PIM2

BACKGROUND: Chemoresistance contributes to relapse in high-risk neuroblastoma. Cancer cells acquire resistance through multiple mechanisms, including drug efflux pumps. In neuroblastoma, multidrug resistance-associated protein-1 (MRP1/ABCC1) efflux pump expression correlates with worse outcomes. These pumps are regulated by PIM kinases, a family of serine-threonine kinases, overexpressed in neuroblastoma. We hypothesized PIM kinase inhibition would sensitize neuroblastoma cells by modulating MRP1...

Mycobacterial plasma membrane, together with the peptidoglycan-arabinogalactan cell wall and waxy outer membrane, creates a robust permeability barrier against xenobiotics. The fact that several anti-tuberculosis drugs target plasma membrane-embedded enzymes underscores the importance of the plasma membrane in bacterial physiology and pathogenesis. Nevertheless, its accurate phospholipid composition remains undefined, with conflicting reports on the abundance of phosphatidylinositol mannosides (PIMs), physiologically important glycolipids evolutionarily conserved among mycobacteria and related bacteria...

Although LncRNA AA465934 expression is reduced in high glucose (HG)-treated podocytes, its role in HG-mediated podocyte injury and diabetic nephropathy (DN) remains unknown. Herein, we investigated the role of AA465934 in HG-mediated podocyte injury and DN using a spontaneous type II diabetic nephropathy (T2DN) model. The model was created by injecting AA465934 overexpressed adeno-associated virus (AAV) or control into mice. The levels of renal function, proteinuria, renal structural lesions, and podocyte apoptosis were then examined...

PIM3 (provirus-integrating Moloney site 3) is a serine/threonine kinase and belongs to the PIM family (PIM1, PIM2, and PIM3). PIM3 is a proto-oncogene that is frequently overexpressed in cancers originating from endoderm-derived tissues, such as the liver, pancreas, colon, stomach, prostate, and breast cancer. PIM3 plays a critical role in activating multiple oncogenic signaling pathways promoting cancer cell proliferation, survival, invasion, tumor growth, metastasis, and progression, as well as chemo- and radiation therapy resistance and immunosuppressive microenvironment...

PIM2, part of the PIM kinase family along with PIM1 and PIM3, is often overexpressed in hematologic cancers, fueling tumor growth. Despite its significance, there are no approved drugs targeting it. In response to this challenge, we devised a thorough virtual screening workflow for discovering novel PIM2 inhibitors. Our process includes molecular docking and diverse scoring methods like molecular mechanics generalized born surface area, XGBOOST, and DeepDock to rank potential inhibitors by binding affinities and interaction potential...

Hyperthermia is a unique treatment option for cancers. Multiple myeloma (MM) remains incurable and innovative therapeutic options are needed. We investigated the efficacy of hyperthermia and carfilzomib in combination against MM cells. Although MM cell lines exhibited different susceptibilities to pulsatile carfilzomib treatment, mild hyperthermia at 43℃ induced MM cell death in all cell lines in a time-dependent manner. Hyperthermia and carfilzomib cooperatively induced MM cell death even under suboptimal conditions...

Resistance to proteasome inhibitors (PIs) has emerged as an important clinical issue. We investigated the mechanisms underlying multiple myeloma (MM) cell resistance to PIs. To mimic their pharmacokinetic/pharmacodynamic (PK/PD) profiles, MM cells were treated with bortezomib and carfilzomib for 1 h at concentrations up to 400 and 1,000 nM, respectively. Susceptibility to these PIs markedly varied among MM cell lines. Pulsatile treatments with PIs suppressed translation, as demonstrated by incorporation of puromycin at 24 h in PI-susceptible MM...

OBJECTIVES: The purpose of this study was to evaluate phytonadione in children with septic shock with disseminated intravascular coagulopathy (DIC). The primary objective was to identify the number of patients with an international normalized ratio (INR), defined as ≤1.2, following phytonadione. Secondary objectives were to compare patients who achieved a normalized INR versus those with INR >1.2 and to determine factors associated with a normalized INR. METHODS: A retrospective study of children <18 years of age receiving phytonadione from October 1, 2013, to August 31, 2020, with a diagnosis of septic shock, were included...

PIM kinases, a serine/threonine kinase family with three isoforms, has been well-known to participate in multiple physiological processes by phosphorylating various downstream targets. Accumulating evidence has recently unveiled that aberrant upregulation of PIM kinases (PIM1, PIM2, and PIM3) are closely associated with tumor cell proliferation, migration, survival, and even resistance. Inhibiting or silencing of PIM kinases has been reported have remarkable antitumor effects, such as anti-proliferation, pro-apoptosis and resensitivity, indicating the therapeutic potential of PIM kinases as potential druggable targets in many types of human cancers...

BACKGROUND: Lung adenocarcinoma (LUAD) is one of the most common subtypes of lung cancer. Finding prognostic biomarkers is helpful in stratifying LUAD patients with different prognosis. METHODS: We explored the correlation of LUAD prognosis and genes associated with chemotherapy in LUAD and obtained data of LUAD patients from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Drug sensitivity data were acquired from the Genomics of Drug Sensitivity in Cancer (GDSC) database...

Objective: To investigate the potential association between Anoikis-related genes, which are responsible for preventing abnormal cellular proliferation, and rheumatoid arthritis (RA). Methods: Datasets GSE89408, GSE198520, and GSE97165 were obtained from the GEO with 282 RA patients and 28 healthy controls. We performed differential analysis of all genes and HLA genes. We performed a protein-protein interaction network analysis and identified hub genes based on STRING and cytoscape. Consistent clustering was performed with subgrouping of the disease...

The serine/threonine-specific Moloney murine leukemia virus (PIM) kinase family (i.e., PIM1, PIM2, and PIM3) has been extensively studied in tumorigenesis. PIM kinases are downstream of several cytokine signaling pathways that drive immune-mediated diseases. Uncontrolled T helper 17 (Th17) cell activation has been associated with the pathogenesis of autoimmunity. However, the detailed molecular function of PIMs in human Th17 cell regulation has yet to be studied. In the present study, we comprehensively investigated how the three PIMs simultaneously alter transcriptional gene regulation during early human Th17 cell differentiation...

Acute myeloid leukemia (AML) patients have frequent mutations in FMS-like receptor tyrosine kinase 3 (FLT3-mut AML), who respond poorly to salvage chemotherapies and targeted therapies such as tyrosine kinase inhibitors (TKIs). Disease relapse is a common reason of treatment failures in FLT3-mut AML patients, but its intracellular refractory mechanism remains to be discovered. In this study, we designed serial in vitro time-course studies to investigate the biomarkers of TKI-resistant blasts and their survival mechanism...

INTRODUCTION: Influenza virus is a common agent of pediatric infections. Most cases are mild, but severe illness and death can occur. We aimed to analyze severe cases associated the influenza virus and compare it with respiratory syncytial virus (RSV). METHODS: This is a retrospective study of 0-17-year-old patients admitted to the intensive care unit (ICU) of Hospital Pediátrico, Centro Hospitalar e Universitário de Coimbra (Pediatric Hospital, Coimbra Hospital and University Center), a tertiary pediatric hospital in Coimbra, Portugal, over the last 15 years (2008-2022) due to influenza virus infection...

Nucleophosmin-anaplastic lymphoma kinase (NPM-ALK), a fusion protein generated by a chromosomal translocation, is a causative gene product of anaplastic large cell lymphoma (ALCL). It induces cell proliferation and tumorigenesis by activating the transcription factor, signal transducer and activator of transcription factor 3 (STAT3). We herein demonstrated that STAT3 underwent acetylation at K685 in a manner that was dependent on the kinase activity of NPM-ALK. To investigate the role of STAT3 acetylation in NPM-ALK-induced oncogenesis, we generated Ba/F3 cells expressing NPM-ALK in which STAT3 was silenced by shRNA, named STAT3-KD cells, and then reconstituted wild-type STAT3 or the STAT3 K685R mutant into these cells...

During critical illness, children my experience various changes in their thyroid hormone levels. Such changes are termed non-thyroidal illness syndrome (NTI). The extent of change correlates with the severity of the illness and its outcomes in critically ill patients. This study aimed to investigate the correlation between the severity of shock and thyroid hormone derangement. This prospective observational study included forty patients aged one month to five years who were admitted to the pediatric intensive care unit (PICU) with shock...

Cardiac troponin-I (cTnI) is a biomarker of myocardial injury with implications for clinical outcomes. May other contributing factors that could affect outcomes have not been uniformly considered in pediatric studies. We hypothesized that there is an association between admission serum cTnI and outcomes in critically ill children taking into account the magnitude of the acute systemic inflammatory response syndrome (SIRS), serum lactate concentrations, and nutritional status. Second, we tested for potential factors associated with elevated serum cTnI...

UNLABELLED: Sepsis is an important cause of pediatric morbidity and mortality, especially in low-income countries. Data on regional prevalence, mortality trends, and their relationship with socioeconomic variables are scarce. OBJECTIVE: to determine the regional prevalence, mortality, and sociodemographic situation of patients diagnosed with severe sepsis (SS) and septic shock (SSh) admitted to Pediatric Intensive Care Units (PICUs). PATIENTS AND METHOD: patients aged 1 to 216 months admitted to 47 participating PICUs with a diagnosis of SS or SSh between January 1, 2010, and December 31, 2018, were included...

BACKGROUND: To determine whether undernutrition affects 60-day mortality in pediatric acute respiratory failure. METHODS: Subjects with acute respiratory failure aged between two months and 13 years were included in the study. The Z-scores were calculated on admission and children were categorized into two groups of undernutrition and normal nutrition. The nutritional intake of the children was measured daily. The outcome was 60-day mortality. RESULTS: A total of 126 patients met the inclusion criteria; 41% were undernourished based on the Z-score of BMI and weight for height, 50% based on the Z-score of height and length for age and 45% based on the Z-score of weight for age...

UNLABELLED: Continuous Renal Replacement Therapy (CRRT) machines are used off-label in patients less than 20 kg. Infant and neonates-dedicated CRRT machines are making their way into current practice, but these machines are available only in select centres. This study assesses the safety and efficacy of CRRT using adult CRRT machines in children ≤ 10 kg and to determines the factors affecting the circuit life in these children. DESIGN: Retrospective cohort study of children ≤ 10 kg who received CRRT (January 2010-January 2018) at a PICU in a tertiary care centre in London, UK...