First-in-human study to evaluate the safety, tolerability, and population pharmacokinetic/pharmacodynamic target attainment analysis of FL058 alone and in combination with meropenem in healthy subjects.

FL058 is a novel diazabicyclooctane ß-lactamase inhibitor. This first-in-human study evaluated the safety, tolerability, and population pharmacokinetic (PK)/pharmacodynamic target attainment analysis of FL058 alone and in combination with meropenem in healthy subjects. The results showed that the maximum tolerated dose of FL058 was 3,000 mg after single-dose infusion. FL058 in combination with meropenem did not cause any grade 3 or higher adverse event when the dose was escalated up to 1,000 mg/2,000 mg. FL058 exposure PK parameters showed dose proportionality. FL058 was excreted primarily in urine. No significant PK interaction was found between FL058 and meropenem. Population PK model analysis indicated that the PK profiles of FL058 and meropenem were consistent with the two-compartment model. The impact of covariates, creatinine clearance, concomitant use of meropenem, body weight, sex, and FL058 dose, on FL058 exposure was less than 10%. FL058/meropenem combination was safe and well tolerated up to a 1,000-mg/2,000-mg dose in healthy adults. The recommended minimum dose of FL058/meropenem combination was 500 mg/1,000 mg by intravenous infusion over 2 h every 8 h based on target attainment analysis. The good safety, tolerability, and satisfactory PK profiles of FL058 alone and in combination with meropenem in this first-in-human study will support further clinical development of FL058 in combination with meropenem in patients with target infections (ClinicalTrials.gov identifiers: NCT05055687, NCT05058118, and NCT05058105).

Safety and pharmacokinetics of antifungal agent VT-1598 and its primary metabolite, VT-11134, in healthy adult subjects: phase 1, first-in-human, randomized, double-blind, placebo-controlled study of single-ascending oral doses of VT-1598.

VT-1598 is a novel fungal CYP51 inhibitor and 1-tetrazole-based antifungal drug candidate with improved selectivity minimizing off-target binding to and inhibition of human CYP450 enzymes. Data are presented from this first clinical study in the evaluation of the safety and pharmacokinetic (PK) of single ascending doses of 40, 80, 160, 320, and 640 mg VT-1598, comprising a 160 mg cohort in both fasting and fed states. Eight healthy adults per dose were randomized to receive either oral VT-1598 or placebo (3:1). Over the dose range, exposures were with relatively high variation. The maximum plasma concentrations (Cmax) for VT-1598 were 31.00-279.4 ng/ml and for its primary metabolite, VT-11134, were 27.80-108.8 ng/ml. The plasma area under the concentration-time curve to the last measurable concentration (AUC0-last) for VT-1598 were 116.1-4507 ng*h/ml, and for VT-11134 were 1140-7156 ng*h/ml. The dose proportionality was inconclusive based on the results of the power model. The peak concentration time (Tmax) was 4-5 h for VT-1598 and for VT-11134. Half-life was 103-126 h for VT-11134. After food intake, Cmax of VT-1598 increased by 44% (geometric mean ratio (GMR), 1.44; 90%CI [0.691, 2.19]) and AUC0-last by 126% (GMR, 2.26; 90%CI [1.09, 3.44]), while exposure of VT-11134 was decreased 23% for Cmax (GMR, 0.77; 90%CI [0.239, 1.31]) and unchanged for AUC0-last (GMR, 1.02; 90%CI [0.701, 1.33]). Neither VT-1598 nor VT-11134 were detected in urine. No serious adverse events (AEs) or AEs leading to early termination were observed. The safety and PK profiles of VT-1598 support its further clinical development.

VT-1598 is a tetrazole antifungal with improved selectivity and demonstrated a high survival rate when murine infected with invasive aspergillosis, coccidiodomycosis, cryptococcosis, and candidiasis. We report a first-in-human study to evaluate safety and pharmacokinetics after an oral dose of VT-1598.

Diverse impacts of red palm olein, extra virgin coconut oil and extra virgin olive oil on cardiometabolic risk markers in individuals with central obesity: a randomised trial.

PURPOSE: Dietary fats with an abundance of phytonutrients have garnered public attention beyond fatty acids per se. This study was set to investigate the impact of consuming diets with red palm olein (RPOO), extra virgin coconut oil (EVCO) and extra virgin olive oil (EVOO, as a control) on cardiometabolic risk biomarkers and lipid profile. METHODS: We recruited a total of 156 individuals with central obesity, aged 25-45 years, with waist circumference ≥ 90 cm for men and ≥ 80 cm for women in a parallel single-blind 3-arm randomised controlled trial. The participants consumed isocaloric diets (~ 2400 kcal) enriched with respective test fats (RPOO, EVCO or EVOO) for a 12-week duration. RESULTS: The mean of the primary outcome plasma high sensitivity C-reactive protein was statistically similar between the three diets after a 12-week intervention. EVOO resulted in significantly lower mean LDL cholesterol compared with RPOO and EVCO, despite similar effects on LDL and HDL cholesterol subfractions. The RPOO diet group showed elevated mean α and ß -carotenes levels compared with EVCO and EVOO diet groups (P < 0.05), corresponding with the rich carotenoid content in RPOO. CONCLUSION: The three oils, each of which has unique phytonutrient and fatty acid compositions, manifested statistically similar cardiometabolic effects in individuals with central obesity at risk of developing cardiovascular diseases with distinct circulating antioxidant properties. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov (NCT05791370).

Differences in Metabolite Profiles of Dihydroberberine and Micellar Berberine in Caco-2 Cells and Humans-A Pilot Study.

We investigated the pharmacokinetic pathway of berberine and its metabolites in vitro, in Caco-2 cells, and in human participants following the administration of dihydroberberine (DHB) and micellar berberine (LipoMicel®, LMB) formulations. A pilot trial involving nine healthy volunteers was conducted over a 24 h period; blood samples were collected and subjected to Ultra High-Performance Liquid Chromatography-High Resolution Mass Spectrometry (UHPLC-HRMS) analyses to quantify the concentrations of berberine and its metabolites. Pharmacokinetic correlations indicated that berberrubine and thalifendine follow distinct metabolic pathways. Additionally, jatrorrhizine sulfate appeared to undergo metabolism differently compared to the other sulfated metabolites. Moreover, berberrubine glucuronide likely has a unique metabolic pathway distinct from other glucuronides. The human trial revealed significantly higher blood concentrations of berberine metabolites in participants of the DHB treatment group compared to the LMB treatment group-except for berberrubine glucuronide, which was only detected in the LMB treatment group. Similarly, results from in vitro investigations showed significant differences in berberine metabolite profiles between DHB and LMB. Dihydroberberine, dihydroxy-berberrubine/thalifendine and jatrorrhizine sulfate were detected in LMB-treated cells, but not in DHB-treated cells; thalifendine and jatrorrhizine-glucuronide were detected in DHB-treated cells only. While DHB treatment provided higher blood concentrations of berberine and most berberine metabolites, both in vitro (Caco-2 cells) and in vivo human studies showed that treatment with LMB resulted in a higher proportion of unmetabolized berberine compared to DHB. These findings suggest potential clinical implications that merit further investigation in future large-scale trials.

Assessment of the plasticizer exposure of hospital workers regularly handling medical devices: A pilot study.

Plastic medical devices, e.g. infusion sets, blood bags or tubing material, that are used manifold in the medical treatment of hospital patients, usually contain considerable amounts of plasticizers. Whereas several studies showed highly elevated inner plasticizer levels of patients treated with plasticized medical devices, little is known about the exposure situation of hospital staff. The present pilot study aimed to evaluate the urinary plasticizer metabolite levels of selected hospital workers of the blood bank (medical technical assistants, MTA) and of perfusionists that are regularly handling plasticized medical devices in order to estimate the work-related amount of the inner individual plasticizer exposure. The study subjects were asked to collect pre- and post-shift spot urine samples over the course of a working week, that were subsequently analyzed for selected urinary metabolites of the plasticizers DEHP, DINCH, DEHTP and TEHTM. Although the observed differences were rather low, a differentiated approach revealed a perceptible impact of the respective workplace environment on the individual urinary plasticizer metabolite levels. Thus, the group of blood bank MTA showed significantly elevated increment levels of urinary DEHP and DINCH metabolites, while the group of perfusionists, showed a considerable higher detection frequency of the main urinary TEHTM metabolite. All in all, however, it can be cautiously concluded by the results of the presented pilot study that a regular handling of plasticized medical devices by hospital employees (via inhalation or dermal contact) contributes demonstrably but yet only marginally to the individual internal plasticizer exposure.

Development and validation of an HPLC coupled with tandem mass spectrometry method for the determination of HSK7653, a novel super long-acting dipeptidyl peptidase-4 inhibitor, in human plasma and urine and its application to a pharmacokinetic study.

HSK7653 is a novel super long-acting dipeptidyl peptidase-4 inhibitor, which is promising for the treatment of type 2 diabetes mellitus with the twice-monthly dosing regimen. In this article, a robust and sensitive HPLC coupled with tandem mass spectrometry method for determining the concentration of HSK7653 in human plasma and urine was developed and validated for the first time. Plasma and urine samples were prepared by protein precipitation. After that, the extracts were analyzed using an LC-20A HPLC system coupled with API 4000 tandem MS equipped with an electrospray ionization source in positive mode. Separation was obtained using an XBridge Phenyl column (2.1 × 50 mm, 3.5 µm) with a gradient elution of acetonitrile and water containing 0.1% formic acid and 5% acetonitrile at room temperature. This bioanalysis method has been fully validated and the results showed good sensitivity and specificity. In brief, the standard curves were linear over the concentration range of 2.00-2000 ng/ml for plasma and 20.0-20,000 ng/ml for urine, respectively. In addition, the precisions of inter- and intra-run of HSK7653 were less than 12.7% and the accuracies were -3.3% to 6.3% for both plasma and urine. Finally, this method was successfully applied to explore the pharmacokinetic characteristics of HSK7653 in Chinese healthy volunteers in a first-in-human study.

A Bayesian Network Approach to Explainable Reinforcement Learning with Distal Information.

Nowadays, Artificial Intelligence systems have expanded their competence field from research to industry and daily life, so understanding how they make decisions is becoming fundamental to reducing the lack of trust between users and machines and increasing the transparency of the model. This paper aims to automate the generation of explanations for model-free Reinforcement Learning algorithms by answering "why" and "why not" questions. To this end, we use Bayesian Networks in combination with the NOTEARS algorithm for automatic structure learning. This approach complements an existing framework very well and demonstrates thus a step towards generating explanations with as little user input as possible. This approach is computationally evaluated in three benchmarks using different Reinforcement Learning methods to highlight that it is independent of the type of model used and the explanations are then rated through a human study. The results obtained are compared to other baseline explanation models to underline the satisfying performance of the framework presented in terms of increasing the understanding, transparency and trust in the action chosen by the agent.

Human Monoclonal Antibody Cocktail for the Treatment or Prophylaxis of Middle East Respiratory Syndrome Coronavirus.

BACKGROUND: REGN3048 and REGN3051 are human monoclonal antibodies (mAb) targeting the spike glycoprotein on the Middle East respiratory syndrome coronavirus (MERS-CoV), which binds to the receptor dipeptidyl peptidase-4 (DPP4) and is necessary for infection of susceptible cells. METHODS: Preclinical study: REGN3048, REGN3051 and isotype immunoglobulin G (IgG) were administered to humanized DPP4 (huDPP4) mice 1 day prior to and 1 day after infection with MERS-CoV (Jordan strain). Virus titers and lung pathology were assessed. Phase 1 study: healthy adults received the combined mAb (n = 36) or placebo (n = 12) and followed for 121 days. Six dose levels were studied. Strict safety criteria were met prior to dose escalation. RESULTS: Preclinical study: REGN3048 plus REGN3051, prophylactically or therapeutically, was substantially more effective for reducing viral titer, lung inflammation, and pathology in huDPP4 mice compared with control antibodies and to each antibody monotherapy. Phase 1 study: REGN3048 plus REGN3051 was well tolerated with no dose-limiting adverse events, deaths, serious adverse events, or infusion reactions. Each mAb displayed pharmacokinetics expected of human IgG1 antibodies; it was not immunogenic. CONCLUSIONS: REGN3048 and REGN3051 in combination were well tolerated. The clinical and preclinical data support further development for the treatment or prophylaxis of MERS-CoV infection.

Human safety study of a selective neuronal adenylate cyclase 1 inhibitor NB001 which relieves the neuropathic pain and blocks ACC in adult mice.

Calcium-dependent, neuronal adenylyl cyclase subtype 1 (AC1) is critical for cortical potentiation and chronic pain. NB001 is a first-in-class drug acting as a selective inhibitor against AC1. The present study delineated the pharmacokinetic (PK) properties of human-used NB001 (hNB001) formulated as immediate-release tablet. This first-in-human (FIH) study was designed as randomized, double-blind, placebo-controlled trial. hNB001 showed placebo-like safety and good tolerability in healthy volunteers. A linear dose-exposure relationship was demonstrated at doses between 20 mg and 400 mg. The relatively small systemic exposure of hNB001 in human showed low bioavailability of this compound through oral administration, which can be improved through future dosage research. Food intake had minimal impact on the absorption of hNB001 tablet. Animal experiments further confirmed that hNB001 had strong analgesic effect in animal models of neuropathic pain. In brain slice prepared from the anterior cingulate cortex (ACC), bath application of hNB001 blocked the induction of long-term potentiation (LTP). These results from both rodents and human strongly suggest that hNB001 can be safely used for the future treatment of different types of chronic pain in human patients.

Sex bias in alcohol research: A 20-year comparative study.

We aimed to assess the sex-inclusive and sex-based analysis bias in alcohol research for the past 20 years. Data were abstracted from 2988 original research articles published from 2000 through 2019 in 51 representative journals across 9 biomedical disciplines. An analysis in 5-year intervals revealed that the percentage of studies using participants of both sexes was significantly higher between 2015 and 2019 than between 2000 and 2014. When stratified, clinical studies showed a higher percentage of both-sex studies compared to basic studies using animals. The reasons for the use of single-sex cohorts mainly included insufficient participant numbers and misconceptions surrounding the hormonal variability of females. Implementation of the NIH SABV policy promoted the ratio of NIH-funded papers with sex-based analyses. In conclusion, sex bias in alcohol-related biomedical studies has improved over the past 20 years, particularly after the implementation of the SABV policy. Although clinical studies increasingly included sex-based analysis, basic studies were biased towards the use of males.

First-in-human assessment of the novel LAT1 targeting PET probe 18F-FIMP.

In the first-in-human PET study, we evaluated the biodistribution and tumor accumulation of the novel PET probe, (S)-2-amino-3-[3-(2-18F-fluoroethoxy)-4-iodophenyl]-2-methylpropanoic acid (18F-FIMP), which targets the tumor-related L-type amino acid transporter 1 (LAT1), and compared it with L-[methyl-11C]methionine (11C-MET) and 2-Deoxy-2-18F-fluoro-D-glucose (18F-FDG). 18F-FIMP biodistribution was revealed by whole-body and brain scans in 13 healthy controls. Tumor accumulation of 18F-FIMP was evaluated in 7 patients with a brain tumor, and compared with those of 11C-MET and 18F-FDG. None of the subjects had significant problems due to probe administration, such as adverse effects or abnormal vital signs. 18F-FIMP was rapidly excreted from the kidneys to the urinary bladder. There was no characteristic physiological accumulation in healthy controls. 18F-FIMP PET resulted in extremely clear images in patients with suspected glioblastoma compared with 11C-MET and 18F-FDG. 18F-FIMP could be a useful novel PET probe for LAT1-positive tumor imaging including glioblastoma.

Metabolomics analysis of type 2 diabetes remission identifies 12 metabolites with predictive capacity: a CORDIOPREV clinical trial study.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is one of the most widely spread diseases, affecting around 90% of the patients with diabetes. Metabolomics has proven useful in diabetes research discovering new biomarkers to assist in therapeutical studies and elucidating pathways of interest. However, this technique has not yet been applied to a cohort of patients that have remitted from T2DM. METHODS: All patients with a newly diagnosed T2DM at baseline (n = 190) were included. An untargeted metabolomics approach was employed to identify metabolic differences between individuals who remitted (RE), and those who did not (non-RE) from T2DM, during a 5-year study of dietary intervention. The biostatistical pipeline consisted of an orthogonal projection on the latent structure discriminant analysis (O-PLS DA), a generalized linear model (GLM), a receiver operating characteristic (ROC), a DeLong test, a Cox regression, and pathway analyses. RESULTS: The model identified a significant increase in 12 metabolites in the non-RE group compared to the RE group. Cox proportional hazard models, calculated using these 12 metabolites, showed that patients in the high-score tercile had significantly (p-value < 0.001) higher remission probabilities (Hazard Ratio, HR, high versus low = 2.70) than those in the lowest tercile. The predictive power of these metabolites was further studied using GLMs and ROCs. The area under the curve (AUC) of the clinical variables alone is 0.61, but this increases up to 0.72 if the 12 metabolites are considered. A DeLong test shows that this difference is statistically significant (p-value = 0.01). CONCLUSIONS: Our study identified 12 endogenous metabolites with the potential to predict T2DM remission following a dietary intervention. These metabolites, combined with clinical variables, can be used to provide, in clinical practice, a more precise therapy. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00924937.

Arterial spin labeling MR image denoising and reconstruction using unsupervised deep learning.

Arterial spin labeling (ASL) imaging is a powerful magnetic resonance imaging technique that allows to quantitatively measure blood perfusion non-invasively, which has great potential for assessing tissue viability in various clinical settings. However, the clinical applications of ASL are currently limited by its low signal-to-noise ratio (SNR), limited spatial resolution, and long imaging time. In this work, we propose an unsupervised deep learning-based image denoising and reconstruction framework to improve the SNR and accelerate the imaging speed of high resolution ASL imaging. The unique feature of the proposed framework is that it does not require any prior training pairs but only the subject's own anatomical prior, such as T1-weighted images, as network input. The neural network was trained from scratch in the denoising or reconstruction process, with noisy images or sparely sampled k-space data as training labels. Performance of the proposed method was evaluated using in vivo experiment data obtained from 3 healthy subjects on a 3T MR scanner, using ASL images acquired with 44-min acquisition time as the ground truth. Both qualitative and quantitative analyses demonstrate the superior performance of the proposed txtc framework over the reference methods. In summary, our proposed unsupervised deep learning-based denoising and reconstruction framework can improve the image quality and accelerate the imaging speed of ASL imaging.

Infrapatellar fat pad-derived mesenchymal stromal cell product for treatment of knee osteoarthritis: a first-in-human study with evaluation of the potency marker.

BACKGROUND AIMS: Infrapatellar fat pad-derived mesenchymal stromal cells (IFP-MSCs) have not yet been used in a human clinical trial. In this open-label phase 1 study, patients with knee osteoarthritis (OA) received a single intra-articular injection of autologous IFP-MSCs. Safety was assessed through physical examination of the knee joint, vital signs, laboratory tests and adverse events. Efficacy was evaluated with regard to pain and function using questionnaires, x-ray and magnetic resonance imaging (MRI). Indoleamine-2,3-dioxygenase (IDO) expression in IFP-MSCs primed with interferon gamma was used as an in vitro potency measurement in investigating the correlations of clinical outcomes. METHODS: Twelve patients with symptomatic knee OA were recruited. IFP adipose tissue was harvested from each patient's knee through surgical excision for IFP-MSC manufacturing. Cryopreserved IFP-MSCs (5 × 107 cells) were injected into the knee joint immediately after thawing. RESULTS: No significant adverse events were observed. Patients who received IFP-MSCs exhibited clinically significant pain and functional improvement at 48-week follow-up. The MRI Osteoarthritis Knee Score average was also significantly reduced from 100.2 before injection to 85.0 at 48 weeks after injection. The IDO expression of the primed IFP-MSCs of the 12 patients was correlated with clinical outcomes after injection. CONCLUSIONS: A single intra-articular injection of IFP-MSCs appears to be a safe therapy for treating knee OA and may improve disease symptoms. IDO measurement of primed IFP-MSCs has potential as a potency marker of MSC products for immunomodulatory therapy.

Mesenchymal stem cell therapy for focal epilepsy: A systematic review of preclinical models and clinical studies.

Drug-resistant epilepsy (DRE) is characterized by recurrent seizures despite appropriate treatment with antiseizure medication (ASM). Due to their regenerative and immunomodulatory potential, therapies with biologics such as mesenchymal stem cells (MSCs) offer a potential therapeutic benefit for structural causes of epilepsy, such as hippocampal sclerosis. In this article, we report a systematic review of the literature evaluating the preclinical and clinical studies of MSCs for DRE. Medline, Ovid EMBASE, Scopus, and the Cochrane Databases were searched electronically from their dates of inception to November 2021 using the following keywords: (("mesenchymal") AND ("stem cell")) AND (("epilepsy") OR ("convulsion") OR ("seizures")). This review followed Preferred Reporting Items for Systemic Reviews and Meta-Analyses (PRISMA) guidelines. The initial query identified 488 studies representing 323 unique manuscripts. After application of selection criteria, 15 studies were included in this systematic review; 11 were preclinical studies and 4 were clinical studies. All preclinical studies were performed in rodents and all clinical studies were phase 1 trials. Thus far, therapy with MSCs appears to be safe for use in humans, as no severe adverse events related directly to the therapy were reported. Furthermore, MSC therapy appears to provide a statistically significant clinical benefit by reducing the seizure burden of patients, reducing the electrophysiological biomarkers of epilepsy, and improving their comorbidities, such as depression and anxiety. In addition, animal studies reveal that the therapy exerts its effect by reducing aberrant mossy fiber sprouting (reduce excitatory pathways) and increasing γ-aminobutyric acid (GABA)ergic interneurons (increase inhibitory pathways). Both preclinical and clinical studies have shown MSC therapy to be safe and preliminary effective, thus warranting further studies to investigate its therapeutic potential.

A Pilot Study Evaluating the Feasibility of Testing for an Acute Impact of Human Exposure to a Power-line Frequency Magnetic Field on Blood Cortisol and Thyroid-Stimulating Hormone.

Numerous studies have been carried out on the potential effects of an extremely low frequency (ELF-0-300 Hz) magnetic field (MF) on human health. However, there is limited data on the effect of a high exposure level to ELF MFs for a prolonged period. Therefore, the objective of this pilot work was to demonstrate the feasibility of a study evaluating the stress hormone concentrations resulting from a 10-min exposure to a 60 Hz MF of several tens of thousands of µT. In this pilot study, human volunteers were thus exposed for the first time to a 60 Hz, 50 mT MF for a duration of 10 min. Stress hormone levels were measured before (once), during (twice) and after (once) this 10-min exposure period. The small sample size (n = 5) did not allow to conduct standard inferential statistical tests and no conclusion regarding the exposure effects can be drawn. However, this study demonstrates the feasibility of using a simple blood testing material in a protocol testing for the effect of a 10-min exposure to a high MF level in healthy human volunteers. © 2022 Bioelectromagnetics Society.

Postsynaptic Proteins at Excitatory Synapses in the Brain-Relationship with Depressive Disorders.

Depressive disorders (DDs) are an increasingly common health problem that affects all age groups. DDs pathogenesis is multifactorial. However, it was proven that stress is one of the most important environmental factors contributing to the development of these conditions. In recent years, there has been growing interest in the role of the glutamatergic system in the context of pharmacotherapy of DDs. Thus, it has become increasingly important to explore the functioning of excitatory synapses in pathogenesis and pharmacological treatment of psychiatric disorders (including DDs). This knowledge may lead to the description of new mechanisms of depression and indicate new potential targets for the pharmacotherapy of illness. An excitatory synapse is a highly complex and very dynamic structure, containing a vast number of proteins. This review aimed to discuss in detail the role of the key postsynaptic proteins (e.g., NMDAR, AMPAR, mGluR5, PSD-95, Homer, NOS etc.) in the excitatory synapse and to systematize the knowledge about changes that occur in the clinical course of depression and after antidepressant treatment. In addition, a discussion on the potential use of ligands and/or modulators of postsynaptic proteins at the excitatory synapse has been presented.

A pathogenic DMC1 frameshift mutation causes nonobstructive azoospermia but not primary ovarian insufficiency in humans.

Nonobstructive azoospermia (NOA) and diminished ovarian reserve (DOR) are two disorders that can lead to infertility in males and females. Genetic factors have been identified to contribute to NOA and DOR. However, the same genetic factor that can cause both NOA and DOR remains largely unknown. To explore the candidate pathogenic gene that causes both NOA and DOR, we conducted whole-exome sequencing (WES) in a non-consanguineous family with two daughters with DOR and a son with NOA. We detected one pathogenic frameshift variant (NM_007068:c.28delG, p. Glu10Asnfs*31) following a recessive inheritance mode in a meiosis gene DMC1 (DNA meiotic recombinase 1). Clinical analysis showed reduced antral follicle number in both daughters with DOR, but metaphase II oocytes could be retrieved from one of them. For the son with NOA, no spermatozoa were found after microsurgical testicular sperm extraction. A further homozygous Dmc1 knockout mice study demonstrated total failure of follicle development and spermatogenesis. These results revealed a discrepancy of DMC1 action between mice and humans. In humans, DMC1 is required for spermatogenesis but is dispensable for oogenesis, although the loss of function of this gene may lead to DOR. To our knowledge, this is the first report on the homozygous frameshift mutation as causative for both NOA and DOR and demonstrating that DMC1 is dispensable in human oogenesis.

First-in-human, phase I/IIa study of CRLX301, a nanoparticle drug conjugate containing docetaxel, in patients with advanced or metastatic solid malignancies.

Background This was a phase I/IIa study to investigate the tolerability, efficacy and pharmacokinetics (PK)/ pharmacodynamics (PD) of CRLX301, CDP-based nanoparticle formulation of docetaxel. Methods The study was conducted in two parts. In part 1, dose-escalation using a standard 3 + 3 design was performed in two dosing schedules (every week (QW) and every 3 weeks (Q3W)). Part 2 was comprised of a dose expansion at 75 mg/m2 Q3W. PK studies were performed on both dosing schedules. Results Forty-two patients were recruited onto the study with a median age of 64(range 38-76); median number of prior systemic therapies was 5(range 0-10). Grade 3/4 treatment-related toxicities included: neutropenia (21.4 %), infusion related reaction (11.9 %), anemia (7.1 %), fatigue (4.8 %), diarrhea (4.8 %), and peripheral neuropathy (4.8 %). The maximum tolerated dose was 75 mg/m2 given on the Q3W schedule and was not determined on the QW schedule. In this heavily pre-treated population, four patients (12.9 %) achieved stable disease (SD) ≥ 4 months and 2 patients (6.5 %) achieved partial response (PR) for a clinical benefit rate (CBR) of 19.4 % (6/31 patients). The PRs were seen in prostate and breast adenocarcinoma (one each). CRLX301 exhibited some PK advantages over docetaxel including higher retention of drug in plasma, slower clearance and controlled slow release of docetaxel from the carrier. Conclusions In this heavily pretreated patient population, the safety profile was acceptable for CRLX301 therapy. There was some evidence of preliminary tumor efficacy, but further work is necessary to find the optimal dose and schedule of this formulation.Clinicaltrials.gov trial registration number: NCT02380677 (Date of registration: March 2, 2015).

Assessment of test-retest reproducibility of [18F]SynVesT-1, a novel radiotracer for PET imaging of synaptic vesicle glycoprotein 2A.

PURPOSE: Synaptic abnormalities are associated with many brain disorders. Recently, we developed a novel synaptic vesicle glycoprotein 2A (SV2A) radiotracer [18F]SynVesT-1 and demonstrated its excellent imaging and binding properties in nonhuman primates. The aim of this study was to perform dosimetry calculations in nonhuman primates and to evaluate this tracer in humans and assess its test-retest reliability in comparison with [11C]UCB-J. METHODS: Three rhesus monkeys underwent whole body dynamic PET scanning to estimate the absorbed dose. PET scans in six healthy human subjects were acquired. Time-activity curves (TACs) were generated with defined regions of interest (ROI). Reproducibility of distribution volume (VT) values and its sensitivity to scan duration were assessed with the one-tissue compartment (1TC) model. Non-displaceable binding potential (BPND) was calculated using centrum semiovale as the reference region. RESULTS: The dosimetry study showed high uptake in the urinary bladder and brain. In humans, [18F]SynVesT-1 displayed high uptake with maximum SUV of ~10 and appropriate kinetics with a quick rise in tracer uptake followed by a gradual clearance. Mean 1TC VT values (mL/cm3) ranged from 3.4 (centrum semiovale) to 19.6 (putamen) and were similar to those of [11C]UCB-J. Regional BPND values were 2.7-4.7 in gray matter areas, and mean BPND values across all ROIs were ~ 21% higher than those of [11C]UCB-J. The absolute test-retest variability of VT and BPND was excellent (< 9%) across all brain regions. CONCLUSIONS: [18F]SynVesT-1 demonstrates outstanding characteristics in humans: fast and high brain uptake, appropriate tissue kinetics, high levels of specific binding, and excellent test-retest reproducibility of binding parameters. As such, [18F]SynVesT-1 is proved to be a favorable radiotracer for SV2A imaging and quantification in humans.