Neurons that produce gonadotropin-releasing hormone (GnRH) are the final common pathway by which the brain regulates reproduction. GnRH neurons are regulated by an afferent network of ...kisspeptin-producing neurons. Kisspeptin binds to its cognate receptor on GnRH neurons and stimulates their activity, which in turn provides an obligatory signal for GnRH secretion, thus gating down-stream events supporting reproduction. We have developed kisspeptin antagonists to facilitate the direct determination of the role of kisspeptin neurons in the neuroendocrine regulation of reproduction. In vitro and in vivo studies of analogues of kisspeptin-10 with amino substitutions have identified several potent and specific antagonists. A selected antagonist was shown to inhibit the firing of GnRH neurons in the brain of the mouse and to reduce pulsatile GnRH secretion in female pubertal monkeys; the later supporting a key role of kisspeptin in puberty onset. This analog also inhibited the kisspeptin-induced release of luteinizing hormone (LH) in rats and mice and blocked the postcastration rise in LH in sheep, rats, and mice, suggesting that kisspeptin neurons mediate the negative feedback effect of sex steroids on gonadotropin secretion in mammals. The development of kisspeptin antagonists provides a valuable tool for investigating the physiological and pathophysiological roles of kisspeptin in the regulation of reproduction and could offer a unique therapeutic agent for treating hormone-dependent disorders of reproduction, including precocious puberty, endometriosis, and metastatic prostate cancer.
Focal adhesion kinase (FAK) is a key mediator of tumour progression and metastasis. To date, clinical trials of FAK inhibitors have reported disappointing efficacy for oncology indications. We report ...the design and characterisation of GSK215, a potent, selective, FAK‐degrading Proteolysis Targeting Chimera (PROTAC) based on a binder for the VHL E3 ligase and the known FAK inhibitor VS‐4718. X‐ray crystallography revealed the molecular basis of the highly cooperative FAK‐GSK215‐VHL ternary complex, and GSK215 showed differentiated in‐vitro pharmacology compared to VS‐4718. In mice, a single dose of GSK215 induced rapid and prolonged FAK degradation, giving a long‐lasting effect on FAK levels (≈96 h) and a marked PK/PD disconnect. This tool PROTAC molecule is expected to be useful for the study of FAK‐degradation biology in vivo, and our results indicate that FAK degradation may be a differentiated clinical strategy versus FAK inhibition for the treatment of cancer.
A PROTAC with an unusually short linker potently degrades focal adhesion kinase (FAK). SPR and X‐ray crystallography revealed a highly cooperative FAK‐PROTAC‐VCB ternary complex, and FAK degradation showed enhanced effects on 3D cell growth compared to FAK inhibitors. In mice, GSK215 induced rapid and sustained degradation of FAK with a profound PK/PD disconnect.
In the MONALEESA-3 Phase III trial of patients with hormone receptor–positive human epidermal growth factor receptor–negative advanced breast cancer, ribociclib plus fulvestrant significantly ...improved progression-free survival (PFS) and overall survival (OS). Here, we present patient-reported outcomes from the trial, including health-related quality of life (HRQOL).
Patients were randomized (2:1) to receive ribociclib plus fulvestrant or placebo plus fulvestrant. Time to definitive 10% deterioration (TTD) from baseline in HRQOL (global health status GHS from the EORTC QLQ-C30 questionnaire) and pain (BPI-SF questionnaire) were assessed using Kaplan-Meier estimates; a stratified Cox regression model was used to estimate the hazard ratio (HR) and 95% CIs.
Deterioration ≥10% in the EORTC-QLQ-C30 GHS was observed in 33% of patients in the ribociclib group vs 34% of patients in the placebo (reference) group (HR for TTD ≥ 10% = 0.81 95% CI, 0.62–1.1). Similar findings were noted for TTD ≥5% (HR = 0.79 95% CI, 0.61–1.0) and TTD ≥15% (HR = 0.81 95% CI, 0.60–1.08). TTD ≥10% in emotional functioning (HR = 0.76 95% CI, 0.57–1.01) trended in favor of the ribociclib group, whereas results for fatigue and pain were similar between arms. TTD ≥10% in BPI-SF pain severity index score (HR = 0.77 95% CI, 0.57–1.05) and worst pain item score (HR = 0.81 95% CI, 0.58–1.12) trended in favor of ribociclib vs placebo.
In addition to significantly prolonging PFS and OS compared with placebo plus fulvestrant, adding ribociclib to fulvestrant maintains HRQOL.
•Ribociclib + fulvestrant allowed maintenance of global health status (GHS).•Time to deterioration (TTD) by 10% can convey duration until worsening of QOL.•TTD ≥10% was delayed with ribociclib in GHS and emotional functioning.•Ribociclib also demonstrated trends toward delayed TTD vs placebo in pain outcomes.
Bioactive ceramic scaffolds for bone regeneration consisting of a three-dimensional mesh of interpenetrating struts with square section were fabricated via Digital Light Processing (DLP). The ability ...of the technique to manufacture 3D porous structures from β-tricalcium phosphate (β-TCP) powders with different dimensions of struts and pores was evaluated, identifying the possibilities and limitations of the manufacturing process. Small pore sizes were found to seriously complicate the elimination of excess slurry from the scaffold’s innermost pores. The effect of the strut/pore size on the mechanical performance of the scaffolds under compressive stresses was also evaluated, but no significant influence was found. Under compressive stresses, the structures resulted weaker when tested perpendicularly to the printing plane due to interlayer shear failure. Interlayer superficial grooves are proposed as potential failure-controlling defects, which could also explain the lack of a Weibull size effect on the mechanical strength of the fabricated DLP scaffolds.
Mental comorbidities in patients with type 1 diabetes mellitus (T1D) are common, and can have a negative impact on acute blood glucose levels and long-term metabolic control. Information on the ...association of T1D and comorbid posttraumatic stress disorder (PTSD) with diabetes-related outcomes is limited. The aim was to examine the associations between a clinical diagnosis of PTSD and diabetes-related outcomes in patients with T1D. Patients with T1D and comorbid documented PTSD from the DPV database (n = 179) were compared to a group with T1D without PTSD (n = 895), and compared to a group with T1D without comorbid mental disorder (n = 895) by matching demographics (age, gender, duration of diabetes, therapy and migration background) 1:5. Clinical diabetes-related outcomes {body mass index (BMI), hemoglobin A1c (hbA1c), daily insulin dose, diabetic ketoacidosis (DKA), hypoglycemia, number of hospital admissions, number of hospital days} were analyzed, stratified by age groups (≤ 25 years vs. > 25 years). Patients with comorbid PTSD aged ≤ 25 years compared with patients without PTSD or patients without mental disorders had significantly higher HbA1c (8.71 vs. 8.30 or 8.24%), higher number of hospital admissions (0.94 vs. 0.44 or 0.32 per year) and higher rates of DKA (0.10 vs. 0.02 or 0.01 events/year). Patients with comorbid PTSD aged ≤ 25 years compared with patients without PTSD had significantly higher BMI (0.85 vs. 0.59) and longer hospital stays (15.89 vs.11.58 days) than patients without PTSD. Patients with PTSD > 25 years compared with patients without PTSD or without any mental comorbidities had significantly fewer hospital admissions (0.49 vs. 0.77 or 0.69), but a longer hospital length of stay (20.35 vs. 11.58 or 1.09 days). We found that PTSD in younger patients with T1D is significantly related to diabetes outcome. In adult patients with T1D, comorbid PTSD is associated with fewer, but longer hospitalizations. Awareness of PTSD in the care of patients with T1D should be raised and psychological intervention should be provided when necessary.
Imaging biomarkers can assess disease progression or prognoses and are valuable tools to help guide interventions. Particularly in lung imaging, biomarkers present an opportunity to extract regional ...information that is more robust to the patient's condition prior to intervention than current gold standard pulmonary function tests (PFTs). This regional aspect has particular use in functional avoidance radiation therapy (RT) in which treatment planning is optimized to avoid regions of high function with the goal of sparing functional lung and improving patient quality of life post-RT. To execute functional avoidance, detailed dose-response models need to be developed to identify regions which should be protected. Previous studies have begun to do this, but for these models to be clinically translated, they need to be validated. This work validates two metrics that encompass the main components of lung function (ventilation and perfusion) through post-mortem histopathology performed in a novel porcine model. With these methods validated, we can use them to study the nuanced radiation-induced changes in lung function and develop more advanced models.
Polycystic Ovary Syndrome (PCOS) is an endocrine-metabolic disorder that affects approximately 6-10% of women of child-bearing age. Although preliminary studies suggest that certain pollutants may ...act as endocrine disruptors in animals, little is known about their potential association with PCOS. The objective of this case-control pilot study is to determine whether women with PCOS have higher concentrations of specific environmental contaminants compared to women who have not developed PCOS.
Fifty-two PCOS case-patients (diagnosed using the National Institutes of Health 1990 definition) and 50 controls were recruited in 2007-2008, from an urban academic medical center in Los Angeles, CA. Brominated diphenyl ethers, polychlorinated biphenyls (PCBs), organochlorine pesticides, and perfluorinated compounds (PFCs) were measured in serum, and phthalates metabolites and bisphenol A (BPA) in urine.
PCOS case-patients had significantly higher geometric mean (GM) serum concentrations of two PFCs: perfluorooctanoate (PFOA) (GMcases = 4.1 μg/L, GMcontrols = 2.3 μg/L; p = 0.001) and perfluorooctane sulfonate (PFOS) (GMcases = 8.2 μg/L, GMcontrols = 4.9 μg/L; p = 0.01), and lower urinary concentrations of monobenzyl phthalate (mBzP) (GMcases = 7.5 μg/g creatinine, GMcontrols = 11.7 μg/g creatinine; p = 0.02). Logistic regression, controlling for body mass index, age and race, identified an increased likelihood of PCOS in subjects with higher serum concentrations of PFOA and PFOS (adjusted-ORs = 5.8-6.9, p < 0.05), and with lower urine concentrations of mBzP and mono-n-butyl phthalate (mBP) (aORs = 0.14-0.25, p < 0.05).
Our data suggest that PCOS case-patients may differ from controls in their environmental contaminant profile. PCOS subjects had higher serum concentrations of two PFCs, PFOA and PFOS, and lower urine concentrations of mBP and mBzP. Future studies are needed to confirm these preliminary findings and determine if these chemicals or their precursors may have a role in the pathogenesis of PCOS.
Safe and effective non-surgical treatments are an important part of the knee osteoarthritis (OA) treatment algorithm. Cooled radiofrequency ablation (CRFA) and hyaluronic acid (HA) injections are two ...commonly used modalities to manage symptoms associated with knee OA.
A prospective 1:1 randomized study was conducted in 177 patients comparing CRFA to HA injection with follow-ups at 1, 3, 6 and 12 months. HA subjects with unsatisfactory outcomes at 6-months were allowed to crossover and receive CRFA. Knee pain (numeric rating scale = NRS), WOMAC Index (pain, stiffness and physical function), overall quality of life (global perceived effect = GPE, EQ-5D-5 L), and adverse events were measured.
At 12-months, 65.2% of subjects in the CRFA cohort reported ≥50% pain relief from baseline. Mean NRS pain score was 2.8 ± 2.4 at 12 months (baseline 6.9 ± 0.8). Subjects in the CRFA cohort saw a 46.2% improvement in total WOMAC score at the 12-month timepoint. 64.5% of subjects in the crossover cohort reported ≥50% pain relief from baseline, with a mean NRS pain score of 3.0 ± 2.4 at 12 months (baseline 7.0 ± 1.0). After receiving CRFA, subjects in the crossover cohort had a 27.5% improvement in total WOMAC score. All subjects receiving CRFA reported significant improvement in quality of life. There were no serious adverse events related to either procedure and overall adverse event profiles were similar.
A majority of subjects treated with CRFA demonstrated sustained knee pain relief for at least 12-months. Additionally, CRFA provided significant pain relief for HA subjects who crossed over 6 months after treatment.
This trial was registered on ClinicalTrials.gov, NCT03381248. Registered 27 December 2017.
Abstract
STUDY QUESTION
Are urinary phthalate metabolites associated with reduced antral follicle growth among women in an infertility setting?
SUMMARY ANSWER
Higher urinary concentrations of ...di(2-ethylhexyl) phthalate (DEHP) metabolites were associated with significant decreases in antral follicle count (AFC) among women seeking infertility care.
WHAT IS KNOWN ALREADY
Experimental animal studies show that DEHP accelerates primordial follicle recruitment and inhibits antral follicle growth. Whether phthalates also reduce the growing antral follicle pool in humans remains unknown.
STUDY DESIGN, SIZE, DURATION
We examined the association between urinary phthalate metabolites and AFC using prospective data from 215 females recruited between 2004 and 2012 in the Environment and Reproductive Health (EARTH) study.
PARTICIPANTS/MATERIALS, SETTING, METHODS
We quantified the urinary concentrations of 11 phthalate metabolites. We estimated the geometric mean for all urine samples provided prior to unstimulated day 3 AFC assessment for each woman. We evaluated the association of AFC with ∑DEHP (molar sum of four DEHP metabolites) and individual phthalate metabolites using Poisson regression, adjusting for age, BMI and smoking.
MAIN RESULTS AND THE ROLE OF CHANCE
We observed significant decreases in mean AFC for all higher quartiles of ∑DEHP as compared with the lowest quartile. Compared with women in the first quartile of ∑DEHP, women in the second, third and fourth quartiles had a −24% (95% confidence interval (CI): −32%, −16%), −19% (95% CI: −27%, −9%), and −14% (95% CI: −23%, −5%) decrease in mean AFC. The absolute mean AFC in the first quartile was 14.2 follicles (95% CI: 13.2, 15.2) compared with 10.7 follicles (95% CI: 9.9, 11.6) in the second quartile. We observed similar trends among the four individual DEHP metabolites. There was no consistent change in AFC among the remaining phthalate metabolite concentrations evaluated.
LIMITATIONS, REASONS FOR CAUTION
We demonstrated a negative association between DEHP and a well-established marker of ovarian reserve among a subfertile population. However these findings may not be generalizable to women without fertility concerns, and we cannot rule out co-exposure to other chemicals.
WIDER IMPLICATIONS OF THE FINDINGS
Environmental chemicals that inhibit the size of the growing antral follicle pool can impair fertility and reduce fecundity. This study suggests evidence in need of further investigation on the impact of phthalates on the human oocyte and follicular development.
STUDY FUNDING/COMPETING INTERESTS
Work supported by grants ES009718, ES022955, ES000002, and T32ES007069 from the National Institute of Environmental Health Sciences (NIEHS) and grant T32 DK007703-16 from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). C.M. was supported by a post-doctoral training award from the Canadian Institutes of Health Research. There are no competing interests to declare.
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