PARP inhibition can induce anti-neoplastic effects when used as monotherapy or in combination with chemo- or radiotherapy in various tumor settings; however, the basis for the anti-metastasic ...activities resulting from PARP inhibition remains unknown. PARP inhibitors may also act as modulators of tumor angiogenesis. Proteomic analysis of endothelial cells revealed that vimentin, an intermediary filament involved in angiogenesis and a specific hallmark of EndoMT (endothelial to mesenchymal transition) transformation, was down-regulated following loss of PARP-1 function in endothelial cells. VE-cadherin, an endothelial marker of vascular normalization, was up-regulated in HUVEC treated with PARP inhibitors or following PARP-1 silencing; vimentin over-expression was sufficient to drive to an EndoMT phenotype. In melanoma cells, PARP inhibition reduced pro-metastatic markers, including vasculogenic mimicry. We also demonstrated that vimentin expression was sufficient to induce increased mesenchymal/pro-metastasic phenotypic changes in melanoma cells, including ILK/GSK3-β-dependent E-cadherin down-regulation, Snail1 activation and increased cell motility and migration. In a murine model of metastatic melanoma, PARP inhibition counteracted the ability of melanoma cells to metastasize to the lung. These results suggest that inhibition of PARP interferes with key metastasis-promoting processes, leading to suppression of invasion and colonization of distal organs by aggressive metastatic cells.
Background
The measurement of blood glucose in critically ill patients is still performed in many ICUs with glucose meters and capillary samples. Several prevalent factors in these patients affect ...the accuracy of the results and should be interpreted with caution. A weak recommendation from the Surviving Sepsis Campaign (SSC) suggests the use of arterial blood rather than capillary blood for point of care testing using glucose meters.
Aims and objectives
To analyse the agreement between arterial, central venous, and capillary blood samples of glucose values measured by glucose meter in critically ill patients and study potential confounding factors.
Design
Prospective cross‐sectional study in a general intensive care unit (ICU). Patients needing insulin treatment (subcutaneous or intravenous) and blood glucose control were included.
Methods
Standardized collection of blood samples and measurement of glucose values with a glucometer. Agreement was studied by the Bland–Altman method and stratified analysis of disagreement‐survival plots was used to study the influence of haematocrit, pH range, SOFA score, capillary refilling time, intravenous insulin infusion, and lactic acid.
Results
A total of 297 measurements from 54 patients were included. The mean arterial blood glucose was 150.42 (range 31–345 mg/dL). In the graphical analysis, there is a poor agreement both in capillary and venous central to arterial samples, but in opposite direction (underestimation of capillary and overestimation of central venous). Factors associated with a reduction in the agreement between arterial and capillary samples were elevated lactate, poor capillary refilling, and hemodynamic failure. Patients without hemodynamic compromise have an acceptable agreement with values for absolute differences of 16 mg/dL for a disagreement of 10%.
Conclusions
In critically ill patients, the measurement of blood glucose with a glucose meter should be performed with arterial samples whenever possible. Capillary samples do not accurately estimate arterial blood glucose values in patients with shock and/or vasoactive drugs and underestimate the values in the range of hypoglycemia. Venous samples are subject to error because of potential contamination.
Relevance to clinical practice
This study adds support to the recommendation of using arterial blood rather than capillary or venous blood when using glucose meters in critically ill patients, especially in those with hemodynamic failure.
Poly(ADP-ribose) polymerase (PARP)-1, an enzyme that catalyzes the attachment of ADP ribose to target proteins, acts as a component of enhancer/promoter regulatory complexes. In the present study, we ...show that pharmacologic inhibition of PARP-1 with 3,4-dihydro-5-4-(1-piperidinyl)butoxyl-1(2H)-isoquinolinone (DPQ) results in a strong delay in tumor formation and in a dramatic reduction in tumor size and multiplicity during 7,12-dimethylbenz(a)anthracene plus 12-O-tetradecanoylphorbol-13-acetate-induced skin carcinogenesis. This observation was parallel with a reduction in the skin inflammatory infiltrate in DPQ-treated mice and tumor vasculogenesis. Inhibition of PARP also affected activator protein-1 (AP-1) activation but not nuclear factor-kappaB (NF-kappaB). Using cDNA expression array analysis, a substantial difference in key tumor-related gene expression was found between chemically induced mice treated or not with PARP inhibitor and also between wild-type and parp-1 knockout mice. Most important differences were found in gene expression for Nfkbiz, S100a9, Hif-1alpha, and other genes involved in carcinogenesis and inflammation. These results were corroborated by real-time PCR. Moreover, the transcriptional activity of hypoxia-inducible factor-1alpha (HIF-1alpha) was compromised by PARP inhibition or in PARP-1-deficient cells, as measured by gene reporter assays and the expression of key target genes for HIF-1alpha. Tumor vasculature was also strongly inhibited in PARP-1-deficient mice and by DPQ. In summary, this study shows that inhibition of PARP on itself is able to control tumor growth, and PARP inhibition or genetic deletion of PARP-1 prevents from tumor promotion through their ability to cooperate with the activation AP-1, NF-kappaB, and HIF-1alpha.
To determine the incidence of primary caregiver burden in a cohort of family members of critically ill patients admitted to ICU and to identify risk factors related to its development in both the ...patient and the family member.
Prospective observational cohort study was conducted for 24 months.
Hospital Universitario Clínico San Cecilio, Granada.
The sample was the primary caregivers of all patients with risk factors for development of PICS (Post-Intensive Care Syndrome).
The follow-up protocol consisted of evaluation 3 months after discharge from the ICU in a specific consultation.
The scales used in patients were Barthel, SF-12, HADS, Pfeiffer, IES-6 and in relatives the Apgar and Zarit.
A total of 93 patients and caregivers were included in the follow-up. 15 relatives did not complete the follow-up questionnaires and were excluded from the study. The incidence of PICS-F (Family Post Intensive Care Syndrome) defined by the presence of primary caregiver burden in our cohort of patients is 34.6% (n=27), 95% CI 25.0-45.7. The risk factors for the development of caregiver burden are the presence of physical impairment, anxiety or post-traumatic stress in the patient, with no relationship found with the characteristics studied in the family member.
One out of 3 relatives of patients with risk factors for the development of PICS presents at 3 months caregiver burden. This is related to factors dependent on the patient's state of health.
Artificial intelligence (AI) is rapidly fuelling a fundamental transformation in the practice of pathology. However, clinical integration remains challenging, with no AI algorithms to date in routine ...adoption within typical anatomic pathology (AP) laboratories. This survey gathered current expert perspectives and expectations regarding the role of AI in AP from those with first-hand computational pathology and AI experience.
Perspectives were solicited using the Delphi method from 24 subject matter experts between December 2020 and February 2021 regarding the anticipated role of AI in pathology by the year 2030. The study consisted of three consecutive rounds: 1) an open-ended, free response questionnaire generating a list of survey items; 2) a Likert-scale survey scored by experts and analysed for consensus; and 3) a repeat survey of items not reaching consensus to obtain further expert consensus.
Consensus opinions were reached on 141 of 180 survey items (78.3%). Experts agreed that AI would be routinely and impactfully used within AP laboratory and pathologist clinical workflows by 2030. High consensus was reached on 100 items across nine categories encompassing the impact of AI on (1) pathology key performance indicators (KPIs) and (2) the pathology workforce and specific tasks performed by (3) pathologists and (4) AP lab technicians, as well as (5) specific AI applications and their likelihood of routine use by 2030, (6) AI's role in integrated diagnostics, (7) pathology tasks likely to be fully automated using AI, and (8) regulatory/legal and (9) ethical aspects of AI integration in pathology.
This systematic consensus study details the expected short-to-mid-term impact of AI on pathology practice. These findings provide timely and relevant information regarding future care delivery in pathology and raise key practical, ethical, and legal challenges that must be addressed prior to AI's successful clinical implementation.
No specific funding was provided for this study.
Introduction: KDRI/KDPI are tools use in kidney donor evaluation. It has been proposed as a substitute of, or complementary to preimplantation renal biopsy. These scores have not been validated in ...Spain. Objective: (1) To investigate the concordance between KDPI and histological scores (preimplantation renal biopsy) and (2) to assess the relationship between KDRI, KDPI and histological score on graft survival in the expanded criteria donors group. Methodology: Retrospective cohort study from 1 January 1998 to 31 December 2010. Results: During the study 120 donors were recruited, that resulted in 220 preimplantation renal biopsies. 144 (65%) grafts were considered suitable for kidney transplantation. 76 (34.5%) were discarded. Median follow up has been 6.4 years (sd 3.9). Median age 63.1 years (sd 8.2), males (145; 65.9%), non-diabetic (191; 86.8%) and without another cardiovascular risk factors (173; 78.6%). 153 (69.5%) donors died of cerebrovascular disease. There were significant differences in KDRI/KDPI score in both groups 1.56/89 (sd 0.22) vs 1.66/93 (sd 0.15), p < 0.01. The KDPI showed moderate concordance and correlation with the histological score (AUC 0.64/correlation coefficient 0.24, p < 0.01). KDPI (HR 24.3, p < 0.01) and KDRI (HR 23.3, p < 0.01) scores were associated with graft survival in multivariate analysis. Conclusion: (1) KPDI and histological scores show moderate concordance. The utility of both scores as combined tools it has to be determined. (2) KDPI score, and especially KDRI score, are valid for estimating graft survival and combined with the biopsy can help to individualized decision making in the expanded criteria donors pool. Resumen: Introducción: El KDRI y su variante KDPI son dos herramientas utilizadas para la valoración del donante renal. Se ha propuesto la utilidad del KDPI como sustituto/complementario a la biopsia renal preimplantación. Estos scores no están validados en España. Objetivo: 1) Investigar la concordancia entre los scores KDPI e histológico (biopsia renal preimplantación), y 2) valorar la relación entre el KDRI, KDPI y la puntuación histológica sobre la supervivencia del injerto, en donantes con criterios expandidos (ECD). Metodología: Estudio de cohortes, unicéntrico, retrospectivo desde el 1 de enero de 1998 hasta el 31 de diciembre de 2010. Resultados: Se reclutaron 120 donantes y 220 biopsias preimplantación. Ciento cuarenta y cuatro (65,5%) injertos fueron aptos para trasplante. Setenta y seis (34,5%) fueron descartados. Tiempo medio de seguimiento 6,4 años (ds 3,9). Edad media de los donantes 63,1 años (ds 8,2), varones (145; 65,9%), no diabéticos (191; 86,8%) y sin otros factores de riesgo cardiovascular (173; 78,6%). Causa de muerte mayoritaria ACV hemorrágico (153; 69,5%). La puntuación KDPI media entre los grupos riñón válido (1,56/89; ds 0,22) y no válido (1,66/93; ds 0,15) es estadísticamente significativa (p < 0,01). El KDPI mostró una concordancia y correlación moderadas con el score histológico (AUC 0,64/coeficiente de correlación 0,24, p < 0,01). Los scores KDPI (HR 24,3, p < 0,01) y KDRI (HR 23,3, p < 0,01) están relacionados con la supervivencia del injerto en el análisis multivariante. Conclusión: 1) Los scores KDPI e histológico presentan una concordancia moderada. 2) Las puntuaciones KDPI, y sobre todo KDRI, son válidas para estimar la supervivencia de los injertos y pueden ser utilizadas de forma combinada con la biopsia para la toma de decisiones individualizadas en el grupo de donantes con criterios expandidos. Keywords: Expanded criteria donors, KDPI, Renal kidney graft survival, Preimplantation kidney biopsy, Palabras clave: Donante con criterios expandidos, KDPI, Supervivencia del injerto renal, Biopsia preimplantación
We investigate the clinical and pathological features related to variations in colorectal tumour apoptosis, proliferation and angiogenesis and the influence of the latter in short-term mortality (2 ...years); 551 tumour samples from a prospective cohort of patients with colorectal cancer were examined and tumour biology markers were determined as follows: percentage of apoptotic cells, by the terminal deoxynucleotidyl transferase (TdT) dUTP Nick-End Labeling technique; Ki-67 antigen, as a cell proliferation marker and density of microvessels (as a marker of angiogenesis). An increase in the percentage of cellular apoptosis is significantly related to the presence of poorly differentiated tumours, with vascular invasion (p < 0.001). The CD105 angiogenesis marker is not related to any clinical–pathological parameter except that of higher frequency in older patients (p = 0.03). Ki-67 is more frequently expressed in tumours with less nervous invasion (p = 0.05). Neither apoptosis nor angiogenesis present any significant association with short-term survival. The only marker clearly related to 2-year survival is Ki-67, which is shown to be a good prognostic factor in the multivariate analysis (hazard ratio = 0.49; 95% confidence interval = 0.27–0.90). Therefore, in a prospective cohort of colorectal cancer patients, only Ki-67 is a marker of good prognosis in short-term follow-up.
Background
Small cell lung cancer (SCLC) is a leading cause of death all over the world. Diagnostic and therapeutic arsenals have improved in recent years, but we are unsure as to whether these ...advances have been transferred to clinical practice. The aim of this study was to evaluate differences in SCLC diagnostic processes and short‐term survival rates between two recent cohorts.
Methods
A prospective, observational study was conducted with patients diagnosed with SCLC (either at extensive or limited stages) in the 2011‐2016 period. Patients were divided into two cohorts (2011‐2013 and 2014‐2016) and followed up for 1 year after diagnosis.
Results
Around 713 patients with lung cancer were selected, 134 of whom had SCLC (74 patients in the 2011‐2013 cohort and 60 in the 2014‐2016 cohort). We observed a chronological increase in the use of endobronchial ultrasound transbronchial needle aspiration (EBUS‐TBNA) and positron emission tomography‐computed tomography (PET‐CT) between the cohorts. Overall, short‐term survival was similar between the two groups and improved survival was associated with age and limited stage.
Conclusions
Changes in diagnostic process in SCLC have been observed towards a more precise stadification. Although short‐term survival has not changed for SCLC, it is unclear that the real benefit of PET‐CT and EBUS‐TBNA is far from correct disease staging.
Familial Platelet Disorder with associated Myeloid Malignancy (FPDMM) is a rare platelet disorder caused by mutations in RUNX1. We generated an iPSC line (GENYOi005-A) from a FPDMM patient with a ...non-previously reported variant p.Thr196Ala. Non-integrative Sendai viruses expressing the Yamanaka reprogramming factors were used to reprogram peripheral blood mononuclear cells from this FPDMM patient. Characterization of GENYOi005-A included genetic analysis of RUNX1 locus, Short Tandem Repeats profiling, alkaline phosphatase enzymatic activity, expression of pluripotency-associated factors and differentiation studies in vitro and in vivo. This iPSC line will provide a powerful tool to study developmental alterations of FPDMM patients.
Non-small cell lung cancer (NSCLC) is a leading cause of death all over the world. Diagnostic and therapeutic arsenals have improved in recent years, but we are unsure as to whether these advances ...have been transferred to clinical practice. The aim of this study was to evaluate differences in NSCLC diagnostic processes and short-term survival rates between two recent cohorts.
A prospective, observational study was conducted with patients diagnosed with NSCLC in the period of 2011-2016. Patients were divided into two cohorts (2011-2013 and 2014-2016), and monitored for up to 1 year after diagnosis.
A total of 713 patients with lung cancer were selected, 500 of whom had NSCLC (222 patients in the 2011-2013 cohort, and 278 in the 2014-2016 cohort). We observed a chronological increase in the use of endobronchial ultrasound transbronchial needle aspiration (EBUS-TBNA) and ultrasound-guided transthoracic puncture (US-TTP) between the cohorts. Overall short-term survival was similar between the two groups, both for locally and for advanced disease. Treatment with tyrosine kinase inhibitors (TKI) was the only therapeutic factor associated with an improved likelihood of survival.
Changes in diagnostic process in NSCLC have been observed towards a more precise stratification. Although short-term survival has not changed for advanced NSCLC, some of the newer therapeutic options are associated with increased survival in real-world scenarios.
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