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•Immunecheckpoint inhibitors have a definite place in the management of endometrial cancer.
The incidence of endometrial cancer (EC) is increasing worldwide. The prognosis for ...patients diagnosed with early-stage remains good, whereas for patients with recurrent or metastatic disease, the prognosis is poor and treatment options, until recently, were limited. In 2017, pembrolizumab was approved by the US Food and Drug Administration (FDA) for those patients with mistmach repair deficiency (MMRd) or high microsatellite instability (MSI-H) tumors. However, only 20–30 % of EC have MSI, and just over half of these patients benefit from treatment. In 2019, the FDA granted breakthrough therapy designation to lenvatinib in combination with pembrolizumab for the potential treatment of patients with advanced microsatellite stable EC that has progressed after treatment with at least one previous systemic therapy. It appears clear that immune check-point inhibitors will have a definite place in the management of EC, both as single agent or in combination with other targeted agents. In this review, we summarize the current evidence of immune check point blockade and the identification of potential biomarkers, beyond MSI-H or MMRd, that could help to predict response to this agents in correlation with the genomic EC subtypes.
Ischaemic stroke may be a major complication of SARS-CoV-2 infection. Studying and characterising the different aetiological subtypes, clinical characteristics, and functional outcomes may be ...valuable in guiding patient selection for optimal management and treatment.
Data were collected retrospectively on consecutive patients with COVID-19 who developed acute focal brain ischaemia (between 1 March and 19 April 2020) at a tertiary university hospital in Madrid (Spain).
During the study period, 1594 patients were diagnosed with COVID-19. We found 22 patients with ischaemic stroke (1.38%), 6 of whom did not meet the inclusion criteria. The remaining 16 patients were included in the study (15 cases of ischaemic stroke and one case of transient ischaemic attack). Median baseline National Institutes of Health Stroke Scale score was 9 (interquartile range: 16), and mean (standard deviation) age was 73 years (12.8). Twelve patients (75%) were men. Mean time from COVID-19 symptom onset to stroke onset was 13 days. Large vessel occlusion was identified in 12 patients (75%). We detected elevated levels of D-dimer in 87.5% of patients and C-reactive protein in 81.2%. The main aetiology was atherothrombotic stroke (9 patients, 56.3%), with the predominant subtype being endoluminal thrombus (5 patients, 31.2%), involving the internal carotid artery in 4 cases and the aortic arch in one. The mortality rate in our series was 44% (7 of 16 patients).
In patients with COVID-19, the most frequent stroke aetiology was atherothrombosis, with a high proportion of endoluminal thrombus (31.2% of patients). Our clinical and laboratory data support COVID-19-associated coagulopathy as a relevant pathophysiological mechanism for ischaemic stroke in these patients.
We report a survey of genetic variation at three coding loci in Giardia duodenalis of assemblages A and B obtained from stool samples of patients from Santiago de Compostela (Galicia, NW-Iberian ...Peninsula). The mean pooled synonymous diversity for assemblage A was nearly five times lower than for assemblage B (0.77%±0.30% and 4.14%±1.65%, respectively). Synonymous variation in both assemblages was in mutation-drift equilibrium and an excess of low-frequency nonsynonymous variants suggested the action of purifying selection at the three loci. Differences between isolates contributed to 40% and 60% of total genetic variance in assemblages A and B, respectively, which revealed a significant genetic structure. These results, together with the lack of evidence for recombination, support that (i) Giardia assemblages A and B are in demographic equilibrium and behave as two genetically isolated populations, (ii) infections are initiated by a reduced number of individuals, which may be genetically diverse and even belong to different assemblages, and (iii) parasites reproduce clonally within the host. However, the observation of invariant loci in some isolates means that mechanisms for the homogenization of the genetic content of the two diploid nuclei in each individual must exist.
•G. duodenalis assemblages A and B behave as two genetically isolated populations.•High between-isolate variation reflects a genetically structured population.•Infections are likely caused by a reduced number of distinct individuals.•Mechanisms for the homogenization of the genomes of the two nuclei must exist.
Resolution of inflammation is orchestrated by specialized proresolving lipid mediators (SPMs), and this would be impaired in some cardiovascular diseases. Among SPMs, resolvins (Rv) have beneficial ...effects in cardiovascular pathologies, but little is known about their effect on cardiovascular damage in hypertension.
Aorta, small mesenteric arteries, heart, and peritoneal macrophages were taken from C57BL/6J mice, infused or not with angiotensin II (AngII; 1.44 mg/kg/day, 14 days) in presence or absence of resolvin D2 (RvD2) (100 ng/mice, every second day) starting 1 day before or 7 days after AngII infusion.
Enzymes and receptors involved in SPMs biosynthesis and signaling were increased in aorta or heart from AngII-infused mice. We also observed a differential regulation of SPMs in heart from these mice. Preventive treatment with RvD2 partially avoided AngII-induced hypertension and protected the heart and large and small vessels against functional and structural alterations induced by AngII. RvD2 increased the availability of vasoprotective factors, modified SPMs profile, decreased cardiovascular fibrosis, and increased the infiltration of pro-resolving macrophages. When administered in hypertensive animals with established cardiovascular damage, RvD2 partially improved cardiovascular function and structure, decreased fibrosis, reduced the infiltration of neutrophils, and shifted macrophage phenotype toward a pro-resolving phenotype.
There is a disbalance between proinflammatory and resolution mediators in hypertension. RvD2 protects cardiovascular function and structure when administered before and after the development of hypertension by modulating vascular factors, fibrosis and inflammation. Activating resolution mechanisms by treatment with RvD2 may represent a novel therapeutic strategy for the treatment of hypertensive cardiovascular disease.
Chitosan (CS) and carboxymethylcellulose (CMC) sodium interpolymer complexes were formed using the novel method “tablets-in-capsule” for stomach drug delivery. The aim of this study was to ...investigate the influence of the molecular weight (M.wt.) of CS and the proportion CS/CMC on physical properties and clarithromycin (CAM) release.
Swelling was dependent on CS M.wt., on medium pH and on proportion polymer/polymer. The higher M.wt., the major presence of protonated amined moieties that can be ionized and modify the swelling/eroding and dissolution medium uptake capacity. Swelling kinetics at pH 1.2, were close to Fickian diffusion, whereas at pH 4.2 were non-Fickian. Furthermore, dissolution medium uptake capacity can be adjusted to an exponential equation at pH 1.2 (
r
2
≥
0.96), and to a linear equation at pH 4.2 (
r
2
≥
0.99), showing that at low pHs the repulsion among ionized chains is higher.
CAM release rates have shown to be dependent on pH and on polymer proportion. At pH 1.2, the fastest profile was obtained when using high M.wt. CS. Drug diffusion was Fickian, so the process is governed by swelling/eroding. Whereas at pH 4.2, CAM release followed zero-order kinetics with no influence on M.wt. So, release is controlled by CAM low solubility.
to analyze the sleep characteristics of the parents of children admitted to a pediatric intensive care unit (PICU), the possible risk factors and impact of sleep quality on their daily life ...activities.
Parents of children admitted to PICU for at least 48 h filled in a survey. Demographic data, sleep characteristics before and during admission and its impact on daily life activities measured by the FOSQ-10 questionnaire, were collected.
100 surveys from parents of 53 children admitted to the PICU were collected. Most children (74%) were cardiac patients. 55% of them had had previous PICU admissions. 45% of parents lived in a different city. They spent a median of 14 h a day (IQR 12–16) at the hospital and 89.2% did not attend work. Parents had significantly worse subjective sleep quality (p = 0.001), less sleeping hours/day (p = 0.001), more difficulty falling asleep (p = 0.001) and more night arousals (p = 0.001) during PICU admission than before. 77% of parents also had a bad FOSQ-10 score. Perceived sleep quality and FOSQ-10 score had a good correlation (p = 0.00, Kappa 0.43). Significant risk factors were living in a different city (p = 0.03), programmed admissions (p = 0.001), previous PICU admissions (p = 0.001), prolonged PICU length of stay (p = 0.03) and longer distance from home (p = 0.03).
Three quarters of the parents of children admitted to PICU suffer from sleep disorders, which negatively affects their personal lives. Perceived sleep quality had a good correlation with FOSQ-10 score. Institutional support is needed to optimize parents’ resting conditions during their child's hospitalization.
•Assess sleep quality of the parents comparing its characteristics before and during hospitalization.•Personal and family risk factors correlation with sleep disturbances and daily life activities.•Previous admissions to the PICU and programmed admissions were significant risk factors.•Significant risk factors: long duration of admission, long home-hospital distance and number of nights at PICU.•Living in another city was a significant risk factor.
This study is a comparison of the efficiency of three technologies used for Y chromosome capture and the next-generation sequencing (NGS) technologies applied for determining its whole sequence. Our ...main findings disclose that streptavidin-biotin magnetic particle-based capture methodology offers better and a deeper sequence coverage for Y chromosome capture, compared to chromosome sorting and microdissection procedures. Moreover, this methodology is less time consuming and the most selective for capturing only Y chromosomal material, in contrast with other methodologies that result in considerable background material from other, non-targeted chromosomes. NGS results compared between two platforms, NextSeq 500 and SOLID 5500xl, produce the same coverage results. This is the first study to explore a methodological comparison of Y chromosome capture and genetic analysis. Our results indicate an improved strategy for Y chromosome research with applications in several scientific fields where this chromosome plays an important role, such as forensics, medical sciences, molecular anthropology and cancer sciences.
In the setting of localized colon cancer (CC), circulating tumor DNA (ctDNA) monitoring in plasma has shown potential for detecting minimal residual disease (MRD) and predicting higher risk of ...recurrence. With the tumor-only sequencing approach, however, germline variants may be misidentified as somatic variations, precluding the possibility of tracking in up to 11% of patients due to a lack of known somatic mutations. In this study comprising 148 prospectively recruited localized CC patients, a custom 29-gene panel was utilized to sequence both tumor tissue and matched white blood cells (WBCs) to enhance the accuracy of sequencing results. Performing targeted sequencing of paired tumor tissue and WBCs samples detected additional somatic mutations and increased the number of patients eligible for MRD tracking in plasma, although MRD detection sensitivity was not increased. Furthermore, the germline testing approach revealed the presence of pathogenic germline variants, thereby helping identify patients at elevated risk of hereditary cancer syndromes.
•Tumor and matched WBCs sequencing detected additional somatic mutations, increasing eligible patients for plasma MRD tracking.•Tumor-only sequencing can misidentify germline variants as somatic, hindering tracking in 11% of patients.•Germline testing found pathogenic variants, helping identify high-risk patients for hereditary cancer syndromes.
Patients with glioma whose tumors carry a mutation in isocitrate dehydrogenase 1 (IDH1
) are younger at diagnosis and live longer.
mutations co-occur with other molecular lesions, such as 1p/19q ...codeletion, inactivating mutations in the tumor suppressor protein 53
) gene, and loss-of-function mutations in alpha thalassemia/mental retardation syndrome X-linked gene (
). All adult low-grade gliomas (LGGs) harboring ATRX loss also express the IDH1
mutation. The current molecular classification of LGGs is based, partly, on the distribution of these mutations. We developed a genetically engineered mouse model harboring IDH1
,
and
inactivating mutations, and activated NRAS G12V. Previously, we established that ATRX deficiency, in the context of wild-type IDH1, induces genomic instability, impairs nonhomologous end-joining DNA repair, and increases sensitivity to DNA-damaging therapies. In this study, using our mouse model and primary patient-derived glioma cultures with IDH1 mutations, we investigated the function of IDH1
in the context of TP53 and ATRX loss. We discovered that IDH1
expression in the genetic context of
and
gene inactivation (i) increases median survival in the absence of treatment, (ii) enhances DNA damage response (DDR) via epigenetic up-regulation of the ataxia-telangiectasia-mutated (ATM) signaling pathway, and (iii) elicits tumor radioresistance. Accordingly, pharmacological inhibition of ATM or checkpoint kinases 1 and 2, essential kinases in the DDR, restored the tumors' radiosensitivity. Translation of these findings to patients with IDH1
glioma harboring TP53 and ATRX loss could improve the therapeutic efficacy of radiotherapy and, consequently, patient survival.
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