 of these variables are altered), a score of 0-1 is associated with longer survival time (11.6 vs. 8.6 months; p = 0.005) and overall response (17 vs. 7.6%; p = 0.003).

Conclusion: The predictive Madrid score, based on the BMI, number of prior lines of treatment, and ALP levels, might be helpful to accurately select patients who would benefit from oncology phase I clinical trials.
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http://dx.doi.org/10.1159/000515031DOI Listing
July 2021

Corneal Stromal Regeneration: A Review of Human Clinical Studies in Keratoconus Treatment.

Front Med (Lausanne) 2021 23;8:650724. Epub 2021 Feb 23.

Faculty of Sciences, GSBT Genomic Surveillance and Biotherapy Team, Mont Michel Campus, Lebanese University, Beirut, Lebanon.

The use of advanced therapies with stem cells to reconstruct the complex tissue of corneal stroma has gained interest in recent years. Besides, collagen-based scaffolds bioengineering has been offered as another alternative over the last decade. The outcomes of the first clinical experience with stem cells therapy on corneal stroma regeneration in patients with advanced keratoconus were recently reported. Patients were distributed into three experimental groups: Group 1 (G-1) patients underwent implantation of autologous adipose-derived adult stem cells ( alone, Group 2 (G-2) received a 120 μm decellularized donor corneal stromal laminas, and Group 3 (G-3) received a 120 μm recellularized donor laminas with . A follow up of 36 months of clinical data, and 12 months of confocal microscopy study was performed, the authors found significant clinical improvement in almost all studied mean values of primary and secondary outcomes. Corneal confocal microscopy demonstrated an increase in cell density in the host stroma, as well as in the implanted tissue. Using different approaches, allogenic small incision lenticule extraction implantation was applied in cases with advanced keratoconus. Some authors reported the implantation of intrastromal lenticules combined with accelerated collagen cross-linking. Others performed intrastromal implantation of negative meniscus-shaped corneal stroma lenticules. Others have compared the outcomes of penetrating keratoplasty () vs. small-incision Intralase femtosecond (IFS) intracorneal concave lenticule implantation (). Femtosecond laser-assisted small incision sutureless intrasotromal lamellar keratoplasty ( has been also investigated. The published evidence shows that the implantation of autologous , decellularized or recellularized human corneal stroma, allogenic lenticules corneal inlay, and recombinant cross-linked collagen have shown initially to be potentially effective for the treatment of advanced keratoconus. In light of the present evidence available, it can be said that the era of corneal stromal regeneration therapy has been already started.
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http://dx.doi.org/10.3389/fmed.2021.650724DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940685PMC
February 2021

Efficacy and safety of lurbinectedin and doxorubicin in relapsed small cell lung cancer. Results from an expansion cohort of a phase I study.

Invest New Drugs 2021 Oct 11;39(5):1275-1283. Epub 2021 Mar 11.

START Madrid - HM CIOCC, Hospital Madrid Norte Sanchinarro, Madrid, Spain.

Background A phase I study found remarkable activity and manageable toxicity for doxorubicin (bolus) plus lurbinectedin (1-h intravenous [i.v.] infusion) on Day 1 every three weeks (q3wk) as second-line therapy in relapsed small cell lung cancer (SCLC). An expansion cohort further evaluated this combination. Patients and methods Twenty-eight patients with relapsed SCLC after no more than one line of cytotoxic-containing chemotherapy were treated: 18 (64%) with sensitive disease (chemotherapy-free interval [CTFI] ≥90 days) and ten (36%) with resistant disease (CTFI <90 days; including six with refractory disease [CTFI ≤30 days]). Results Ten patients showed confirmed response (overall response rate [ORR] = 36%); median progression-free survival (PFS) = 3.3 months; median overall survival (OS) = 7.9 months. ORR was 50% in sensitive disease (median PFS = 5.7 months; median OS = 11.5 months) and 10% in resistant disease (median PFS = 1.3 months; median OS = 4.6 months). The main toxicity was transient and reversible myelosuppression. Treatment-related non-hematological events (fatigue, nausea, decreased appetite, vomiting, alopecia) were mostly mild or moderate. Conclusion Doxorubicin 40 mg/m and lurbinectedin 2.0 mg/m on Day 1 q3wk has shown noteworthy activity in relapsed SCLC and a manageable safety profile. The combination is being evaluated as second-line therapy for SCLC in an ongoing, randomized phase III trial. Clinical trial registration www.ClinicalTrials.gov code: NCT01970540. Date of registration: 22 October, 2013.
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http://dx.doi.org/10.1007/s10637-020-01025-xDOI Listing
October 2021

Corneal Stromal Regeneration Therapy for Advanced Keratoconus: Long-term Outcomes at 3 Years.

Cornea 2021 06;40(6):741-754

GSBT Genomic Surveillance and Biotherapy Team, Faculty of Sciences, Lebanese University, Hadath, Lebanon.

Purpose: To report the 3-year clinical outcomes of corneal stromal cell therapy consisting of the intrastromal implantation with autologous adipose-derived adult stem cells (ADASCs), and decellularized or ADASC-recellularized human donor corneal laminas in advanced keratoconus.

Methods: Fourteen patients were enrolled in 3 experimental groups. Group 1 (G-1) patients underwent implantation of ADASCs alone (3 × 10⁶ cells/1 mL) (n = 5). Group 2 (G-2) patients received a 120-μm decellularized corneal stroma lamina (n = 5). Group 3 (G-3) patients received a 120-μm lamina recellularized with ADASCs (1 × 10⁶ cells/1 mL) (n = 4). ADASCs were obtained by elective liposuction. Implantation was performed into a femtosecond pocket under topical anesthesia.

Results: At 3 years, a significant improvement of 1 to 2 logMAR lines in uncorrected distance visual acuity was observed in all groups. A statistically significant decrease in corrected distance visual acuity was obtained in G-2 and G-3 (P < 0.001) when compared with that of G-1. Rigid contact lens distance visual acuity showed a statistically significant worsening in G-2 (P < 0.001) compared with that of G-1. A statistically significant increase in central corneal thickness was observed in G-2 (P = 0.012) and G-3 (P < 0.001); in the Scheimpflug corneal topography, the thinnest point was observed in G-2 (P = 0.007) and G-3 (P = 0.001) when compared with that of G-1.

Conclusions: Intrastromal implantation of ADASCs and decellularized or ADASC-recellularized human corneal stroma laminas did not have complications at 3 years. The technique showed a moderate improvement in (uncorrected distance visual acuity) and (corrected distance visual acuity) in advanced keratoconus.
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http://dx.doi.org/10.1097/ICO.0000000000002646DOI Listing
June 2021

Glucose Oxidation to Pyruvate Is Not Essential for Biovar 5 Virulence in the Mouse Model.

Front Microbiol 2020 14;11:620049. Epub 2021 Jan 14.

Department of Microbiology and Parasitology, Facultad de Medicina, ISTUN Instituto de Salud Tropical, University of Navarra, Pamplona, Spain.

species cause brucellosis, a worldwide extended zoonosis. The brucellae are related to free-living and plant-associated α2- and, since they multiply within host cells, their metabolism probably reflects this adaptation. To investigate this, we used the rodent-associated biovar 5, which in contrast to the ruminant-associated and and other biovars, is fast-growing and conserves the ancestral Entner-Doudoroff pathway (EDP) present in the plant-associated relatives. We constructed mutants in Edd (glucose-6-phosphate dehydratase; first EDP step), PpdK (pyruvate phosphate dikinase; phosphoenolpyruvate ⇌ pyruvate), and Pyk (pyruvate kinase; phosphoenolpyruvate → pyruvate). In a chemically defined medium with glucose as the only C source, the Edd mutant showed reduced growth rates and the triple Edd-PpdK-Pyk mutant did not grow. Moreover, the triple mutant was also unable to grow on ribose or xylose. Therefore, biovar 5 sugar catabolism proceeds through both the Pentose Phosphate shunt and EDP, and EDP absence and exclusive use of the shunt could explain at least in part the comparatively reduced growth rates of and . The triple Edd-PpdK-Pyk mutant was not attenuated in mice. Thus, although an anabolic use is likely, this suggests that hexose/pentose catabolism to pyruvate is not essential for biovar 5 multiplication within host cells, a hypothesis consistent with the lack of classical glycolysis in all species and of EDP in and . These results and those of previous works suggest that within cells, the brucellae use mostly 3 and 4 C substrates fed into anaplerotic pathways and only a limited supply of 5 and 6 C sugars, thus favoring the EDP loss observed in some species.
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http://dx.doi.org/10.3389/fmicb.2020.620049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7840955PMC
January 2021

Blocking TIM-3 in Treatment-refractory Advanced Solid Tumors: A Phase Ia/b Study of LY3321367 with or without an Anti-PD-L1 Antibody.

Clin Cancer Res 2021 Apr 29;27(8):2168-2178. Epub 2021 Jan 29.

START Madrid, Centro Integral Oncológico Clara Campal, Madrid, Spain.

Purpose: T-cell immunoglobulin and mucin-domain-containing molecule-3 (TIM-3) blunts anticancer immunity and mediates resistance to programmed death 1 (PD-1) and PD ligand 1 (PD-L1) inhibitors. We assessed a novel, first-in-class, TIM-3 mAb, LY3321367, alone or in combination with the anti-PD-L1 antibody, LY300054 in patients with advanced solid tumor.

Patients And Methods: This open-label, multicenter, phase Ia/b study aimed to define the safety/tolerability and recommended phase II dose (RP2D) of LY3321367 with or without LY300054. Secondary objectives included pharmacokinetics/pharmacodynamics, immunogenicity, and efficacy. Biomarkers were assessed in exploratory analysis.

Results: No dose-limiting toxicities were observed in the monotherapy ( = 30) or combination ( = 28) dose escalation. LY3321367 treatment-related adverse events (≥2 patients) included pruritus, rash, fatigue, anorexia, and infusion-related reactions. Dose-proportional increase in LY3321367 concentrations was not affected by either LY300054 or antidrug antibodies (observed in 50%-70% of patients). Pharmacokinetic/pharmacodynamic modeling indicated 100% target engagement at doses ≥600 mg. LY3321367 RP2D was 1,200 mg biweekly for four doses followed by 600 mg every 2 weeks thereafter. In the non-small cell lung cancer monotherapy expansion cohort, outcomes varied by prior anti-PD-1 therapy response status: anti-PD-1/L1 refractory patients [ = 23, objective response rate (ORR) 0%, disease control rate (DCR) 35%, progression-free survival (PFS) 1.9 months] versus anti-PD-1/L1 responders ( = 14, ORR 7%, DCR 50%, PFS 7.3 months). In combination expansion cohorts ( = 91), ORR and DCR were 4% and 42%; CD8 infiltration in paired biopsies increased in approximately half these patients.

Conclusions: LY3321367 exhibited acceptable safety profile with favorable pharmacokinetics/pharmacodynamics but only modest antitumor activity. The therapeutic relevance of TIM-3 blockade requires further investigation.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-4405DOI Listing
April 2021

Safety and Clinical Activity of a New Anti-PD-L1 Antibody as Monotherapy or Combined with Targeted Therapy in Advanced Solid Tumors: The PACT Phase Ia/Ib Trial.

Clin Cancer Res 2021 Mar 23;27(5):1267-1277. Epub 2020 Nov 23.

Sarah Cannon Research Institute/Tennessee Oncology, Nashville, Tennessee.

Purpose: This phase Ia/Ib PACT study evaluated the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of a new programmed cell death ligand 1 (PD-L1) inhibitor, LY3300054, as monotherapy or in combination with ramucirumab, abemaciclib, or merestinib (a type II MET kinase inhibitor) in patients with advanced, refractory solid tumors (NCT02791334).

Patients And Methods: Patients were enrolled into cohorts of escalating LY3300054 dose (phase Ia) as monotherapy ( = 15) or combined with ramucirumab ( = 10), abemaciclib ( = 24), or merestinib ( = 12). The phase Ib dose expansion enrolled 8 patients with melanoma in the monotherapy arm and 12 patients with pancreatic cancer in the merestinib combination arm. Combination treatments were administered concurrently from day 1 of each cycle. A 14-day lead-in abemaciclib arm was also explored. Primary endpoints were dose-limiting toxicity (DLT) and safety.

Results: Treatment-related adverse events included fatigue and nausea in the monotherapy arm (13% for each), hypothyroidism (30%) in the ramucirumab arm, diarrhea (54%) in the abemaciclib arm, and nausea (25%) in the merestinib arm. DLTs associated with hepatoxicity were observed in 3 of 4 patients in the abemaciclib lead-in cohorts. No DLTs or grade 3 or 4 hepatoxicity were reported in the concurrent abemaciclib arm. Pharmacokinetic characteristics were comparable with other PD-L1 inhibitors. One patient in each arm experienced a partial response per RECIST v1.1 lasting ≥7 months.

Conclusions: LY3300054 was well tolerated without unexpected safety concerns when administered alone or concurrently with ramucirumab, abemaciclib, or merestinib. Lead-in abemaciclib before combining with LY3300054 was not feasible due to hepatotoxicity. Durable clinical benefits were seen in all regimens.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-2821DOI Listing
March 2021

Corneal Stroma Regeneration: New Approach for the Treatment of Cornea Disease.

Asia Pac J Ophthalmol (Phila) 2020 Dec;9(6):571-579

Cornea, Cataract, and Refractive Surgery Unit, Vissum Corporación, Alicante, Spain.

Corneal grafting is one of the most common forms of human tissue transplantation. The corneal stroma is responsible for many characteristics of the cornea. For these reasons, an important volume of research has been made to replicate the corneal stroma in the laboratory to find an alternative to classical corneal transplantation techniques.There is an increasing interest today in cell therapy of the corneal stroma using induced pluripotent stem cells or mesenchymal stem cells since these cells have shown to be capable of producing new collagen within the host stroma and even to improve its transparency.The first clinical experiment on corneal stroma regeneration in advanced keratoconus cases has been reported and included. Fourteen patients were randomized and enrolled into 3 experimental groups: (1) patients underwent implantation of autologous adipose-derived adult stem cells alone, (2) patients received decellularized donor corneal stroma laminas, and (3) patients received implantation of recellularized donor laminas with adipose-derived adult stem cells. Clinical improvement was detected with all cases in their visual, pachymetric, and topographic parameters of the operated corneas.Other recent studies have used allogenic SMILE implantation lenticule corneal inlays, showing also an improvement in different visual, topographic, and keratometric parameters.In the present report, we try to summarize the available preclinical and clinical evidence about the emerging topic of corneal stroma regeneration.
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http://dx.doi.org/10.1097/APO.0000000000000337DOI Listing
December 2020

Corneal stroma regeneration: Preclinical studies.

Exp Eye Res 2021 01 24;202:108314. Epub 2020 Oct 24.

Cornea, Cataract and Refractive Surgery Unit, Vissum (Miranza Group), Alicante, Spain; Division of Ophthalmology, Universidad Miguel Hernández, Alicante, Spain. Electronic address:

Corneal grafting is one of the most common and successful forms of human tissue transplantation in the world, but the need for corneal grafting is growing and availability of human corneal donor tissue to fulfill this increasing demand is not assured worldwide. The stroma is responsible for many features of the cornea, including its strength, refractive power and transparency, so enormous efforts have been put into replicating the corneal stroma in the laboratory to find an alternative to classical corneal transplantation. Unfortunately this has not been yet accomplished due to the extreme difficulty in mimicking the highly complex ultrastructure of the corneal stroma, and none of the obtained substitutes that have been assayed has been able to replicate this complexity yet. In general, they can neither match the mechanical properties nor recreate the local nanoscale organization and thus the transparency and optical properties of a normal cornea. In this context, there is an increasing interest in cellular therapy of the corneal stroma using Induced Pluripotent Stem Cells (iPSCs) or mesenchymal stem cells (MSCs) from either ocular or extraocular sources, as they have proven to be capable of producing new collagen within the host stroma, modulate preexisting scars and enhance transparency by corneal stroma remodeling. Despite some early clinical data is already available, in the current article we will summary the available preclinical evidence about the topic corneal stroma regeneration. Both, in vitro and in vivo experiments in the animal model will be shown.
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http://dx.doi.org/10.1016/j.exer.2020.108314DOI Listing
January 2021

Comparison of radiological criteria for hyperprogressive disease in response to immunotherapy.

Cancer Treat Rev 2020 Dec 29;91:102116. Epub 2020 Oct 29.

START Madrid-HM CIOCC, Centro Integral Oncológico Clara Campal, Hospital Universitario HM Sanchinarro, Calle Oña, 10, 28050 Madrid, Spain. Electronic address:

Hyperprogressive disease (HPD) is a concerning paradoxical acceleration of cancer growth induced by immune drugs. The lack of standard radiological criteria makes its study challenging. We reviewed the literature and compared the main criteria for HPD proposed by Ferté, Le Tourneau, Garralda and Caramella to address this relevant unmet need in Immune-oncology. Among 182 consecutive patients with advanced cancer treated with immunotherapy in early-phase clinical trials, 71 with progressive disease at the first evaluation were eligible. HPD patients were studied regarding tumor growth dynamics and clinical impact. HPD occurred in 17 (23.9%), 17 (23.9%), 23 (32.4%) and 6 (8.4%) patients, as defined by Ferté, Le Tourneau, Garralda and Caramella, respectively. The strongest association was found between the Ferté and Le Tourneau criteria (Kappa = 0.61), and the Jaccard similarity index varied from 55% (Ferté and Le Tourneau) to 21% (Le Tourneau and Caramella). The Ferté and Le Tourneau criteria showed statistically significant differences between pre-baseline and post-baseline tumor growth rate in patients with HPD, which could not be confirmed with the Caramella and Garralda criteria. Significant differences in progression-free survival were observed between non-hyperprogressors and hyperprogressors, with all criteria. The proportion of patients that could not receive additional lines of therapy was higher in the HPD group. HPD is an immunotherapy-related acceleration of tumor growth kinetics, with a consequent negative clinical impact. Pre-baseline CT scans and tumor growth rate evaluations are required to identify HPD. Our analysis favors the use of the Le Tourneau method, as it captures adequately the HPD phenomenon and is more convenient to use.
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http://dx.doi.org/10.1016/j.ctrv.2020.102116DOI Listing
December 2020

Intermittent schedules of the oral RAF-MEK inhibitor CH5126766/VS-6766 in patients with RAS/RAF-mutant solid tumours and multiple myeloma: a single-centre, open-label, phase 1 dose-escalation and basket dose-expansion study.

Lancet Oncol 2020 11 28;21(11):1478-1488. Epub 2020 Oct 28.

Drug Development Unit, The Institute of Cancer Research and the Royal Marsden NHS Foundation Trust, London, UK. Electronic address:

Background: CH5126766 (also known as VS-6766, and previously named RO5126766), a novel MEK-pan-RAF inhibitor, has shown antitumour activity across various solid tumours; however, its initial development was limited by toxicity. We aimed to investigate the safety and toxicity profile of intermittent dosing schedules of CH5126766, and the antitumour activity of this drug in patients with solid tumours and multiple myeloma harbouring RAS-RAF-MEK pathway mutations.

Methods: We did a single-centre, open-label, phase 1 dose-escalation and basket dose-expansion study at the Royal Marsden National Health Service Foundation Trust (London, UK). Patients were eligible for the study if they were aged 18 years or older, had cancers that were refractory to conventional treatment or for which no conventional therapy existed, and if they had a WHO performance status score of 0 or 1. For the dose-escalation phase, eligible patients had histologically or cytologically confirmed advanced or metastatic solid tumours. For the basket dose-expansion phase, eligible patients had advanced or metastatic solid tumours or multiple myeloma harbouring RAS-RAF-MEK pathway mutations. During the dose-escalation phase, we evaluated three intermittent oral schedules (28-day cycles) in patients with solid tumours: (1) 4·0 mg or 3·2 mg CH5126766 three times per week; (2) 4·0 mg CH5126766 twice per week; and (3) toxicity-guided dose interruption schedule, in which treatment at the recommended phase 2 dose (4·0 mg CH5126766 twice per week) was de-escalated to 3 weeks on followed by 1 week off if patients had prespecified toxic effects (grade 2 or worse diarrhoea, rash, or creatinine phosphokinase elevation). In the basket dose-expansion phase, we evaluated antitumour activity at the recommended phase 2 dose, determined from the dose-escalation phase, in biomarker-selected patients. The primary endpoints were the recommended phase 2 dose at which no more than one out of six patients had a treatment-related dose-limiting toxicity, and the safety and toxicity profile of each dosing schedule. The key secondary endpoint was investigator-assessed response rate in the dose-expansion phase. Patients who received at least one dose of the study drug were evaluable for safety and patients who received one cycle of the study drug and underwent baseline disease assessment were evaluable for response. This trial is registered with ClinicalTrials.gov, NCT02407509.

Findings: Between June 5, 2013, and Jan 10, 2019, 58 eligible patients were enrolled to the study: 29 patients with solid tumours were included in the dose-escalation cohort and 29 patients with solid tumours or multiple myeloma were included in the basket dose-expansion cohort (12 non-small-cell lung cancer, five gynaecological malignancy, four colorectal cancer, one melanoma, and seven multiple myeloma). Median follow-up at the time of data cutoff was 2·3 months (IQR 1·6-3·5). Dose-limiting toxicities included grade 3 bilateral retinal pigment epithelial detachment in one patient who received 4·0 mg CH5126766 three times per week, and grade 3 rash (in two patients) and grade 3 creatinine phosphokinase elevation (in one patient) in those who received 3·2 mg CH5126766 three times per week. 4·0 mg CH5126766 twice per week (on Monday and Thursday or Tuesday and Friday) was established as the recommended phase 2 dose. The most common grade 3-4 treatment-related adverse events were rash (11 [19%] patients), creatinine phosphokinase elevation (six [11%]), hypoalbuminaemia (six [11%]), and fatigue (four [7%]). Five (9%) patients had serious treatment-related adverse events. There were no treatment-related deaths. Eight (14%) of 57 patients died during the trial due to disease progression. Seven (27% [95% CI 11·6-47·8]) of 26 response-evaluable patients in the basket expansion achieved objective responses.

Interpretation: To our knowledge, this is the first study to show that highly intermittent schedules of a RAF-MEK inhibitor has antitumour activity across various cancers with RAF-RAS-MEK pathway mutations, and that this inhibitor is tolerable. CH5126766 used as a monotherapy and in combination regimens warrants further evaluation.

Funding: Chugai Pharmaceutical.
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http://dx.doi.org/10.1016/S1470-2045(20)30464-2DOI Listing
November 2020

T-cell-engaging Therapy for Solid Tumors.

Clin Cancer Res 2021 Mar 20;27(6):1595-1603. Epub 2020 Oct 20.

START Madrid-HM Centro Integral Oncológico Clara Campal (CIOCC) Early Phase Program, HM Sanchinarro University Hospital, Madrid, Spain.

T-cell engagers (TCE) are a rapidly evolving novel group of treatments that have in common the concurrent engagement of a T-cell surface molecule and a tumoral cell antigen. Bispecific antibodies and genetically engineered adoptive cell therapies, as chimeric antigen receptors or T-cell receptors, have similarities and differences among their mechanisms of action, toxicity profiles, and resistance pathways. Nevertheless, the success observed in the hematologic field has not been obtained with solid tumors yet, as they are biologically more complex and have few truly tumor-specific cell surface antigens that can be targeted with high avidity T cells. Different strategies are under study to improve their short-term perspective, such as new generations of more active TCEs, multi-target or combination of different treatments approaches, or to improve the manufacturing processes. A comprehensive review of TCEs as a grouped treatment class, their current status, and research directions in their application to solid tumors therapeutics are discussed here.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-2448DOI Listing
March 2021

Evidence of ongoing complement activation on adipose tissue from an 11-year-old girl with Barraquer-Simons syndrome.

J Dermatol 2020 Dec 5;47(12):1439-1444. Epub 2020 Sep 5.

Complement Research Group, Hospital La Paz Institute for Health Research (IdiPAZ), La Paz University Hospital, Madrid, Spain.

Barraquer-Simons syndrome (BSS), a form of acquired partial lipodystrophy, is a rare condition characterized by gradual loss of adipose tissue from the upper body, keeping intact the white adipose tissue of the lower extremities. The etiology of BSS is not well understood, and clinical follow-up studies have not been assessed in these patients. Moreover, no histological studies have been conducted during the active phase of the disease, and complement system activation products have not been sought in the affected areas. The objective of this work was to analyze the clinical, immunological and histological events in an 11-year-old girl with BSS over a 5-year follow-up period. Clinical data were collected during six regular visits for a time period of 5 years. The circulating levels of C3, C3adesArg (a product released upon C3 activation), C4 and immunoglobulins (Ig) were quantified in serum while fat tissue from lipoatrophic areas was examined by immunohistochemical and immunofluorescence approaches. In her regular visits, no clinical or laboratory abnormalities had been observed in the patient, except for the progression of lipoatrophy linked to the C3 hypocomplementemia and the occurrence of C3 nephritic factor. Adipose tissue from the patient showed atrophied and dead adipocytes, an abnormal production of extracellular matrix, and a remarkable accumulation of infiltrating CD68 macrophages and adipocyte precursors (marked by c-Kit positiveness). Simultaneous detection of IgG, C3, C5a and C5b-9 proved the ongoing complement activity and complement-directed injury within the adipose tissue. Our results showed the first evidence that the complement system hyperactivation occurs within the adipose tissue and is linked with fat loss in patients with BSS.
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http://dx.doi.org/10.1111/1346-8138.15570DOI Listing
December 2020

Clinical Challenges of Immune Checkpoint Inhibitors.

Cancer Cell 2020 09 3;38(3):326-333. Epub 2020 Aug 3.

START Madrid-HM CIOCC, Centro Integral Oncológico Clara Campal, Hospital Universitario HM Sanchinarro, Calle Oña, 10, 28050 Madrid, Spain. Electronic address:

Even though the immuno-oncology (IO) era has achieved many successes, some signs of research development deceleration are arising. Recently, the number of FDA immunotherapy approvals has decreased concurrently with a decline in the relative number of patients recruited to these trials. Identifying the unique features of IO treatments and taking them into consideration on clinical research will lead to a better evaluation of these agents and patient outcomes. In this review, we discuss current challenges and new potential approaches to implement rationally designed clinical trials of IO drugs, particularly those targeting immune checkpoints.
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http://dx.doi.org/10.1016/j.ccell.2020.07.004DOI Listing
September 2020

Development of attenuated live vaccine candidates against swine brucellosis in a non-zoonotic B. suis biovar 2 background.

Vet Res 2020 Jul 23;51(1):92. Epub 2020 Jul 23.

Instituto de Salud Tropical (ISTUN), Instituto de Investigación Sanitaria de Navarra (IdiSNA) and Dpto. de Microbiología y Parasitología, Universidad de Navarra, c/Irunlarrea 1, 31008, Pamplona, Spain.

Brucella is a genus of gram-negative bacteria that cause brucellosis. B. abortus and B. melitensis infect domestic ruminants while B. suis (biovars 1-3) infect swine, and all these bacteria but B. suis biovar 2 are zoonotic. Live attenuated B. abortus S19 and B. melitensis Rev1 are effective vaccines in domestic ruminants, though both can infect humans. However, there is no swine brucellosis vaccine. Here, we investigated the potential use as vaccines of B. suis biovar 2 rough (R) lipopolysaccharide (LPS) mutants totally lacking O-chain (Bs2ΔwbkF) or only producing internal O-chain precursors (Bs2Δwzm) and mutants with a smooth (S) LPS defective in the core lateral branch (Bs2ΔwadB and Bs2ΔwadD). We also investigated mutants in the pyruvate phosphate dikinase (Bs2ΔppdK) and phosphoenolpyruvate carboxykinase (Bs2ΔpckA) genes encoding enzymes bridging phosphoenolpyruvate and the tricarboxylic acid cycle. When tested in the OIE mouse model at the recommended R or S vaccine doses (10 and 10 CFU, respectively), CFU/spleen of all LPS mutants were reduced with respect to the wild type and decreased faster for the R than for the S mutants. At those doses, protection against B. suis was similar for Bs2ΔwbkF, Bs2Δwzm, Bs2ΔwadB and the Rev1 control (10 CFU). As described before for B. abortus, B. suis biovar 2 carried a disabled pckA so that a double mutant Bs2ΔppdKΔpckA had the same metabolic phenotype as Bs2ΔppdK and ppdK mutation was enough to generate attenuation. At 10 CFU, Bs2ΔppdK also conferred the same protection as Rev1. As compared to other B. suis vaccine candidates described before, the mutants described here simultaneously carry irreversible deletions easy to identify as vaccine markers, lack antibiotic-resistance markers and were obtained in a non-zoonotic background. Since R vaccines should not elicit antibodies to the S-LPS and wzm mutants carry immunogenic O-chain precursors and did not improve Bs2ΔwbkF, the latter seems a better R vaccine candidate than Bs2Δwzm. However, taking into account that all R vaccines interfere in ELISA and other widely used assays, whether Bs2ΔwbkF is advantageous over Bs2ΔwadB or Bs2ΔppdK requires experiments in the natural host.
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http://dx.doi.org/10.1186/s13567-020-00815-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7376850PMC
July 2020

Increased vulnerability of clinical research units during the COVID-19 crisis and their protection.

Cancer 2020 09 2;126(17):3907-3911. Epub 2020 Jun 2.

START Madrid-HM Centro Integral Oncológico Clara Campal (CIOCC) Early Phase Program, HM Sanchinarro University Hospital, Madrid, Spain.

Lay Summary: Currently, the complexity of clinical trial development in oncology is being further complicated by the coronavirus disease 2019 (COVID-19) pandemic, which is reducing the resources needed to comply with protocol-specific procedures while putting patients in units, who are already vulnerable, at increased general risk not only for COVID-19 infection but also with respect to their baseline disease. Individualizing the management of patients while ensuring their safety and adherence to the study protocol, establishing specific staff contingency plans, and maintaining sponsor and contract research organization (CRO) alignment are some of the key issues for maintaining the continuity of cancer patients' investigational treatment and minimizing their infection risk as well as the risk to staff members of the unit, sponsors, and CROs while maintaining the integrity of data quality and compliance with good clinical practice.
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http://dx.doi.org/10.1002/cncr.32980DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7300769PMC
September 2020

Reorganizing a Medicine Residency Program in Response to the COVID-19 Pandemic in New York.

Acad Med 2020 11;95(11):1670-1673

S. Chandra is program director, Internal Medicine Residency Program, associate vice chair of education, Department of Medicine, and associate professor of medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Columbia University Vagelos College of Physicians and Surgeons, New York, New York.

The COVID-19 pandemic has been particularly severe in New York City, resulting in a rapid influx of patients into New York-Presbyterian Hospital/Columbia University Irving Medical Center. The challenges precipitated by this pandemic have required urgent changes to existing models of care. Internal medicine residents are at the forefront of caring for patients with COVID-19, including the critically ill. This article describes the exigent restructuring of the New York-Presbyterian Hospital/Columbia University Internal Medicine Residency Program. Patient care and educational models were fundamentally reconceptualized, which required a transition away from traditional hierarchical team structures and a significant expansion in the program's capacity and flexibility to care for large numbers of patients with disproportionately high levels of critical illness. These changes were made while the residency program maintained the priorities of patient care and safety, resident safety and well-being, open communication, and education. The process of adapting the residency program to the demands of the pandemic was iterative given the unprecedented nature of this crisis. The goal of this article is to share the experiences and lessons learned from this crisis, communicate the solutions that were designed, and inform others who may be facing the prospect of creating similar disaster response measures.
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http://dx.doi.org/10.1097/ACM.0000000000003548DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7309644PMC
November 2020

Corneal Stroma Cell Density Evolution in Keratoconus Corneas Following the Implantation of Adipose Mesenchymal Stem Cells and Corneal Laminas: An In Vivo Confocal Microscopy Study.

Invest Ophthalmol Vis Sci 2020 04;61(4):22

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Purpose: To report the corneal stroma cell density evolution identified by in vivo corneal confocal microscopy in humans using injected autologous adipose-derived adult stem cells (ADASCs) and corneal decellularized laminas in corneas with advanced keratoconus.

Methods: Interventional prospective, consecutive, randomized, comparative series of cases. A total of 14 keratoconic patients were randomly distributed into three groups for three types of surgical interventions: group 1 (G-1), autologous ADASC implantation (n = 5); group 2 (G-2), decellularized human corneal stroma (n = 5); and group 3 (G-3), autologous ADASCs + decellularized human corneal stroma (n = 4).

Results: A gradual and significant increase (P < 0.001) was observed in the cellularity in the anterior and posterior stroma of patients in G-1, G-2, and G-3 a year after the surgery in comparison with the preoperative density level. The same result was observed at the mid-corneal stroma in G-1 and at the anterior and posterior surfaces and within the laminas in G-2 and G-3. The cell density of patients receiving ADASC recellularized laminas (G-3) was statistically significantly higher (P = 0.011) at the anterior surface and within the lamina (P = 0.029) and at the posterior surface than in those implanted only with decellularized laminas (G-2).

Conclusions: A significant increase in cell density occurred up to 1 postoperative year at the corneal stroma following the implantation of ADASCs alone, as well as in those cases implanted with decellularized and recellularized laminas at the different levels of the analysis. However, this increase was significantly higher in the ADASC recellularized laminas.
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http://dx.doi.org/10.1167/iovs.61.4.22DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7401496PMC
April 2020

Correction to: Rev1 wbdR tagged vaccines against Brucella ovis.

Vet Res 2020 Feb 19;51(1):13. Epub 2020 Feb 19.

Instituto de Salud Tropical (ISTUN), Instituto de Investigación Sanitaria de Navarra (IdiSNA) and Dpto. de Microbiología y Parasitología, Universidad de Navarra, c/Irunlarrea 1, 31008, Pamplona, Spain.

In the original publication of this article [1], the corresponding author points out Pilar M. Muñoz and Raquel Conde‑Alvarez contributed equally to this work.
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http://dx.doi.org/10.1186/s13567-020-00752-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7029569PMC
February 2020

Catathrenia resolved with the lowest CPAP pressure settings.

Pulmonology 2020 Mar - Apr;26(2):107-110. Epub 2020 Jan 30.

Pneumology Department, Hospital Fundación Jiménez Díaz, Spain. Electronic address:

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http://dx.doi.org/10.1016/j.pulmoe.2019.07.010DOI Listing
December 2020

Treatment of corneal endothelial damage in a rabbit model with a bioengineered graft using human decellularized corneal lamina and cultured human corneal endothelium.

PLoS One 2019 21;14(11):e0225480. Epub 2019 Nov 21.

Cell Engineering Laboratory, La Paz Hospital Research Institute, iDIPAZ, Madrid, Spain.

Objective: We aimed to investigate the functionality of human decellularized stromal laminas seeded with cultured human corneal endothelial cells as a tissue engineered endothelial graft (TEEK) construct to perform endothelial keratoplasty in an animal model of corneal endothelial damage.

Methods: Engineered corneal endothelial grafts were constructed by seeding cultured human corneal endothelial cell (hCEC) suspensions onto decellularized human corneal stromal laminas with various coatings. The functionality and survival of these grafts with cultured hCECs was examined in a rabbit model of corneal endothelial damage after central descemetorhexis. Rabbits received laminas with and without hCECs (TEEK and control group, respectively).

Results: hCEC seeding over fibronectin-coated laminas provided an optimal and consistent endothelial cell count density and polygonal shape on the decellularized laminas, showing active pump fuction. Surgery was performed uneventfully as standard Descemet stripping automated endothelial keratoplasty (DSAEK). Corneal transparency gradually recovered in the TEEK group, whereas haze and edema persisted for up to 4 weeks in the controls. Histologic examination showed endothelial cells of human origin covering the posterior surface of the graft in the TEEK group.

Conclusions: Grafting of decellularized stroma carriers re-surfaced with human corneal endothelial cells ex vivo can be a readily translatable method to improve visual quality in corneal endothelial diseases.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0225480PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6871783PMC
March 2020

Rev1 wbdR tagged vaccines against Brucella ovis.

Vet Res 2019 Nov 15;50(1):95. Epub 2019 Nov 15.

Instituto de Salud Tropical (ISTUN), Instituto de Investigación Sanitaria de Navarra (IdiSNA) and Dpto. de Microbiología y Parasitología, Universidad de Navarra, c/Irunlarrea 1, 31008, Pamplona, Spain.

Sheep brucellosis is a worldwide extended disease caused by B. melitensis and B. ovis, two species respectively carrying smooth or rough lipopolysaccharide. Vaccine B. melitensis Rev1 is used against B. melitensis and B. ovis but induces an anti-smooth-lipopolysaccharide response interfering with B. melitensis serodiagnosis, which precludes its use against B. ovis where B. melitensis is absent. In mice, Rev1 deleted in wbkC (Brucella lipopolysaccharide formyl-transferase) and carrying wbdR (E. coli acetyl-transferase) triggered antibodies that could be differentiated from those evoked by wild-type strains, was comparatively attenuated and protected against B. ovis, suggesting its potential as a B. ovis vaccine.
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http://dx.doi.org/10.1186/s13567-019-0714-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6858679PMC
November 2019
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