Effect of novel agents in myeloma

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Factor XI deficiency case reports on congenital and acquired Hemophilia C - A case report

Introduction: Factor XI deficiency or hemophilia C is a very rare coagulation factor deficiency, with a global incidence of 1 in 1 million. Although it is an under-recognized entity, it can cause significant bleeding, resulting in life-threatening complications. Materials and Methods: Coagulation parameters were analyzed using a Sysmex CS-2400 coagulation analyzer. Factor XI levels were detected using Factor XI deficient plasma from Siemens. Activated Partial Thromboplastin Time (APTT) testing was performed using Actin FSL from Siemens. Results: Here, we report the two cases of Factor XI deficiency, one genetic and the other a very rare acquired deficiency due to sepsis, detected during the workup of an isolated APTT prolongation. Conclusion: Factor XI deficiency is a rare bleeding disorder that presents as prolonged isolated APTT. Careful clinical evaluation and complete coagulation workup are necessary for the efficient management of patients, which can prevent life-threatening events

INVESTIGATION OF ANTI-SARS COV-2 ACTIVITY OF SOME TETRAHYDRO CURCUMIN DERIVATIVES: AN IN SILICO STUDY

Objective: In the current study, an in silico approach has been utilized to investigate the anti-SARS CoV 2 activity of some derivatives of Tetrahydro curcumin (THC), a curcumin metabolite. Methods: BioVia Draw 2017 was used to design 168 THC derivatives. All of the derivatives were docked using Maestro Schrodinger programme. Depending on the docking score, the ADME, drug-likeness, and toxicity prediction of a few THC derivatives were conducted. Results: 168 THC derivatives were designed. 14 derivatives exhibited a better binding score than Remdesivir. All 14 derivatives' pharmacokinetic characteristics were discovered to be within the acceptable range. Lipinski's rule of five was violated by all derivatives, including the reference drug, yet they all stayed within the recommended range. The greatest docking score among the 14 derivatives was displayed by Structure 21. A study on molecular dynamic (MD) stimulation showed that the protein-ligand complex was relatively stable. Toxicity prediction showed that 14 derivatives were non-hepatotoxic, non-cytotoxic, immunotoxic (except S21), non-mutagenic (except S31) and half of the developed structures were carcinogenic, while the other half, including the standard drug, was non-carcinogenic. Conclusion: Among 168 THC derivatives, 14 derivatives exhibited better binding score than the reference drug. For all 14 derivatives, pharmacokinetic, drug-likeness, and toxicity prediction were found to be satisfactory. It was discovered that the protein-ligand complex was thermodynamically stable. All 14 compounds present exciting prospects for further in vitro and in vivo investigation.</jats:p

INVESTIGATION OF ANTI-SARS COV-2 ACTIVITY OF SOME TETRAHYDROCURCUMIN DERIVATIVES: AN IN-SILICO STUDY

Objective: In the current study, an in-silico approach has been utilized to investigate the anti-SARS CoV 2 activity of some derivatives of Tetrahydro curcumin (THC), a curcumin metabolite. Methods: BioVia Draw 2017 was used to design 168 THC derivatives. All of the derivatives were docked using Maestro Schrodinger programme. Depending on the docking score, the ADME, drug likeness, and toxicity prediction of a few THC derivatives were conducted. Results: 168 THC derivatives were designed. 14 derivatives exhibited better binding score than Remdesivir. All 14 derivatives' pharmacokinetic characteristics were discovered to be within the acceptable range. Lipinski's rule of five was violated by all derivatives, including the reference drug, yet they all stayed within the recommended range. The greatest docking score among the 14 derivatives was displayed by Structure 21. A study on molecular dynamic (MD) stimulation showed that the protein ligand complex was relatively stable. Toxicity prediction showed that 14 derivatives were non-hepatotoxic, non-cytotoxic, immunotoxic (except S21), non-mutagenic (except S31) and half of the developed structures were carcinogenic, while the other half, including the standard drug, were non-carcinogenic. Conclusion: Among 168 THC derivatives, 14 derivatives exhibited better binding score than the reference drug. For all 14 derivatives, pharmacokinetic, drug likeness, and toxicity prediction were found to be satisfactory. It was discovered that the protein ligand complex was thermodynamically stable. All 14 compounds present exciting prospects for further in vitro and in vivo investigation

Three cardiac biomarkers and their efficacy: A review

Objectives: This study belongs to the overview of three versatile cardiac biomarkers for specific diagnosis and prognosis in cardiac patients. Methods: A search performed in different search sites such as Web of Science, Pub Med, and Google scholar searches for relevant studies from 2015 to 2022. Search names included were “heart disease,” “cardiac troponin,” “acute coronary disease,” “coronary artery disease,” “new biomarker,” “non–ST-elevation acute coronary syndrome,” etc. Studies were included if they were prospective, retrospective, randomized controlled trials or reviews. Findings: Troponin I &amp;T along with CPK-MB can increase the diagnostic sensitivity and specificity when used collectively in the diagnosis of Myocardial infarction either acute or chronic conditions. These cardiac versatile biomarkers can diagnose re-infarct also with serial testing. Whereas sensitivity and specificity of Troponins I &amp;T ranges from 84 to 96 and 80 to 95% respectively. When all three cardiac markers were combined, sensitivity and specificity will reach up to approximately 100%. Novelty/ Improvement: This article provides the best available three versatile specific cardiac biomarkers in the diagnosis of myocardial infarction and reinfarction with about 100% accuracy. Keywords: Cardiovascular Disease (CVD), Myocardial Infarction (MI), Acute Myocardial Infarction (AMI), Lactate Dehydrogenase (LDH), Creatine Kinase (CK), Heart type fatty acid binding protein (H-FABP)

The Combination of Velcade, Idarubicin and Melphalan (VIM) Demonstrates Significant Clinical Activity in Relapsed/Refractory Myeloma Patients.

Abstract Dexamethasone is an important drug in the treatment of myeloma and is widely used in novel combinations, however, resistance can develop and clinical intolerance is frequent. Novel regimens that are effective and dexamethasone sparing are therefore required. Bortezomib (Velcade), the first-in-class proteasome inhibitor, has shown to be effective for the treatment of relapsed refractory myeloma, and has been shown to enhance the antitumor efficacy of both Melphalan and Anthracyclines. Early clinical results have demonstrated the efficacy and tolerability of combinations of Velcade with either of these agents. We have carried out a dose-escalating phase 1 study is to assess the safety, tolerability and response rate of the Velcade/Idarubicin/Melphalan (VIM) combination. Patients with relapsed/refractory myeloma who were either resistant or intolerant to dexamethasone were recruited. The study aimed to recruit 6 cohorts of 3 patients with standard dose Velcade and increasing doses of Melphalan and Idarubicin. Velcade (1.3 mg/m2) was administered on days 1, 4, 8 and 11 on a 28-day cycle with total number of 3 cycles, with the single dose of Melphalan (10, 15 or 20 mg/m2, i.v.) on day 4 and Idarubicin (5 or 10mg/m2) on days 4,5,(6 and 7). NCI CTCAE v3.0 was used for toxicity assessment; DLT was defined as any grade 3 or 4 non-haem toxicity (excluding neuropathy) or any grade 4 haem toxicity (excluding neutropenia) which does not resolve to a grade 2 within 2 weeks of completing a course. As of July 2007, 14 patients were enrolled in cohorts 1–3 with a median age of 59 (range 36–68). The median number of prior therapies was 2.5 (range 1–5), including 10 pts with prior high dose therapy, 11 with Anthracyclines, and 13 with Thalidomide. In patients assessable for response 9/13 achieved a response with 2 CR, 5 PR and 2 MR according to EBMT criteria. The side effect profile was manageable and no unexpected toxicities were seen. Grade 3 toxicities were mostly related to myelosuppression with 79% thrombocytopenia and 71% neutropenia. 12 patients received GCSF to maintain their neutrophil count and 10 pts received platelet transfusions. Despite the myelosuppression no increase in infections or serious bleeding was observed. 5 patients required a dose reduction of Velcade and/or course delay due to low counts and 1 patient also required Melphalan dose reduction. Other side effects included upper respiratory tract infection (36%), peripheral neuropathy (29%) and shingles (14%), resulting in a recommendation of aciclovir prophylaxis for all patients. New/worsening neuropathy led to dose reduction of Velcade in 2 patients and discontinuation of treatment in 1 patient. One DLT of G3 respiratory tract infection was observed in cohort 3 (Mel 15 mg/m2, Idarubicin 5 mg/m2 on day 4–7), therefore another 3 patients will be enrolled to this cohort. The study indicates that VIM had a manageable toxicity profile with significant clinical activity in this dexamethasone refractory group of patients.</jats:p

Autophagy Is a Key Myeloma Survival Pathway That Can Be Manipulated Therapeutically to Enhance Apoptosis

Abstract Abstract 4083 In normal cells, autophagy is up-regulated under conditions of stress ensuring cell survival, suggesting that if it is inhibited cell death will ensue. In some cancer settings however it has been shown to enhance cell death. Therefore if autophagy is to be a target for anti-cancer therapy, it is important to determine whether to promote or inhibit the process. Cellular entry to autophagy can be manipulated via the PI3K/AKT/mTOR pathway, a pathway known to be important for myeloma cell growth and survival. In this study we investigated the effects of PI-103, a dual Class I PI3K and mTOR inhibitor, which activates autophagy, and used it as a tool to investigate the interaction of autophagy with other myeloma therapies. As the PI3K/AKT/mTOR pathway has been suggested to be a central pathway controlling entry into autophagy, we first determined the basal expression of key members of the pathway in a panel of myeloma cell lines. PI3K alpha, beta delta and gamma isoforms were expressed to varying degrees and constitutive activation of the pathway, (pAKT or pMTOR), was seen in the majority of cell lines. As predicted, treatment with PI-103 induced autophagy in myeloma cells as demonstrated by an increase in cellular inclusions staining positively with acridine orange, cleavage of the autophagosome marker, LC3, and a decrease in p62. PI-103 was shown to inhibit proliferation of all the myeloma cell lines and patient cells tested to varying degrees, although 100% growth inhibition was not seen. Bone marrow stromal cells were unaffected. The main mode of action of PI-103 was autophagy activation, and in keeping with this the extent of cell death measured by Annexin V/PI binding and trypan blue exclusion, was minimal. Cell cycle analysis demonstrated an increase in G0-G1 phase. The unfolded protein response (UPR) is important in myeloma cells and UPR activation and autophagy have been reported to be interlinked. Following exposure to PI-103, splicing of XBP1 mRNA to its active form, XBP1s, was seen, CHOP and ATF4 mRNA levels were also increased, consistent with activation of at least two branches of the UPR in response to PI3K/mTOR inhibition and autophagy induction. As myeloma cells activate autophagy as a pro-survival pathway following PI3-kinase inhibition, we were interested to understand the effect of blocking autophagy in this context. When PI-103 was combined with the autophagy inhibitor, Bafilomycin greatly enhanced apoptosis was seen. This increased apoptosis was seen in cells constitutively expressing p-AKT, with a complete loss of both phospho- and total levels of AKT and mTOR, an increase in the cleaved forms of caspase 3 and Bcl2, and massive activation of the IRE1 and PERK branches of the UPR. This effect was not seen in cells lacking p-AKT, a phenomenon described as ‘context-dependent oncogene addiction' suggesting that measurement of p-AKT may be a useful predictive marker for response to joint PI3K/autophagy inhibition. Importantly the pro-apoptotic effects of the combination are not overcome by the presence of bone marrow cytokines, a more representative model of the physiological situation in vivo. In conclusion our data highlights the interplay between known myeloma growth and survival pathways and autophagy and suggests that combining PI3K inhibitors, with agents that target autophagy, may be beneficial for the treatment of myeloma, particularly in &gt;50% of patients that express p-AKT. Disclosures: No relevant conflicts of interest to declare. </jats:sec

Aminopeptidase Inhibition as a Targeted Treatment Strategy in Myeloma.

Abstract Myeloma cells are highly dependent on the unfolded protein response to assemble folded immunoglobulins correctly. Therefore targeting protein handling within a myeloma cell by inhibiting the aminopeptidase enzyme system that catalyses the hydrolysis of amino acids from the N terminus of proteins may be a novel therapeutic approach. The effect of the aminopeptidase inhibitor CHR-2797 on myeloma cell proliferation and survival, gene expression, protein turnover, cell migration and myeloma-bone marrow stromal cell interactions was determined on a panel of myeloma cell lines and patient cells. CHR-2797 is able to inhibit the proliferation of myeloma cell lines and primary patient cells, whereas its derivative CHR-79888, an acid metabolite with low cell membrane permeability fails to induce myeloma cell death. This occurs though apoptosis as demonstrated by trypan blue exclusion and annexin V/PI staining, and is proceeded by G1 growth arrest. Western blot analysis demonstrates apoptosis occurs via a non-caspase dependant mechanism. Importantly CHR-2797 is able to induce apoptosis in cells known to be resistant to conventional chemotherapeutic agents. Analysis of the pathways involved using Affymetrix gene expression arrays demonstrates CHR-2797 causes an upregulation of many genes involved in the proteasome/ubiquitin pathway, as well as amino acid deprivation response genes and some aminopeptidases. A further mechanism contributing to cell death is activation of the unfolded protein response with activation of all three UPR pathways demonstrated by splicing of XBP1 to its active from XBP1s, an increase in CHOP with activation of the PERK pathway and cleavage of ATF6. Cytoplasmic inclusions are also present on light microscopy suggestive of the build up of misfolded proteins within the cytoplasm. CHR-2797 causes minimal inhibition of the proliferation of bone marrow stroma, but is able to overcome the protective effects of the micro-environment on myeloma cells, as the drug is still able to inhibit the proliferation of myeloma cells when they are bound to bone marrow stromal cells. Aminopeptidase inhibition is also able to inhibit the increase VEGF that occurs when myeloma cells and bone marrow stroma are bound together. Combination experiments of CHR-2797 with dexamethasone demonstrate synergy, in keeping with the different mechanisms of action the two drugs. CHR-2797 in combination with the proteasome inhibitor bortezomib demonstrates an additive effect. Although both drugs target intracellular protein turnover, gene expression studies of cells treated with CHR-2797 or bortezomib show deregulation of a number of genes specific to aminopeptidase inhibition, as well as a series of genes characteristic of protein turnover. These differences in the mechanism of action of the two drugs are also reflected in the Western blot analysis that demonstrates a predominately non-caspase mediated cell death in CHR2797 compared to a caspase mediated cell death with bortezomib. In summary inhibiting intracellular protein turnover using the aminopeptidase inhibitor CHR-2797 results in myeloma cell death and represents a novel therapeutic approach for the treatment of myeloma. A phase 1 clinical trial has been initiated in haematological malignancies and the results will also be presented at this meeting.</jats:p