Translational research in myelodysplastic syndromes

The myelodysplastic syndromes (MDS) are receiving unusual attention recently as great strides have been made in understanding the biology. Recognition that excessive cytokine-induced apoptosis plays a significant role in the cytopenias of the majority of patients opened the doors to anti-cytokine therapy, with thalidomide being used with success in approximately 20% patients. Other therapies that have emerged include the thalidomide analog lenalidomide which is particularly beneficial for 5q- patients as well as a subset of non-5q- patients with low or intermediate-1 risk MDS. Other targeted therapies include vitamins, agents that are cytoprotective, differentiation inducers, anti-angiogenic, or immune modulatory. In addition, inhibitors of proteasome, methylation, histone deacetylation, farnesylation, receptor tyrosine kinases, topoisomerase, and matrix mettaloproteinases have yielded encouraging responses in subsets of patients. Specific therapies have also been developed for genetic abnormalities that lead to fusion genes (TEL-PDGFR-beta, or FIP1L1-PDGFR-alpha), or abnormal proteins due to mutations/functional inactivation (FLT3), dysregulated expression (EVI-1). In a short span of ten years, the field has evolved from having no effective therapy to offer the majority of MDS patients save chemotherapy, to having one FDA approved drug, several on the way to approval, and a number of novel agents producing exciting clinical results. This chapter summarizes the novel targets and targeted therapies in the rapidly evolving therapeutic landscape of MDS.     

A novel thermodynamic relationship based on Kramers Theory for studying enzyme kinetics under high viscosity

In most studies of enzyme kinetics it has been found sufficient to use the classical Transition State Theory (TST) of Eyring and others. This theory was based on the solvent being an ideal dilute substance treated as a heat bath. However, enzymes found in organisms adapted to very low (psychrophiles) and very high (thermophiles) temperatures are also subjected to variable solute concentrations and viscosities. Therefore, the TST may not always be applicable to enzyme reactions carried out in various solvents with viscosities ranging from moderate to very high. There have been numerous advances in the theory of chemical reactions in realistic non-ideal solvents such as Kramers Theory. In this paper we wish to propose a modified thermodynamic equation, which have contributions from kcat, Km and the viscosity of the medium in which the enzyme reaction is occurring. These could be very useful for determining the thermodynamics of enzymes catalyzing reactions at temperature extremes in the presence of substrate solutions of different compositions and viscosities.     

caP4 : A 2.97 KDa Cationic Antibacterial Peptide from Curcuma pseudomontana L.

The present investigation reports the sequence of a 2.97KDa low molecular weight, cationic antibacterial peptide, caP4 isolated from wild variety of turmer     

Role of ACE and PAI-1 Polymorphisms in the Development and Progression of Diabetic Retinopathy

In the present study we determined the association of angiotensin converting enzyme (ACE) and plasminogen activator inhibitor-1 (PAI-1) gene polymorphisms with diabetic retinopathy (DR) and its sub-clinical classes in Pakistani type 2 diabetic patients. A total of 353 diabetic subjects including 160 DR and 193 diabetic non retinopathy (DNR) as well as 198 healthy controls were genotyped by allele specific polymerase chain reaction (PCR) for ACE Insertion/Deletion (ID) polymorphism, rs4646994 in intron 16 and PAI-1 4G/5G (deletion/insertion) polymorphism, rs1799768 in promoter region of the gene. To statistically assess the genotype-phenotype association, multivariate logistic regression analysis was applied to the genotype data of DR, DNR and control individuals as well as the subtypes of DR. The ACE genotype ID was found to be significantly associated with DR (p = 0.009, odds ratio (OR) 1.870 [95% confidence interval (CI) = 1.04–3.36]) and its sub-clinical class non-proliferative DR (NPDR) (p = 0.006, OR 2.250 [95% CI = 1.098–4.620]), while PAI polymorphism did not show any association with DR in the current cohort. In conclusion in Pakistani population the ACE ID polymorphism was observed to be significantly associated with DR and NPDR, but not with the severe form of the disease i.e. proliferative DR (PDR).     

The chloroplast genome sequence of Syzygium cumini (L.) and its relationship with other angiosperms

Only a few studies to date have conducted comparative genomics in the Myrtaceae family. Here, we report the complete sequence and bioinformatics analysis of the chloroplast genome of Syzygium cumini (L.), one of the family members. The size of S. cumini cp genome was within the range of reported angiosperm chloroplast genomes. Comparison of S. cumini cpDNA sequence with previously reported partial sequences of S. cumini revealed several SNPs that resulted in non-synonymous mutations in maturase K and NADH-plastoquinone oxidoreductase subunit-5. These polymorphic characters might serve as intra-specific markers to address whether lineage sorting from polymorphic ancestry has occurred. Comparison of the S. cumini chloroplast genome with related dicots revealed an expansion in the intergenic spacer located between IRA/large single copy (LSC) border and the first gene of LSC region, driven by sequence of 54 bp. This type of variation in the intergenic regions can be utilized in the development of species-specific vectors for chloroplast genetic engineering. Several of the longer (30–40 bp) repeats were found to be conserved in other dicot species, suggesting that they might be widespread in angiosperm chloroplast genomes.     

Benzothiazole derivatives as anticancer agents

Abstract

Benzothiazole (BTA) belongs to the heterocyclic class of bicyclic compounds. BTA derivatives possesses broad spectrum biological activities such as anticancer, antioxidant, anti-inflammatory, anti-tumour, antiviral, antibacterial, anti-proliferative, anti-diabetic, anti-convulsant, analgesic, anti-tubercular, antimalarial, anti-leishmanial, anti-histaminic and anti-fungal among others. The BTA scaffolds showed a crucial role in the inhibition of the metalloenzyme carbonic anhydrase (CA). In this review an extensive literature survey over the last decade discloses the role of BTA derivatives mainly as anticancer agents. Such compounds are effective against various types of cancer cell lines through a multitude of mechanisms, some of which are poorly studied or understood. The inhibition of tumour associated CAs by BTA derivatives is on the other hand better investigated and such compounds may serve as anticancer leads for the development of agents effective against hypoxic tumours.     

Biochar application to rice with 15N-labelled fertilizers,enhanced leaf nitrogen concentration and assimilation by improving morpho-physiological traits and soil quality

Leaf nitrogen (N) concentration plays an important role in biochemical and physiological functions, and N availability directly influences rice yield. However, excessive N fertilization is considered to be a root cause of environmental issues and low nitrogen use efficiency. Therefore, the selection of appropriate nutrient management practices and organic amendments is key to maximizing nitrogen uptake and maintaining high and sustainable rice production. Here, we evaluated the effects of different ¹⁵N-labelled nitrogen sources (urea, ammonium nitrate, and ammonium sulfate at 315 kg ha⁻¹) with or without biochar (30 t ha⁻¹) on paddy soil properties, root growth, leaf gas exchange, N metabolism enzymes, and N uptake in the early and late seasons of 2019. We found significant differences among N fertilizer sources applied with or without biochar (P < 0.05). Across the seasons, the combination of biochar with N fertilizers significantly increased soil organic carbon by 51.21% and nitrogen availability by 27.51% compared with N fertilizers alone. Correlation analysis showed that rice root morphological traits were strongly related to soil chemical properties, and higher root growth was measured in the biochar treatments. Similarly, net leaf photosynthetic rate averaged 9.34% higher, chlorophyll (Chl) a concentration 12.91% higher, and Chl b concentration 10.05% higher in the biochar treatments than in the biochar-free treatments across the seasons. Notably, leaf ¹⁵N concentration was 23.19% higher in the biochar treatments in both seasons. These results illustrated higher activities of N metabolism enzymes such as NR, GS, and GOGAT by an average 23.44%, 11.26% and 18.16% in the biochar treatments across the seasons, respectively. The addition of biochar with synthetic N fertilizers is an ecological nutrient management strategy that can increase N uptake and assimilation by ameliorating soil properties and improving the morpho-physiological factors of rice.     

Comparison of pretargeted and conventional CC49 radioimmunotherapy using 149Pm, 166Ho, and 177Lu

The therapeutic efficacies of radiolabeled biotin, pretargeted by monoclonal antibody (mAb)-streptavidin fusion protein CC49 scFvSA, were compared to those of radiolabeled mAb CC49, using the three radiolanthanides in an animal model of human colon cancer. The purpose of the present study was to compare antibody pretargeting to conventional radioimmunotherapy using (149)Pm, (166)Ho, or (177)Lu. Nude mice bearing LS174T colon tumors were injected sequentially with CC49 scFvSA, the blood clearing agent biotin-GalNAc(16), and (149)Pm-, (166)Ho-, or (177)Lu-DOTA-biotin. Tumor-bearing mice were alternatively administered (149)Pm-, (166)Ho-, or (177)Lu-MeO-DOTA-CC49. Therapy with pretargeted (149)Pm-,(166)Ho-, and (177)Lu-DOTA-biotin increased the median time of progression to a 1 g tumor to 50, 41, and 50 days post-treatment, respectively. Therapy with (149)Pm-,(166)Ho-, and (177)Lu-MeO-DOTA-CC49 increased the median time to progression to 53, 24, and 67 days post-treatment, respectively. In contrast, saline controls showed a median time to progression of 13 days postinjection. Treatment with pretargeted (149)Pm-, (166)Ho-, and (177)Lu-biotin or (149)Pm-, (166)Ho-, and (177)Lu-CC49 increased tumor doubling time to 18-36 days, compared to 3 days for saline controls. Among treated mice, 23% survived >84 days post-therapy, and 11% survived 6 months, but controls survived <29 days. Long-term survivors showed tumor growth inhibition or partial regression, extensive necrosis in residual masses, and no evidence of nontarget tissue toxicity at necropsy. Both pretargeted and conventional RIT demonstrated considerable efficacy in an extremely aggressive animal model of cancer. Our results identified (177)Lu as an optimal radiolanthanide for future evaluation of these agents in toxicity and multiple-dose therapy studies.     

Abrogation of the twin arginine transport system in Salmonella enterica serovar Typhimurium leads to colonization defects during infection

TatC (STM3975) is a highly conserved component of the Twin Arginine Transport (Tat) systems that is required for transport of folded proteins across the inner membrane in gram-negative bacteria. We previously identified a ΔtatC mutant as defective in competitive infections with wild type ATCC14028 during systemic infection of Salmonella-susceptible BALB/c mice. Here we confirm these results and show that the ΔtatC mutant is internalized poorly by cultured J774-A.1 mouse macrophages a phenotype that may be related to the systemic infection defect. This mutant is also defective for short-term intestinal and systemic colonization after oral infection of BALB/c mice and is shed in reduced numbers in feces from orally infected Salmonella-resistant (CBA/J) mice. We show that the ΔtatC mutant is highly sensitive to bile acids perhaps resulting in the defect in intestinal infection that we observe. Finally, the ΔtatC mutant has an unusual combination of motility phenotypes in Salmonella; it is severely defective for swimming motility but is able to swarm well. The ΔtatC mutant has a lower amount of flagellin on the bacterial surface during swimming motility but normal levels under swarming conditions.