Accurate etiologic diagnosis provides an appropriate secondary prevention and better prognosis in ischemic stroke (IS) patients; still, 45% of IS are cryptogenic, urging us to enhance diagnostic ...precision. We have studied the transcriptomic content of plasma extracellular vesicles (EVs) (
= 21) to identify potential biomarkers of IS etiologies. The proteins encoded by the selected genes were measured in the sera of IS patients (
= 114) and in hypertensive patients with (
= 78) and without atrial fibrillation (AF) (
= 20). IGFBP-2, the most promising candidate, was studied using immunohistochemistry in the IS thrombi (
= 23) and atrium of AF patients (
= 13). In vitro, the IGFBP-2 blockade was analyzed using thromboelastometry and endothelial cell cultures. We identified 745 differentially expressed genes among EVs of cardioembolic, atherothrombotic, and ESUS groups. From these, IGFBP-2 (cutoff > 247.6 ng/mL) emerged as a potential circulating biomarker of embolic IS OR = 8.70 (1.84-41.13)
= 0.003, which was increased in patients with AF vs. controls (
< 0.001) and was augmented in cardioembolic vs. atherothrombotic thrombi (
< 0.01). Ex vivo, the blockage of IGFBP-2 reduced clot firmness (
< 0.01) and lysis time (
< 0.001) and in vitro, diminished endothelial permeability (
< 0.05) and transmigration (
= 0.06). IGFBP-2 could be a biomarker of embolic IS and a new therapeutic target involved in clot formation and endothelial dysfunction.
The debate about surgical resection of primary tumor (PT) in de novo metastatic breast cancer (MBC) patients persists. We explored this approach's outcomes in patients included in a retrospective ...registry, named El Álamo, of breast cancer patients diagnosed in Spain (1990-2001). In this analysis we only included de novo MBC patients, 1415 of whom met the study's criteria. Descriptive, Kaplan-Meier and Cox regression analyses were carried out. Median age was 63.1 years, 49.2% of patients had single-organ metastasis (skin/soft tissue 16.3%, bone 33.8%, or viscera 48.3%). PT surgery (S) was performed in 44.5% of the cases. S-group patients were younger, had smaller tumors, higher prevalence of bone and oligometastatic disease, and lower prevalence of visceral involvement. With a median follow-up of 23.3 months, overall survival (OS) was 39.6 versus 22.4 months (HR = 0.59, p < 0.0001) in the S- and non-S groups, respectively. The S-group OS benefit remained statistically and clinically significant regardless of metastatic location, histological type, histological grade, hormone receptor status and tumor size. PT surgery (versus no surgery) was associated with an OS benefit suggesting that loco-regional PT control may be considered in selected MBC patients. Data from randomized controlled trials are of utmost importance to confirm these results.
Hajdu–Cheney Syndrome: A Systematic Review of the Literature Cortés-Martín, Jonathan; Díaz-Rodríguez, Lourdes; Piqueras-Sola, Beatriz ...
International journal of environmental research and public health,
08/2020, Letnik:
17, Številka:
17
Journal Article
Recenzirano
Odprti dostop
Hajdu–Cheney syndrome (HCS) is a rare genetic disease that causes acroosteolysis and generalized osteoporosis, accompanied by a series of developmental skeletal disorders and multiple clinical and ...radiological manifestations. It has an autosomal dominant inheritance, although there are several sporadic non-hereditary cases. The gene that has been associated with Hajdu-Cheney syndrome is NOTCH2. The described phenotype and clinical signs and symptoms are many, varied, and evolve over time. As few as 50 cases of this disease, for which there is currently no curative treatment, have been reported to date. The main objective of this systematic review was to evaluate the results obtained in research regarding Hajdu–Cheney Syndrome. The findings are reported in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines and were registered on the web PROSPERO under the registration number CRD42020164377. A bibliographic search was carried out using the online databases Orphanet, PubMed, and Scielo; articles from other open access sources were also considered. Finally, 76 articles were included, and after their analysis, we have obtained a series of hypotheses as results that will support further studies on this matter.
Thermoelectric cooling heating unit prototype Martín-Gómez, César; Ibáñez-Puy, María; Bermejo-Busto, Javier ...
Building services engineering research & technology,
07/2016, Letnik:
37, Številka:
4
Journal Article
Recenzirano
The article describes from an architectonical point of view the design, assembly, and energy behavior of a prototype for air-conditioning in residential buildings using Peltier cells, which means the ...application in the field of construction of a technology used in very specific areas. The new system has been designed as an independent, prefabricated, modular construction element that must fit perfectly between the structural floors and is easily adapted to the demands of different buildings. The thermoelectric cooling heating unit is designed to offer a high level of comfort to those living in the building. The only mechanical elements are the dissipation heat fans placed on the outside of the prototype, and heat sinks to transfer the heat from the power elements, reducing the possibilities of failure. The result of all these ideas is the construction of a prefabricated module, consisting of a simplified inhabited housing unit with a thermoelectric installation serving the module, which has obtained a national patent. The results of the thermal and electric behavior demonstrate that the system does not work as well as had been expected; nevertheless, the system has a high potential for its use in buildings associated with photovoltaic.
Practical application: The system opens new ways to the air-conditioning without using the traditional concepts of primary and secondary loop, because the system is highly independent. Their applications could be in building refurbishment where other systems involving the use of water or air are complicated to implement, in spaces where security and resilience are crucial factors (such as surgeries or computer server rooms), or those situations with extreme maximum and minimum temperatures or irregular electrical supply, as those could exist when the army must intervene or an humanitarian disaster occurs.
The aim of this study was to assess the physical activity level of health care professionals, as well as the differences by sex, age, academic background, and among different health care ...professions.This is an cross-sectional study.Health care settings in the Valencian Community, Spain.A total of 647 health care professionals.Physical activity was assessed with the European Health Interview Survey-Physical Activity Questionnaire (EHIS-PAQ) that includes the assessment of work-related physical activity, transport-related physical activity, health-enhancing physical activity, muscle-strengthening physical activity, and total physical activity.93.51% of all health care professionals were physically active at work. Transport-related physical activity and health-enhancing physical activity were significantly lower in women (21.62% vs 41.86%, P < .001; and 50.19% vs 68.99%, P < .001, respectively). In addition, compliance with health-enhancing and muscle-strengthening physical activity guidelines were lower in older professionals (42.7% vs 61.84%, P < .001; and 47.57% vs 61.84%, P < .001, respectively). Those with higher education were more compliant with health-enhancing and muscle-strengthening physical activity guidelines (58.55% vs 45.69%, P = .002; and 60.24% vs 48.28%, P = .003, respectively). Moreover, 67.98% of physiotherapists performed health-enhancing physical activity and 67.54% muscle-strengthening physical activity regularly, and significant differences in all outcomes were observed compared to the rest of health care professionals (P < .05). Technicians showed lower work-related and total physical activity than nurses and nursing assistants (74.55% vs 90.37%, P = .002; and 83.64% vs 95.72%, P < .001, respectively). Additionally, nursing assistants showed higher work-related physical activity compared to nurses (97.18% vs 90.37%, P = .008).Most health care professionals showed an appropriate level of physical activity. Men performed more transport-related and health-enhancing physical activity than women. Younger professionals and those with higher education were more compliant with health-enhancing and muscle-strengthening physical activity guidelines. Physiotherapists were more physically active when compared to the rest of health care professionals.
•Technical description of a second version of a thermoelectric cooling-heating unit.•Performance testing of a thermoelectric cooling-heating unit under real conditions.•Future improvements from a ...theoretical analysis.
A Thermoelectric Cooling-Heating Unit (TCHU) is an innovative technology that uses the thermoelectric phenomena as a heating–cooling system for buildings. In TCHU, a direct current (DC) electrical current supplies the power to a Thermoelectric Equipment (TE) heat-pump system, which can transfer heat in one direction or another depending on the current flow. The unit is integrated in the building envelope.
At this stage of the study, a second prototype of TCHU has been developed using commercially available TE technologies. In this case, a vertical configuration of 16 TE modules is studied for their potential application as a heating and cooling system for residential buildings.
Different nocturnal tests have been developed to evaluate the performance of the new system under real conditions and to determine the coefficient of performance for these TE modules when operating under different voltage regimes. It has been studied not only the cooling mode but also the heating mode.
Based on the measured data, it has been demonstrated that the system can be successfully installed as a heating or cooling system in buildings.
Tests have confirmed the huge relevance of the temperature difference between the two sides of the cells, taking especial relevance in the cooling mode. It has also been demonstrated that for the cooling mode it is better to work with low voltage values.
Besides, some theoretical analyses have been developed in order to find out the most suitable configuration to obtain the best Coefficient of Performance (COP) of the unit in both cooling and heating.
Abstract
Background: CDK 4/6 inhibitors (CDK 4/6i) with endocrine therapy (ET) combination therapy have improved outcomes in patients (pts) with hormonal receptor positive (HR+)/human epidermal ...growth factor receptor negative (HER2-) advanced breast cancer (ABC). However, most pts eventually develop resistance to these drugs, and one third never respond. Aside from HR positivity, predictive markers of clinical benefit from CDK 4/6i remains elusive. We aimed to identify biomarkers of response to palbociclib (PAL) and analyze potential therapeutic targets to reverse resistance. Methods: PEARL trial is a multicenter phase 3 study that assigned 601 postmenopausal HR+/HER2- ABC pts, whose disease progressed on aromatase inhibitors (AIs), to receive PAL + ET vs capecitabine (CAPE). We performed a differential gene expression analysis in pre-treatment tumors in extreme responders to PAL using the HTG EdgeSeq Oncology Biomarker Panel (HTG Molecular Diagnostics, Inc.), containing 2534 cancer related genes. Samples were subset in 2 categories: refractory (progressive disease as best response) vs sensitive (progression-free survival (PFS) within the upper quartile). Cox regression and Significance Analysis of Microarrays (SAM) analysis adjusting for multiple comparisons were performed. Results: We analyzed 455 (75.7%) pts with pre-treatment tumors available from them, PAL + ET arm: 229 (50.3%) pts; CAPE arm: 226 (49.7%) pts. Fifty genes (false discovery rate (FDR)<0.05) were differentially expressed in pts sensitive vs refractory to PAL (E2F target genes, epithelial-to-mesenchymal transition (EMT) and cell cycle genes, mainly). Unsupervised hierarchical clustering of pts based on the expression of these genes revealed two clusters. Cluster 1 is composed mostly of resistant tumors, highly proliferative (Ki67≥20%: 70%) with a great proportion of luminal B (59%) and non-luminal tumors (19%). Cluster 2 is composed of sensitive, low proliferative (Ki67<20%: 58%), mostly luminal A tumors (75%). There was no difference in ESR1 mutations distribution between the two clusters (Table 1). Forty genes were up-regulated and associated with resistance, including CCNE1 and PLK1 (Polo Like Kinase 1). In the whole cohort, pts with high levels (> median) of PLK1 (PLK1-high) treated with PAL, had a worse PFS in a multivariate model (5.7 months (m) vs 9.3 m of median PFS in PLK1-High vs -Low; HR=1.64, 95% CI (1.25-2.34), p=0.0008; adjusted model for confounders: age, site of disease, sites of metastasis, prior chemotherapy and Ki67). There were no differences in population treated with CAPE (9.9 m vs 9.4 m, PLK1-High vs -Low; HR=0.82, 95% CI (0.56-1.21), p=0.3189). In the METABRIC cohort, PLK1-High was associated with worse overall survival in HR+/HER2- BC but not in triple negative nor in HER2+ tumors. Among HR+/HER2- tumors, PLK1 expression was higher in luminal B and HER2-enriched intrinsic subtypes. We interrogated DepMap database and found that in BC cells lines there was an inverse correlation between PLK1 expression and effect on cell viability of CDK4 CRISPR knock-out (Pearson correlation r:0.54, p=0.009), but not of CDK6 knock-out. Also, HR+/HER2-/High Ki67 BC cell lines (HCC1428, EFM19 and MCF7) showed resistance to PAL on cell proliferation assays but sensitivity to the PLK1 inhibitor BI-2536. Conclusion: High expression of PLK1 is associated with intrinsic resistance to PAL and ET, this might be overcome with PLK1 inhibition.
Table 1PATIENT CHARACTERISTICSCluster 1Cluster 2ALLn=57n=47n=104RespondersSensitive42 (73.68%)14 (29.79%)56 (53.85%)Refractory15 (26.32%)33 (70.21%)48 (46.15%)ESR1Mutated9 (15.79%)13 (27.66%)22 (21.15%)Wild type45 (78.95%)34 (72.34%)79 (75.96%)Unknown3 (5.26%)0 (0%)3 (2.88%)PriorQTN42 (73.68%)31 (65.96%)73 (70.19%)Y15 (26.32%)16 (34.04%)31 (29.81%)SubtypeLumA43 (75.44%)10 (21.28%)53 (50.96%)LumB14 (24.56%)28 (59.57%)42 (40.38%)Non Luminal0 (0%)9 (19.15%)9 (8.65%)MetastasisOne21 (36.84%)15 (31.91%)36 (34.62%)Multiple36 (63.16%)32 (68.09%)68 (65.38%)KI67 20%KI67<2033 (57.89%)7 (14.89%)40 (38.46%)KI67≥2016 (28.07%)33 (70.21%)49 (47.12%)Unknown8 (14.04%)7 (14.89%)15 (14.42%)Objective ResponseComplete1 (1.75%)0 (0%)1 (0.96%)Partial16 (28.07%)6 (12.77%)22 (21.15%)Progressive15 (26.32%)33 (70.21%)48 (46.15%)Stable25 (43.86%)8 (17.02%)33 (31.73%)
Citation Format: Angel Guerrero- Zotano, Christoph Zielinski, Miguel Gil-Gil, Manuel Ruiz-Borrego, Eva M. Ciruelos, Montserrat Munoz, Begoña Bermejo, Mireia Margeli, Antonio Antón, Tibor Csöszi, Andrés García-Palomo, Ana Santaballa, Jose Luis Alonso, Antonio Fernández, Massimo Corsaro, Jesús Herranz, Paula López, Rosalia Caballero, Christiane Thallinger, Miguel Martin. Plk1 expression & efficacy of palbociclib in advanced hormonal receptor-positive breast cancer patients from PEARL study (GEICAM 2012-03) abstract. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS2-01.
Abstract Background: Pregnancy-Associated Breast Cancer (PABC) is defined as BC diagnosed during pregnancy, breastfeeding, or within the first year postpartum. This challenging entity has a distinct ...biology and worst prognosis and presents an increased risk for metastasis and death compared to non-PABC patients. Identification of molecular pathways that define this malignancy is crucial to explain its biological characteristics and potential association with pregnancy as well as serve to identify new biomarkers with preventive and clinical implications. This study assesses the gene expression profile of a PABC cohort from the Registry Study of Pregnancy and Breast Cancer (GEICAM/2017-07 EMBARCAM study, NCT04603820) to identify distinct molecular signatures and altered pathways for this entity. Methods: This was a multicenter, observational and ambispective age-matched cohort of PABC patients (n=46) and non-PABC patients (n=49). We analyzed the expression of 776 genes involved in 23 key breast cancer pathways, using the nCounter® Breast Cancer 360™ Panel (NanoString Technologies) on BC tumor samples, including molecular subtypes by PAM50 gene signature. Associations between individual differential genes and epidemiological and clinical features of these patients were explored. Normalized differential expression values were log2-transformed for statistical analysis in nSolver Software (NanoString Technologies). P-values were adjusted within each gene/signature and on the grouping variable level difference t-test using the Benjamini and Yekutieli False Discovery Rate (FDR) adjustment. Results: PABC patients’ clinical subtypes were distributed as 43,5% HR-positive/HER2-negative, 17,4% HER2-positive and 39,1% triple negative BC. These patients reported higher family history of BC/ovarian cancer compared to non-PABC (52.17% vs 26.53%; p=0.0124). Differential gene expression showed distinct molecular profiles in PABC and non-PABC patients: significantly genes enrichment involved in cell proliferation and p53 signature for PABC patients and higher expression of apoptosis, TGF-β, and PTEN signatures for non-PABC (adj p< 0.05). Furthermore, CDK4 expression signature (adj p=0.124) and DNA damage repair signatures Homologous Recombination Deficiency (HDR) (adj p=0.083) and BRCAness (adj p=0.220) were also upregulated in PABC tumors. The most significantly upregulated genes in PABC patients (CCNA2, DEPDC1, FAM83D, CDC20, CDKN3, TRIP13, TTK, MAD2L1, KIF2C, and UBE2C) (adj p< 0.05) were involved in cell cycle regulation and DNA damage repair. PABC basal-like tumors were found to be significantly more prevalent than non-PABC, as per the PAM50 classification (45.7% vs 20.4%; p=0.020). Interestingly, basal-like PABC showed higher expression of ESR1 than basal-like non-PABC (logFC=1.486; p=0.022). In contrast, luminal A PABC tumors exhibited lower ESR1 expression vs non-PABC (logFC=-1.5; p=0.021). Additionally, HER2-enriched PABC tumors displayed lower B7-H3/CD276 expression compared to HER2-enriched non-PABC (adj p=0.031). Conclusions: Our study shows that PABC is potentially a clinical and molecular different entity with predominance of the basal-like subtype. Moreover, our results suggest the activation of oncogenic pathways related to cell proliferation, DNA damage repair and p53 mutations which may lead to a clinically more aggressive phenotype for PABC patients. Likewise, the enrichment of BRCAness and HRD signatures found in PABC patients in our study may suggest an increased genetic instability due to a breakdown in the DNA damage repair. These findings may be clinically relevant and translate to new treatment options in PABC patients, who may benefit from therapies targeting DNA repair or cell-cycle checkpoints, such as PARP inhibitors. Citation Format: Juan de la Haba-Rodríguez, Regina Peña, Marina Pollan, Yolanda Jerez Gilarranz, Jose Ponce, Antonio Fernández Aramburu, Blanca Cantos, Ana Santaballa Bertrán, Elena Galve, María Eva Pérez, Susana de la Cruz, María Helena López-Ceballos, Yolanda Fernández, Fernando Moreno, Sonia González, Manuel Ruíz - Borrego, Isabel Blancas, José L Alonso-Romero, Álvaro Jiménez-Arranz, Raúl Rincón, Silvia Guil, Alejandra Díaz-Chacón, Rosalía Caballero, Begoña Bermejo, Angel Guerrero. Deciphering pregnancy-associated breast cancer: distinctive molecular profile and clinical implications from GEICAM/2017-07 EMBARCAM study abstract. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-13-05.
In hormone receptor-positive (HR+)/HER2- metastatic breast cancer (MBC), it is imperative to identify patients who respond poorly to cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) and to discover ...therapeutic targets to reverse this resistance. Non-luminal breast cancer subtype and high levels of CCNE1 are candidate biomarkers in this setting, but further validation is needed.
We performed mRNA gene expression profiling and correlation with progression-free survival (PFS) on 455 tumor samples included in the phase III PEARL study, which assigned patients with HR+/HER2- MBC to receive palbociclib+endocrine therapy (ET) versus capecitabine. Estrogen receptor-positive (ER+)/HER2- breast cancer cell lines were used to generate and characterize resistance to palbociclib+ET.
Non-luminal subtype was more prevalent in metastatic (14%) than in primary tumor samples (4%). Patients with non-luminal tumors had median PFS of 2.4 months with palbociclib+ET and 9.3 months with capecitabine; HR 4.16, adjusted P value < 0.0001. Tumors with high CCNE1 expression (above median) also had worse median PFS with palbociclib+ET (6.2 months) than with capecitabine (9.3 months); HR 1.55, adjusted P value = 0.0036. In patients refractory to palbociclib+ET (PFS in the lower quartile), we found higher levels of Polo-like kinase 1 (PLK1). In an independent data set (PALOMA3), tumors with high PLK1 show worse median PFS than those with low PLK1 expression under palbociclib+ET treatment. In ER+/HER2- cell line models, we show that PLK1 inhibition reverses resistance to palbociclib+ET.
We confirm the association of non-luminal subtype and CCNE1 with resistance to CDK4/6i+ET in HR+ MBC. High levels of PLK1 mRNA identify patients with poor response to palbociclib, suggesting PLK1 could also play a role in the setting of resistance to CDK4/6i.
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