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Growth hormone (GH) has gained attention as an anti-aging compound enhancing oocyte quality. In fact, GH is known to activate intrafollicular metabolic events for oocyte maturation. Insulin growth factor I (IGF1) is another ovarian growth factor that mediates the FSH and GH actions. Cytokines could also increase IVF outcomes. Indeed, IL-6 is a pleiotropic cytokine with multiple cellular effects that can vary based on the physiological environment. IL-6 may also play an important role in follicular development (Yang et al., J Assist Reprod Genet, 2020, 37 (5), 1171–1176). Clinical studies have been performed to explore the potential role of IL-6 in human oocyte maturation and subsequent embryonic development. To date, the answers are not conclusive. During peri-implantation, many cytokines balances are regulated like pro-inflammatory and anti-inflammatory interleukins. The pro-inflammatory properties of IL-17 and its impact on the tumor microenvironment or autoimmune diseases are characterized, but new dimensions of IL-17 activity that promotes embryo implantation are not well explored. In the search for answers, our study compared concentrations of growth factors IGF1, GH, and interleukins IL-6 and IL-17 in the follicular fluid (FF) from 140 women divided into two groups depending on bad (G1) or good prognosis (G2) and investigated the relationships between these FF components’ levels and the main parameters of IVF. GH, IGF1, and IL-6 were significantly higher for G2. For GH, it was negatively correlated to patient age and positively correlated to maturity rate and IGF1. Moreover, GH and IGF1 were correlated to the top embryo rate and cumulative pregnancy rate. Regarding IL-6, it was correlated to IGF1 level, endometrium thickness, and implantation rate. As for IL-17, it was only correlated to IL-6. Consequently, all these FF components were predictive of oocyte quality except IL-17. GH seemed to be the best biomarker of this quality.

Highly active antiretroviral therapy (HAART) appears to lower blood levels of interleukin-10 and raise blood levels of interleukin-12, according to a study of 12 HIV patients. However, blood levels of interleukin-12 are still below normal when compared to levels in non-infected people.

Background: Mutations in the activation segment of the v-raf murine sarcoma viral oncogene homolog B (BRAF) gene are present in approximately 50% of melanomas. The selective BRAF inhibitor vemurafenib has demonstrated significant clinical benefits in patients with melanomas harboring the most common mutations (V600E, V600K and V600R). However, the clinical activity of BRAF inhibitors in patients with rare mutations of codon 600 and the surrounding codons has not been documented. Case presentation: We used the BRAF inhibitor vemurafenib to treat a patient presenting a rare p. V600_K601delinsD-mutated melanoma. An objective response was evidenced by two months of progression-free survival. By cloning and sequencing BRAF exon 15, we confirmed that a dual mutation was present on a single allele and thus resulted in a BRAFV600DK601del mutant protein. We also performed an in silico crystal structure analysis of the mutated protein, in order to characterize the nature of the putative interaction between vemurafenib and the mutant protein. Conclusion: This clinical experience suggests that (i) patients with BRAFV600DK601del-mutation-positive melanoma can be treated successfully with the oral BRAF inhibitor vemurafenib and (ii) molecular screening in this context should encompass rare and complex mutations. [ABSTRACT FROM AUTHOR]

B-cell chronic lymphocytic leukemia (CLL) is the most frequent adult leukemia in the Western world. It is a heterogeneous disease characterized by clonal proliferation and the accumulation of CD5+ mature B lymphocytes. However, the normal counterpart from which the latter cells arise has not yet been identified. CD27 expression and gene expression profiling data suggest that CLL cells are related to memory B-cells. In vitro, memory B-cells differentiate into plasma cells when stimulated with CpG oligodeoxynucleotide (CpG). The objective of the present study was therefore to investigate the ability of CpG, in the context of CD40 ligation, to induce the differentiation of CLL B-cells into antibody-secreting cells (ASCs). CD20+CD38- CLL B-cells were stimulated with a combination of CpG, CD40 ligand and cytokines (CpG/CD40L/c) in a two-step, 7-day culture system. We found that the CpG/CD40L/c culture system prompted CLL B-cells to differentiate into CD19+CD20+CD27+CD38- ASCs. These cells secreted large amounts of IgM and had the same shape as plasma cells. However, only IgMs secreted by ASCs that had differentiated from unmutated CLL B-cells were poly/autoreactive. Class-switch recombination (CSR) to IgG and IgA was detected in cells expressing the activation-induced cytidine deaminase gene (AICDA). Although these ASCs expressed high levels of the transcription factors PRDM1 (BLIMP1), IRF4, and XBP1s, they did not downregulate expression of PAX5. Our results suggest that CLL B-cells can differentiate into ASCs, undergo CSR and produce poly/autoreactive antibodies. Furthermore, our findings may be relevant for (i) identifying the normal counterpart of CLL B-cells and (ii) developing novel treatment strategies in CLL. [ABSTRACT FROM AUTHOR]

B-chronic lymphocytic leukemia (B-CLL), the most common human leukemia, is characterized by predominantly non-dividing malignant mature CD5+ B lymphocytes with an apoptosis defect. Various microenvironmental stimuli confer a growth advantage on these leukemic cells and extend their survival in vivo. Nevertheless, when cultured in vitro, CLL B-cells rapidly die from apoptosis. Certain cytokines may extend the survival capacity of CLL B-cells in vitro and individual anti-apoptotic effects of several cytokines have been reported. The potential cumulative effect of such cytokines has not been studied. We therefore investigated the effects on CLL B-cells survival in vitro of humoral factors, polyclonal lymphocyte activators and a combination of cytokines known for their anti-apoptotic effects. Purified CLL B-cells were cultured in the presence or absence of various soluble molecules and the leukemic cell response was assessed in terms of viability. Apoptotic cell death was detected by flow cytometry using annexinV and 7-amino-actinomycin. The survival of CLL B-cells in vitro was highly variable. When tested separately, cytokines (IL-2, -6, -10, -12, -15, -21, BAFF and APRIL) improved CLL B cell survival moderately; in combination, they significantly enhanced survival of these cells, even up to 7 days of culture. We also report that humoral factors from autologous serum are important for survival of these malignant cells. Our findings support the concept that the CLL microenvironment is critical and suggest that soluble factors may contribute directly to the prolonged survival of CLL B-cells. Therefore, the combination of cytokines we describe as providing strong resistance to apoptosis in vitro might be used to improve the treatment of CLL. [ABSTRACT FROM AUTHOR]

Background: Mutations in the activation segment of the v-raf murine sarcoma viral oncogene homolog B (BRAF) gene are present in approximately 50% of melanomas. The selective BRAF inhibitor vemurafenib has demonstrated significant clinical benefits in patients with melanomas harboring the most common mutations (V600E, V600K and V600R). However, the clinical activity of BRAF inhibitors in patients with rare mutations of codon 600 and the surrounding codons has not been documented.Case Presentation: We used the BRAF inhibitor vemurafenib to treat a patient presenting a rare p.V600_K601delinsD-mutated melanoma. An objective response was evidenced by two months of progression-free survival. By cloning and sequencing BRAF exon 15, we confirmed that a dual mutation was present on a single allele and thus resulted in a BRAFV(600DK601del) mutant protein. We also performed an in silico crystal structure analysis of the mutated protein, in order to characterize the nature of the putative interaction between vemurafenib and the mutant protein.Conclusion: This clinical experience suggests that (i) patients with BRAFV(600DK601del)-mutation-positive melanoma can be treated successfully with the oral BRAF inhibitor vemurafenib and (ii) molecular screening in this context should encompass rare and complex mutations. [ABSTRACT FROM AUTHOR]

B-chronic lymphocytic leukemia (B-CLL), the most common human leukemia, is characterized by predominantly non-dividing malignant mature CD5+ B lymphocytes with an apoptosis defect. Various microenvironmental stimuli confer a growth advantage on these leukemic cells and extend their survival in vivo. Nevertheless, when cultured in vitro, CLL B-cells rapidly die from apoptosis. Certain cytokines may extend the survival capacity of CLL B-cells in vitro and individual anti-apoptotic effects of several cytokines have been reported. The potential cumulative effect of such cytokines has not been studied. We therefore investigated the effects on CLL B-cells survival in vitro of humoral factors, polyclonal lymphocyte activators and a combination of cytokines known for their anti-apoptotic effects. Purified CLL B-cells were cultured in the presence or absence of various soluble molecules and the leukemic cell response was assessed in terms of viability. Apoptotic cell death was detected by flow cytometry using annexinV and 7-amino-actinomycin. The survival of CLL B-cells in vitro was highly variable. When tested separately, cytokines (IL-2, -6, -10, -12, -15, -21, BAFF and APRIL) improved CLL B cell survival moderately; in combination, they significantly enhanced survival of these cells, even up to 7 days of culture. We also report that humoral factors from autologous serum are important for survival of these malignant cells. Our findings support the concept that the CLL microenvironment is critical and suggest that soluble factors may contribute directly to the prolonged survival of CLL B-cells. Therefore, the combination of cytokines we describe as providing strong resistance to apoptosis in vitro might be used to improve the treatment of CLL. [ABSTRACT FROM AUTHOR]

Background: The aim was to describe the regulatory B and T cells (Breg and Treg) and T helper 17 (Th17) lymphocytes before and under treatment with biologic drugs, and to assess their potential predictive value as biomarkers of response in rheumatoid arthritis (RA)., Methods: This was a non-randomised, single-centre, prospective study. Patients with active RA (American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) 2010) who required the initiation or switch to any biologic drug except rituximab were included. The main judgement criterion was the frequency and absolute number of CD24 hi CD27 + Breg and CD24 hi CD38 hi T2/Breg cells, CD25 hi CD127 low Treg and CD45RA - CD161 + CCR6 + Th17 cells measured at inclusion in both patients and controls, and after 1, 3 and 6 months of treatment (M1, M3 and M6) in patients with RA, and compared with the M6 response to treatment (EULAR response and Disease Activity Score in 28 joints (DAS28) remission)., Results: Thirty-one patients with RA and 17 controls were included. There was a reduction in T2/Breg frequency at M0 in patients (p < 0.001) and absolute numbers (p = 0.014) and in immunopositive vs. immunonegative RA (p = 0.016). DAS28 remission at M6 was associated with increased frequency of Treg (p = 0.01). A higher level of CD24 hi CD27 + Breg at baseline was associated with DAS28 remission at M6 (p = 0.04) and a good EULAR response at M6 for abatacept-treated patients (p = 0.01). A lower M0 level of Th17 was associated with a good EULAR response at M6 (p = 0.007), notably under anti-cytokine drugs (p = 0.048)., Conclusions: Altogether, these data, although preliminary, suggest that phenotyping of T and B cells has potential value for the stratification of biologic drugs, notably with respect to choosing between abatacept and anti-cytokine blockade.

The presence of a dominant clonal T-cell population in skin lesions is an important clue in the diagnosis of cutaneous T-cell lymphoma (CTCL). However, it has never been determined whether dominant T-cell receptor (TCR) rearrangements identified in skin lesions and blood from CTCL patients, displaying strictly identical migration patterns by capillary electrophoresis, actually correspond to identical clones. As this information has potential clinical relevance, TCR-gamma (TCRG) gene-derived amplified fragments from dominant blood and skin T-cell clones featuring either identical or slightly different capillary electrophoresis migration patterns were analyzed in eleven CTCL patients. In nine patients with identical electrophoretic migration patterns, sequence analyses revealed the dominant skin and blood T-cell clones to be identical. In contrast, in two patients displaying slight migration differences between skin and blood samples, the TCRG sequences were distinct. Additionally, capillary electrophoresis appears more sensitive and accurate than heteroduplex analysis and in silico analysis of samples of different origins is possible a posteriori. These results demonstrate the efficacy of capillary electrophoresis in assessing molecular identity and discrepancy of dominant T-cell populations obtained from different tissues or at different times, facilitating diagnosis and follow-up.