Exposure-response relationships of venetoclax in combination with carfilzomib and dexamethasone in relapsed/refractory t(11;14) multiple myeloma patients.

Venetoclax is a first in class BCL-2 inhibitor, currently under investigation for the treatment of t(11;14) multiple myeloma (MM). The objective of this analysis was to characterize the exposure-efficacy and exposure-safety relationships of venetoclax when combined with carfilzomib and dexamethasone (VenKd) in t(11;14)-positive relapsed or refractory (R/R) MM patients from a phase 2 study. Fifty-seven patients receiving VenKd or Kd were included in the analysis. Efficacy endpoints included progression-free survival and clinical response rates of overall response, very good partial response or better and complete response or better. Grade ≥ 3 neutropenia, Grade ≥ 3 infections, Grade ≥ 3 treatment-emergent adverse events and any grade serious treatment-emergent adverse events were evaluated. The analysis demonstrated that adding venetoclax to Kd resulted in increased ORR, ≥VGPR and ≥ CR rates compared to the control arm. Within the venetoclax treatment arms (VenKd), no significant exposure-efficacy relationships were observed for ORR and ≥ VGPR rates. Higher ≥ CR rates trended with higher venetoclax exposures. While both 400 mg and 800 mg venetoclax in VenKd arms were generally tolerated, higher rates of Grade ≥ 3 neutropenia were observed with higher venetoclax exposures. Higher venetoclax exposures however were not associated with increased rates of Grade ≥ 3 treatment-emergent adverse events, Grade ≥ 3 infections, or serious treatment-emergent adverse events (any grade). These results confirm the benefit of adding venetoclax to carfilzomib and dexamethasone and support continued evaluation of venetoclax 400-800 mg once daily in this combination in t(11;14)-positive R/R MM patients. NCT02899052 registered April 18, 2017.

Venetoclax in biomarker-selected multiple myeloma patients: Impact of exposure on clinical efficacy and safety.

Venetoclax, a potent BCL-2 inhibitor, is currently under development for treatment of t(11;14) Multiple myeloma (MM). The objective of this research was to investigate the exposure-response relationships of venetoclax for a phase 1/2 study evaluating venetoclax monotherapy or in combination with dexamethasone in relapsed or refractory MM. A total of 117 patients receiving venetoclax at 300, 600, 800, 900, or 1200 mg were included in the analysis. The impact of venetoclax exposures on efficacy (objective response rate [ORR], progression-free survival [PFS] and overall survival [OS]) as well as safety (treatment-emergent adverse effects (grade ≥3) of neutropenia, infection, and any grade of serious treatment-emergent adverse effects) was evaluated. In the t(11;14)-positive subpopulation, venetoclax exposure relationships to PFS and OS indicated a trend of longer PFS and OS with higher exposures. Moreover, logistic regression analyses for clinical response (ORR and ≥VGPR rate) demonstrated a statistically significant (p < 0.05) relationship with exposure. Evaluation of the exposure-safety relationships demonstrated a lack of a relationship between venetoclax exposures (AUCavg ) and grade ≥3 infections, grade ≥3 neutropenia, grade ≥3 treatment-emergent adverse events or any grade serious treatment-emergent adverse events. These findings support further study of venetoclax at 800 mg QD dose in combination with dexamethasone in the t(11;14)-positive patient population where increased efficacy was observed without an increase in safety events.Clinical Trial: NCT01794520 registered 20 February 2013.

Hereditary Multiple Intestinal Atresia With a Novel TTC7A Pathogenic Variant: Gastrointestinal Manifestations in Two Cases.

Hereditary multiple intestinal atresia (HMIA) with TTC7A mutation is caused by homozygous or compound heterozygous TTC7A gene mutation. It is characterized by multiple small and large intestinal atresias and/or stenoses. TTC7A mutation is described in some patients with inflammatory bowel disease and mild-severe forms of severe combined immunodeficiency without intestinal atresia or stenosis. We present 2 cases of intestinal atresia and documented TTC7A mutation with a novel variant. Both cases had different clinical and pathological manifestations. The first case is a male infant born at 35 weeks of gestation with failure to pass meconium. Intestinal biopsy reveals apoptotic enteropathy with villous atrophy and increased mucosal eosinophils. The second case is referred at birth for antenatally detected umbilical hernia, polyhydramnios and possible upper intestinal obstruction. The resected specimen reveals ileal atresia with partial villous atrophy, decreased number of lamina propria inflammatory cells and absence of plasma cells. In conclusion, these cases reflect an emerging TTC7A pathogenic variant with different histological manifestations and leads to characterization as immune dysregulation disorder. There is a need to differentiate TTC7A mutation associated ones from cases labeled as very early onset IBD and rule out other hereditary immunodeficiencies.

Phase 2 study of ibrutinib plus venetoclax in Japanese patients with relapsed/refractory mantle cell lymphoma.

BACKGROUND: Despite high response rates to initial therapy, most patients with mantle cell lymphoma (MCL) experience relapsed or refractory (R/R) disease. Here, we report the efficacy, safety, and pharmacokinetics of the Phase 2, single-arm M20-075 study (NCT04477486) of ibrutinib and venetoclax combination therapy in Japanese patients with R/R MCL. METHODS: Patients received 560 mg ibrutinib and 400 mg venetoclax (after a 5-week ramp-up from 20 mg) once daily for up to 104 weeks. Primary endpoint was complete response (CR) rate by independent review committee (IRC). Secondary endpoints included overall response rate (ORR), duration of response (DOR), undetectable minimal residual disease (uMRD) rate, progression-free survival (PFS), overall survival (OS), safety including dose-limiting toxicity (DLT) assessment in the first six patients, and pharmacokinetic parameters. Full analysis set (FAS) comprised all treated patients. Per protocol set (PPS) excluded treated patients with non-evaluable disease at baseline by IRC. RESULTS: Thirteen patients were treated (FAS n = 13; PPS, n = 12). Median age was 71 years, patients had a median of two prior treatments. After a median follow-up of 9.6 months, IRC-assessed CR rate and ORR were both 83% (PPS). All six MRD-evaluable patients had uMRD. Median DOR, PFS, and OS were unreached. The most common Grade ≥ 3 treatment-emergent adverse event (TEAE) was neutropenia (23%); 1 patient discontinued due to squamous cell carcinoma of the lung. No DLTs, tumor lysis syndrome, or deaths related to TEAEs were observed. CONCLUSION: Ibrutinib plus venetoclax exhibited high response rates and a well-tolerated safety profile in Japanese patients with R/R MCL.

Assessment of X-ray shielding properties of polystyrene incorporated with different nano-sizes of PbO.

PbO (lead oxide) particles with different sizes were incorporated into polystyrene (PS) with various weight fractions (0, 10, 15, 25, 35%). These novel PS/PbO nano-composites were produced by roll mill mixing and compressing molding techniques and then investigated for radiation attenuation of X-rays (N-series/ISO 4037) typically used in radiology. Properties of the PbO particles were studied by X-ray diffraction (XRD). Filler dispersion and elemental composition of the prepared nano-composites were characterized using scanning electron microscopy (SEM) and energy-dispersive X-ray spectroscopy (EDS), revealing better filler distribution and fewer agglomerations with smaller PbO particle size. Linear and mass attenuation coefficients (µ and µm), total molecular and atomic cross-sections (σmol and σatm), as well as effective atomic number and electron density (Zeff and Neff), were calculated for the energy range N40 to N200. The influence of PbO weight percentage on the enhancement of the shielding parameters of the nano-composites was expected; however, the effect of PbO particle size was surprising. Linear and mass attenuation coefficients for PS/PbO composites increased gradually with increasing PbO concentrations, and composites with a small size of nanoparticles showed best performance. In addition, increasing PbO concentration raised the effective atomic number Zeff of the composite. Hence, the electron density Neff increased, which provided a higher total interaction cross-section of X-rays with the composites. Maximum radiation shielding was observed for PS/PbO(B). It is concluded that this material might be used in developping low-cost and lightweight X-ray shielding to be used in radiology.

Towards Precise Interpretation of Oil Transformers via Novel Combined Techniques Based on DGA and Partial Discharge Sensors.

Power transformers are considered important and expensive items in electrical power networks. In this regard, the early discovery of potential faults in transformers considering datasets collected from diverse sensors can guarantee the continuous operation of electrical systems. Indeed, the discontinuity of these transformers is expensive and can lead to excessive economic losses for the power utilities. Dissolved gas analysis (DGA), as well as partial discharge (PD) tests considering different intelligent sensors for the measurement process, are used as diagnostic techniques for detecting the oil insulation level. This paper includes two parts; the first part is about the integration among the diagnosis results of recognized dissolved gas analysis techniques, in this part, the proposed techniques are classified into four techniques. The integration between the different DGA techniques not only improves the oil fault condition monitoring but also overcomes the individual weakness, and this positive feature is proved by using 532 samples from the Egyptian Electricity Transmission Company (EETC). The second part overview the experimental setup for (66/11.86 kV-40 MVA) power transformer which exists in the Egyptian Electricity Transmission Company (EETC), the first section in this part analyzes the dissolved gases concentricity for many samples, and the second section illustrates the measurement of PD particularly in this case study. The results demonstrate that precise interpretation of oil transformers can be provided to system operators, thanks to the combination of the most appropriate techniques.

Polymeric composite materials for radiation shielding: a review.

The rising use of radioactive elements is increasing radioactive pollution and calling for advanced materials to protect individuals. For instance, polymers are promising due to their mechanical, electrical, thermal, and multifunctional properties. Moreover, composites made of polymers and high atomic number fillers should allow to obtain material with low-weight, good flexibility, and good processability. Here we review the synthesis of polymer materials for radiation protection, with focus on the role of the nanofillers. We discuss the effectivness of polymeric materials for the absorption of fast neutrons. We also present the recycling of polymers into composites.

In-Silico Evaluation of a New Gene From Wheat Reveals the Divergent Evolution of the CAP160 Homologous Genes Into Monocots.

This study reports the evolutionary history and in-silico functional characterization of a novel water-deficit and ABA-responsive gene in wheat. This gene has remote sequence similarity to known abiotic stress-related genes in different plants, including CAP160 in Spinacia oleracea, RD29B in Arabidopsis thaliana, and CDeT11-24 in Craterostigma plantagineum. The study investigated if these genes form a close homologous relationship or if they are a result of convergent evolutionary processes. The results indicated a closely shared homologous relationship between these genes. Bayesian phylogenetic analysis of the protein sequences of the remotely related CAP160 proteins from various plant species indicated the presence of three distinct clades. Further analyses indicated that CAP160 homologous genes have predominantly evolved through neutral processes, with multiple regions experiencing signatures of purifying selection, while others were indicated to be the result of episodic diversifying selection events. Functional predictions revealed that these genes might share at least two functions related to abiotic stress conditions: one similar to the cryoprotective function of LEA protein, and the other a signalling molecule with phosphatidic acid binding specificity. Studies focused on the identification of cold-responsive genes are essential for the development of cold-tolerant crop plants, if we are to increase agricultural productivity throughout temperate regions.

A phase I study of an oral selective gamma secretase (GS) inhibitor RO4929097 in combination with neoadjuvant paclitaxel and carboplatin in triple negative breast cancer.

Upregulation of Notch pathway is associated with poor prognosis in breast cancer. We present the results of a phase I study of an oral selective gamma secretase (GS) inhibitor (critical to Notch signaling), RO4929097 in combination with neoadjuvant chemotherapy for operable triple negative breast cancer. The primary objective was to determine the maximum tolerated dose (MTD) of RO4929097. Secondary objectives were to determine real-time pharmacokinetics of RO4929097 and paclitaxel, safety and pathologic (pCR) complete response to study treatment. Eligible patients, initiated carboplatin at AUC 6 administered intravenously (IV) on day 1, weekly paclitaxel at 80 mg/m2 IV and RO4929097 10 mg daily given orally (PO) on days 1-3, 8-10 and 15-17 for six 21-day cycles. RO4929097 was escalated in 10 mg increments using the 3 + 3 dose escalation design. Two DLTs were observed in 14 patients - Grade (G) 4 thrombocytopenia in dose level 1 (10 mg) and G3 hypertension in dose level 2 (20 mg). Protocol-defined MTD was not determined due to discontinuation of RO4929097 development. However, 4 of 5 patients enrolled to 20 mg dose of RO4929097 required dose reduction to 10 mg due to toxicities (including neutropenia, thrombocytopenia and hypertension) occurring during and beyond the DLT observation period. Thus, 10 mg would have been the likely dose level for further development. G3 or higher hematologic toxicities included neutropenia (N = 8, 57%) and thrombocytopenia (N = 5, 36%) patients. Six (43%) patients had G2-3 neuropathy requiring paclitaxel dose reduction. No signs of drug-drug interaction between paclitaxel and RO4929097 were evident. Five patients (36%) had pCR.

The first consecutive 5000 patients with Coronavirus Disease 2019 from Qatar; a nation-wide cohort study.

BACKGROUND: There are limited data on Coronavirus Disease 2019 (COVID-19) outcomes at a national level, and none after 60 days of follow up. The aim of this study was to describe national, 60-day all-cause mortality associated with COVID-19, and to identify risk factors associated with admission to an intensive care unit (ICU). METHODS: This was a retrospective cohort study including the first consecutive 5000 patients with COVID-19 in Qatar who completed 60 days of follow up by June 17, 2020. The primary outcome was all-cause mortality at 60 days after COVID-19 diagnosis. In addition, we explored risk factors for admission to ICU. RESULTS: Included patients were diagnosed with COVID-19 between February 28 and April 17, 2020. The majority (4436, 88.7%) were males and the median age was 35 years [interquartile range (IQR) 28-43]. By 60 days after COVID-19 diagnosis, 14 patients (0.28%) had died, 10 (0.2%) were still in hospital, and two (0.04%) were still in ICU. Fatal COVID-19 cases had a median age of 59.5 years (IQR 55.8-68), and were mostly males (13, 92.9%). All included pregnant women (26, 0.5%), children (131, 2.6%), and healthcare workers (135, 2.7%) were alive and not hospitalized at the end of follow up. A total of 1424 patients (28.5%) required hospitalization, out of which 108 (7.6%) were admitted to ICU. Most frequent co-morbidities in hospitalized adults were diabetes (23.2%), and hypertension (20.7%). Multivariable logistic regression showed that older age [adjusted odds ratio (aOR) 1.041, 95% confidence interval (CI) 1.022-1.061 per year increase; P < 0.001], male sex (aOR 4.375, 95% CI 1.964-9.744; P < 0.001), diabetes (aOR 1.698, 95% CI 1.050-2.746; P 0.031), chronic kidney disease (aOR 3.590, 95% CI 1.596-8.079, P 0.002), and higher BMI (aOR 1.067, 95% CI 1.027-1.108 per unit increase; P 0.001), were all independently associated with increased risk of ICU admission. CONCLUSIONS: In a relatively younger national cohort with a low co-morbidity burden, COVID-19 was associated with low all-cause mortality. Independent risk factors for ICU admission included older age, male sex, higher BMI, and co-existing diabetes or chronic kidney disease.

Transcriptomic Insights into Phenological Development and Cold Tolerance of Wheat Grown in the Field.

Cold acclimation and winter survival in cereal species is determined by complicated environmentally regulated gene expression. However, studies investigating these complex cold responses are mostly conducted in controlled environments that only consider the responses to single environmental variables. In this study, we have comprehensively profiled global transcriptional responses in crowns of field-grown spring and winter wheat (Triticum aestivum) genotypes and their near-isogenic lines with the VRN-A1 alleles swapped. This in-depth analysis revealed multiple signaling, interactive pathways that influence cold tolerance and phenological development to optimize plant growth and development in preparation for a wide range of over-winter stresses. Investigation of genetic differences at the VRN-A1 locus revealed that a vernalization requirement maintained a higher level of cold response pathways while VRN-A1 genetically promoted floral development. Our results also demonstrated the influence of genetic background on the expression of cold and flowering pathways. The link between delayed shoot apex development and the induction of cold tolerance was reflected by the gradual up-regulation of abscisic acid-dependent and C-REPEAT-BINDING FACTOR pathways. This was accompanied by the down-regulation of key genes involved in meristem development as the autumn progressed. The chromosome location of differentially expressed genes between the winter and spring wheat genetic backgrounds showed a striking pattern of biased gene expression on chromosomes 6A and 6D, indicating a transcriptional regulation at the genome level. This finding adds to the complexity of the genetic cascades and gene interactions that determine the evolutionary patterns of both phenological development and cold tolerance traits in wheat.

A Novel Morphological Analysis of DXA-DICOM Images by Artificial Neural Networks for Estimating Bone Mineral Density in Health and Disease.

One of the best methods for diagnosing bone disease in humans is site-specific and total bone mineral density (BMD) measurements by Dual-energy X-ray Absorptiometry (DXA) machines. The basic disadvantage of this technology is inconsistent BMD measurements among different DXA machines from different manufacturers due to different image analysis algorithms. The objective of the present study was to apply artificial neural networks (ANNs) to estimate total BMD for diagnosing a population of Egyptians with and without pathology, using extracted features from DXA-DICOM images based on the Histogram and Binary algorithms as compared to reference BMD measurements by DXA machine. The sample size comprised 3000 male and female participants with an age range 22-49 years, who were referred to us for diagnosis and/or treatment and for DXA total body scans in the period from January 2016 till December 2017. We constructed an entry computer data-logging visible unit, where we applied morphological operations to get a specific bone image, and used their extracted feature vectors as inputs to ANNs with cascade training, gathering, and testing for DXA-DICOM image processing. The multilayer feed-forward ANN set up its initial weights, carried out training and initiated the recall mode, and finally observed its decision and interaction based on estimated BMD. The ANN construction was carried out using a 3-layer architecture, with one hidden layer of 85 neurons. The input layer has neuron numbers equal to 256 for the Histogram and 77,365 for Binary algorithms, respectively. Total BMD estimation performance based on the Binary algorithm was capable of identifying all DXA-DICOM images with an accuracy of 100% for the training, cross-validation, and testing of the ANN phases. We believe this strategy will represent the means for standardizing bone measurements of all DXA machines, regardless of the manufacturer.

Volatile organic compounds of biofluids for detecting lung cancer by an electronic nose based on artificial neural network.

Lung cancer (LC) incidence represents 11.5% of all new cancers, resulting in 1.72 million deaths worldwide in 2015. With the aim to investigate the capability of the electronic nose (e-nose) technology for detecting and differentiating complex mixtures of volatile organic compounds in biofluids ex-vivo, we enrolled 50 patients with suspected LC and 50 matching controls. Tissue biopsy was taken from suspicious lung mass for histopathological evaluation and blood, exhaled breath, and urine samples were collected from all participants and qualitatively processed using e-nose. Odor-print patterns were further analysed using the principal component analysis (PCA) and artificial neural network (ANN) analysis. Adenocarcinoma, non-small cell LC and squamous cell carcinoma were the predominant pathological types among LC patients. PCA cluster-plots showed a clear distinction between LC patients and controls for all biological samples; where the overall success ratios of classification for principal components #1 and #2 were: 95.46, 82.01, and 91.66% for blood, breath and urine samples, respectively. Moreover, ANN showed a better discrimination between LC patients and controls with success ratios of 95.74, 91.67 and 100% for blood, breath and urine samples, respectively. The e-nose is an easy noninvasive tool, capable of identifying LC patients from controls with great precision.

miR-221 regulates CD44 in hepatocellular carcinoma through the PI3K-AKT-mTOR pathway.

CD44 and miR-221 are upregulated in hepatocellular carcinoma (HCC) cell lines and tumors, however a connection between the two has not been identified. As the expression of miR-221 directly correlated with CD44 in HCC cells, we hypothesized that miR-221 may directly or indirectly regulate CD44 expression. Inhibition of miR-221 with antisense in Sk-Hep-1 or SNU-449 cell lines reduced CD44 protein expression while miR-221 mimic increased CD44 protein levels. miR-221 antisense did not alter the CD44 mRNA levels in Sk-Hep-1 or SNU-449 cells suggesting that regulation of CD44 protein occurs post transcriptionally. To discover miRNAs that may be involved in the miR-221 regulation of CD44, we performed miRNA profiling in SNU-449 cells treated with anti-miR-221. Several miRNAs were increased with miR-221 inhibition including miR-708-5p, a miRNA that targets CD44. As miR-221 targets several regulators of the PI3K-AKT-mTOR pathway and a link between this pathway and CD44 has been previously shown in prostate cancer, we considered miR-221 regulation of CD44 may be through this pathway. Inhibition of miR-221 reduced p-4EBP1, a downstream effector of the PI3K-AKT-mTOR pathway. Likewise, inhibiting the PI3K-AKT-mTOR pathway with the ATP-competitive mTOR inhibitor PP242 reduced CD44 protein in SNU-423 and SNU-449 cells without altering CD44 mRNA levels.

Achieving the Promise of Therapeutic Extracellular Vesicles: The Devil is in Details of Therapeutic Loading.

Extracellular vesicles (EVs) represent a class of cell secreted organelles which naturally contain biomolecular cargo such as miRNA, mRNA and proteins. EVs mediate intercellular communication, enabling the transfer of functional nucleic acids from the cell of origin to the recipient cells. In addition, EVs make an attractive delivery vehicle for therapeutics owing to their increased stability in circulation, biocompatibility, low immunogenicity and toxicity profiles. EVs can also be engineered to display targeting moieties on their surfaces which enables targeting to desired tissues, organs or cells. While much has been learned on the role of EVs as cell communicators, the field of therapeutic EV application is currently under development. Critical to the future success of EV delivery system is the description of methods by which therapeutics can be successfully and efficiently loaded within the EVs. Two methods of loading of EVs with therapeutic cargo exist, endogenous and exogenous loading. We have therefore focused this review on describing the various published approaches for loading EVs with therapeutics.

An integrative approach to identify hexaploid wheat miRNAome associated with development and tolerance to abiotic stress.

BACKGROUND: Wheat is a major staple crop with broad adaptability to a wide range of environmental conditions. This adaptability involves several stress and developmentally responsive genes, in which microRNAs (miRNAs) have emerged as important regulatory factors. However, the currently used approaches to identify miRNAs in this polyploid complex system focus on conserved and highly expressed miRNAs avoiding regularly those that are often lineage-specific, condition-specific, or appeared recently in evolution. In addition, many environmental and biological factors affecting miRNA expression were not yet considered, resulting still in an incomplete repertoire of wheat miRNAs. RESULTS: We developed a conservation-independent technique based on an integrative approach that combines machine learning, bioinformatic tools, biological insights of known miRNA expression profiles and universal criteria of plant miRNAs to identify miRNAs with more confidence. The developed pipeline can potentially identify novel wheat miRNAs that share features common to several species or that are species specific or clade specific. It allowed the discovery of 199 miRNA candidates associated with different abiotic stresses and development stages. We also highlight from the raw data 267 miRNAs conserved with 43 miRBase families. The predicted miRNAs are highly associated with abiotic stress responses, tolerance and development. GO enrichment analysis showed that they may play biological and physiological roles associated with cold, salt and aluminum (Al) through auxin signaling pathways, regulation of gene expression, ubiquitination, transport, carbohydrates, gibberellins, lipid, glutathione and secondary metabolism, photosynthesis, as well as floral transition and flowering. CONCLUSION: This approach provides a broad repertoire of hexaploid wheat miRNAs associated with abiotic stress responses, tolerance and development. These valuable resources of expressed wheat miRNAs will help in elucidating the regulatory mechanisms involved in freezing and Al responses and tolerance mechanisms as well as for development and flowering. In the long term, it may help in breeding stress tolerant plants.

Transcriptome analysis of an mvp mutant reveals important changes in global gene expression and a role for methyl jasmonate in vernalization and flowering in wheat.

The einkorn wheat mutant mvp-1 (maintained vegetative phase 1) has a non-flowering phenotype caused by deletions including, but not limited to, the genes CYS, PHYC, and VRN1. However, the impact of these deletions on global gene expression is still unknown. Transcriptome analysis showed that these deletions caused the upregulation of several pathogenesis-related (PR) and jasmonate-responsive genes. These results suggest that jasmonates may be involved in flowering and vernalization in wheat. To test this hypothesis, jasmonic acid (JA) and methyl jasmonate (MeJA) content in mvp and wild-type plants was measured. The content of JA was comparable in all plants, whereas the content of MeJA was higher by more than 6-fold in mvp plants. The accumulation of MeJA was also observed in vernalization-sensitive hexaploid winter wheat during cold exposure. This accumulation declined rapidly once plants were deacclimated under floral-inductive growth conditions. This suggests that MeJA may have a role in floral transition. To confirm this result, we treated vernalization-insensitive spring wheat with MeJA. The treatment delayed flowering with significant downregulation of both TaVRN1 and TaFT1 genes. These data suggest a role for MeJA in modulating vernalization and flowering time in wheat.

Enhanced radiation shielding efficiency of polystyrene nanocomposites with tailored lead oxide nanoparticles.

In this study, we investigated a novel polymer nano-composite, PS-PbO, containing two distinct nano-sizes of lead oxide nanoparticles (PbO-A and PbO-B), in addition to the bulk size (PbO-K). These nanoparticles were embedded separately in a polystyrene (PS) matrix at different weight percentages (10%, 15%, 25%, and 35%) using roll mill mixing and compressing molding. Our evaluation focused on the radiation attenuation ability of PS-PbO and the effect of particle size, considering gamma-ray energies ranging from 0.06 to 1.3 MeV (from sources like 241Am, 133Ba, 137Cs, and 60Co). The linear attenuation coefficient (LAC) was determined by analyzing samples of the synthesized composite with different thicknesses. Then, various shielding parameters were calculated, including total molecular, atomic, and electronic cross-sections (σmol, σatm, σel), as well as the effective atomic number and the electron density (Zeff and Neff). Surprisingly, modifying PbO particle sizes had a significant impact on shielding efficiency. For instance, the composite with 25 wt% of the smallest PbO-B particles showed a 26.7% increase in LAC at 0.059 keV compared to the composite with 25 wt% of PbO-K (larger particles). Notably, the LAC peaked at low energy (0.059 keV), close to the K-edge of Pb, where interaction is directly proportional to Z4. With increasing PbO concentrations, the LAC of PS-PbO composites increased steadily. Additionally, as PbO concentration increased, the composite's effective atomic number Zeff and the electron density Neff increased, leading to a greater total Gamma-ray interaction cross-section. Furthermore, when comparing the Half-Value Layers of the novel nanocomposite to traditional lead shielding, a 70% reduction in mass was observed. Notably, the composite containing the smallest nano-size of PbO exhibited the highest radiation-shielding efficiency among all combinations and could therefore be used to create inexpensive and lightweight shields.

Dosing of Venetoclax in Pediatric Patients with Relapsed Acute Myeloid Leukemia: Analysis of Developmental Pharmacokinetics and Exposure-Response Relationships.

PURPOSE: This work aimed to characterize the pharmacokinetics and exposure-response relationships of venetoclax in pediatric patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) to identify venetoclax doses to be administered to pediatric patients in the phase 3 study. METHODS: Data from 121 patients across three phase 1 studies enrolling pediatric patients with R/R malignancies were utilized to develop a population pharmacokinetic model to describe venetoclax pharmacokinetics in pediatric patients. Individual patient average venetoclax plasma concentration up to the event of interest, derived based on the population pharmacokinetics analysis, was used to evaluate the exposure-response relationships to efficacy (complete response) and safety (neutropenia and thrombocytopenia) endpoints for patients with AML who received venetoclax in combination with azacitidine, decitabine, or cytarabine (n = 36). The population pharmacokinetic model was then used to simulate exposures in pediatric age- and weight-based subgroups to identify the venetoclax doses for pediatric patients. FINDINGS: The pharmacokinetic data were adequately described by the two-compartment population pharmacokinetic model with first-order absorption and elimination. The model accounted for cytochrome P450 3A developmental changes using a maturation function and incorporated allometric scaling to account for growth and body size effect. Weight was identified as a statistically significant covariate on clearance and volume of distribution and retained in the final model. Population pharmacokinetic estimates were comparable to previously reported estimates in adults. Exposure-response analyses suggested that the clinical efficacy of venetoclax in combination with high-dose cytarabine (HDAC) is maximized at 600 mg adult-equivalent, and higher doses are unlikely to enhance clinical efficacy. Venetoclax 600 mg adult-equivalent was selected for further development in combination with HDAC. Additionally, venetoclax 400 mg adult-equivalent was selected for bridging/maintenance therapy in combination with azacitidine. Flat exposure-response relationships were observed with Grade ≥3 neutropenia and thrombocytopenia. Doses were selected based on weight (allometric scaling) for children aged ≥2 years old and based on weight and CYP3A ontogeny for children aged <2 years. The selected age- and weight-based dosing scheme of venetoclax is projected to achieve venetoclax exposures in pediatric subgroups comparable to those observed in adults receiving venetoclax 400 mg or 600 mg. IMPLICATIONS: This work characterized the pharmacokinetics and exposure-response relationships of venetoclax in pediatric patients and guided the selection of pediatric dosing regimens in support of the venetoclax phase 3 trial in pediatric AML (NCT05183035). CLINICAL STUDIES: NCT03236857, NCT03181126, and NCT03194932.

Coproporphyrin-I as a Selective OATP1B Biomarker Can Be Used to Delineate the Mechanisms of Complex Drug-Drug Interactions: Cedirogant Case Study.

Cedirogant is an inverse agonist of retinoic acid-related orphan receptor gamma thymus developed for the treatment of chronic plaque psoriasis. Cedirogant induces cytochrome P450 (CYP) 3A4 while inhibiting P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transporting polypeptide (OATP) 1B1, and OATP1B3 in vitro. Static drug-drug interactions (DDIs) predictions suggested possible clinical induction of CYP3A4, and inhibition of P-gp, BCRP, and OATP1B1, leading to challenges in interpreting DDI studies between cedirogant and substrates of CYP3A, P-gp, BCRP, and OATP1B1/3. Here the effects of cedirogant on the pharmacokinetics of two statin drugs were investigated in healthy participants. Coproporphyrin-I (CP-I), a selective endogenous OATP1B biomarker, was used to assess the impact of cedirogant on OATP1B. Cedirogant (375 mg once daily) increased rosuvastatin maximum plasma concentration (Cmax) and area under the plasma concentration curve (AUCtau) by 141% and 55%, respectively when co-administered, whereas atorvastatin Cmax increased by 40% with no effect on its AUCtau compared with administration of rosuvastatin/atorvastatin alone. Cedirogant did not increase CP-I exposures, indicating no clinical OATP1B inhibition. The increased rosuvastatin exposure and minimal change in atorvastatin exposure with co-administration of cedirogant is attributed to BCRP inhibition and interplay between P-gp/BCRP inhibition and CYP3A induction, respectively. Correlation analysis with data from two investigational drugs (glecaprevir and flubentylosin) demonstrated that OATP1B1 R-value of > 1.5 and [Cmax,u]/[OATP1B1 IC50] of > 0.1 are associated with > 1.25-fold increase in CP-I Cmax ratio. This demonstrates the utility of CP-I in disentangling mechanisms underlying a complex DDI involving multiple transporters and enzymes and proposes refined criteria for static OATP1B inhibition predictions.