Individualizing breast cancer treatment—The dawn of personalized medicine

Identification of breast cancer not being a single disease but backed by multiple heterogeneous oncogenic subpopulations is of growing interest in developing personalized therapies to provide optimal outcomes. Through this review, we bring attention to evolution of tumor and microenvironment heterogeneity as a predominant challenge in stratifying therapies. Establishment of a ‘precancer niche’ serves as a prerequisite for genetically initiated cells to survive and promote neoplastic evolution towards clinically established cancer through development of tumor and its microenvironment. Additionally, continuous evolutionary interplay between tumor and recruited stromal cells along with many other components in the tumor microenvironment adds up to further complexity in developing targeted therapies. However, through continued excellence in developing high throughput technologies including the advent of single-nucleus sequencing, which makes it possible to sequence individual tumor cells, leads to improved abilities in decoding the heterogenic perturbations through reconstruction of tumor evolutionary lineages. Furthermore, simple liquid-biopsies in form of enumeration/characterization of circulating tumor cells and tumor microvesicles found in peripheral circulation, shed from distinct tumor lesions, show great promise as prospective biomarkers towards better prognosis in tailoring individualized therapies to breast cancer patients. Lastly, by means of network medicinal approaches, it is seemingly possible to develop a map of the cell's intricate wiring network, helping to identify appropriate interconnected protein networks through which the disease spreads, offering a more patient-specific outcome. Although these therapeutic interventions through designing personalized oncology-based trials are promising, owing to continuous tumor evolution, targeting genome instability survival pathways might become an economically viable alternative.     

Decreased Cystathionine-γ-lyase (CSE) Activity in Livers of Type 1 Diabetic Rats and Peripheral Blood Mononuclear Cells (PBMC) of Type 1 Diabetic Patients

The liver plays a major role in the formation of H₂S, a novel signaling molecule. Diabetes is associated with lower blood levels of H₂S. This study investigated the activities of cystathionine-γ-lyase (CSE, the enzyme that catalyzes H₂S formation) in livers of type 1 diabetic (T1D) animals and in peripheral blood mononuclear cells (PBMC) isolated from T1D patients. T1D is associated with both hyperketonemia (acetoacetate and β-hydroxybutyrate) and hyperglycemia. This study also examined the role of hyperglycemia and hyperketonemia per se in decreased CSE activity using U937 monocytes and PBMC isolated from healthy subjects. Livers from streptozotocin-treated T1D rats demonstrated a significantly higher reactive oxygen species production, lower CSE protein expression and activity, and lower H₂S formation compared with those of controls. Studies with T1D patients showed a decrease in CSE protein expression and activity in PBMC compared with those of age-matched normal subjects. Cell culture studies demonstrated that high glucose (25 mm) and/or acetoacetate (4 mm) increased reactive oxygen species, decreased CSE mRNA expression, protein expression, and enzymatic activity, and reduced H₂S levels; however, β-hydroxybutyrate treatment had no effect. A similar effect, which was also observed in PBMC treated with high glucose alone or along with acetoacetate, was prevented by vitamin D supplementation. Studies with CSE siRNA provide evidence for a relationship between impaired CSE expression and reduced H₂S levels. This study demonstrates for the first time that both hyperglycemia and hyperketonemia mediate a reduction in CSE expression and activity, which can contribute to the impaired H₂S signaling associated with diabetes.     

Visceral Dracunculiasis: A Case Report from East Medinipore District,West Bengal,India

A case of visceral dracunculiasis in a female patient is reported from east Medinipur district, West Bengal, India. It is the first report from the eastern India. The patient from rural West Bengal underwent laparoscopic cholecystectomy on 13th March 2002 and after 3 days the patient was released with a drain in the upper abdomen because of persistence of fluid of about 50 ml per day. The patient was to readmit after 8 days with a history of expulsion of one worm through the drain tube and next day another four living worms were expelled through the tube. Subsequently the drain dried up and the patient was released after removing the tube. The worms are identified as Dracunculus medinensis, possibly remaining within the abscess developing adjacent to the gall bladder and it is a case of visceral dracunculiasis reported first time from eastern India.     

Superoxide activates mTOR–eIF4E–Bax route to induce enhanced apoptosis in leukemic cells

Mammalian target of rapamycin (mTOR) is a central kinase that regulates cell survival, proliferation and translation. Reactive oxygen species (ROS) are second messengers with potential in manipulating cellular signaling. Here we report that two ROS generating phytochemicals, hydroxychavicol and curcumin synergize in leukemic cells in inducing enhanced apoptosis by independently activating both mitogen activated protein kinase (MAPK) (JNK and P³⁸) and mTOR pathways. Low level transient ROS generated after co-treatment with these phytochemicals led to activation of these two pathways. Both mTOR and MAPK pathways played important roles in co-treatment-induced apoptosis, by knocking down either mTOR or MAPKs inhibited apoptosis. Activation of mTOR, as evident from phosphorylation of its downstream effector eukaryotic translation initiation factor 4E-binding protein 1, led to release of eukaryotic translation initiation factor 4E (eIF4E) which was subsequently phosphorylated by JNK leading to translation of pro-apoptotic proteins Bax and Bad without affecting the expression of anti-apoptotic protein Bcl-xl. Our data suggest that mTOR and MAPK pathways converge at eIF4E in co-treatment-induced enhanced apoptosis and provide mechanistic insight for the role of mTOR activation in apoptosis.     

ICB3E induces iNOS expression by ROS-dependent JNK and ERK activation for apoptosis of leukemic cells

The role of c-Jun N terminal Kinase (JNK) has been well documented in various cellular stresses where it leads to cell death. Similarly, extracellular signal-regulated kinase (ERK) which was identified as a signalling molecule for survival pathway has been shown recently to be involved in apoptosis also. Recently we reported that ICB3E, a synthetic analogue of Piper betle leaf-derived apoptosis-inducing agent hydroxychavicol (HCH), possesses anti-chronic myeloid leukemia (CML) acitivity in vitro and in vivo without insight on mechanism of action. Here we report that ICB3E is three to four times more potent than HCH in inducing apoptosis of leukemic cells without having appreciable effects on normal human peripheral blood mononuclear cells, mouse fibroblast cell line NIH3T3 and monkey kidney epithelial cell line Vero. ICB3E causes early accumulation of mitochondria-derived reactive oxygen species (ROS) in K562 cells. Unlike HCH, ICB3E treatment caused ROS dependent activation of both JNK, ERK and induced the expression of iNOS leading to generation of nitric oxide (NO). This causes cleavage of caspase 9, 3 and PARP leading to apoptosis. Lack of cleavage of caspase 8 and inability of blocking chimera antibody to DR5 or neutralizing antibody to Fas to reverse ICB3E-mediated apoptosis suggest the involvement of only intrinsic pathway. Our data reveal a novel ROS-dependent JNK/ERK-mediated iNOS activation pathway which leads to NO mediated cell death by ICB3E.     

Structural and functional consequences of mutating a proteobacteria-specific surface residue in the catalytic domain of Escherichia coli GluRS

Nucleotides whose mutations seriously affect glutamylation efficiency are experimentally known for Escherichia coli tRNA(Glu). However, not much is known about functional hotspots on the complementary enzyme, glutamyl-tRNA synthetase (GluRS). From structural and functional studies on an Arg266Leu mutant of E. coli GluRS, we demonstrate that Arg266 is essential for efficient glutamylation of tRNA(Glu). Consistent with this result, we found that Arg266 is a conserved signature of proteobacterial GluRS. In contrast, most non-proteobacterial GluRS contain Leu, and never Arg, at this position. Our results imply a unique strategy of glutamylation of tRNA(Glu) in proteobacteria under phylum-specific evolutionary compulsions.     

Inhibition of amine oxidases activity by 1-acetyl-3,5-diphenyl-4,5-dihydro-(1H)-pyrazole derivatives

A novel series of 1-acetyl-3,5-diphenyl-4,5-dihydro-(1H)-pyrazole derivatives have been synthesised and investigated for the ability to inhibit selectively monoamine oxidases, swine kidney oxidase, and bovine serum amine oxidase. The newly synthesised compounds 1–6 proved to be reversible and non-competitive inhibitors of all types of the assayed amine oxidases. Compounds inhibit monoamine oxidases potently, displaying low I₅₀ values of particular interest. In particular 1-acetyl-3-(2,4-dihydroxyphenyl)-5-(3-methylphenyl)-4,5-dihydro-(1H)-pyrazole 6 showed to be a potent monoamine oxidase inhibitor with a K_i of about 10⁻⁸ M. Further insights in the theoretical evaluation of the possible interactions between the compounds and monoamine oxidase B have been developed through a computational approach.     

A 3D supramolecular network of cobalt(II)(bis(4-pyridyl)ethylene) with terephthalate dianions

A three dimensional supramolecular network, {[Co(bpee)(H₂O)₄] · (tp) · 2(H₂O)}_n (1) [bpee = trans-1,2 bis(4-pyridyl)ethylene; tp = terephthalate dianion] has been synthesized and characterized by X-ray single crystal structure, magnetic measurement and thermal analysis. The structure determination reveals that the cobalt(II) ions, bridged by bpee and coordinated by four water molecules, give rise to covalently linked 1D polymeric chain. The parallel chains get involved in H-bonding with tp resulting in a 3D architecture. Upon heating 1, which is pink in color, transforms to [Co(bpee)(tp)] (1a, blue). The deaquated species (1a) reverts on keeping in humid atmosphere. Low temperature magnetic data indicate weak antiferromagnetic coupling.     

Two Cases of Vaginitis Caused by Itraconazole-Resistant Saccharomyces cerevisiae and a Review of Recently Published Studies

Genitourinary infections caused by non-Candida yeasts are uncommon, and especially due to Saccharomyces cerevisiae. We describe the cases of two adult females with vulvovaginal infections caused by itraconazole-resistant S. cerevisiae who made a full recovery after oral fluconazole therapy. We also provide a concise review of recently published studies on this topic.