Structure-based drug design and characterization of novel pyrazine hydrazinylidene derivatives with a benzenesulfonate scaffold as noncovalent inhibitors of DprE1 tor tuberculosis treatment.

In this study, we present a novel series of (E)-4-((2-(pyrazine-2-carbonyl) hydrazineylidene)methyl)phenyl benzenesulfonate (T1-T8) and 4-((E)-(((Z)-amino(pyrazin-2-yl)methylene)hydrazineylidene)methyl)phenyl benzenesulfonate (T9-T16) derivatives which exert their inhibitory effects on decaprenylphosphoryl-ß-D-ribose 2'-epimerase (DprE1) through the formation of hydrogen bonds with the pivotal active site Cys387 residue. Their effectiveness against the M. tuberculosis H37Rv strain was examined and notably, three compounds (namely T4, T7, and T12) exhibited promising antitubercular activity, with a minimum inhibitory concentration (MIC) of 1.56 µg/mL. The target compounds were screened for their antibacterial activity against a range of bacterial strains, encompassing S. aureus, B. subtilis, S. mutans, E. coli, S. typhi, and K. pneumoniae. Additionally, their antifungal efficacy against A. fumigatus and A. niger also was scrutinized. Compounds T6 and T12 demonstrated significant antibacterial activity, while compound T6 exhibited substantial antifungal activity. Importantly, all of these active compounds demonstrated exceedingly low toxicity without any adverse effects on normal cells. To deepen our understanding of these compounds, we have undertaken an in silico analysis encompassing Absorption, Distribution, Metabolism, and Excretion (ADME) considerations. Furthermore, molecular docking analyses against the DprE1 enzyme was conducted and Density-Functional Theory (DFT) studies were employed to elucidate the electronic properties of the compounds, thereby enhancing our understanding of their pharmacological potential.

Cytogenetic Risk Stratification of B-Acute Lymphoblastic Leukemia and Its Correlation with Other Prognostic Factors.

Purpose of current study was to categorize WHO defined B-Acute Lymphoblastic Leukemia (B-ALL) cases into 3 cytogenetic risk groups (good, intermediate and poor) and to see their correlation with age, NCI risk criteria and treatment response. Clinical and diagnostic details were collected for 78 newly diagnosed B-ALL patients which included bone marrow morphology, flow cytometry immunophenotyping, karyotyping, FISH and RT-PCR. Study cohort comprised 44/78 (56.4%) children including 3 infants and 34/78 (43.6%) adults. Median age for paediatric group was 6 years (3 months-17 years) and for adults was 40.5 years (18 to 75 years). According to NCI risk criteria, excluding infants, 54 (72%) were high risk and 21 (28%) were standard risk. Clonal cytogenetic abnormality was detected in 59/78 cases (75.6%), while 19/78 (24.4%) cases showed normal karyotype. There was significant association of cytogenetic risk groups to age distribution (p value < 0.001) and NCI risk groups (p value < 0.001). There was no significant correlation of CNS involvement with cytogenetic risk groups (p = 0.064). Association of Day 8 steroid response and Day 15 bone marrow status with cytogenetic risk groups was significant (p = 0.006 and p = 0.003 respectively). Post treatment bone marrow status on Day 33 and Day 79 was available for 52 and 42 cases respectively. 9 adults died during induction phase. Day 33 post induction morphological remission was achieved in 51/52 cases (98%) and 1/52 (2.0%) were not in remission. Day 79 post induction morphological remission was achieved in 41/42 cases (98%) and 1/42 (2.0%) were not in remission. Day 33 or End of induction flow MRD (measurable residual disease) was negative in 39/52 (75.0%) patients and positive in 13/52 (25.0%) patients. Day 79 flow MRD was negative in 37/42 (88.1%) and positive in 5/42 (11.9%). Cytogenetic risk groups showed statistically significant Day 33 and Day 79 treatment response (morphologic remission: p = 0.009 and 0.003, flow MRD: p = 0.004 and p = 0.012 respectively). We concluded that cytogenetic risk groups showed statistically significant association with age, NCI risk criteria and treatment response.

Investigating the Electronic Portal Imaging Device for Small Radiation Field Measurements.

PURPOSE: With the advent of state-of-the-art treatment technologies, the use of small fields has increased, and dosimetry in small fields is highly challenging. In this study, the potential use of Varian electronic portal imaging device (EPID) for small field measurements was explored for 6 and 15 MV photon beams. MATERIALS AND METHODS: The output factors and profiles were measured for a range of jaw-collimated square field sizes starting from 0.8 cm × 0.8 cm to 10 cm × 10 cm using EPID. For evaluation purpose, reference data were acquired using Exradin A16 microionization chamber (0.007 cc) for output factors and stereotactic field diode for profile measurements in a radiation field analyzer. RESULTS: The output factors of EPID were in agreement with the reference data for field sizes down to 2 cm × 2 cm and for 2 cm × 2 cm; the difference in output factors was +2.06% for 6 MV and +1.56% for 15 MV. For the lowest field size studied (0.8 cm × 0.8 cm), the differences were maximum; +16% for 6 MV and +23% for 15 MV photon beam. EPID profiles of both energies were closely matching with reference profiles for field sizes down to 2 cm × 2 cm; however, penumbra and measured field size of EPID profiles were slightly lower compared to its counterpart. CONCLUSIONS: EPID is a viable option for profile and output factor measurements for field sizes down to 2 cm × 2 cm in the absence of appropriate small field dosimeters.

Transformation of a 4-membered ring zinc phosphate SBU to a sodalite-related 3-dimensional structure through a linear chain structure.

A zero-dimensional zinc phosphate, comprising a 4-membered ring, is shown to spontaneously transform at room temperature, to a linear chain structure consisting of corner-shared 4-membered rings, the latter transforming to a 3-dimensional sodalite-related structure under mild conditions.

EphA2 is a critical oncogene in melanoma.

EphA2 is a member of the Eph family of receptor tyrosine kinases and is highly expressed in many aggressive cancer types, including melanoma. We recently showed that EphA2 is also upregulated by ultraviolet radiation and is able to induce apoptosis. These findings suggest that EphA2 may have different, even paradoxical, effects on viability depending on the cellular context and that EphA2 mediates a delicate balance between life and death of the cell. To functionally clarify EphA2's role in melanoma, we analyzed a panel of melanoma cell lines and found that EphA2 levels are elevated in a significant fraction of the samples. Specific depletion of EphA2 in high-expressing melanoma cells using short hairpin RNA led to profound reductions in cellular viability, colony formation and migration in vitro and a dramatic loss of tumorigenic potential in vivo. Stable introduction of EphA2 into low-expressing cell lines enhanced proliferation, colony formation and migration, further supporting its pro-malignant phenotype. Interestingly, transient expression of EphA2 and/or Braf(V600E) in non-transformed melanocytes led to significant and additive apoptosis. These results verify that EphA2 is an important oncogene and potentially a common source of 'addiction' for many melanoma cells. Moreover, acute induction of EphA2 may purge genetically susceptible cells, thereby uncovering a more aggressive population that is in fact dependent on the oncogene.