Value of plasma alpha- and beta-synuclein levels in the diagnosis, severity, and functional outcome of acute ischemic stroke.

Objective: We aimed to determine the role of plasma alpha- and beta-synuclein levels and other routine inflammatory parameters in the diagnosis, outcome, and mortality of acute ischemic stroke (AIS).

Methods: In our study, serum alpha- and beta-synuclein levels and clinical data were prospectively evaluated in 93 subjects (43 controls and 50 AIS patients) admitted to the emergency department. The outcome status and prognostic classification were performed according to the modified Rankin Scale (mRS) scores on the 30 day from hospital admission.

Multifaceted impact of adipose conditioned media: Obesity-driven promotion of prostate cancer and cancer stem cell dynamics.

Obesity is an established risk factor for the development and progression of prostate cancer (PC). This study used adipose conditioned media (ACM) from differentiated adipocytes to assess its effect on PC development and aggressiveness. Due to limited research on ACM's impact on isolated PC stem cells (PCSCs), we also examined CD44 PCSCs.

Association Between Plasma Asprosin Levels and Gestational Diabetes Mellitus.

Purpose: This study sought to investigate whether asprosin can be used in the diagnosis of GDM or for diagnostic purposes in high-risk pregnancies, along with a review of other parameters that may be associated with serum asprosin levels.

Patients And Methods: The study investigated the association between gestational diabetes mellitus (GDM) and asprosin levels. A total of 93 participants; 30 patients with GDM, 33 healthy pregnant women with normal glucose tolerance (NGT), and 30 healthy non-diabetic women (control group) at the Endocrinology and Metabolic Diseases outpatient clinic of a tertiary care university hospital were enrolled in the study.

A novel biomarker in acute cholecystitis: YKL-40.

Background: The lack of a specific biomarker that can be used in the diagnosis of acute cholecystitis, a common cause of admission to the emergency department, delays physician efforts to diagnose and treat these patients. Therefore, the aim of this study was to measure plasma YKL-40 levels and investigate their diagnostic value in patients with acute cholecystitis (AC).

Methods: This study was carried out between February 2020 and September 2020 in the adult emergency department of a tertiary university hospital.

The synergistic anticancer effect of salinomycin combined with cabazitaxel in CD44+ prostate cancer cells by downregulating wnt, NF-κB and AKT signaling.

Background: Tumor-initiating or cancer stem cells (CSCs) reduce the effectiveness of conventional therapy. Thus, it is crucial to eliminate CSCs while killing bulky cancer cells using a combination of conventional chemotherapy and anti-CSC drugs. Salinomycin is a selective inhibitor against CSCs and shows promise in combination applications.

Midkine silencing enhances the anti-prostate cancer stem cell activity of the flavone apigenin: cooperation on signaling pathways regulated by ERK, p38, PTEN, PARP, and NF-κB.

Prostate cancer (PCa) is the most common cancer in men worldwide. Midkine (MK) is overexpressed in PCa, as well as in tumor-initiating cells termed cancer stem cells (CSCs). Apigenin is a dietary flavone with considerable anti-tumor activities.

Midkine downregulation increases the efficacy of quercetin on prostate cancer stem cell survival and migration through PI3K/AKT and MAPK/ERK pathway.

Aims: To examine the functions of growth factor midkine (MK) and a flavonoid quercetin on survival, apoptosis and migration of prostate cancer (PCa) stem cells (CSCs).

Main Methods: CD44/CD133 and CD44 stem cells were isolated from PC3 and LNCaP cells, respectively by magnetic-activated cell sorting system. 3D cell culture was used to evaluate the ability of quercetin, MK siRNA, and the combination of both to inhibit spheroid formation, apoptosis and cell cycle arrest.

The flavonoid apigenin reduces prostate cancer CD44(+) stem cell survival and migration through PI3K/Akt/NF-κB signaling.

Aims: Cancer stem cells (CSCs) are involved in drug resistance, metastasis and recurrence of cancers. The efficacy of apigenin on cell survival, apoptosis, migration and stemness properties were analyzed in CSCs.

Main Methods: Prostate CSCs (CD44(+)) were isolated from human prostate cancer (PCa) PC3 cells using a magnetic-activated cell sorting system.

Rational design of an immunoconjugate for selective knock-down of leukemia-specific E2A-PBX1 fusion gene expression in human Pre-B leukemia.

The t(1;19)(q23;p13) is one of the most common chromosomal translocations in acute lymphoblastic leukemia (ALL) and results in production of the transforming oncoprotein E2A-PBX1. Here we first report a novel, biomarker-guided biotherapy strategy for personalized treatment of t(1;19)(+) ALL. A supervised interrogation of the gene expression profiles of primary leukemic cells from a cohort of 207 children with high risk B-lineage ALL identified up-regulated CD19 gene expression as a biomarker for t(1;19)(+) ALL.

In vitro and in vivo chemosensitizing activity of LFM-A13, a dual-function inhibitor of Bruton's tyrosine kinase and polo-like kinases, against human leukemic B-cell precursors.

The present study documents the chemosensitizing anti-leukemic activity of the leflunomide metabolite (LFM) analog, LFM-A13, a dual-function inhibitor of Bruton's tyrosine kinase (BTK) and Polo-like kinases (PLK), against human leukemic B-cell precursors. The results in 135 xenografted NOD/SCID mice regarding the anti-leukemic activity of GMP-grade LFM-A13, obtained with only 4-days of LFM-A13 therapy at nontoxic dose levels corresponding to 1-20% of its NOAEL (no observable advserse effect level), alone or in combination with the standard chemotherapy drug vincristine, demonstrate the potential of LFM-A13 as a new anti-leukemic drug candidate. All 82 LFM-A13-treated mice, including those receiving a combination of vincristine + LFM-A13 at the highest dose level of LFM-A13, tolerated their treatments well without weight loss, diarrhea, lethargy/ paralysis, other signs of morbidity, or mortality.

Chemoprevention of colorectal cancer by targeting Janus kinase 3 with a rationally designed small molecule inhibitor.

The effects of the rationally designed JAK3 inhibitor JANEX-1 on the development of intestinal tumors in the APC(min) mouse model of familial adenomatous polyposis were examined. At a non-toxic dose level, >4 times lower than its day 30 LD(10), JANEX-1 was highly effective in preventing intestinal tumor development in Min mice, resulting in markedly improved survival outcomes. JAK3 inhibitors may, therefore, be useful in the chemoprevention of colorectal cancer.

CD22 EXON 12 deletion as a pathogenic mechanism of human B-precursor leukemia.

Here, we report that primary leukemic cells from infants with newly diagnosed B-precursor leukemia express a truncated and functionally defective CD22 coreceptor protein that is unable to transmit apoptotic signals because it lacks most of the intracellular domain, including the key regulatory signal transduction elements and all of the cytoplasmic tyrosine residues. Expression of this structurally and functionally abnormal CD22 protein is associated with a very aggressive in vivo growth of patients' primary leukemia cells causing disseminated overt leukemia in SCID mice. The abnormal CD22 coreceptor is encoded by a profoundly aberrant mRNA arising from a splicing defect that causes the deletion of exon 12 (c.

Augmentation of the antileukemia potency of total-body irradiation (TBI) by a novel P-site inhibitor of spleen tyrosine kinase (SYK).

A novel spleen tyrosine kinase (SYK) P-site inhibitor, 1,4-Bis (9-O dihydroquinidinyl) phthalazine/hydroquinidine 1,4-phathalazinediyl diether (C-61), (but not vehicle) markedly enhanced H(2)O(2)-induced apoptosis of primary leukemia cells from each of five relapsed B-lineage acute lymphoblastic leukemia (ALL) patients, as measured by in vitro TUNEL assays. A highly radiation-resistant subclone of the murine B-lineage leukemia cell line BCL-1 was next used to investigate the in vivo radiosensitizing effects of C-61. C-61 enhanced the antileukemia potency of 7 Gy total-body irradiation (TBI) in the context of syngeneic bone marrow transplantation (BMT) at 20% of its nonobservable adverse effect level (NOAEL) that does not exhibit detectable single-agent activity against BCL-1 leukemia in vivo.

Prevention of UVB-induced skin inflammation, genotoxicity, and photocarcinogenesis in mice by WHI-P131, a dual-function inhibitor of Janus kinase 3 and EGF receptor kinase.

The current study examined the chemopreventive potential of the dual-function JAK3/EGFR tyrosine kinase inhibitor WHI-P131 (CAS 202475-60-3) in photocarcinogenesis of non-melanoma skin cancer (NMSC). Prophylactic WHI-P131 exhibited significant anti-inflammatory activity in the SKH-1 mouse model of sunburn and afforded significant protection against the inflammatory skin damage that results from UVB exposure. UVB exposure (400 mJ/cm2) increased the mutation rate of the transgene target in UVB-exposed skin of BigBlue mice by a factor of 3.

Therapeutic nanoparticle constructs of a JAK3 tyrosine kinase inhibitor against human B-lineage ALL cells.

WHI-P131 (CAS 202475-60-3) is a dual-function inhibitor of JAK3 tyrosine kinase that demonstrated potent in vivo anti-inflammatory and anti-leukemic activity in several preclinical animal models. This is the first report of the development of nanoparticle (NP) constructs ofWHI-P131. Fourty-eight distinct NP formulations were prepared and WHI-P131 encapsulation efficiencies > 95% and intraliposomal WHI-P131 concentrations >10 mg/mL were achieved in lead NP formulations.

Targeting JAK3 tyrosine kinase-linked signal transduction pathways with rationally-designed inhibitors.

Inhibitors of Janus Kinase 3 (JAK3) show potential as a new class of apoptosis-inducing anti-cancer drugs. In addition, JAK3 inhibitors may also be useful as immunosuppressive agents. Rationally designed selective inhibitors of JAK3 such as JANEX-1, that do not inhibit other Janus kinases have recently undergone extensive preclinical testing that revealed a favorable pharmacodynamic profile.

Anti-breast cancer activity of LFM-A13, a potent inhibitor of Polo-like kinase (PLK).

Molecular modeling studies led to the identification of LFM-A13 (alpha-cyano-beta-hydroxy-beta-methyl-N-(2,5-dibromophenyl)propenamide) as a potent inhibitor of Polo-like kinase (Plk). LFM-A13 inhibited recombinant purified Plx1, the Xenopus homolog of Plk, in a concentration-dependent fashion, as measured by autophosphorylation and phosphorylation of a substrate Cdc25 peptide. LFM-A13 was a selective Plk inhibitor.

In vitro and in vivo pharmacokinetic features and metabolism of the novel cytotoxic nucleoside analog 3'-azidothymidine 5'-[p-methoxyphenyl methoxyalaninyl phosphate] (Compound 003).

The pharmacokinetic features and metabolism of the novel cytotoxic nucleoside analog Compound 003 (3'-azidothymidine 5'-[p-methoxyphenyl methoxyalaninyl phosphate], CAS 149560-32-7) were studied in both human cancer cells and mice. In mice, Compound 003 was rapidly converted into ala-AZT-MP (CAS 209214-06-2) and zidovudine (azidothymidine, AZT, CAS 30516-87-1). Maximum ala-AZT-MP concentrations were reached almost immediately (tmax < 5 min), while 50.

Anti-cancer activity profile of 3'-azidothymidine 5'-[p-methoxyphenyl methoxyalaninyl phosphate] (Compound 003), a novel nucleoside analog.

The novel cytotoxic nucleoside analog Compound 003 (3'-azidothymidine 5'-[p-methoxyphenyl methoxyalaninyl phosphate], CAS 149560-32-7) prevented bipolar mitotic spindle assembly and caused a G2 arrest in human cancer cells. Compound 003 was very well tolerated by both mice and rats without any toxicity at cumulative dose levels >2 g/kg. Notably, Compound 003 prolonged cancer-free survival in the MMTVneu transgenic mouse model of HER2 positive breast cancer.

Stimulation of Bruton's tyrosine kinase (BTK) and inositol 1,4,5-trisphosphate production in leukemia and lymphoma cells exposed to low energy electromagnetic fields.

We examined the effects of low energy electromagnetic field (EMF) exposure on the BTK kinase activity in B18-2 ([Btk-, rBTK(wt)] DT40) chicken lymphoma B cells and NALM-6 leukemic pre-B cells. Exposure of B 18-2 cells to EMF resulted in activation of BTK within 1 to 15 minutes in 8 of 8 independent experiments with stimulation indexes ranging from 1.2 to 13.

Targeting Janus kinase 3 in mast cells prevents immediate hypersensitivity reactions and anaphylaxis.

Janus kinase 3 (JAK3), a member of the Janus family protein-tyrosine kinases, is expressed in mast cells, and its enzymatic activity is enhanced by IgE receptor/FcepsilonRI cross-linking. Selective inhibition of JAK3 in mast cells with 4-(4'-hydroxylphenyl)-amino-6, 7-dimethoxyquinazoline) (WHI-P131) blocked the phospholipase C activation, calcium mobilization, and activation of microtubule-associated protein kinase after lgE receptor/FcepsilonRI cross-linking. Treatment of IgE-sensitized rodent as well as human mast cells with WHI-P131 effectively inhibited the activation-associated morphological changes, degranulation, and proinflammatory mediator release after specific antigen challenge without affecting the functional integrity of the distal secretory machinery.

Electromagnetic field-induced stimulation of Bruton's tyrosine kinase.

Here we present evidence that exposure of DT40 lymphoma B-cells to low energy electromagnetic fields (EMF) results in activation of phospholipase C-gamma 2 (PLC-gamma2), leading to increased inositol phospholipid turnover. PLC-gamma2 activation in EMF-stimulated cells is mediated by stimulation of the Bruton's tyrosine kinase (BTK), a member of the Src-related TEC family of protein tyrosine kinases, which acts downstream of LYN kinase and upstream of PLC-gamma2. B-cells rendered BTK-deficient by targeted disruption of the btk gene did not show enhanced PLC-gamma2 activation in response to EMF exposure.

TXU (anti-CD7)-pokeweed antiviral protein as a potent inhibitor of human immunodeficiency virus.

We have evaluated the clinical potential of TXU (anti-CD7)-pokeweed antiviral protein (PAP) immunoconjugate (TXU-PAP) as a new biotherapeutic anti-human immunodeficiency virus (anti-HIV) agent by evaluating its anti-HIV type 1 (anti-HIV-1) activity in vitro, as well as in a surrogate human peripheral blood lymphocyte-severe combined immunodeficient (Hu-PBL-SCID) mouse model of human AIDS. The present report documents in a side-by-side comparison the superior in vitro anti-HIV-1 activity of TXU-PAP compared to the activities of zidovudine, 2',3'-didehydro-2',3'-dideoxythymidine, unconjugated PAP, and B53-PAP, an anti-CD4-PAP immunoconjugate. Notably, TXU-PAP elicited potent anti-HIV activity in the Hu-PBL-SCID mouse model of human AIDS without any side effects and at doses that were very well tolerated by cynomolgus monkeys.

Stimulation of Src family protein-tyrosine kinases as a proximal and mandatory step for SYK kinase-dependent phospholipase Cgamma2 activation in lymphoma B cells exposed to low energy electromagnetic fields.

Here, we present evidence that exposure of DT40 lymphoma B cells to low energy electromagnetic field (EMF) results in a tyrosine kinase-dependent activation of phospholipase Cgamma2 (PLC-gamma2) leading to increased inositol phospholipid turnover. B cells rendered PLC-gamma2-deficient by targeted disruption of the PLC-gamma2 gene as well as PLC-gamma2-deficient cells reconstituted with Src homology domain 2 (SH2) domain mutant PLC-gamma2 did not show any increase in inositol-1,4,5-trisphosphate levels after EMF exposure, providing direct evidence that PLC-gamma2 is responsible for EMF-induced stimulation of inositol phospholipid turnover, and its SH2 domains are essential for this function. B cells rendered SYK-deficient by targeted disruption of the syk gene did not show PLC-gamma2 activation in response to EMF exposure.