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Additional progesterone administration during the luteal phase enhances reproductive outcomes in Hormone Replacement Therapy Frozen Embryo Transfer (HRT-FET) cycles in patients with low serum progesterone (P4). In this study we wanted to explore the use of urine P4 as a diagnostic tool during the luteal phase. This prospective observational cohort included a total of 464 HRT-FET cycles. The protocol entailed oral oestradiol (6 mg/24 h), followed by vaginal micronised progesterone (400 mg/12 h). On the day of blastocyst transfer, urine and serum samples were collected. Urine samples were analysed using an ARCHITECT automated immunoassay. A significant difference was found in median urine P4 between patients with serum P4 higher or lower than 11 ng/mL: 6400 ng/mL IQR [2528; 11,930] vs. 3408 ng/mL IQR [592; 6688], p < 0.001. The optimal cut-off to achieve live birth was a urine P4 ≥ 4000 ng/mL. The live birth rate was significantly higher in patients with urine P4 ≥ 4000 ng/mL, 48% (107/222) vs. 35% (45/130), respectively (p = 0.013). The odds ratio for live birth was 1.8 in patients with urine P4 ≥ 4000 ng/mL, 95% CI [1.067; 3.018], p = 0.028. The findings of the present study suggest that urine progesterone could be a valuable diagnostic tool to evaluate the need for additional progesterone in HRT-FET cycles.

Background Chemoradiotherapy (CRT) modulates the tumor immune microenvironment of multiple cancer types, including esophageal cancer, which potentially induces both immunogenicity and immunosuppression by upregulating the presentation of tumor-specific antigens and immune checkpoint molecules in tumors, respectively. The prognostic effects of immune modification by CRT in esophageal squamous cell carcinoma (ESCC) remain controversial because of the lack of detailed immunological analyses using paired clinical specimens before and after CRT. We aimed to clarify the immunological changes in the tumor microenvironment caused by CRT and elucidate the predictive importance of clinical response and prognosis and the rationale for the necessity of subsequent programmed cell death protein 1 (PD-1) inhibitor treatment. Methods In this study, we performed a comprehensive immunological analysis of paired biopsy specimens using multiplex immunohistochemistry before and after CRT in patients with unresectable locally advanced ESCC. Results CRT significantly increased the intra-tumoral infiltration and PD-1 expression of CD8 + T cells and conventional CD4 + T cells but decreased those of regulatory T cells and the accumulation of tumor-associated macrophages. Multivariate analysis of tumor-infiltrating T-cell phenotypes revealed that the density of PD-1 + CD8 + T cells in the tumor after CRT could predict a confirmed complete response and favorable survival. Conclusions This study showed that CRT improved the immunological characteristics of unresectable locally advanced ESCC and identified the density of PD-1 + CD8 + T cells as a predictive factor for prognosis. This finding supports the rationale for the necessity of subsequent PD-1 inhibitor treatment.

VEGF-A activity is tightly regulated by ligand and receptor availability. Here we investigate the physiological function of heterodimers between VEGF receptor-1 (VEGFR-1; Flt-1) and VEGFR-2 (KDR; Flk-1) (VEGFR 1−2 ) in endothelial cells with a synthetic ligand that binds specifically to VEGFR 1−2 . The dimeric ligand comprises one VEGFR-2-specific monomer (VEGF-E) and a VEGFR-1-specific monomer (PlGF-1). Here we show that VEGFR 1−2 activation mediates VEGFR phosphorylation, endothelial cell migration, sustained in vitro tube formation and vasorelaxation via the nitric oxide pathway. VEGFR 1−2 activation does not mediate proliferation or elicit endothelial tissue factor production, confirming that these functions are controlled by VEGFR-2 homodimers. We further demonstrate that activation of VEGFR 1−2 inhibits VEGF-A-induced prostacyclin release, phosphorylation of ERK1/2 MAP kinase and mobilization of intracellular calcium from primary endothelial cells. These findings indicate that VEGFR-1 subunits modulate VEGF activity predominantly by forming heterodimer receptors with VEGFR-2 subunits and such heterodimers regulate endothelial cell homeostasis. Vascular endothelial growth factor receptors (VEGFRs) assemble in dimers, the composition of which is thought to influence their function. Here, Cudmore et al . create a synthetic ligand that specifically activates VEGFR-1:VEGFR-2 heterodimers and explore their role in regulating endothelial cell function.

Background High-sensitivity cardiac troponin testing is a promising tool for cardiovascular risk prediction, but whether serial testing can dynamically predict risk is uncertain. We evaluated the trajectory of cardiac troponin I in the years prior to a cardiovascular event in the general population, and determine whether serial measurements could track risk within individuals. Methods In the Whitehall II cohort, high-sensitivity cardiac troponin I concentrations were measured on three occasions over a 15-year period. Time trajectories of troponin were constructed in those who died from cardiovascular disease compared to those who survived or died from other causes during follow up and these were externally validated in the HUNT Study. A joint model that adjusts for cardiovascular risk factors was used to estimate risk of cardiovascular death using serial troponin measurements. Results In 7,293 individuals (mean 58 ± 7 years, 29.4% women) cardiovascular and non-cardiovascular death occurred in 281 (3.9%) and 914 (12.5%) individuals (median follow-up 21.4 years), respectively. Troponin concentrations increased in those dying from cardiovascular disease with a steeper trajectory compared to those surviving or dying from other causes in Whitehall and HUNT ( P interaction  < 0.05 for both). The joint model demonstrated an independent association between temporal evolution of troponin and risk of cardiovascular death (HR per doubling, 1.45, 95% CI,1.33–1.75). Conclusions Cardiac troponin I concentrations increased in those dying from cardiovascular disease compared to those surviving or dying from other causes over the preceding decades. Serial cardiac troponin testing in the general population has potential to track future cardiovascular risk.

Background Patients with unresectable pancreatic cancer (PC) sometimes experience gastrointestinal bleeding (GIB) due to tumor invasion of the gastrointestinal tract (tumor bleeding); no standard treatment has been established yet for this complication. Palliative radiotherapy (PRT) could be promising, however, there are few reports of PRT for tumor bleeding in patients with unresectable PC. Therefore, we evaluated the outcomes of PRT for tumor bleeding in patients with unresectable PC. Methods We reviewed the medical records of patients with unresectable PC diagnosed at our institution between May 2013 and January 2022, and identified patients with endoscopically confirmed tumor bleeding who had received PRT. PRT was administered at a total dose of 30 Grays (Gy) in 10 fractions, 20 Gy in 5 fractions, or 8 Gy in a single fraction, and the dose selection was left to the discretion of the attending radiation oncologists. Results During the study period, 2562 patients were diagnosed as having unresectable PC at our hospital, of which 225 (8.8%) developed GIB. Among the 225 patients, 63 (2.5%) were diagnosed as having tumor bleeding and 20 (0.8%) received PRT. Hemostasis was achieved in 14 of the 20 patients (70%) who received PRT, and none of these patients developed grade 3 or more adverse events related to the PRT. The median time to hemostasis was 8.5 days (range 7–14 days). The rebleeding rate was 21.4% (3/14). The median hemoglobin level increased significantly ( p  < 0.001) from 5.9 to 9.1 g/dL, and the median volume of red blood cell transfusion tended ( p  = 0.052) to decrease, from 1120 mL (range 280–3360 mL) to 280 mL (range 0–5560 mL) following the PRT. The median overall survival (OS) was 52 days (95% confidence interval [CI] 39–317). Of the 14 patients in whom hemostasis was achieved following PRT, chemotherapy could be started/resumed in seven patients (50%), and the median OS in these patients was 260 days (95% CI 76–not evaluable [NE]). Three patients experienced rebleeding (21.4%), on days 16, 22, and 25, after the start of PRT. Conclusion This study showed that PRT is an effective and safe treatment modality for tumor bleeding in patients with unresectable PC.

Background Ischemic heart disease is common in COPD and associated with worse prognosis. This study aimed to investigate the presence and prognostic impact of biomarkers of myocardial injury and ischemia among individuals with COPD and normal lung function, respectively. Methods In 2002–04, all individuals with airway obstruction (FEV 1 /VC < 0.70, n  = 993) were identified from population-based cohorts, together with age and sex-matched non-obstructive referents. At re-examination in 2005, spirometry, Minnesota-coded ECG and analyses of high-sensitivity cardiac troponin I (hs-cTnI) were performed in individuals with COPD ( n  = 601) and those with normal lung function ( n  = 755). Deaths were recorded until December 31st, 2010. Results Hs-cTnI concentrations were above the risk stratification threshold of ≥5 ng/L in 31.1 and 24.9% of those with COPD and normal lung function, respectively. Ischemic ECG abnormalities were present in 14.8 and 13.4%, while 7.7 and 6.6% had both elevated hs-cTnI concentrations and ischemic ECG abnormalities. The 5-year cumulative mortality was higher in those with COPD than those with normal lung function (13.6% vs. 7.7%, p  < 0.001). Among individuals with COPD, elevated hs-cTnI both independently and in combination with ischemic ECG abnormalities were associated with an increased risk for death (adjusted hazard ratio [HR]; 95% confidence interval [CI] 2.72; 1.46–5.07 and 4.54; 2.25–9.13, respectively). Similar associations were observed also among individuals with COPD without reported ischemic heart disease. Conclusions In this study, elevated hs-cTnI concentrations in combination with myocardial ischemia on the electrocardiogram were associated with a more than four-fold increased risk for death in a population-based COPD-cohort, independent of disease severity.

PurposeEndothelial dysfunction is central to the pathogenesis of acute coronary syndrome. The study of diseased endothelium is very challenging due to inherent difficulties in isolating endothelial cells from the coronary vascular bed. We sought to isolate and characterise coronary endothelial cells from patients undergoing thrombectomy for myocardial infarction to develop a patient-specific in vitro model of endothelial dysfunction.MethodsIn a prospective cohort study, 49 patients underwent percutaneous coronary intervention with thrombus aspiration. Specimens were cultured, and coronary endothelial outgrowth (CEO) cells were isolated. CEO cells, endothelial cells isolated from peripheral blood, explanted coronary arteries, and umbilical veins were phenotyped and assessed functionally in vitro and in vivo.ResultsCEO cells were obtained from 27/37 (73%) atherothrombotic specimens and gave rise to cells with cobblestone morphology expressing CD146 (94 ± 6%), CD31 (87 ± 14%), and von Willebrand factor (100 ± 1%). Proliferation of CEO cells was impaired compared to both coronary artery and umbilical vein endothelial cells (population doubling time, 2.5 ± 1.0 versus 1.6 ± 0.3 and 1.2 ± 0.3 days, respectively). Cell migration was also reduced compared to umbilical vein endothelial cells (29 ± 20% versus 85±19%). Importantly, unlike control endothelial cells, dysfunctional CEO cells did not incorporate into new vessels or promote angiogenesis in vivo.ConclusionsCEO cells can be reliably isolated and cultured from thrombectomy specimens in patients with acute coronary syndrome. Compared to controls, patient-derived coronary endothelial cells had impaired capacity to proliferate, migrate, and contribute to angiogenesis. CEO cells could be used to identify novel therapeutic targets to enhance endothelial function and prevent acute coronary syndromes.

BackgroundAlthough definitive chemoradiotherapy (CRT) is the standard therapy for patients with unresectable locally advanced esophageal squamous cell carcinoma (ESCC), poor survival has been reported. Although the complete response (CR) rate is strongly correlated with good prognosis, the predictive factors for CR have not been elucidated.MethodsThis registry study aimed to identify predictors of CR to definitive CRT in patients with unresectable locally advanced ESCC. “Unresectable” was defined as the primary lesion invading unresectable adjacent structures such as the aorta, vertebral body, and trachea (T4b), or the regional and/or supraclavicular lymph nodes invading unresectable adjacent structures (LNT4b).ResultsOverall, 175 patients who started definitive CRT between January 2013 and March 2020 were included. The confirmed CR (cCR) rate was 24% (42/175). The 2-year progression-free survival (PFS) and overall survival (OS) rates of cCR cases vs. non-cCR cases were 59% vs. 2% (log-rank p < 0.001) and 90% vs. 31% (log-rank p < 0.001), with a median follow-up period of 18.5 and 40.5 months, respectively. Multivariate analysis of clinicopathological factors revealed that tumor length ≥ 6 cm [odds ratio (OR) 0.446; 95% CI 0.220–0.905; p = 0.025] was a predictor of cCR.ConclusionsFavorable PFS and OS rates were observed in patients with cCR. Tumor length was a predictive factor for cCR.

BackgroundGuidelines recommend the use of risk scores to select patients for further investigation after myocardial infarction has been ruled out but their utility to identify those with coronary artery disease is uncertain.MethodsIn a prospective cohort study, patients with intermediate high-sensitivity cardiac troponin I concentrations (5 ng/L to sex-specific 99th percentile) in whom myocardial infarction was ruled out were enrolled and underwent coronary CT angiography (CCTA) after hospital discharge. History, ECG, Age, Risk factors, Troponin (HEART), Emergency Department Assessment of Chest Pain Score (EDACS), Global Registry of Acute Coronary Event (GRACE), Thrombolysis In Myocardial Infarction (TIMI), Systematic COronary Risk Evaluation 2 and Pooled Cohort Equation risk scores were calculated and the odds ratio (OR) and diagnostic performance for obstructive coronary artery disease were determined using established thresholds.ResultsOf 167 patients enrolled (64±12 years, 28% female), 29.9% (50/167) had obstructive coronary artery disease. The odds of having obstructive disease were increased for all scores with the lowest and highest increase observed for an EDACS score ≥16 (OR 2.2 (1.1–4.6)) and a TIMI risk score ≥1 (OR 12.9 (3.0–56.0)), respectively. The positive predictive value (PPV) was low for all scores but was highest for a GRACE score >88 identifying 39% as high risk with a PPV of 41.9% (30.4–54.2%). The negative predictive value (NPV) varied from 77.3% to 95.2% but was highest for a TIMI score of 0 identifying 26% as low risk with an NPV of 95.2% (87.2–100%).ConclusionsIn patients with intermediate cardiac troponin concentrations in whom myocardial infarction has been excluded, clinical risk scores can help identify patients with and without coronary artery disease, although the performance of established risk thresholds is suboptimal for utilisation in clinical practice.Trial registration numberNCT04549805.