Winning the Fight Against Cancer.

Advances in cytotoxic chemotherapy, surgical oncology, genomic medicine, targeted small molecule treatment, cancer immunotherapy and biology-driven precision radiation oncology have resulted in significant improvements in outcomes of cancer treatment, with an increasing number of patients achieving long-term disease control or even being potentially cured. Concurrent advances in palliative care and geriatric oncology have also helped to ensure that patients are managed holistically by considering their physical, social, psychological and emotional needs in a personalised manner.

A cohort study to evaluate the effect of combination Vitamin D, Magnesium and Vitamin B12 (DMB) on progression to severe outcome in older COVID-19 patients.

ObjectiveTo determine the clinical outcomes of older COVID-19 patients who received DMB compared to those who did not. We hypothesized that fewer patients administered DMB would require oxygen therapy and/or intensive care support than those who did not. MethodologyCohort observational study of all consecutive hospitalized COVID-19 patients aged 50 and above in a tertiary academic hospital who received DMB compared to a recent cohort who did not. Patients were administered oral vitamin D3 1000 IU OD, magnesium 150mg OD and vitamin B12 500mcg OD (DMB) upon admission if they did not require oxygen therapy. Primary outcome was deterioration post-DMB administration leading to any form of oxygen therapy and/or intensive care support. ResultsBetween 15 January and 15 April 2020, 43 consecutive COVID-19 patients aged [≥]50 were identified. 17 patients received DMB and 26 patients did not. Baseline demographic characteristics between the two groups was significantly different in age. In univariate analysis, age and hypertension showed significant influence on outcome while DMB retained protective significance after adjusting for age or hypertension separately in multivariate analysis. Fewer DMB patients than controls required initiation of oxygen therapy during their hospitalization (17.6% vs 61.5%, P=0.006). DMB exposure was associated with odds ratios of 0.13 (95% CI: 0.03 - 0.59) and 0.20 (95% CI: 0.04 - 0.93) for oxygen therapy and/or intensive care support on univariate and multivariate analyses respectively. ConclusionsDMB combination in older COVID-19 patients was associated with a significant reduction in proportion of patients with clinical deterioration requiring oxygen support and/or intensive care support. This study supports further larger randomized control trials to ascertain the full benefit of DMB in ameliorating COVID-19 severity.

The Singapore Myeloma Study Group Consensus Guidelines for the management of patients with multiple myeloma

Multiple myeloma (MM) is an incurable plasma cell neoplasm with an incidence of 100 patients per year in Singapore. Major advances have been made in the diagnosis, risk stratification and treatment of MM in the recent past. The reclassification of a subset of patients with smouldering MM, based on high-risk biomarkers, and the development of the revised international staging system are among the key new developments in diagnosis and staging. The use of novel agent-based treatment has resulted in significant improvements in the survival and quality of life of many patients with MM. Determining the optimal use of proteasome inhibitors, immunomodulators and, more recently, monoclonal antibodies is an area of ongoing investigation. In this guideline, we aim to provide an overview of the management of MM, incorporating the latest developments in diagnosis and treatment.

Improved native isolation of endogenous Protein A-tagged protein complexes.

Here we report a modified peptide reagent useful for the rapid, native elution of protein complexes containing a Protein-A-tagged component. We tested this reagent for the elution of tagged endogenous protein complexes from yeast (Nup53p/Nup170p dimer; Nup1p/Kap95p/Kap60p trimer; pentameric GINS complex) and bacteria (RNAP holoenzyme). The majority of the affinity-isolated material is released within 15 minutes under mild conditions, and the elution reagent itself is readily depleted from the elution mixture by simple spin column gel filtration. This reagent is ideal for eluting protein complexes after Protein A / IgG affinity isolation when protease cleavage is not possible or not desirable and facile depletion of the elution reagent is needed.

Reductive glutaraldehydation of amine groups for identification of protein N-termini.

In the present work, reductive alkylation of proteins and peptides with glutaraldehyde (reductive glutaraldehydation) is reported. The reaction is highly efficient and forms piperidine at the N-terminus as well as the side chain of lysine residues. The complete modification of protein amines was achieved by reductive glutaraldehydation in solution or in the gel in less than 15 min. The glutaraldehyde-modified peptides display an enhanced intensity in mass spectra and show higher retention time in reversed phase chromatography in comparison to unmodified peptides. Fragmentation of glutaraldehyde-modified proteins and peptides generates a1 fragment ions with enhanced intensity in MS/MS spectra. Thus, a method based on reductive glutaraldehydation and LC-MS/MS analysis has been developed to determine the N-terminal residue of proteins with free N-termini.

Selective growth inhibition of tumor cells by a novel histone deacetylase inhibitor, NVP-LAQ824.

We have synthesized a histone deacetylase inhibitor, NVP-LAQ824, a cinnamic hydroxamic acid, that inhibited in vitro enzymatic activities and transcriptionally activated the p21 promoter in reporter gene assays. NVP-LAQ824 selectively inhibited growth of cancer cell lines at submicromolar levels after 48-72 h of exposure, whereas higher concentrations and longer exposure times were required to retard the growth of normal dermal human fibroblasts. Flow cytometry studies revealed that both tumor and normal cells arrested in the G(2)-M phase of the cell cycle after compound treatment. However, an increased sub-G(1) population at 48 h (reminiscent of apoptotic cells) was observed only in the cancer cell line. Annexin V staining data supported our hypothesis that NVP-LAQ824 induced apoptosis in tumor and transformed cells but not in normal cells. Western blotting experiments showed an increased histone H3 and H4 acetylation level in NVP-LAQ824-treated cancer cells, suggesting that the likely in vivo target of NVP-LAQ824 was histone deacetylase(s). Finally, NVP-LAQ824 exhibited antitumor effects in a xenograft animal model. Together, our data indicated that the activity of NVP-LAQ824 was consistent with its intended mechanism of action. This novel histone deacetylase inhibitor is currently in clinical trials as an anticancer agent.

N-hydroxy-3-phenyl-2-propenamides as novel inhibitors of human histone deacetylase with in vivo antitumor activity: discovery of (2E)-N-hydroxy-3-[4-[[(2-hydroxyethyl)[2-(1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2-propenamide (NVP-LAQ824).

A series of N-hydroxy-3-phenyl-2-propenamides were prepared as novel inhibitors of human histone deacetylase (HDAC). These compounds were potent enzyme inhibitors, having IC(50)s < 400 nM in a partially purified enzyme assay. However, potency in cell growth inhibition assays ranged over 2 orders of magnitude in two human carcinoma cell lines. Selected compounds having cellular IC(50) < 750 nM were tested for maximum tolerated dose (MTD) and for efficacy in the HCT116 human colon tumor xenograft assay. Four compounds having an MTD > or = 100 mg/kg were selected for dose-response studies in the HCT116 xenograft model. One compound, 9 (NVP-LAQ824), had significant dose-related activity in the HCT116 colon and A549 lung tumor models, high MTD, and low gross toxicity. On the basis, in part, of these properties, 9 has entered human clinical trials in 2002.

A novel somatostatin mimic with broad somatotropin release inhibitory factor receptor binding and superior therapeutic potential.

A rational drug design approach, capitalizing on structure-activity relationships and involving transposition of functional groups from somatotropin release inhibitory factor (SRIF) into a reduced size cyclohexapeptide template, has led to the discovery of SOM230 (25), a novel, stable cyclohexapeptide somatostatin mimic that exhibits unique high-affinity binding to human somatostatin receptors (subtypes sst1-sst5). SOM230 has potent, long-lasting inhibitory effects on growth hormone and insulin-like growth factor-1 release and is a promising development candidate currently under evaluation in phase I clinical trials.