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A Phase I/II Clinical Trial to evaluate the efficacy of baricitinib to prevent respiratory insufficiency progression in onco-hematological patients affected with COVID19: A structured summary of a study protocol for a randomised controlled trial.

OBJECTIVES: Baricitinib is supposed to have a double effect on SARS-CoV2 infection. Firstly, it reduces the inflammatory response through the inhibition of the Januse-Kinase signalling transducer and activator of transcription (JAK-STAT) pathway. Moreover, it reduces the receptor mediated viral endocytosis by AP2-associated protein kinase 1 (AAK1) inhibition. We propose the use of baricinitib to prevent the progression of the respiratory insufficiency in SARS-CoV2 pneumonia in onco-haematological patients. In this phase Ib/II study, the primary objective in the safety cohort is to describe the

Combination trial of duvelisib (IPI-145) with rituximab or bendamustine/rituximab in patients with non-Hodgkin lymphoma or chronic lymphocytic leukemia.

Duvelisib, a potent δ- and γ-PI3K inhibitor, is a potential therapeutic for hematologic malignancies. Rituximab and bendamustine have demonstrated activity in non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Combining duvelisib with either rituximab alone or rituximab and bendamustine may improve response rates and remission durability. We conducted this Phase one study in relapsed/refractory NHL and CLL patients. During expansion, each arm enrolled to disease-specific cohorts to assess efficacy. Arm one received rituximab 375 mg/m2 IV weekly for two 4-week cycles plus duveli

Comparison of arsenic methylation capacity and polymorphisms of arsenic methylation genes between bladder cancer and upper tract urothelial carcinoma.

Arsenic exposure is an environmental risk factor for urothelial carcinoma (UC). The natural history of upper tract urothelial carcinoma (UTUC) differs from that of bladder cancer (BC). However, the risk factors of BC and UTUC are not exactly the same and should be discussed separately. The aims of this study were to evaluate 1) the association between arsenic methylation capacity and UTUC and/or BC, separately, and 2) the association between polymorphisms of the arsenic metabolism-related genes AS3MT, GSTOs, and PNP against BC and/or UTUC, separately. We conducted a hospital-based study and co

[Effects of the phosphoinostitide-3'-kinase delta inhibitor, CAL-101, in combination with Bortezomib on mantle lymophma cells and exploration of its related mechanism].

OBJECTIVE: To investigate the effect of CAL-101, a selective inhibitor of PI3Kδ, in combination with bortezomib on the proliferation and apoptosis in human mantle cell lymphoma cell lines Z138, HBL-2 and Jeko-1 in vitro, to explore its mechanisms and provide the foundation for effective treatment strategies against mantle cell lymphoma. METHODS: MTT assay was applied to detect the inhibitory effects of CAL-101 and bortezomib either alone or combined on Z138, HBL-2 and Jeko-1 cells. Calcusyn software was used to analyze the synergistic cytotoxicity. Western blot was used to detect the expressi

MNK kinases facilitate c-myc IRES activity in rapamycin-treated multiple myeloma cells.

When mTOR inhibitor rapalogs prevent cap-dependent translation of cell-cycle proteins like c-myc, continuing tumor cell growth depends on cap-independent translation, which is mediated by internal ribosome entry sites (IRESes) located in the 5'-UTR (untranslated region) of transcripts. To investigate if rapalog-induced activation of MNK kinases had a role in such IRES activity, we studied multiple myeloma (MM) cells. Rapamycin (RAP)-activated MNK1 kinase activity in MM cell lines and primary specimens by a mitogen-activated protein kinase-dependent mechanism. Pharmacological inhibition of MNK

Phosphorylation of TRPC6 channels at Thr69 is required for anti-hypertrophic effects of phosphodiesterase 5 inhibition.

Activation of Ca(2+) signaling induced by receptor stimulation and mechanical stress plays a critical role in the development of cardiac hypertrophy. A canonical transient receptor potential protein subfamily member, TRPC6, which is activated by diacylglycerol and mechanical stretch, works as an upstream regulator of the Ca(2+) signaling pathway. Although activation of protein kinase G (PKG) inhibits TRPC6 channel activity and cardiac hypertrophy, respectively, it is unclear whether PKG suppresses cardiac hypertrophy through inhibition of TRPC6. Here, we show that inhibition of cGMP-selective

Inhibition of HTLV-1 transcription by cyclin dependent kinase inhibitors.

HTLV-1 is the etiologic agent for adult T-cell leukemia/lymphoma (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), where viral replication and transformation are largely dependent upon modification of regulatory and host cell cycle proteins. The mechanism of HTLV-1 transformation appears to be distinct from that of many known chronic or acute leukemia viruses and is related to the viral activator Tax. Here we show that cyclin E, can associate tightly with the coactivator p300 and Pol II complex in HTLV-1 infected cells. The cyclin E associated complex is kinase act

[Enzyme deficiencies in glycolysis and nucleotide metabolism of red blood cells in nonspherocytic hemolytic anemia (author's transl)].

The detection of enzyme deficiencies in glycolytic and nucleotide metabolism of human red blood cells has enriched the pathophysiological knowledge on the origin of nonspherocytic hemolytic anemias (NSHA). So far for 11 of 13 glycolytic enzymes deficiencies have been described which are connected with alterations of biochemical enzymatic properties. The most frequent enzyme deficiencies are those of GPI and PK. By performance of special electrophoretic techniques genetic studies allow the demonstration of homozygote and double heterozygote defect carriers. Up to now only adenylate kinase and p

Mechanism and active ingredients of Gancao Qinlian Granules in ameliorating ulcerative colitis:integrated in vivo, in vitro, network pharmacology and untargeted metabolomics investigation.

ETHNOPHARMACOLOGICAL RELEVANCE: Gancao Qinlian Granules (GQG) are a granulated formulation of the classical prescription Gancao Xiexin Tang, originally documented by Zhang Zhongjing in the Treatise on Febrile and Miscellaneous Diseases (Shang Han Za Bing Lun, c. 220 CE). This formula comprises six medicinal components: Glycyrrhiza glabra L. (Gancao), the radix of Scutellaria baicalensis Georgi (Huangqin), Ziziphus jujuba Mill. (Dazao), the rhizomes of Zingiber officinale Roscoe (Ganjiang), the dried tuber of Pinellia ternata (Thunb.) Breit (Banxia), and the rhizoma of Coptis chinensis Franch (

Computational Analysis of SPI1 Missense Mutations and ADMET-Guided Molecular Docking of Cinnamic Acid Targeting the PU.1 ETS Domain: Implications for Hematopoietic Dysregulation and Leukemogenesis.

Spi-1 Proto-Oncogene (SPI1) encodes Purine-rich box 1 Transcription Factor (PU.1), a transcription factor of the ETS family that regulates hematopoietic lineage commitment and immune cell differentiation. Alteration of PU.1 dose or ETS domain integrity may interfere with transcriptional programs, which adds to hematopoietic dysregulation and leukemogenesis. Even though changes in SPI1 expression have been associated with acute myeloid leukemia (AML), the structural and regulatory effects of missense mutations at the PU.1 ETS domain have not been entirely studied, and targeting the PU.1 ETS dom

Nucleotide Metabolism in Health and Disease.

Nucleotide metabolism is a fundamental biochemical process, providing the building blocks for DNA and RNA synthesis while driving critical cellular functions like energy transfer, signal transduction, and coenzyme synthesis. The precise regulation of nucleotide de novo synthesis, salvage, and degradation pathways is imperative for maintaining genomic stability and tissue homeostasis. Aberrations in these networks are increasingly recognized as primary drivers in various pathologies; notably, cancer cells exploit metabolic-functional reprogramming to enable rapid proliferation and therapeutic r

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… There are two salvage pathways for purine nucleotide synthesis [ 42 ]. The first involves the reuse of existing purine bases or nucleosides to synthesize purine nucleotides, which is simpler and less energy consuming. … Purine nucleotide antimetabolites are analogs of purines, amino acids, or folates [ 46 ]. …

Molecular Targeting and Rational Chemotherapy in Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is a molecularly complex disease with multiple aberrant genetic pathways involved in its pathogenesis. Approximately one-third to one-half of patients with AML would relapse, and no standard therapy is established for relapsing and/or refractory AML (RR-AML) yet. It is unlikely that blockage of only one specific pathway will lead to prolonged remissions and cures in all fractions of the AML patients population. Nowadays, novel therapeutic agents with rational combination are being recognized which improve the cure rate for relapsed AML. These drugs and their metabo

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… The basic mechanism of action of purine and pyrimidine antimetabolites is quite similar ( Figures 1 and 2 ). … Consequently, the methylation of DNA is remarkably impaired and methyl donors are reduced, whereby inducing cell death in leukemic blasts. 1 , 6 , 19 , 23 Purine Anti-Metabolites (Thiopurines, Clofarabine, Cladribine, Fludarabine) Until now, five purine deoxynucleoside analogs have been approved for …

A prospective cross-screening study on G-protein-coupled receptors: lessons learned in virtual compound library design.

We present the systematic prospective evaluation of a protein-based and a ligand-based virtual screening platform against a set of three G-protein-coupled receptors (GPCRs): the β-2 adrenoreceptor (ADRB2), the adenosine A(2A) receptor (AA2AR), and the sphingosine 1-phosphate receptor (S1PR1). Novel bioactive compounds were identified using a consensus scoring procedure combining ligand-based (frequent substructure ranking) and structure-based (Snooker) tools, and all 900 selected compounds were screened against all three receptors. A striking number of ligands showed affinity/activity for GPCR

The nuclear factor erythroid 2-like 2 activator, tert-butylhydroquinone, improves cognitive performance in mice after mild traumatic brain injury.

Traumatic Brain injury affects at least 1.7 million people in the United States alone each year. The majority of injuries are categorized as mild but these still produce lasting symptoms that plague the patient and the medical field. Currently treatments are aimed at reducing a patient's symptoms, but there is no effective method to combat the source of the problem, neuronal loss. We tested a mild, closed head traumatic brain injury model for the effects of modulation of the antioxidant transcription factor Nrf2 by the chemical activator, tert-butylhydroquinone (tBHQ). We found that post-injur

[Etravirine drug interactions].

Etravirine (ETR) belongs to the family of non-nucleoside analogue reverse transcriptase inhibitors (NNRTIs), with antiviral activity in patients with resistance to first-generation NNRTIs. The drug interactions caused by ETR are due to its dual effect on the CYP450 system. ETR acts as an inducer of CYP3A4 and inhibitor of CYP2C9 and CYP2C19. This drug shows few clinically significant drug interactions, the most important of which involve the unboosted protease inhibitors, the NNRTIs efavirenz and nevirapine, full-dose ritonavir and tipranavir/ritonavir. Interaction with fosamprenavir/ritonavir

Refined mapping of genomic rearrangements involving the short arm of chromosome 9 in acute lymphoblastic leukemias and other hematologic malignancies.

Deletions of chromosomal band 9p21 have been detected in various tumor types as well as in more than 20% of acute lymphoblastic leukemia (ALL). These deletions frequently include the entire interferon (IFN) gene cluster as well as the methylthioadenosine phosphorylase (MTAP) gene. Recently, the CDKN2 gene (p16INK4A, MTS I, CDK41) was proposed as a candidate tumor-suppressor gene on 9p21 because it is frequently deleted in cell lines derived from multiple tumor types. To determine if CDKN2 or another closely related gene on 9p is the target of 9p deletions in ALL and other hematologic malignanc

A guide to immunotherapy for COVID-19.

Immune dysregulation is an important component of the pathophysiology of COVID-19. A large body of literature has reported the effect of immune-based therapies in patients with COVID-19, with some remarkable successes such as the use of steroids or anti-cytokine therapies. However, challenges in clinical decision-making arise from the complexity of the disease phenotypes and patient heterogeneity, as well as the variable quality of evidence from immunotherapy studies. This Review aims to support clinical decision-making by providing an overview of the evidence generated by major clinical trial

PI3K/mTOR dual-inhibition with VS-5584 enhances anti-leukemic efficacy of ponatinib in blasts and Ph-negative LSCs of chronic myeloid leukemia.

Ponatinib is used for advanced treatment of chronic myeloid leukemia (CML), although low doses to prevent side effects do not suppress survival pathways and eradicate leukemia stem cells (LSCs). We evaluated the potential of ponatinib and PI3K/mTOR dual-inhibitor VS-5584 combination (PoVS) therapy to increase the anti-leukemic effects of ponatinib and investigated the underlying mechanisms at the molecular level. We measured the cytotoxicities of ponatinib, VS-5584, and PoVS (CCK-8 assay), and used the median-effect equation for combination analyses. We investigated the effects of inhibitory c

CD69 expression potentially predicts response to bendamustine and its modulation by ibrutinib or idelalisib enhances cytotoxic effect in chronic lymphocytic leukemia.

BACKGROUND: We aimed to determine the risk factors for retinopathy of prematurity (ROP) and investigate the effects of the expanded screening criteria according to the 2021 update of the Turkish Neonatology Society guidelines on the clinical outcomes of premature infants and the incidence of severe ROP. MATERIALS AND METHOD: Patient records of infants treated in the neonatal intensive care unit (NICU) between January-December 2020 and January-December 2023, who were identified as at-risk for ROP were retrospectively analyzed. Infants with severe ROP were compared with those without ROP or wit

MCL-1 and BCL-xL-dependent resistance to the BCL-2 inhibitor ABT-199 can be overcome by preventing PI3K/AKT/mTOR activation in lymphoid malignancies.

Overexpression of anti-apoptotic BCL-2 family members is a hallmark of many lymphoid malignancies, including chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL) that can be targeted with small molecule inhibitors. ABT-199 is a rationally designed BCL-2 homology (BH)-3 mimetic that specifically binds to BCL-2, but not to MCL-1 and BCL-xL. Although the thrombocytopenia that occurs with navitoclax treatment has not been a problem with ABT-199, clinical trials in CLL could benefit by lowering the ABT-199 concentration through targeting other survival pathways. In this study, we inves