Discovery and Preclinical Pharmacology of NX-2127, an Orally Bioavailable Degrader of Bruton's Tyrosine Kinase with Immunomodulatory Activity for the Treatment of Patients with B Cell Malignancies.

Bruton's tyrosine kinase (BTK), a member of the TEC family of kinases, is an essential effector of B-cell receptor (BCR) signaling. Chronic activation of BTK-mediated BCR signaling is a hallmark of many hematological malignancies, which makes it an attractive therapeutic target. Pharmacological inhibition of BTK enzymatic function is now a well-proven strategy for the treatment of patients with these malignancies.

NRX-0492 degrades wild-type and C481 mutant BTK and demonstrates in vivo activity in CLL patient-derived xenografts.

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.

Diagnostic accuracy and ability to reduce unnecessary FNAC: A comparison between four Thyroid Imaging Reporting Data System (TI-RADS) versions.

Background: Thyroid Imaging Reporting Data System (TI-RADS) is used to characterize thyroid nodules while reducing unnecessary FNAC. Over the years, several versions of TI-RADS have been developed but there is no consensus on which TI-RADS is the best system. This study aimed to compare the diagnostic accuracy and ability of ACR TI-RADS, EU TI-RADS, K TI-RADS, AI TI-RADS to eliminate unnecessary FNAC.

Human mannose-binding lectin inhibitor prevents Shiga toxin-induced renal injury.

Hemolytic uremic syndrome caused by Shiga toxin-producing Escherichia coli (STEC HUS) is a worldwide endemic problem, and its pathophysiology is not fully elucidated. Here we tested whether the mannose-binding lectin (MBL2), an initiating factor of lectin complement pathway activation, plays a crucial role in STEC HUS. Using novel human MBL2-expressing mice (MBL2 KI) that lack murine Mbls (MBL2(+/+)Mbl1(-/-)Mbl2(-/-)), a novel STEC HUS model consisted of an intraperitoneal injection with Shiga toxin-2 (Stx-2) with or without anti-MBL2 antibody (3F8, intraperitoneal).

Puberty-specific promotion of mammary tumorigenesis by a high animal fat diet.

Introduction: Increased animal fat consumption is associated with increased premenopausal breast cancer risk in normal weight, but not overweight, women. This agrees with our previous findings in obesity-resistant BALB/c mice, in which exposure to a high saturated animal fat diet (HFD) from peripuberty through adulthood promoted mammary tumorigenesis. Epidemiologic and animal studies support the importance of puberty as a life stage when diet and environmental exposures affect adult breast cancer risk.

Human mannose-binding lectin inhibitor prevents myocardial injury and arterial thrombogenesis in a novel animal model.

Myocardial infarction and coagulation disorders are leading causes of disability and death in the world. An important role of the lectin complement pathway in myocardial infarction and coagulation has been demonstrated in mice genetically deficient in lectin complement pathway proteins. However, these studies are limited to comparisons between wild-type and deficient mice and lack the ability to examine reversal/inhibition of injury after disease establishment.

Contrasting voltammetric behavior of different forms of vitamin A in aprotic organic solvents.

Six of the major vitamers and provitamins comprising vitamin A (β-carotene, retinoic acid, retinol, retinyl palmitate, retinyl acetate, and retinal) were examined using voltammetric and controlled potential electrolysis techniques in the aprotic organic solvents acetonitrile and dichloromethane at glassy carbon and platinum electrodes. All of the compounds underwent oxidation and reduction processes and displayed a number of similarities and differences in terms of the number of redox processes and chemical reversibility of the voltammetric responses. The electrochemical properties of the compounds were strongly influenced by the functional groups on the unsaturated phytyl chains (carboxylic acid, alcohol, ester, or aldehyde groups), and not only on the fully conjugated hydrocarbon unit which is common to all forms of vitamin A.

Epidermal growth factor receptor (EGFR) signaling is a key mediator of hormone-induced leukocyte infiltration in the pubertal female mammary gland.

It is well documented that macrophages and eosinophils play important roles in normal murine pubertal mammary gland development. Although it is accepted that estrogen (E) and progesterone (P) are key players in mammary gland development, the roles these hormones might play in regulating the actions of leukocytes in that process is an understudied area. We show here that P and E, respectively, induce unique, but overlapping, sets of proinflammatory and angiogenic cytokines and chemokines, in the pubertal female BALB/c mammary gland, as well as induce infiltration of macrophages and eosinophils to the mammary periepithelium.

Pubertal high fat diet: effects on mammary cancer development.

Introduction: Epidemiological studies linking dietary fat intake and obesity to breast cancer risk have produced inconsistent results. This may be due to the difficulty of dissociating fat intake from obesity, and/or the lack of defined periods of exposure in these studies. The pubertal mammary gland is highly sensitive to cancer-causing agents.

Competing hydrogen-bonding, decomposition, and reversible dimerization mechanisms during the one- and two-electron electrochemical reduction of retinal (vitamin A).

Retinal (R) can be sequentially voltammetrically reduced in CH3CN in two one-electron processes to form first the anion radical (R(•-)) at -1.75 (±0.04) V vs Fc/Fc(+) (Fc = ferrocene) then the dianion (R(2-)) at -2.

Perfluorooctanoic acid effects on ovaries mediate its inhibition of peripubertal mammary gland development in Balb/c and C57Bl/6 mice.

Exposure to perfluorooctanoic acid (PFOA), a synthetic perfluorinated compound and an agonist of peroxisome proliferator-activated receptor α (PPARα), causes stunted mouse mammary gland development in various developmental stages. However, the underlying mechanisms remain poorly understood. We found that peripubertal PFOA exposure significantly inhibited mammary gland growth in both Balb/c and C57Bl/6 wild type mice, but not in C57Bl/6 PPARα knockout mice, and Balb/c mice were more sensitive to PFOA inhibition.

Mannose-binding lectin-associated serine protease-1 is a significant contributor to coagulation in a murine model of occlusive thrombosis.

Bleeding disorders and thrombotic complications constitute a major cause of death and disability worldwide. Although it is known that the complement and coagulation systems interact, no studies have investigated the specific role or mechanisms of lectin-mediated coagulation in vivo. FeCl(3) treatment resulted in intra-arterial occlusive thrombogenesis within 10 min in wild-type (WT) and C2/factor B-null mice.

The role of low levels of water in the electrochemical oxidation of α-tocopherol (vitamin E) and other phenols in acetonitrile.

The phenol, α-tocopherol, can be electrochemically oxidised in a -2e(-)/-H(+) process to form a diamagnetic cation that is long-lived in dry organic solvents such as acetonitrile and dichloromethane, but in the presence of water quickly reacts to form a hemiketal. Variable scan rate cyclic voltammetry experiments in acetonitrile with carefully controlled amounts of water between 0.010 M-0.

Electron-transfer reactions between the diamagnetic cation of α-tocopherol (vitamin E) and β-carotene.

β-Carotene (β-Car) was chemically oxidized in a -2e(-) process using 2 mol equiv of NOSbF(6) in a 4:1 ratio (v/v) of dichloromethane:acetonitrile to form the β-carotene dication (β-Car(2+)). Voltammetric monitoring of the chemical oxidation experiments over a range of temperatures indicated that the half-life of β-Car(2+) was approximately 20 min at -60 °C, and approximately 1 min at -30 °C. α-Tocopherol (α-TOH) was chemically oxidized in a -2e(-)/-H(+) process using 2 mol equiv of NOSbF(6) to form the diamagnetic cation (α-TO(+)) which survives indefinitely at -60 °C in a 4:1 ratio (v/v) of dichloromethane:acetonitrile.

Perfluorooctanoic acid effects on steroid hormone and growth factor levels mediate stimulation of peripubertal mammary gland development in C57BL/6 mice.

Perfluorooctanoic acid (PFOA) is a synthetic, widely used perfluorinated carboxylic acid and a persistent environmental pollutant. It is an agonist of peroxisome proliferator-activated receptor alpha (PPARalpha). Studies have shown that PFOA causes hepatocellular hypertrophy, tumorigenesis, and developmental toxicity in rodents, and some of its toxicity depends on the expression of PPARalpha.

Voltammetrically controlled electron transfer reactions from alkanethiol modified gold electrode surfaces to low molecular weight molecules deposited within lipid (lecithin) bilayers.

A procedure was developed for initiating electron transfer from a gold electrode to a low molecular weight electron acceptor present inside supported lipid (lecithin) bilayers, followed by further electron transfer to an electron acceptor present in an aqueous solution. The electron acceptors present in the lecithin bilayers and aqueous phase were 7,7,8,8-tetracyanoquinodimethane (TCNQ) and [Fe(III)(CN)(6)](3-), respectively. A polished planar gold disk electrode was first coated via self-assembly procedures with an alkanethiol monolayer.

Progesterone receptor A-regulated gene expression in mammary organoid cultures.

Progesterone, through the progesterone receptor (PR), promotes development of the normal mammary gland and is implicated in the etiology of breast cancer. We identified PRA-regulated genes by microarray analysis of cultured epithelial organoids derived from pubertal and adult mouse mammary glands, developmental stages with differing progesterone responsiveness. Microarray analysis showed significant progestin (R5020)-regulation of 162 genes in pubertal organoids and 104 genes in adult organoids, with 68 genes regulated at both developmental stages.

Differential effects of peripubertal exposure to perfluorooctanoic acid on mammary gland development in C57Bl/6 and Balb/c mouse strains.

Perfluorooctanoic acid (PFOA), a common and persistent industrial byproduct detected in human sera, has raised health concerns. PFOA is detrimental to lactational function and postnatal mammary gland development in CD-1 mice after gestational exposure. We have examined the peripubertal period (21 through 50 days of age) as an important window of mammary gland susceptibility to environmental exposures that may affect breast cancer risk later in life.

Comparative temporal toxicogenomic analysis of TCDD- and TCDF-mediated hepatic effects in immature female C57BL/6 mice.

Temporal analyses were performed on hepatic tissue from immature female C57BL/6 mice in order to compare the gene expression profiles for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and 2,3,7,8-tetrachlorodibzofuran (TCDF). Time course studies conducted with a single oral dose of 300 microg/kg TCDF or 30 microg/kg TCDD were used to compare differential gene expression on complementary DNA microarrays containing 13,361 features, representing 8194 genes at 2, 4, 8, 12, 24, 72, 120, and 168 h. One hundred and ninety-five genes were identified as differentially regulated by TCDF, of which 116 genes were in common with TCDD, with 109 exhibiting comparable expression profiles (correlation coefficients > 0.

Temporal relationship between renal cyst development, hypertension and cardiac hypertrophy in a new rat model of autosomal recessive polycystic kidney disease.

Background/methods: We have examined the hypothesis that cyst formation is key in the pathogenesis of cardiovascular disease in a Lewis polycystic kidney (LPK) model of autosomal-recessive polycystic kidney disease (ARPKD), by determining the relationship between cyst development and indices of renal function and cardiovascular disease.

Results: In the LPK (n = 35), cysts appear at week 3 (1.1 +/- 0.