Does LH addition to FSH in vitro recover the human primary granulosa lutein cell (hGLC) sub/poor-response?
A picomolar concentration of LH may recover the FSH-induced cAMP and progesterone production ...of hGLC from sub/poor-responder women.
Clinical studies suggested that FSH and LH co-treatment may be beneficial for the ovarian response of sub/poor-responders undergoing ovarian stimulation during ART.
hGLC samples from 286 anonymous women undergoing oocyte retrieval for ART were collected from October 2017 to February 2021.
hGLCs from women undergoing ovarian stimulation during ART were blindly purified, cultured, genotyped and treated in vitro by increasing concentrations of FSH (nM) ±0.5 nM LH. cAMP and progesterone levels produced after 3 and 24 h, respectively, were measured. In vitro data were stratified a posteriori, according to the donors' ovarian response, into normo-, sub- and poor-responder groups and statistically compared. The effects of LH addition to FSH were compared with those obtained by FSH alone in all the groups as well.
hGLCs from normo-responders were shown to have higher sensitivity to FSH treatment than sub-/poor-responders in vitro. Equimolar FSH concentrations induced higher cAMP (about 2.5- to 4.2-fold), and progesterone plateau levels (1.2- to 2.1-fold), in cells from normo-responder women than those from sub-/poor-responders (ANOVA; P < 0.05). The addition of LH to the cell treatment significantly increased overall FSH efficacy, indicated by cAMP and progesterone levels, within all groups (P > 0.05). Interestingly, these in vitro endpoints, collected from the normo-responder group treated with FSH alone, were similar to those obtained in the sub-/poor-responder group under FSH + LH treatment. No different allele frequencies and FSH receptor (FSHR) gene expression levels between groups were found, excluding genetics of gonadotropin and their receptors as a factor linked to the normo-, sub- and poor-response. In conclusion, FSH elicits phenotype-specific ovarian lutein cell response. Most importantly, LH addition may fill the gap between cAMP and steroid production patterns between normo- and sub/poor-responders.
Although the number of experimental replicates is overall high for an in vitro study, clinical trials are required to demonstrate if the endpoints evaluated herein reflect parameters of successful ART. hGLC retrieved after ovarian stimulation may not fully reproduce the response to hormones of granulosa cells from the antral follicular stage.
This in vitro assay may describe the individual response to personalize ART stimulation protocol, according to the normo-, sub- and poor-responder status. Moreover, this in vitro study supports the need to conduct optimally designed, randomized clinical trials exploring the personalized use of LH in assisted reproduction.
This study was supported by Merck KGaA. M.L. and C.C. are employees of Merck KGaA or of the affiliate Merck Serono SpA. Other authors have no competing interests to declare.
N/A.
Prognostic factors in patients with single mediastinal station (sN2) involvement continues to be a debated issue.
Data on 213 adenocarcinoma patients with sN2 involvement and who had undergone ...complete anatomical lung resection and lymphadenectomy, were retrospectively reviewed. Clinical and pathological characteristics together with adjuvant therapy (AD) and node (N) status classifications (number of resected nodes (#RN), number of metastatic nodes (#MN), and node ratio (#MN/#RN = NR) were analyzed.
Univariable analysis confirmed that age (0.009), #MN (0.009), NR (0.003), #N1 involved stations (
= 0.003), and skip metastases (
= 0.005) were related to overall survival (OS). Multivariable analysis confirmed, as independent prognostic factors, age <66 years and NR with a three-year OS (3YOS) of 78.7% in NR < 10% vs. 46.6% in NR > 10%. In skip metastases, NR (HR 2.734, 95% CI 1.417-5.277,
= 0.003) and pT stage (HR2.136, 95% CI 1.001-4.557,
= 0.050) were confirmed as independent prognostic factors. AD did not influence the OS of patients with singular positive lymph nodes (
= 0.41), while in patients with multiple lymph nodes and AD, a significantly better 3YOS was demonstrated, i.e., 49.1% vs. 30% (
= 0.004). In patients with N2 + N1 involvement, age (
= 0.002) and AD (
= 0.022) were favorable prognostic factors.
Adenocarcinoma patients with single N2 station involvement had a favorable outcome in the case of skip metastases and low NR. Adjuvant therapy improves survival with multiple nodal involvement, while its role in single node involvement should be clarified.
Over the last few decades, the need to reduce and optimize patient medical radiation exposure has prompted the introduction of novel reconstruction algorithms in computed tomography (CT). Against ...this backdrop, the present study aimed to assess whether reduced radiation dose CT images reconstructed with the new-generation adaptive statistical iterative reconstruction (ASiR-V) maintain the same image quality as that of routine image reconstruction. In addition, the optimization of image quality parameters for the ASiR-V algorithm (e.g., an optimal combination of blending percentage and noise index (NI)) was investigated. An abdominal reference phantom was imaged using the routine clinical protocol (fixed noise index of 18 and 40% ASiR reconstruction). Reduced radiation dose CT scans were performed with varying NI (22, 24, and 30) and using the ASiR-V reconstruction algorithm. Quantitative and qualitative analyses of image noise, contrast, and resolution were performed against NI and reconstruction blending percentages. Our results confirm the ability of the ASiR-V algorithm to provide images of high diagnostic quality while reducing the patient dose. All the parameters were improved in ASiR-V images as compared to ASiR. Both quantitative and qualitative analyses showed that the best agreement was obtained for the images reconstructed using ASiR-V with NI24 and a high percentage of blending (70–100%). This preliminary study results show that ASiR-V allows for a significant reduction in patient dose (about 40%) while maintaining a good overall image quality when appropriate NI (i.e., 24) is used.
Cancer and coagulation activation are tightly related. The extent to which factors related to both these pathologic conditions concur to patient prognosis intensely animates the inherent research ...areas. The study herein presented aimed to the development of a tool for the assessment and stratification of risk of death and disease recurrence in early breast cancer.
Between 2008 and 2010, two hundreds thirty-five (N: 235) patients diagnosed with stage I-IIA breast cancer were included. Data on patient demographics and clinic-pathologic features were collected in course of face-to-face interviews or actively retrieved from clinical charts. Plasma levels of plasminogen activator inhibitor type 1 (PAI-1), fragment 1 + 2 (F1 + 2), thrombin antithrombin complex (TAT), factor VIII (FVIII), and D-dimer (DD) were measured at breast cancer diagnosis and prior to any therapeutic procedure, including breast surgery. The risk of death was computed in terms of overall survival (OS), which was the primary outcome. For a subset of patients (N = 62), disease free survival (DFS) was also assessed as a measure of risk of disease recurrence.
Median follow up was 95 months (range 6-112 months). Mean age at diagnosis was 60.3 ± 13.4 years. Cancer cases were more commonly intraductal carcinomas (N: 204; 86.8%), pT1 (131; 55.7%), pN0 (141; 60%) and G2 (126; 53.6%). Elevated levels of PAI-1 (113; 48.1%) represented the most frequent coagulation abnormality, followed by higher levels of F1 + 2 (97; 41.3%), DD (63; 27.0%), TAT (34; 40%), and FVIII (29; 12.3%). In univariate models of OS, age, pT, DD, FVIII were prognostically relevant. In multivariate models of OS, age (p = 0.043), pT (p = 0.001), levels of DD (p = 0.029) and FVIII (p = 0.087) were confirmed. In the smaller subgroup of 62 patients, lymph node involvement, percent expression of estrogen receptors and levels of FVIII impacted DFS significantly.
We developed a risk assessment tool for OS including patient- and cancer-related features along with biomarkers of coagulation activation in a cohort of early BC patients. Further studies are warranted to validate our prognostic model in the early setting and eventually extend its application to risk evaluation in the advanced setting for breast and other cancers.
Abstract
Background/Introduction
Ischemic heart diseases (IHD) are not synonymous with obstructive flow-limiting coronary artery disease (CAD), especially in women. Platelet dysfunction is suggested ...as a potential mechanism favouring ischemia in non-obstructive CAD. However, it is unknown whether sex differences in platelet function of patients with non-obstructive CAD exist.
Purpose
We assessed for sex differences in in-vivo markers of platelet activation among patients with the acute coronary syndrome and chronic stable angina, with or without obstructive CAD
Methods
From the “Endocrine Vascular disease Approach” (EVA) study, we selected IHD patients undergoing urgent or elective coronary angiography with complete baseline clinical characteristics and angiographic data. Non-obstructive CAD was defined as the presence of coronary stenosis <50%. Thromboxane B2 (TxB2) and soluble P-selectin (sP-s) were measured at baseline. A sex-stratified analysis of platelet biomarkers was performed.
Results
Among two-hundred-seventy-seven patients (mean age 67±11, 37% women), non-obstructive CAD was documented in 25% of patients. Acute coronary syndrome (ACS) was the reason for angiography in 61% of cases. Women had more frequently ACS, as compared with men (54.8% vs 41.3%, p=0.001), with predominantly non-obstructive CAD. Median serum TxB2 (121.5 92.7–174.0 vs 103.5 83.0–140.2 pg/ml, p=0.005) and plasma sP-s (27.0 18.7–35.0 vs 22.0 16.0–30.0 ng/ml, p=0.006) levels were higher in patients with ACS as compared with the ones with stable chronic angina. The median concentration of TxB2 was significantly increased in women as compared with men, regardless of the clinical presentation and the coronary stenosis degree (all comparison, p<0.001). However, women with non-obstructive CAD were the group with the highest serum levels of TxB2 (140.0 111.0–152.0 pg/ml). Sex differences in the plasma sP-s level were also observed among patients with stable chronic angina (women, 26 20.0–34.0 vs men, 21 16.6–27.7 ng/ml, p=0.002) and with non-obstructive CAD (women, 26 20.5–34.5 vs men, 18.5 16.6–26.0 ng/ml, p=0.003).
Conclusion(s)
Women with IHD and non-obstructive CAD had increased level of TxB2 and sP-s as compared with men, independently by the clinical presentation. Further investigations are warranted to verify the role of platelet hyperactivation in the pathogenesis of myocardial ischemia with non-obstructive coronary artery disease among women.
Acknowledgement/Funding
Scientific Independence of Young Researchers Program (RBSI14HNVT) - Ministry of Education, University and Research (MIUR)
Colorectal cancer patients have a median age of incidence >65years although they are largely under-represented in phase-III trials. This large population contains patients unfit for treatment, those ...suitable for monotherapy or for doublets and the impact of chemotherapy outside clinical trial is unclear. The aim of the study was to retrospectively analyse Overall Survival(OS) of elderly metastatic colorectal cancer(mCRC) patients treated with chemotherapy in daily practice.
Kaplan-Meir method was used for OS, the log-rank or Tarone-Ware test for differences between subgroups, Cox's proportional hazard model to assess the impact of known prognostic factors and treatment.
751 patients with mCRC observed between January 2000 and January 2013 were collected. Median age was 79 year(75-93); Male/Female 61/39%, ECOG-PS 0-1/2 85/15%; colon/rectum 74/26%; multiple metastatic sites 34%, only liver metastasis in 41% of patients. KRAS status was studied in 35% of patients: 44% of them showed gene mutation. 20.5% of patients did not received any kind of treatment including surgery. Comorbidities observed: cardiovascular 34%, diabetes 14%, hypertension 50%. Primary tumor was resected in 80.6%; surgery of liver metastasis was done in 19% of patients (2.3% of patients >80years). 78% of patients underwent chemotherapy. Median follow up was 12 months(range 1-124). Median OS was 17 months (CI 95%15-19);median OS in no-treated patients was 5 months (4-6); mOS of patients with at least one treatment was 20 months (18-22). In KRAS mutated group median OS was 19months (15-23) while in KRAS wild type patients median OS was 25 months (20-30). At multivariate analysis sex(Female), age(<80y), performance status(0-1), chemotherapy, Surgery of metastasis, Surgery of primary tumor and Site of metastasis(liver) were prognostic factors for OS.
The results of our study show that in clinical practice treatment has a positive impact on OS of elderly patients, confirmed at multivariate analysis, included patients with age >80 years old or with a poor performance status (respectively p<0.0001 and p<0.0001). KRAS analysis deserve further evaluation.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background
A rapid immune response is critical to ensure effective protection against COVID‐19. Platelets are first‐line sentinels of the vascular system able to rapidly alert and stimulate the ...immune system. However, their role in the immune response to vaccines is not known.
Objective
To identify features of the platelet‐immune crosstalk that would provide an early readout of vaccine efficacy in adults who received the mRNA‐based COVID‐19 vaccine (BNT162b2).
Methods
We prospectively enrolled 11 young healthy volunteers (54% females, median age: 28 years) who received two doses of BNT162b2, 21 days apart, and we studied their platelet and immune response before and after each dose of the vaccine (3 and 10 ± 2 days post‐injection), in relation to the kinetics of the humoral response.
Results
Participants achieving an effective level of neutralizing antibodies before the second dose of the vaccine (fast responders) had a higher leukocyte count, mounted a rapid cytokine response that incremented further after the second dose, and an elevated platelet turnover that ensured platelet count stability. Their circulating platelets were not more reactive but expressed lower surface levels of the immunoreceptor tyrosine‐based inhibitory motif (ITIM)‐coupled receptor CD31 (PECAM‐1) compared to slow responders, and formed specific platelet‐leukocyte aggregates, with B cells, just 3 days after the first dose, and with non‐classical monocytes and eosinophils.
Conclusion
We identified features of the platelet‐immune crosstalk that are associated with the development of a rapid humoral response to an mRNA‐based vaccine (BNT162b2) and that could be exploited as early biomarkers of vaccine efficacy.
•The benefit of bevacizumab maintenance in metastatic colorectal cancer is unclear.•This is the first individual patient data meta-analysis on bevacizumab maintenance.•A significant, but limited, PFS ...increase for bevacizumab maintenance was observed.•A differential effect of bevacizumab maintenance according to RAS status was showed.•Maintenance with bevacizumab single agent can be considered in selected cases.
The real impact of bevacizumab maintenance as single agent in metastatic colorectal cancer (mCRC) remains unclear. SAKK-41/06 and PRODIGE-9 failed to demonstrate the non-inferiority and superiority of bevacizumab versus no maintenance, respectively, while AIO-KRK-0207 showed the non-inferiority of maintenance bevacizumab versus bevacizumab and fluoropyrimidines for time to strategy failure.
Bibliography electronic databases (PubMed, MEDLINE, Embase, Scopus, Web of Science, and the Cochrane Central Register of Controlled Trials) were searched for English published clinical trials prospectively randomizing mCRC patients to receive bevacizumab maintenance or not after first-line chemotherapy plus bevacizumab. Individual patients’ data (IPD) were provided by investigators for all included trials. Primary end-points were progression-free survival (PFS) and overall survival (OS), both from the start of induction and maintenance. Univariate and multivariate analyses for PFS and OS were performed.
Three phase III studies - PRODIGE-9, AIO-KRK-0207 and SAKK-41/06 – were included. Considering the different timing of randomization, IPD of patients not progressed during induction and starting maintenance phase entered the analysis. 909 patients were included, 457 (50%) received bevacizumab maintenance. Median PFS from induction start was 9.6 and 8.9 months in bevacizumab group versus no maintenance group, respectively (HR 0.78; 95%CI: 0.68–0.89; p < 0.0001). Subgroups analysis for PFS showed a significant interaction according for RAS status (p = 0.048), with a maintenance benefit limited to RAS wild-type patients. No difference in terms of OS was observed.
Despite the statistically significant PFS improvement for bevacizumab maintenance, the absolute benefit appears limited. Subgroup analysis shows a differential effect of bevacizumab maintenance in favor of RAS wild-type patients. Considering these results, maintenance therapy with fluoropyrimidine with or without bevacizumab remains the first option. Single agent bevacizumab maintenance can be considered in selected cases, such as cumulative toxicity or patient’s refusal, in particular for RAS wild-type patients.
Episodic memory (EM) is defined as a long-term memory system that stores information that can be retrieved along with details of the context of the original events (binding). Several studies have ...shown that manipulation of attention during encoding can impact subsequent memory performance. An influential model of attention distinguishes between three partially independent attentional networks: the alerting, the orienting and the executive or conflict resolution component. To date, the impact of the engagement of these sub-systems during encoding on item and relational context binding has not been investigated. Here, we developed a new task combining the Attentional Network Test and an incidental episodic memory encoding task to study this issue. We reported that when the alerting network was not solicited, resolving conflict hindered item encoding. Moreover, resolving conflict, independently of the cueing condition, had a negative impact on context binding. These novel findings could have a potential impact in the understanding EM formation, and memory disorders in different populations, including healthy elderly people.
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