Clinical relevance of long non-coding RNA in acute myeloid leukemia: A systematic review with meta-analysis.

BACKGROUND: Long noncoding RNAs (lncRNAs) may function as prognostic biomarkers in acute myeloid leukaemia (AML). However, it is still unknown exactly how significant lncRNAs are for the prognosis of AML. With a focus on their prognostic and therapeutic potential, the study aimed to provide a comprehensive review of the literature regarding the role of lncRNAs in AML. METHOD: Pub Med, The Cochrane Library, Embase, Science Direct, Web of science, Scopus, and Google scholar were searched until November, 2023. Original publications of any type exploring the prognostic and therapeutic potential of lncRNAs in AML patients were included. Heterogeneity and publication bias were examined using the I2 test and a funnel plot, respectively. To quantify the relationship between various lncRNA expression in AML patient survival, odds ratios (ORs) or hazards ratios (HRs) with 95 % confidence intervals (CIs) were pooled. Quality of studies was assessed using the Critical Appraisal Checklists for Studies created by the Joanna Briggs Institute (JBI). RESULTS: Twenty-seven studies including 5665 subjects were selected for the final analysis. In patients with AML, abnormal lncRNA expression has been associated with significant worse overall survival (pooled HR = 2.05, 95 % CI = 1.79-2.30, P <0.001), shorter disease-free survival (pooled HR = 2.17, 95 % CI = 1.13-3.22, P< 0.001), and lower complete remission rate (pooled HR = 0.27, 95 % CI = 0.11-0.43, P< 0.001). Poor prognoses have been attributed to increased expression of HOX transcript antisense intergenic RNA (HOTAIR), Promoter Of CDKN1A Antisense DNA Damage Activated RNA (PANDAR), Metastasis Associated Lung Adenocarcinoma Transcript 1 (MALAT1), RP11-222K16.2, Taurine Upregulated Gene 1 (TUG1), Small Nucleolar RNA Host Gene 5 (SNHG5), Growth Arrest Specific 5 (GAS5), and H19 and decreased expression of IGF1R Antisense Imprinted Non-Protein Coding RNA (IRAIN). CONCLUSION: The prognoses of AML patients are significantly associated with abnormally expressed lncRNAs, which may be used as prognostic indicators for predicting the patient outcomes.

In the Quest for Potent and Selective Malic Enzyme 3 Inhibitors for the Treatment of Pancreatic Ductal Adenocarcinoma.

The genome of pancreatic ductal adenocarcinoma (PDAC) is associated with frequent deletion of the tumor suppressor gene SMAD family member 4 (SMAD4) with collateral deletion of its chromosomal neighbor malic enzyme 2 (ME2). In SMAD4 -/- /ME2 -/- PDAC cells, ME3 takes over the function of the ME2 enzyme, and hence therapeutic targeting of ME3 is expected to arrest tumor growth. Hitherto no selective small molecule inhibitor of ME3 has been reported in the context of PDAC. Based on the molecular docking studies and structure-activity relationships with the reported ME1 inhibitor, several analogues of 6-piperazin-1-ylpyridin-3-ol amides have been synthesized and screened for their ME inhibition activity. Among them, compound 16b is identified as the most potent and selective ME3 inhibitor with an IC50 of 0.15 µM on ME3, and with 15- and 9-fold selectivity over ME1 and ME2, respectively. In the cell viability assay, compound 16b exhibited an IC50 of 3.5 µM on ME2-null PDAC cells, viz., BxPC-3.

Topical SCD-153, a 4-methyl itaconate prodrug, for the treatment of alopecia areata.

Alopecia areata is a chronic hair loss disorder that involves autoimmune disruption of hair follicles by CD8+  T cells. Most patients present with patchy hair loss on the scalp that improves spontaneously or with topical and intralesional steroids, topical minoxidil, or topical immunotherapy. However, recurrence of hair loss is common, and patients with extensive disease may require treatment with oral corticosteroids or oral Janus kinase (JAK) inhibitors, both of which may cause systemic toxicities with long-term use. Itaconate is an endogenous molecule synthesized in macrophages that exerts anti-inflammatory effects. To investigate the use of itaconate derivatives for treating alopecia areata, we designed a prodrug of 4-methyl itaconate (4-MI), termed SCD-153, with increased lipophilicity compared to 4-MI (CLogP 1.159 vs. 0.1442) to enhance skin and cell penetration. Topical SCD-153 formed 4-MI upon penetrating the stratum corneum in C57BL/6 mice and showed low systemic absorption. When added to human epidermal keratinocytes stimulated with polyinosinic-polycytidylic acid (poly I:C) or interferon (IFN)γ, SCD-153 significantly attenuated poly I:C-induced interleukin (IL)-6, Toll-like receptor 3, IL-1ß, and IFNß expression, as well as IFNγ-induced IL-6 expression. Topical application of SCD-153 to C57BL/6 mice in the resting (telogen) phase of the hair cycle induced significant hair growth that was statistically superior to vehicle (dimethyl sulfoxide), the less cell-permeable itaconate analogues 4-MI and dimethyl itaconate, and the JAK inhibitor tofacitinib. Our results suggest that SCD-153 is a promising topical candidate for treating alopecia areata.

Discovery of Potent, Selective, and State-Dependent NaV1.7 Inhibitors with Robust Oral Efficacy in Pain Models: Structure-Activity Relationship and Optimization of Chroman and Indane Aryl Sulfonamides.

Voltage-gated sodium channel NaV1.7 is a genetically validated target for pain. Identification of NaV1.7 inhibitors with all of the desired properties to develop as an oral therapeutic for pain has been a major challenge. Herein, we report systematic structure-activity relationship (SAR) studies carried out to identify novel sulfonamide derivatives as potent, selective, and state-dependent NaV1.7 inhibitors for pain. Scaffold hopping from benzoxazine to chroman and indane bicyclic system followed by thiazole replacement on sulfonamide led to identification of lead molecules with significant improvement in solubility, selectivity over NaV1.5, and CYP2C9 inhibition. The lead molecules 13, 29, 32, 43, and 51 showed a favorable pharmacokinetics (PK) profile across different species and robust efficacy in veratridine and formalin-induced inflammatory pain models in mice. Compound 51 also showed significant effects on the CCI-induced neuropathic pain model. The profile of 51 indicated that it has the potential for further evaluation as a therapeutic for pain.

Discovery and Characterization of Potent Pan-Genotypic HCV NS5A Inhibitors Containing Novel Tricyclic Central Core Leading to Clinical Candidate.

The identification of a novel class of potent pan-genotypic NS5A inhibitors with good pharmacokinetic profile suitable for potential use in treating HCV infections is disclosed here. The present series of compounds are with less complex tricyclic central core, identified through a systematic SAR study carried out on biphenyl moiety. The SAR outcome has confirmed the requirement of near planar and linear conformation of the molecule to achieve the best pan-genotypic activity. In addition, SAR with substituted imidazoles on improvement of antiviral activity is disclosed. The newly identified compounds 12, 16, 19-21 have shown desirable pharmacokinetic profiles with a favorable uptake of compounds in liver and maintained a significant concentration for up to 8 h in the liver. In addition, compounds 20 and 21 have shown superior pan-genotypic anti-HCV activity compared to ledipasvir and daclatasvir. Additional characterization and preliminary safety assessment resulted in the identification of compound 20 as a potential clinical candidate.

Prediction of volume of distribution in preclinical species and humans: application of simplified physiologically based algorithms.

The present study was aimed at developing simplified physiologically based semi-mechanistic algorithms to predict Vss and interspecies scaling factors to predict tissue-Kps which require minimum input parameters, diminish the computing complexity and have better predictability. Vss of 86 structurally diverse compounds in preclinical species and 27 compounds in humans were predicted using only lung- and muscle-Kp as inputs. Interspecies scaling factor (s) were developed based on fold-differences in individual tissue lipid contents, relative organ blood flow: relative organ weight ratio between two species. Tissue-Kps were predicted for 34 compounds using the newly developed interspecies scaling factors. The predicted-to-experimental Vss values for all the 113 compounds was 1.3 ± 0.9 with 83% values being within a factor of two. The tissue-Kps in rat, dog and human were predicted using experimental tissue-Kp data in rodents and interspecies scaling factors and here also, 83% of tissue-Kps were within two-fold of the experimental values. In conclusion, simplified physiologically based algorithms have been developed to predict both volume of distribution and tissue-Kps, in which required input parameters as well as computing complexity have been noticeably reduced.

Combination of APD668, a G protein-coupled receptor 119 agonist with linagliptin, a DPPIV inhibitor, prevents progression of steatohepatitis in a murine model of non-alcoholic steatohepatitis with diabetes.

Non-alcoholic steatohepatitis (NASH) is characterized by the presence of hepatic steatosis, oxidative stress, inflammation, and hepatocyte injury with or without fibrosis. In this study, we explored the effect of APD668, a GPR119 agonist alone or in combination with linagliptin, a DPPIV inhibitor, on the progression of steatohepatitis in a murine model of NASH with diabetes. A novel NASH model with diabetes was generated by administration of streptozotocin injection to neonatal C57BL/6 mice (2-3 days old) combined with a high-fat diet feeding from the age of 4 weeks. The plasma biochemical parameters, oxidative stress, inflammation and histopathological changes were assessed. APD668 alone showed reduction in plasma glucose (- 39%, P < 0.05) and triglyceride level (- 26%) whereas a combined treatment of APD668 with linagliptin resulted in a more pronounced reduction in plasma glucose (- 52%, P < 0.001) and triglyceride (- 50%, P < 0.05) in NASH mice. In addition, co-administration of APD668 with linagliptin demonstrated a significant decrease in hepatic triglyceride, NAS score, hepatic TBARS and hepatic TNF-α in NASH mice with diabetes. These findings suggest that GPR119 receptor agonists in combination with DPPIV inhibitors may represent a promising therapeutic strategy for the treatment of NASH.

Co-administration of APD668, a G protein-coupled receptor 119 agonist and linagliptin, a DPPIV inhibitor, prevents progression of steatohepatitis in mice fed on a high trans-fat diet.

Non-Alcoholic SteatoHepatitis (NASH) is the more severe form of Non-Alcoholic Fatty Liver Disease (NAFLD) and is characterized by the presence of hepatic steatosis, oxidative stress, inflammation, hepatocyte injury with or without fibrosis. Recently, GPR119 receptor has emerged as a novel therapeutic target for the treatment of dyslipidemia and non-alcoholic steatohepatitis. In the present study, we investigated the effect of APD668, a GPR119 agonist alone or in combination with linagliptin, a DPPIV inhibitor on the progression of steatohepatitis in mice fed on a high trans-fat diet. In this study, monotherapy with either APD668 or linagliptin caused a reduction in the levels of ALT, AST, glucose, cholesterol and epididymal fat mass but the effect was more pronounced upon treatment with combination of both drugs. On the other hand, combined treatment of APD668 with linagliptin demonstrated a non-significant additive effect in reduction of hepatic triglyceride (-78%) and cholesterol (-56%) compared to monotherapy groups. Moreover, co-administration of APD668 and linagliptin resulted in enhanced levels of active GLP-1 with additional benefit of significant synergistic decrease in body weight gain (-19%) in mice. We speculated that the enhanced effect observed with the combination treatment could be due to either 1) direct activation of GPR119 receptors present in liver and intestine or 2) enhanced active GLP-1 levels or 3) decreased degradation of GLP-1 in-vivo through DPPIV inhibition. Therefore, these findings clearly suggest that GPR119 receptor agonists in combination with DPPIV inhibitors may represent a promising therapeutic strategy for the treatment of non-alcoholic steatohepatitis.

Design and optimization of quinazoline derivatives as melanin concentrating hormone receptor 1 (MCHR1) antagonists.

Melanin concentrating hormone (MCH) is an important mediator of energy homeostasis and plays a role in metabolic and CNS disorders. The modeling-supported design, synthesis and multi-parameter optimization (biological activity, solubility, metabolic stability, hERG) of novel quinazoline derivatives as MCHR1 antagonists are described. The in vivo proof of principle for weight loss with a lead compound from this series is exemplified. Clusters of refined hMCHR1 homology models derived from the X-ray structure of the ß2-adrenergic receptor, including extracellular loops, were developed and used to guide the design.

Design and optimization of quinazoline derivatives as melanin concentrating hormone receptor 1 (MCHR1) antagonists: part 2.

Melanin concentrating hormone receptor 1 (MCHR1) antagonists have potential for the treatment of obesity and several CNS disorders. In the preceding article, we have described a novel series of quinazolines as MCHR1 antagonists and demonstrated in vivo proof of principle with an early lead. Herein we describe the detailed SAR and SPR studies to identify an optimized lead candidate having good efficacy in a sub-chronic DIO model with a good cardiovascular safety window.

Structure-activity relationship studies of novel pyrazole and imidazole carboxamides as cannabinoid-1 (CB1) antagonists.

The synthesis and biological evaluation of novel pyrazole and imidazole carboxamides as CB1 antagonists are described. As a part of eastern amide SAR, various chemically diverse motifs were introduced on rimonabant template. The central pyrazole core was also replaced with its conformationally constrained motif and imidazole moieties. In general, a range of modifications were well tolerated. Several molecules with low- and sub-nanomolar potencies were identified as potent CB1 receptor antagonists. The in vivo proof of principle for weight loss is demonstrated with a lead compound in DIO mice model.

Cannabinoid 1 (CB1) receptor--pharmacology, role in pain and recent developments in emerging CB1 agonists.

Cannabinoids are antinociceptive in animal models of acute pain, tissue injury and nerve injury induced nociception and act via their cognate receptors, cannabinoid receptor 1 and 2. This review examines the underlying biology of the endocannabinoids and behavioural, neurophysiological, neuroanatomical evidence supporting the notion of pain modulation by these ligands with a focus on the current evidence encompassing the pharmacological characterization of CB1 agonists in this therapy. Separating the psychotropic effects of CB1 agonists from their therapeutic benefits is the major challenge facing researchers in the field today and with the discovery of peripherally acting agonists there seems to be a ray of hope emerging for the diverse potential therapeutic applications of this class of ligands.

Novel pyrazole-3-carboxamide derivatives as cannabinoid-1 (CB1) antagonists: journey from non-polar to polar amides.

The synthesis and biological evaluation of novel pyrazole-3-carboxamide derivatives as CB1 antagonists are described. As a part of eastern amide SAR, various chemically diverse motifs were introduced. In general, a range of modifications were well tolerated. Several molecules with high polar surface area were also identified as potent CB1 receptor antagonists. The in vivo proof of principle for weight loss is exemplified with a lead compound from this series.

Discovery of novel, orally available benzimidazoles as melanin concentrating hormone receptor 1 (MCHR1) antagonists.

Melanin concentrating hormone (MCH) is an important mediator of energy homeostasis and plays role in several disorders such as obesity, stress, depression and anxiety. The synthesis and biological evaluation of novel benzimidazole derivatives as MCHR1 antagonists are described. The in vivo proof of principle for weight loss with a lead compound from this series is exemplified.

Stabilization of RelB requires multidomain interactions with p100/p52.

The NF-kappaB family member RelB has many properties not shared by other family members such as restricted subunit association and lack of regulation by the classical IkappaB proteins. We show that the protein level of RelB is significantly reduced in the absence of p100 and reduced even more when both p100 and p105 are absent. RelB stabilizes itself by directly interacting with p100, p105, and their processed products. However, RelB forms complexes with its partners using different interaction modes. Although the C-terminal ankyrin repeat domain of p105 is not involved in the RelB-p105 complex formation, all domains and flexible regions of each protein are engaged in the RelB-p100 complex. In several respects the RelB-p52 and RelB-p100 complexes are unique in the NF-kappaB family. The N-terminal domain of p100/p52 interacts with RelB but not RelA. The transcriptional activation domain of RelB, but not RelA, directly interacts with the processing region of p100. These unique protein-protein contacts explain why RelB prefers p52 as its dimeric partner for transcriptional activity and is retained in the cytoplasm as an inhibited complex by p100. This association-mediated stabilization of RelB implies a possible role for RelB in the processing of p100 into p52.

Inhibitor kappaB kinase beta binding by inhibitor kappaB kinase gamma.

Activation of a large multisubunit protein kinase, called the inhibitor kappaB kinase (IKK) complex, is central to the induction of the family of transcription factors nuclear factor kappaB. IKK is comprised of two catalytic subunits, IKKalpha and IKKbeta, and a regulatory IKKgamma subunit. It is known that the catalytic IKKbeta and regulatory IKKgamma subunits associate through interactions mediated by the N-terminal region of IKKgamma and an 11-mer peptide located near the C-terminus of IKKbeta. In this study, we have defined the minimal IKKgamma segment that binds IKKbeta and determined the binding affinity of the IKKbeta/IKKgamma complex. We identified that the N-terminal segment spanning residues 40-130 of IKKgamma binds the IKKbeta C-terminal domain (residues 665-756) with Kd approximately 25 nM. Several smaller N-terminal IKKgamma deletion mutants within the N-terminal 130 residues, although in some cases retained IKKbeta binding activity, showed a tendency to aggregate and formed covalently linked complexes. However, expansion of the C-terminus of these fragments to residue 210 completely changed the solution behavior of the IKKgamma N-terminus without affecting the IKKbeta binding affinity. We also found that the IKKbeta C-terminal domain formed a dimer in solution and the basic unit of the IKKbeta/IKKgamma complex was a dimer/dimer.

Differentiation of Fanconi anemia from idiopathic aplastic anemia by induced chromosomal breakage study using mitomycin-C (MMC).

This study was conducted to differentiate between Fanconi anemia (FA) and "idiopathic" aplastic anemia on the basis of induced chromosomal breakage study with mitomycin C (MMC). MMC-stress test was conducted on peripheral blood lymphocytes from 29 patients with aplastic anemia. Ten patients with very high percentage of chromosomal breakage and four patients exhibiting somatic mosaicism were diagnosed as FA on the basis of chromosomal breakage study. Six of these patients exhibited congenital anomalies at presentation while another eight lacked such anomalies or had minor physical problems. The present study illustrates that MMC stress test provides an unequivocal means of differentiation between Fanconi anemia and 'idiopathic' aplastic anemia. Further, the study, first of its kind from India, stresses on the need for conducting this test in all aplastic anemia cases, even those without congenital anomalies, for accurate and timely diagnosis of Fanconi anemia to implement appropriate therapy.

Human molecular cytogenetics: diagnosis, prognosis, and disease management.

The year 2001 witnessed the sequencing of 90% of the euchromatic region in the human genome but the ultimate goal to delineate the positions of all genes is yet to be achieved. Fluorescence In Situ Hybridization (FISH) is one of the methods for localizing genes on chromosomes. In the present study, diagnostic utility of single-, dual-, and multicolor FISH was evaluated for prenatal diagnosis, cancer genetics, and screening of various congenital anomalies (sex chromosomal and autosomal). Centromeric probes for chromosomes X and Y were used for screening minor aneuploid cell lines (XXY, XO, and XXX) in the cases of primary amenorrhea and suspected Klinefelter syndrome. The cases with ambiguous genitalia were analyzed using a probe specific for the sex-determining region (SRY). Suspected cases of Down syndrome were subjected to FISH using probe specific for chromosome 21. FISH was also used to study gene alterations in retinoblastoma and myeloid leukemias. Prenatal diagnosis was done to screen for aneuploidies of chromosomes 13, 18, 21, X, and Y using FISH on uncultured cells from amniotic fluid and chorionic villi sampling. The screening for common aneuploidies was extended to abortuses from spontaneous abortions. Using FISH, low-level mosaicism could be identified in some cases of primary amenorrhea and suspected Klinefelter syndrome. Submicroscopic gene rearrangements could be detected using FISH in cases of ambiguous genitalia and cancers. Further interphase FISH could provide results within 24 hours. To conclude, FISH adds to the diagnostic utility of routine cytogenetics and its use on interphase nuclei overcomes the difficulty of conventional cytogenetics, thereby reducing the time between sampling and diagnosis to 24 hr.

A case of chronic myeloid leukemia complicated with minimal change nephrotic syndrome.

We present a 28-year-old patient with chronic myeloid leukemia (CML) in chronic phase complicated with nephrotic syndrome. The bone marrow cells revealed the presence of Philadelphia chromosome, the cytogenetic hallmark of CML, that results from a balanced, reciprocal translocation between the long arms of chromosomes 9 and 22, t(9;22)(q34;q11). This reciprocal translocation leads to the formation of the BCR/ABL fusion gene, the presence of which was confirmed using the highly sensitive fluorescence in situ hybridization technique. The renal biopsy was compatible with minimal change nephrotic syndrome. To the best of our knowledge, this is the first case of minimal change nephrotic syndrome associated with CML before the administration of any therapy.