Synthesis, Anticancer Activity, and In Silico Studies of 5-(3-Bromophenyl)-N-aryl-4H-1,2,4-triazol-3-amine Analogs.

In the current study, we described the synthesis of ten new 5-(3-Bromophenyl)-N-aryl-4H-1,2,4-triazol-3-amine analogs (4a-j), as well as their characterization, anticancer activity, molecular docking studies, ADME, and toxicity prediction. The title compounds (4a-j) were prepared in three steps, starting from substituted anilines in a satisfactory yield, followed by their characterization via spectroscopic techniques. The National Cancer Institute (NCI US) protocol was followed to test the compounds' (4a-j) anticancer activity against nine panels of 58 cancer cell lines at a concentration of 10-5 M, and growth percent (GP) as well as percent growth inhibition (PGI) were calculated. Some of the compounds demonstrated significant anticancer activity against a few cancer cell lines. The CNS cancer cell line SNB-75, which showed a PGI of 41.25 percent, was discovered to be the most sensitive cancer cell line to the tested compound 4e. The mean GP of compound 4i was found to be the most promising among the series of compounds. The five cancer cell lines that were found to be the most susceptible to compound 4i were SNB-75, UO-31, CCRF-CEM, EKVX, and OVCAR-5; these five cell lines showed PGIs of 38.94, 30.14, 26.92, 26.61, and 23.12 percent, respectively, at 10-5 M. The inhibition of tubulin is one of the primary molecular targets of many anticancer agents; hence, the compounds (4a-j) were further subjected to molecular docking studies looking at the tubulin-combretastatin A-4 binding site (PDB ID: 5LYJ) of tubulin. The binding affinities were found to be efficient, ranging from -6.502 to -8.341 kcal/mol, with two major electrostatic interactions observed: H-bond and halogen bond. Ligand 4i had a binding affinity of -8.149 kcal/mol with the tubulin-combretastatin A-4 binding site and displayed a H-bond interaction with the residue Asn258. The ADME and toxicity prediction studies for each compound were carried out using SwissADME and ProTox-II software. None of the compounds' ADME predictions showed that they violated Lipinski's rule of five. All of the compounds were also predicted to have LD50 values between 440 and 500 mg/kg, putting them all in class IV toxicity, according to the toxicity prediction. The current discovery could potentially open up the opportunity for further developments in cancer.

Bioremediation of polycyclic aromatic hydrocarbons in crude oil by bacterial consortium in soil amended with Eisenia fetida and rhamnolipid.

The present study investigated the concerted effort of Eisenia fetida and rhamnolipid JBR-425 in combination with a five-member bacterial consortium exhibiting elevated degradation levels of low and high molecular weight polycyclic aromatic hydrocarbons (PAH) from soil contaminated with Digboi crude oil. Application of bacterial consortium (G2) degraded 30-89% of selected PAH from the artificial soil after a 45-day post-exposure, in which chrysene showed the highest level of degradation with 89% and benzo(a)pyrene is the lowest with 30%, respectively. Moreover, an acute exposure study observed that earthworm biomass decreased, and mortality rates increased with increasing crude oil concentrations (0.25 to 2%). Earthworms with a 100% survival rate at 1% crude oil exposure suggest the tolerance potential and its mutual involvement in the bioremediation of crude oil with selected bacterial consortia. Bacterial consortium assisted with E. fetida (G3) showed 98% chrysene degradation with a slight change in benzo(a)pyrene degradation (35%) in crude oil spiked soil. Besides, the most dominant PAH in crude oil found in the current work, fluoranthene, undergoes 93% and 70% degradation in G3 and G5 groups, respectively. However, rhamnolipid JBR-425 coupled with the bacterial consortium (G5) has resulted in 97% degradation of chrysene and 33% for benzo(a)pyrene. Overall, bacterial consortium assisted with earthworm group has shown better degradation of selected PAH than bacterial consortium with biosurfactant. Catalase (CAT), glutathione reductase (GST) activity and MDA content was found to be reduced in earthworms after sub-lethal exposure, suggesting oxidative stress prevalence via reactive oxygen species (ROS). Hence, the findings of the present work suggest that the application of a bacterial consortium, along with earthworm E. fetida, has huge potential for field restoration of contaminated soil with PAH and ecosystem sustainability.

Can we lower the platelet threshold of ≥ 50 × 109/L for performing a lumbar puncture safely in patients with hematological malignancies?

Lumbar punctures (LP) are routinely used to administer intrathecal chemotherapy for children and adults with hematologic malignancies. The current guidelines suggest a platelet threshold of ≥ 50 × 109/L prior to LP for intrathecal chemotherapy (ITC). This can be challenging in patients with hematological malignancies who are thrombocytopenic. We conducted a retrospective chart review of 900 LPs for ITC and compared adverse events in patients with a platelet count of ≥ 50 × 109/L and < 50 × 109/L. Cohort 1 included 682 LPs (75.8%) with a pre-procedure platelet count ≥ 50 × 109/L, and cohort 2 included 218 LPs (24.2%) with a pre-procedure platelet count < 50 × 109/L. Cohort 2 was further subdivided into pre-procedure platelet counts of 41 × 109/L-49 × 109/L (n = 43), 31 × 109/L-40 × 109/L (n = 77), 21 × 109/L-30 × 109/L (n = 84), and 11 × 109/L-20 × 109/L (n = 14). Among 900 LP procedures, a pre-procedure platelet count < 50 × 109/L did not demonstrate a higher rate of post-procedure adverse events (6.5% vs 6.8%, p = 0.8237). When cohort 2 was further stratified, the cohort with a pre-procedure platelet count of 21 × 109/L-30 × 109/L had the highest percentage of complications from LP (9.5%) and the highest rates of traumatic taps with observed LP RBC count > 200 (35.7%, p = 0.0015). The rate of red blood cells (RBC) in the CSF was significantly higher in the group with platelets < 50 × 109/L with observed LP RBC count ≥ 200 (31.2% vs 20.5%, p = 0.0016), ≥ 500 (27.1% vs 14.6%, p < 0.0001), and ≥ 1000 (23% vs 11.6%, p < 0.0001). No instances of epidural hematomas were seen. We found no significant difference in bleeding complications between patients undergoing LPs for ITC with a platelet count above or below 50 × 109/L.

Sustainable strategies for combating hydrocarbon pollution: Special emphasis on mobil oil bioremediation.

The global rise in industrialization and vehicularization has led to the increasing trend in the use of different crude oil types. Among these mobil oil has major application in automobiles and different machines. The combustion of mobil oil renders a non-usable form that ultimately enters the environment thereby causing problems to environmental health. The aliphatic and aromatic hydrocarbon fraction of mobil oil has serious human and environmental health hazards. These components upon interaction with soil affect its fertility and microbial diversity. The recent advancement in the omics approach viz. metagenomics, metatranscriptomics and metaproteomics has led to increased efficiency for the use of microbial based remediation strategy. Additionally, the use of biosurfactants further aids in increasing the bioavailability and thus biodegradation of crude oil constituents. The combination of more than one approach could serve as an effective tool for efficient reduction of oil contamination from diverse ecosystems. To the best of our knowledge only a few publications on mobil oil have been published in the last decade. This systematic review could be extremely useful in designing a micro-bioremediation strategy for aquatic and terrestrial ecosystems contaminated with mobil oil or petroleum hydrocarbons that is both efficient and feasible. The state-of-art information and future research directions have been discussed to address the issue efficiently.

Copper-Catalyzed Covalent Dimerization of Near-Infrared Fluorescent Cyanine Dyes: Synergistic Enhancement of Photoacoustic Signals for Molecular Imaging of Tumors.

Photoacoustic (PA) imaging relies on the absorption of light by chromophores to generate acoustic waves used to delineate tissue structures and physiology. Here, we demonstrate that Cu(II) efficiently catalyzes the dimerization of diverse near-infrared (NIR) cyanine molecules, including a peptide conjugate. NMR spectroscopy revealed a C-C covalent bond along the heptamethine chains, creating stable molecules under conditions such as a wide range of solvents and pH mediums. Dimerization achieved >90% fluorescence quenching, enhanced photostability, and increased PA signals by a factor of about 4 at equimolar concentrations compared to the monomers. In vivo study with a mouse cancer model revealed that dimerization enhanced tumor retention and PA signal, allowing cancer detection at doses where the monomers are less effective. While the dye dimers highlighted peritumoral blood vessels, the PA signal for dimeric tumor-targeting dye-peptide conjugate, LS301, was diffuse throughout the entire tumor mass. A combination of the ease of synthesis, diversity of molecules that are amenable to Cu(II)-catalyzed dimerization, and the high acoustic wave amplification by these stable dimeric small molecules ushers a new strategy to develop clinically translatable PA molecular amplifiers for the emerging field of molecular photoacoustic imaging.

Efficacy and safety of direct oral anticoagulants for secondary prevention of cancer associated thrombosis: a meta-analysis of randomized controlled trials.

Direct oral anticoagulants (DOACs) may be good alternatives to low molecular weight heparin (LMWH) or vitamin K antagonists (VKA) for treatment of cancer associated thrombosis (CAT). We conducted a meta-analysis of ten randomized clinical trials to evaluate the efficacy and safety of DOACs in patients with CAT. All had study populations composed in entirety or in part of patients with CAT. The primary outcome (efficacy) was recurrent VTE and the secondary outcomes (safety outcomes) included major bleeding, clinically relevant non-major bleeding (CRNMB), and all bleeding (major bleeding + CRNMB). Participants treated with DOACs had lower risk of recurrent VTE, overall (RR 0.63; 95% CI 0.51-0.79; p < 0.0001), compared to LMWH (RR 0.57; 95% CI 0.40-0.83; p = 0.003), but not compared to VKA (RR 0.69; 95% CI 0.44-1.06; p = 0.09). Compared to LMWH, DOACs showed no difference in major bleeding risk (RR 1.31; 95% CI 0.78-2.18; p = 0.31), though had higher risk of CRNMB (RR 1.60; 95% CI 1.13-2.26; p = 0.008) and all bleeding (RR 1.49; 95% CI 1.10-2.01; p = 0.010). These results indicate that DOACs are more effective than LMWH for prevention of recurrent VTE with CAT though carry an increased risk for non-major bleeding compared to standard of care, LMWH.

Chronic exposure to Pb2+ perturbs ChREBP transactivation and coerces hepatic dyslipidemia.

Dysregulated hepatic de novo lipogenesis contributes to the pathogenesis of nonalcoholic fatty liver disease in both humans and rodents. Clinical evidence suggests fatty liver to have a positive correlation with serum lead (Pb2+ ) levels. However, an exact mechanism of Pb2+ -induced fatty liver progression is still unknown. Here, we show that exposure to Pb2+ regulates ChREBP-dependent hepatic lipogenesis. Presence of Pb2+ ions within the hepatocytes reduces transcript and protein levels of sorcin, a cytosolic adaptor partner of ChREBP. Adenovirus-mediated overexpression of sorcin in Pb2+ exposed hepatocytes and an in vivo mouse model ameliorates liver steatosis and hepatotoxicity. Hereby, we present Pb2+ exposure to be a lethal disruptor of lipid metabolism in hepatocytes and highlight sorcin as a novel therapeutic target against Pb2+ -induced hepatic dyslipidemia.