Opening Doors: Fertility Preservation for Adolescents and Young Adults Facing Gonadotoxic Therapy.

As long-term survival rates continue to rise in adolescents and young adults receiving a diagnosis of cancer, the focus of oncologic care has shifted from survival to both survival and quality of life after treatment.and quality of life after treatment. For many individuals in the AYA age group, a commonly cited survivorship concern is reproductive function and the ability to have biological children in the future.1 Unfortunately, cancer and cancer-related therapies can have a significant detrimental impact on future fertility and reproductive function in both men and women of reproductive age.

Adipose-derived stem cell-secreted factors promote early stage follicle development in a biomimetic matrix.

Development of primary follicles in vitro benefits from a three-dimensional matrix that is enriched with paracrine factors secreted from feeder cells and mimics the in vivo environment. In this study, we investigated the role of paracrine signaling from adipose-derived stem cells (ADSCs) in supporting primary follicle development in a biomimetic poly(ethylene glycol) (PEG)-based matrix. Follicles co-cultured with ADSCs and follicles cultured in conditioned medium from ADSCs encapsulated in gels (3D CM) exhibited significantly (p < 0.01 and p = 0.09, respectively) improved survival compared to follicles cultured in conditioned medium collected from ADSCs cultured in flasks (2D CM) and follicles cultured without paracrine support. The gene expression of ADSCs suggested that the stem cells maintained their multipotency in the 3D PEG environment over the culture period, regardless of the presence of the follicles, while under 2D conditions the multipotency markers were downregulated. The differences in cytokine signatures of follicles exposed to 3D and 2D ADSC paracrine factors suggest that early cytokine interactions are key for follicle survival. Taken together, the biomimetic PEG scaffold provides a three-dimensional, in vivo-like environment to induce ADSCs to secrete factors which promote early stage ovarian follicle development and survival.

Histone demethylase KDM4A and KDM4B expression in granulosa cells from women undergoing in vitro fertilization.

PURPOSE: To assess expression of the histone demethylases KDM4A and KDM4B in granulosa collected from women undergoing oocyte retrieval and to determine if expression was related to pregnancy outcome. METHODS: Cumulus and mural granulosa cells were obtained from women undergoing oocyte retrieval. KDM4A and KDM4B mRNA expression was determined by qRT-PCR. KDM4A and KDM4B proteins were immunohistochemically localized in ovarian tissue sections obtained from archival specimens. RESULTS: KDM4A and KDM4B protein was localized to oocytes, granulosa cells, and theca and luteal cells in ovaries from reproductive-aged women. KDM4A and KDM4B mRNA expression was overall higher in cumulus compared to mural granulosa. When comparing granulosa demethylase gene expression, KDM4A and KDM4B mRNA expression was higher in both cumulus and mural granulosa from not pregnant patients compared to patients in the pregnant-live birth group. CONCLUSIONS: Histone demethylases KDM4A and KDM4B mRNA are differentially expressed in cumulus and mural granulosa. Expression of both KDM4A and KDM4B mRNA was lower in cumulus granulosa and mural granulosa from pregnant compared to not pregnant patients. These findings suggest that altered expression of histone demethylases may impact epigenetic changes in granulosa cells associated with pregnancy.

Strategies to Maintain Fertility in Young Breast Cancer Patients.

Breast cancer is the most frequently occurring cancer in women of reproductive age. Treatments for breast cancer may eliminate or diminish fertility, making discussions about fertility preservation essential prior to initiation of gonadotoxic therapies. Additionally, even in patients who do not require chemotherapy, the use of adjuvant endocrine therapy will often push patients out of the reproductive window before treatment is completed. The only established methods for fertility preservation are oocyte or embryo cryopreservation, but experimental methods, such as ovarian suppression with GnRH agonists and ovarian tissue cryopreservation, show great promise. Early referral to a fertility specialist for interested patients affords patients the most fertility preservation options, with only minimal delay to cancer treatment.

A prospective, observational study comparing the PK/PD relationships of generic Meropenem (Mercide®) to the innovator brand in critically ill patients.

INTRODUCTION: Clinicians' skepticism, fueled by evidence of inferiority of some multisource generic antimicrobial products, results in the underutilization of more cost-effective generics, especially in critically ill patients. The aim of this observational study was to demonstrate equivalence between the generic or comparator brand of meropenem (Mercide®) and the leading innovator brand (Meronem®) by means of an ex vivo technique whereby antimicrobial activity is used to estimate plasma concentration of the active moiety. METHODS: Patients from different high care and intensive care units were recruited for observation when prescribed either of the meropenem brands under investigation. Blood samples were collected over 6 hours after a 30 minute infusion of the different brands. Meropenem concentration curves were established against United States Pharmacopeia standard meropenem (Sigma-Aldrich) by using standard laboratory techniques for culture of Klebsiella pneumoniae. Patients' plasma samples were tested ex vivo, using a disc diffusion assay, to confirm antimicrobial activity and estimate plasma concentrations of the two brands. RESULTS: Both brands of meropenem demonstrated similar curves in donor plasma when concentrations in vials were confirmed. Patient-specific serum concentrations were determined from zones of inhibition against a standard laboratory Klebsiella strain ex vivo, confirming at least similar in vivo concentrations as the concentration curves (90% confidence interval) overlapped; however, the upper limit of the area under the curve for the ratio comparator/innovator exceeded the 1.25-point estimate, i.e., 4% higher for comparator meropenem. CONCLUSION: This observational, in-practice study demonstrates similar ex vivo activity and in vivo plasma concentration time curves for the products under observation. Assay sensitivity is also confirmed. Current registration status of generic small molecules is in place. The products are therefore clinically interchangeable based on registration status as well as bioassay results, demonstrating sufficient overlap for clinical comfort. The slightly higher observed comparator meropenem concentration (4%) is still clinically acceptable due to the large therapeutic index and should ally fears of inferiority.

Phase 1 clinical study of the acute and subacute safety and proof-of-concept efficacy of carbohydrate-derived fulvic acid.

BACKGROUND: The purpose of this research was to determine the acute and subacute safety and proof-of-concept efficacy of carbohydrate-derived fulvic acid (CHD-FA). METHODS: In this double-blind study, 30 male volunteers with predetermined atopy were randomly assigned to either Group A or Group B, each consisting of 15 participants. In part 1 of the study, the groups were administered increasing amounts of CHD-FA, ranging from 5 mL to 40 mL, provided that no adverse events had occurred at the previous dosage. In part 2, Group A participants received 20 mL of 3.8% CHD-FA twice daily for 3 days and were monitored for a week. Because no adverse events occurred, Group B received 40 mL of 3.8% CHD-FA twice daily for a period of 3 days. In part 3, both groups received either 40 mL of 3.8% CHD-FA or placebo twice daily for a period of one week, followed by a one-week washout period before crossover to the alternative treatment schedule. Parameters used to establish safety were electrocardiography, a physical examination, a health questionnaire, and hematology and biochemistry, determined at baseline, during regular calculated intervals, and at the end of each part of the study. A skin prick test was done as part of the screening process and, from the result, the allergen the participant was most allergic to was then selected, along with the positive histamine and negative control to be repeated at the start and end of each respective stage. RESULTS: Safety parameters remained constant throughout the trial. A significant decrease in skin prick test results was observed. CONCLUSION: No severe adverse events occurred, establishing that CHD-FA to be safe at doses up to 40 mL twice daily for a week and that at this dosage CHD-FA acts as an anti-inflammatory agent. These findings confirm earlier animal data.

The in vitro antitumour activity of novel, mitochondrial-interactive, gold-based lipophilic cations.

In this study we compared the effects of two previously described antimitochondrial gold complexes, that is, [A] [Au(dppe)(2)]Cl and [B] [Au(d4pype)(2)]Cl with two novel lipophilic cations, that is, [C] [Au(dpmaaH(2))(dpmaaSnMe(2))]Cl and [D] [Au(dpmaaSnMe(2))(2)]Cl as antimitochondrial agents. The results of this study indicate that [C] and [D] have intermediate partition coefficients and exhibited a selective uptake by cells. They exhibited a higher selectivity for the various cell lines than [A] but were more cytotoxic than [B]. There is a significant correlation between the cytotoxic potential of [A], [B], [C], and [D] and their octanol/water partition coefficients in both MCF-7 (breast cancer) and MCF-12A (nonmalignant breast) cells, whereas their cytotoxic potential and ability to induce the release of cytochrome c correlated only in the case of the MCF-12A cells. Complexes [C] and [D] are promising new chemotherapeutic drugs. These compounds target the mitochondrial membranes of certain cancer cells exploiting the differences between the mitochondrial membrane potential of these cells and normal cells. Although the concentrations of these compounds necessary to eradicate cancer cells are very high, the results provide a basis for the synthesis of a new family of compounds with intermediate partition coefficients compared to [A] and [B] but with increased activity against cancer cells.

An in vitro investigation of the anti-inflammatory properties of potassium humate.

In this study the anti-inflammatory potential of potassium humate, derived from bituminous coal, has been investigated in vitro. Exposure of resting and phorbol-12-myristate-13-acetate (PMA) stimulated human neutrophils to potassium humate resulted in a decreased expression of CR3 by activated, but not resting cells, in a dose-related way. Humate also inhibited the adhesion of PMA-stimulated neutrophils to a baby hamster kidney cell line expressing ICAM1 (the CR3 ligand) (BHK331-7). Similar results were obtained using normal BHK cells indicating that this inhibition does not only target specific adhesion molecules on the neutrophil and eosinophil membrane by activated phagocytes, but also affects other mechanisms involved in cell adhesion. Opsonised Sephadex or FMLP/Cyto B-induced degranulation of neutrophils and eosinophils were also decreased by humate treatment. Inhibition of the adhesion of activated phagocytes, as well as inhibition of the release of granule polypeptides, both of which are responsible for tissue damage during inflammatory processes, are attractive targets for anti-inflammatory drugs. Because humate is well tolerated with an excellent safety profile it merits further evaluation in patients suffering from inflammatory conditions.

Investigation of the immunostimulatory properties of oxihumate.

A unique process has been developed to convert bituminous coal by controlled wet oxidation followed by base treatment to a water-soluble humate called oxihumate. The effects of oxihumate on the proliferative response of lymphocytes has been studied in vitro and ex vivo. Oxihumate increased the proliferative response of phytohaemagglutinin-stimulated human lymphocytes, from a concentration of 20 microg/ml and upwards. This response was even more striking in the case of lymphocytes from HIV-infected patients and was not limited to the in vitro setting since similar effects were observed ex vivo following administration of a non-toxic dosage of 4 g oxihumate per day to HIV-positive individuals for two weeks. Mechanistic studies revealed that stimulation of the proliferative response of lymphocytes by oxihumate is associated with an increased production of IL-2, as well as expression of the IL-2 receptor in the setting of decreased production of IL-10. Oxihumate therefore holds promise for the treatment of immunocompromized patients.