Cunninghambynum6305

The toxicity of organophosphate esters (OPEs) on embryonic development is well noted in animal experiments, but epidemiological studies are still lacking. This study evaluated the prenatal exposure of OPEs and its trimester-specific and gender-specific effects on fetal growth. The correlations between OPE exposure and fetal growth were investigated by linear mixed-effect models and multivariable linear regression analyses. Prenatal exposure to tributyl phosphate (TBP) was negatively associated with a z-score of fetal abdominal circumference (AC), biparietal diameter (BPD), femur length (FL), and head circumference (HC). In the second trimester, the serum concentration of TBP was inversely related to the z-score of AC, BPD, and HC. In the third trimester, serum concentration of TBP was inversely related to AC, BPD, and FL z-scores. Prenatal exposure to tri-m-cresyl phosphate (TMCP) was inversely related to the z-score of AC, BPD, and HC. In the second trimester, TMCP was negatively correlated with AC, BPD, FL, and HC z-scores. After stratification by gender, male fetuses were more sensitive to OPE exposure. The above results remained robust after excluding pregnant women who gave preterm birth or those with low or high pre-pregnancy BMI. Our findings suggested that health effects of typical OPEs, particularly TBP and TMCP, should be taken into consideration in future works.Realizing Effectiveness Across Continents with Hydroxyurea (REACH, NCT01966731) provides hydroxyurea at maximum tolerated dose (MTD) for children with sickle cell anemia (SCA) in sub-Saharan Africa. Beyond reducing sickle-related clinical events, documented treatment benefits include ~50% malaria incidence. To identify associations and propose mechanisms by which hydroxyurea could be associated with lower malaria rates, infections were recorded across all clinical sites (Angola, Democratic Republic of Congo, Kenya, and Uganda). Hazard ratios (HR) with 95% Confidence Intervals (CI) for baseline demographic, and time-varying laboratory and clinical parameters were estimated in a modified Cox gap-time model for repeated events. A total of 717 clinical malaria episodes occurred in 336 of 606 study participants over 3,387 patient-years of hydroxyurea treatment; over half were confirmed by blood smear and/or rapid diagnostic testing with 97.8% Plasmodium falciparum. In univariate analysis limited to 4 confirmed infections per child, malaria risk was significantly associated with absolute neutrophil count (ANC), splenomegaly, hemoglobin, and achieving MTD; age, malaria season, MTD dose, fetal hemoglobin, a-thalassemia, and G6PD deficiency had no effect. In multivariable regression of confirmed infections, ANC was significant (HR=1.37 per doubled value, CI=1.10-1.70, p=0.0052) and ANC values <3.0 x 109/L were associated with lower malaria incidence. Compared to non-palpable, 1-4cm splenomegaly also was associated with higher malaria risk (HR=2.01, CI=1.41-2.85, p=0.0001). Hydroxyurea at MTD is associated with lower malaria incidence in SCA through incompletely defined mechanisms, but treatment-associated mild myelosuppression with ANC <3.0 x 109/L is salutary. Splenomegaly represents an unexplained risk factor for malaria infections among children with SCA in Africa.Transthyretin amyloidosis (ATTR) is a progressive and fatal disease caused by transthyretin (TTR) amyloid fibril accumulation in tissues, which disrupts organ function. As the TTR protein is primarily synthesized by the liver, liver transplantation can cure familial ATTR but is not an option for the predominant age-related wild-type ATTR. Approved treatment approaches include TTR stabilizers and an RNA-interference therapeutic, but these require regular re-administration. Gene editing could represent an effective one-time treatment. We evaluated adeno-associated virus (AAV) vector-delivered, gene-editing meganucleases to reduce TTR levels. We used engineered meganucleases targeting two different sites within the TTR gene. AAV vectors expressing TTR meganuclease transgenes were first tested in immunodeficient mice expressing the human TTR sequence delivered using an AAV vector and then against the endogenous TTR gene in rhesus macaques. Following a dose of 3 × 1013 genome copies per kilogram, we detected on-target editing efficiency of up to 45% insertions and deletions (indels) in the TTR genomic DNA locus and >80% indels in TTR RNA, with a concomitant decrease in serum TTR levels of >95% in macaques. The significant reduction in serum TTR levels following TTR gene editing indicates that this approach could be an effective treatment for ATTR.Bruton tyrosine kinase (BTK) is essential for B-cell receptor (BCR) signaling, a driver of chronic lymphocytic leukemia (CLL). Covalent inhibitors bind C481 in the active site of BTK and have become a preferred CLL therapy. Disease progression on covalent BTK inhibitors is commonly associated with C481 mutations. Here, we investigated a targeted protein degrader, NRX-0492, that links a non-covalent BTK binding domain to cereblon, an adaptor protein of the E3 ubiquitin ligase complex. NRX-0492 selectively catalyzes ubiquitylation and proteasomal degradation of BTK. In primary CLL cells, NRX-0492 induced rapid and sustained degradation of both wild-type and C481 mutant BTK at half maximal degradation concentration (DC50) of ≤0.2 nM and DC90 of ≤0.5 nM, respectively. Sustained degrader activity was maintained for at least 24 hours after washout and was equally observed in high-risk (deletion 17p) and standard-risk (deletion 13q only) CLL subtypes. In in vitro testing against treatment-naïve CLL samples, NRX-0492 was as effective as ibrutinib at inhibiting BCR mediated signaling, transcriptional programs, and chemokine secretion. In patient-derived xenografts, orally administered NRX-0492 induced BTK degradation and inhibited activation and proliferation of CLL cells in blood and spleen and remained efficacious against primary C481S mutant CLL cells collected from a patient progressing on ibrutinib. Oral bioavailability, >90% degradation of BTK at sub-nanomolar concentrations and sustained pharmacodynamic effects after drug clearance make this class of targeted protein degraders uniquely suitable for clinical translation, in particular as a strategy to overcome BTK inhibitor resistance. Clinical studies testing this approach have been initiated (NCT04830137, NCT05131022).Understanding the functional role of mutated genes in cancer is required to translate the findings of cancer genomics into therapeutic improvement. BTG1 is recurrently mutated in the MCD/C5 subtype of diffuse large B cell lymphoma (DLBCL), which is associated with extranodal dissemination. There, we provide evidence that Btg1 knock-out accelerates the development of a lethal lymphoproliferative disease driven by Bcl2 overexpression. We further show that the scaffolding protein BCAR1 is a BTG1 partner. Furthermore, following BTG1 deletion or expression of BTG1 mutations observed in DLBCL patients, the overactivation of the BCAR1-RAC1 pathway confers increased migration ability in vitro and in vivo. These modifications are targetable with the SRC inhibitor dasatinib, which opens novel therapeutic opportunities in BTG1 mutated DLBCL.Cytogenetics abnormalities (CA) are known to be the preponderant prognostic factor in multiple myeloma (MM). Our team has recently developed a prognostic score based on 6 CA, where del(1p32) appears to be the second worst abnormality after del(17p). The aim of this study was to confirm the adverse impact of 1p32 deletion on newly-diagnosed multiple myeloma (NDMM) patients. Among 2551 NDMM patients, 11% were harboring del(1p32). Their overall survival (OS) was significantly inferior compared to patients without del(1p32) (median OS 49 months vs. Akt inhibitor 124 months). Likewise, progression-free survival was significantly shorter. More importantly, biallelic del(1p32) conferred a dramatically poorer prognosis than a monoallelic del(1p32) (median OS 25 months vs. 60 months). As expected, the OS of del(1p32) patients significantly decreased when this abnormality was associated with other high-risk CA (del(17p), t(4;14) or gain(1q)). In the multivariate analysis, del(1p32) appeared as a negative prognostic factor; after adjustment for age and treatment, the risk of progression was 1.3 times higher among patients harboring del(1p32), and the risk of death was 1.9 times higher. At the dawn of risk-adapted treatment strategies, we have confirmed the adverse impact of del(1p32) in MM and the relevance of its assessment at diagnosis.Mesoporous silica nanoparticles have highly versatile structural properties that are suitable for a plethora of applications including catalysis, separation, and nanotherapeutics. We report a one-pot synthesis strategy that generates bimodal mesoporous silica nanoparticles via coassembly of a structure-directing Gemini surfactant (C16-3-16) with a tetraethoxysilane/(3-aminopropyl)triethoxysilane-derived sol additive. Synthesis temperature enables control of the nanoparticle shape, structure, and mesopore architecture. Variations of the aminosilane/alkylsilane molar ratio further enable programmable adjustments of hollow to core-shell and dense nanoparticle morphologies, bimodal pore sizes, and surface chemistries. The resulting Gemini-directed aminated mesoporous silica nanoparticles have excellent carbon dioxide adsorption capacities and antimicrobial properties against Escherichia coli. Our results provide an enhanced understanding of the structure formation of multiscale mesoporous inorganic materials that are desirable for numerous applications such as carbon sequestration, water remediation, and biomedical-related applications.The rigidity of polymeric micelles plays an important role in their biological behaviors. However, how drug loading affects the rigidity of polymeric micelles remains elusive. Herein, the indomethacin (IMC)-loaded Pluronic F127 micelle is used as a model system to illustrate the impact of drug loading on the rigidity and biological behaviors of polymeric micelles. Against expectations, micelles with moderate drug loading show higher cellular uptake and more severe cytotoxicity as compared to both high and low drug loading counterparts. Extensive one- and two-dimensional nuclear magnetic resonance (NMR) measurements are employed to reveal that the higher drug loading induces stronger interaction between IMC and hydrophilic block to boost the micellar rigidity; consequently, the moderate drug loading imparts micelles with appropriate rigidity for satisfactory cellular uptake and cytotoxicity. In summary, NMR spectroscopy is an important tool to gain insight into drug loading regulated micellar rigidity, which is helpful to understand their biological behaviors.

V600 mutations occur in many childhood cancers, including approximately 20% of low-grade gliomas (LGGs). Here, we describe a phase I/II study establishing pediatric dosing and pharmacokinetics of trametinib with or without dabrafenib, as well as efficacy and safety in a disease-specific cohort with

V600-mutant LGG; other cohorts will be reported elsewhere.

This is a four-part, phase I/II study (ClinicalTrials.gov identifier NCT02124772) in patients age < 18 years with relapsed/refractory malignancies trametinib monotherapy dose finding (part A) and disease-specific expansion (part B), and dabrafenib + trametinib dose finding (part C) and disease-specific expansion (part D). The primary objective assessed in all patients in parts A and C was to determine pediatric dosing on the basis of steady-state pharmacokinetics. Disease-specific efficacy and safety (across parts A-D) were secondary objectives.

Overall, 139 patients received trametinib (n = 91) or dabrafenib + trametinib (n = 48). Trametinib dose-limiting toxicities in > 1 patient (part A) included mucosal inflammation (n = 3) and hyponatremia (n = 2).