- AMH prevents primordial ovarian follicle loss and fertility alteration in cyclophosphamide-treated mice. [Journal Article]
- FJFASEB J 2018 Aug 16; :fj201801089R
- The follicular ovarian reserve, constituted by primordial follicles (PMF), is established early in life, then keeps declining regularly along reproductive life. The maintenance of a normal female rep...
The follicular ovarian reserve, constituted by primordial follicles (PMF), is established early in life, then keeps declining regularly along reproductive life. The maintenance of a normal female reproductive function implies the presence of a vast amount of dormant PMF. This process involves a continuous repression of PMF activation into early growing follicle through the balance between factors activating the initiation of follicular growth, mainly actors of the PI3K signaling pathway, and inhibiting factors such as anti-Müllerian hormone (AMH). Any disruption of this balance may induce follicle depletion and subsequent infertility. It has been recently proposed that cyclophosphamide (Cy), an alkylating agent commonly used for treating breast cancer, triggers PMF activation, further leading to premature ovarian insufficiency. Preventing chemotherapy-induced ovarian dysfunction might represent an interesting option for preserving optimal chances of natural or medically assisted conceptions after healing. The aim of the present study was to evaluate, in a model of Cy-treated pubertal mice, whether AMH administration might restrain PMF depletion. The counting of the total PMF number within mouse ovaries showed that recombinant AMH prevented Cy-induced PMF loss. Western blot analysis revealed activation of PI3K signaling pathway after Cy administration. After AMH injection, FOXO3A phosphorylation, a main actor of PMF activation, was significantly decreased. Taken together, these results support a protective role of AMH against Cy-induced follicular loss. We also provide evidence for a possible role of autophagy in the preservation of follicular pool reserve. Therefore, concomitant recombinant AMH administration during chemotherapy might offer a new option for preserving young patients' fertility.-Sonigo, C., Beau, I., Grynberg, M., Binart, N. AMH prevents primordial ovarian follicle loss and fertility alteration in cyclophosphamide-treated mice.
- Epigenetic modification enhances the cytotoxicity of busulfan and 4-hydroperoxycyclophosphamide in AML cells. [Journal Article]
- EHExp Hematol 2018 Aug 10
- The combination of DNA alkylating agents busulfan (Bu) and cyclophosphamide is the most commonly used myeloablative pre-transplant conditioning therapy for myeloid leukemias. However, it is associate...
The combination of DNA alkylating agents busulfan (Bu) and cyclophosphamide is the most commonly used myeloablative pre-transplant conditioning therapy for myeloid leukemias. However, it is associated with significant non-relapse mortality, which prohibits dose-escalation to control relapse. We hypothesized that combining these two drugs with an epigenetic modifier would increase anti-leukemic efficacy without jeopardizing patient safety. A pre-clinical study was performed to determine the synergistic cytotoxicity of Bu, 4-hydroperoxycyclophosphamide (4HC) and the hypomethylating agent decitabine (DAC) in human AML cell lines. Exposure of KBM3/Bu2506 (P53-null) and OCI-AML3 (P53-wild-type) cells to [Bu+4HC] inhibited cell proliferation by ∼35-39%; addition of DAC increased the inhibition to ∼60-62%. The observed synergistic interactions correlated with DNA-damage response activation, increased production of reactive oxygen species, decreased mitochondrial membrane potential, release of mitochondrial proapoptotic proteins into the cytoplasm, and induction of caspase-dependent programmed cell death. The [Bu+4HC+DAC] combination further caused chromatin trapping of DNMT1 with a concomitant increase in DNA damage. In contrast, FLT3-ITD-positive AML cell lines were not sensitized to [Bu+4HC] by inclusion of DAC; addition of the FLT3 kinase inhibitor sorafenib (Sor) sensitized the FLT3-ITD-positive MV4-11 and MOLM13 cell lines to the triple drug combination by inhibiting the FLT3 signal transduction pathway. Our results therefore provide a rationale for the development of personalized conditioning therapy for patients with P53-mutated and FLT3-ITD-positive AML.
- Proteasome inhibitors for multiple myeloma. [Journal Article]
- JJJpn J Clin Oncol 2018 Aug 09
- Therapeutic strategies for multiple myeloma have dramatically changed in the last two decades, especially after the introduction of proteasome inhibitors. The first-in-class proteasome inhibitor, bor...
Therapeutic strategies for multiple myeloma have dramatically changed in the last two decades, especially after the introduction of proteasome inhibitors. The first-in-class proteasome inhibitor, bortezomib, was approved by the US Food and Drug Administration in 2003. Since then, it has been a backbone therapy for not only relapsed or refractory myeloma patients but also newly diagnosed multiple myeloma patients. Second-generation proteasome inhibitors, such as carfilzomib and ixazomib, have been approved, and three proteasome inhibitors were incorporated into several regimens with other cytotoxic agents, such as alkylating agents, immunomodulatory drugs and monoclonal antibodies. Because each proteasome inhibitor shows different properties with respect to adverse events, understanding and managing each adverse event of proteasome inhibitors are necessary for the continuation of therapy with minimal interruption of treatment. This review summarizes the recent advances in proteasome inhibitors used in the treatment of multiple myeloma.
- Cobalt Complexes as an Emerging Class of Catalysts for Homogeneous Hydrogenations. [Journal Article]
- ACAcc Chem Res 2018 Aug 09
- Catalytic hydrogenation using molecular hydrogen represents a green and practical approach for reductions of all kinds of organic chemicals. Traditionally, in the majority of these processes the pres...
Catalytic hydrogenation using molecular hydrogen represents a green and practical approach for reductions of all kinds of organic chemicals. Traditionally, in the majority of these processes the presence of transition metal catalysts is required. In this regard, noble-metal-based catalysts have largely been implemented, such as the application of iridium, palladium, rhodium, ruthenium, and others. Recently, the employment of earth-abundant 3d metals has emerged to replace the utilization of scarce noble metals because of their availability, lower cost, and often reduced toxicity. In this respect, several cobalt complexes, in the form of either molecularly well-defined or in situ-formed complexes, are receiving increasing attention from the scientific community. Importantly, the stability and reactivity of the complexes have greatly been supported by multidentate ligands under steric and/or electronic influences. For instance, tridentate or tetradentate phosphine ligands indirectly tune the reactivity of the metal center to accelerate the overall process, whereas direct participation of the ligand in pincer-type complexes through ligand-metal cooperation regulates the elementary steps in the catalytic cycle. In this Account, we emphasize specifically the advancements in cobalt-catalyzed hydrogenations using molecular hydrogen accomplished in our group. A variety of substrate classes ranging from simple molecules (e.g., carbon dioxide) to complex compounds were explored under the mild and efficient catalytic conditions. Notable examples include the reduction of carbon dioxide to afford either formates using a Co(BF4)2·6H2O/Tetraphos catalyst system or methanol employing a Co(acac)3/Triphos complex in the presence of HNTf2. As interesting examples of the synthesis of fine chemicals, cobalt-promoted hydrogenations of nitriles to primary amines and reductive alkylations of indoles using carboxylic acids as alkylating agents are highlighted. Moreover, highly selective hydrogenations of N-heteroarenes under additive-free conditions were possible by the application of specific cobalt complexes. More recently, a set of carboxylic esters could be hydrogenated to the corresponding alcohols with high efficiency by the use of a well-defined cobalt-PNP pincer catalyst. In particular, the decent reactivity of cobalt catalysts enabled high selectivity and functional group tolerance to be achieved. Throughout our studies, it was found that the pairing of a suitable cobalt precursor and an appropriate tridentate or tetradentate phosphine ligand plays a crucial role harnessing the desired reactivity, while other monodentate and bidentate phosphine ligands showed no reactivity in these investigations. Our developments could provide supervisory information for the future exploration of cobalt-catalyzed hydrogenation reactions and other types of reactions involving cobalt catalysis. Furthermore, relevant contributions from other groups, remaining challenges, and future perspectives in this research area are also presented.
- In silico prediction of chromosome damage: comparison of three (Q)SAR models. [Journal Article]
- MMutagenesis 2018 Jul 28
- Two major endpoints for genotoxicity tests are gene mutation and chromosome damage (CD), which includes clastogenicity and aneugenicity detected by chromosomal aberration (CA) test or micronucleus (M...
Two major endpoints for genotoxicity tests are gene mutation and chromosome damage (CD), which includes clastogenicity and aneugenicity detected by chromosomal aberration (CA) test or micronucleus (MN) test. Many in silico prediction systems for bacterial mutagenicity (i.e. Ames test results) have been developed and marketed. They show good performance for prediction of Ames mutagenicity. On the other hand, it seems that in silico prediction of CD does not progress as much as Ames prediction. Reasons for this include different mechanisms and detection methods, many false positives and conflicting test results. However, some (quantitative) structure-activity relationship ((Q)SAR) models (e.g. Derek Nexus [Derek], ADMEWorks [AWorks] and CASE Ultra [MCase]) can predict CA test results. Therefore, performances of the three (Q)SAR models were compared using the expanded Carcinogenicity Genotoxicity eXperience (CGX) dataset for understanding current situations and future development. The constructed dataset contained 440 chemicals (325 carcinogens and 115 non-carcinogens). Sensitivity, specificity, accuracy or applicability of each model were 56.0, 86.9, 68.6 or 89.1% in Derek, 67.7, 61.5, 65.2 or 99.3% in AWorks, and 91.0, 64.9, 80.5 or 97.7% in MCase, respectively. The performances (sensitivity and accuracy) of MCase were higher than those of Derek or AWorks. Analysis of predictivity of (Q)SAR models of certain chemical classes revealed no remarkable differences among the models. The tendency of positive prediction by (Q)SAR models was observed in alkylating agents, aromatic amines or amides, aromatic nitro compounds, epoxides, halides and N-nitro or N-nitroso compounds. In an additional investigation, high sensitivity but low specificity was noted in in vivo MN prediction by MCase. Refinement of test data to be used for in silico system (e.g. consideration of cytotoxicity or re-evaluation of conflicting test results) will be needed to improve performance of CD prediction.
- Facile one-pot syntheses of new C-28 esters of oleanolic acid and studies on their antiproliferative effect on T cells. [Journal Article]
- ZNZ Naturforsch C 2018 Aug 03
- Structure-activity relationship studies on oleanolic acid (1) have resulted in facile syntheses of its new C-28 esters 2-7 by way of one-pot reaction of 1 with a variety of alkylating agents. Oleanol...
Structure-activity relationship studies on oleanolic acid (1) have resulted in facile syntheses of its new C-28 esters 2-7 by way of one-pot reaction of 1 with a variety of alkylating agents. Oleanolic acid and its new esters were studied for their in vitro antiproliferative effect on healthy human peripheral blood mononuclear cell isolated phytohemagglutinin activated T cells. Results showed that compounds 1, 3, and 5 exhibited significant inhibitory activity on T-cell proliferation. Compound 5 was found to be the most potent, with an IC50 value of 4.249 μg/mL, among all tested compounds, and its activity could be attributed to the presence of bromine atom in the molecule.
- Successful hematopoietic cell transplantation in Fanconi anemia patients with renal impairment using ultra-reduced doses of cyclophosphamide and fludarabine. [Journal Article]
- PBPediatr Blood Cancer 2018 Aug 01; :e27371
- Hematopoietic cell transplantation (HCT) remains until now the only curative modality for hematological manifestations in patients with Fanconi anemia (FA). The doses of alkylating agents used in the...
Hematopoietic cell transplantation (HCT) remains until now the only curative modality for hematological manifestations in patients with Fanconi anemia (FA). The doses of alkylating agents used in the conditioning of this patient population before HCT are usually significantly decreased due to the genomic instability of the FA cells. FA patients with renal impairment represent a dilemma because of the need to further modify the conditioning regimen according to the degree of renal impairment to avoid additional toxicity. At our institution, we successfully transplanted three FA patients using an ultra-modified regimen.
- Brainstem Glioblastoma Multiforme in a Patient with NF1. [Case Reports]
- ARAnticancer Res 2018; 38(8):4897-4900
- This case report presents the first known case of a brainstem glioblastoma multiforme (GBM) in a patient with neurofibromatosis type 1 (NF1). While research has proposed that larger germ-line mutatio...
This case report presents the first known case of a brainstem glioblastoma multiforme (GBM) in a patient with neurofibromatosis type 1 (NF1). While research has proposed that larger germ-line mutations in NF1 may be the driving factor that predisposes patients with NF1 to high-grade astrocytomas, this patient had a nonsense mutation in the NF1 gene, suggesting a variant tumorigenesis. Limited data on targeted immunotherapy for NF1 patients with a GBM have been reported and more data are required before targeted therapies could be proven as second-line treatment options.
- Spermatogonial quantity in human prepubertal testicular tissue collected for fertility preservation prior to potentially sterilizing therapy. [Journal Article]
- HRHum Reprod 2018 Jul 25
- Does chemotherapy exposure (with or without alkylating agents) or primary diagnosis affect spermatogonial quantity in human prepubertal testicular tissue?
Does chemotherapy exposure (with or without alkylating agents) or primary diagnosis affect spermatogonial quantity in human prepubertal testicular tissue?
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- Cardiovascular adverse events in modern myeloma therapy - incidence and risks. A review from European Myeloma Network (EMN) and Italian Society of Arterial Hypertension (SIIA). [Journal Article]
- HHaematologica 2018 Jul 26
- Cardiovascular disease in myeloma patients may derive from factors unrelated to the disease (age, diabetes, dyslipidemia, obesity, prior cardiovascular diseases), related to the disease (cardiac AL-a...
Cardiovascular disease in myeloma patients may derive from factors unrelated to the disease (age, diabetes, dyslipidemia, obesity, prior cardiovascular diseases), related to the disease (cardiac AL-amyloidosis, hyperviscosity, high-output failure, arteriovenous shunting, anemia, renal dysfunction) and linked to antimyeloma treatment (anthracyclines, corticosteroids, alkylating agents, immunomodulatory drugs, proteasome inhibitors). An accurate knowledge of cardiovascular events, effective dose reductions, prevention and management of early and late cardiovascular side effects of chemotherapeutic agents are essential in current clinical practice. Myeloma experts are obliged to carefully balance drugs' efficacy and toxicity for each individual patient. This review summarizes current data and novel insights on cardiovascular adverse events of today's antimyeloma treatment, focusing on carfilzomib, which is the starting point to develop consensus recommendations on preventing and managing cardiovascular side effects in myeloma patients.