EXPLORING EFFICACY OF AN ANTI-MALARIAL NANOMEDICINE IN NON-SMALL CELL LUNG CANCER TREATMENT

New drug and dosage form development faces significant challenges, especially in oncology, due to longer development cycle and associated scale-up complexities. Repurposing of existing drugs with potential anti-cancer activity into new therapeutic regimens provides a feasible alternative. In this project, amodiaquine (AQ), an anti-malarial drug, has been explored for its anti-cancer efficacy through formulating inhalable nanoparticulate systems using high-pressure homogenization (HPH) with scale-up feasibility and high reproducibility. A 32 multifactorial design was employed to better understand critical processes and formulation parameters so as to ensure product quality with improved anticancer efficacy in non-small cell lung cancer (NSCLC). Optimized AQ loaded nanoparticles (AQ NP) were evaluated for physicochemical properties, stability profile, in-vitro aerosol deposition behavior, cytotoxic potential against NSCLC cells in-vitro and in 3D simulated tumor spheroid model while the results confirming the significance of nanoparticle encapsulation for an enhanced anti-cancer efficacy. Furthermore, targeting potential of transferrin ligand conjugated AQ-loaded nanoparticles (Tf-AMQ NPs) was investigated, also evaluated for their physicochemical properties. Tf-AMQ NP (liquid state) exhibited an aerodynamic diameter of 4.4±0.1 µm and fine particle fraction of 83.2±3.0%, indicating drug deposition in the respirable airways. Cytotoxicity studies in NSCLC cell line with overexpressed transferrin receptors revealed significant reduction in IC50 values with Tf-decorated AQ-loaded nanoparticles compared to plain drug or non-targeted NPs, along with significant apoptosis induction (caspase assay) and reduced % colony growth in A549 and H1299 cells with Tf-AMQ NP. Moreover, 3D simulated spheroid studies (~ 7-fold reduction in spheroid volume compared to AMQ NPs) revealed efficacy of conjugated nanoparticles in penetration to tumor core, and growth inhibition. AQ’s autophagy inhibition ability significantly increased with nanoparticle encapsulation and transferrin conjugation. Further, another ligand folic acid has been explored for its ability to be conjugated to nanoparticles and to enhance anti-cancer efficacy and were found to exhibit superior anti-cancer efficacy in multiple cancer types such as breast cancer and cervical cancer. To conclude, amodiaquine can be a promising candidate for repurposing to treat NSCLC while delivering inhalable transferrin conjugated nanoparticles developed using a scalable HPH process to the target site, thus reducing the dose, side effects

Isolation and characterization of phthalates from Brevibacterium mcbrellneri that cause cytotoxicity and cell cycle arrest

Bacteria belonging to the family Brevibacterieae are ubiquitous Gram positive organisms that are responsible for the feet odour and cheese aroma. Brevibacterium mcbrellneri is a relatively new member belonging to Brevibac- terieae. In the current manuscript we discuss isolation of biologically active metabolites from Brevibacterium mcbrellneri. Two aromatic esters were isolated from Brevibacterium mcbrellneri by “Bioassay guided fractiona- tion strategy” and identified as di-(2-ethylhexyl) phthalate and dibutyl phthalate by chemical characterization using biophysical techniques. The phthalate compounds show broad spectrum antibacterial activity and mosquito larvi-cidal activity. Mosquito larvicidal activity has been attributed to inhibition of acetylcholinesterase enzyme activity. These compounds were found to be cytotoxic in multiple cell lines causing cell cycle arrest in G1 phase

The electronic self report assessment and intervention for cancer: promoting patient verbal reporting of symptom and quality of life issues in a randomized controlled trial

Background: The electronic self report assessment - cancer (ESRA-C), has been shown to reduce symptom distress during cancer therapy The purpose of this analysis was to evaluate aspects of how the ESRA-C intervention may have resulted in lower symptom distress (SD). Methods: Patients at two cancer centers were randomized to ESRA-C assessment only (control) or the Web-based ESRA-C intervention delivered to patients’ homes or to a tablet in clinic. The intervention allowed patients to self-monitor symptom and quality of life (SxQOL) between visits, receive self-care education and coaching to report SxQOL to clinicians. Summaries of assessments were delivered to clinicians in both groups. Audio-recordings of clinic visits made 6 weeks after treatment initiation were coded for discussions of 26 SxQOL issues, focusing on patients’/caregivers’ coached verbal reports of SxQOL severity, pattern, alleviating/aggravating factors and requests for help. Among issues identified as problematic, two measures were defined for each patient: the percent SxQOL reported that included a coached statement, and an index of verbalized coached statements per SxQOL. The Wilcoxon rank test was used to compare measures between groups. Clinician responses to problematic SxQOL were compared. A mediation analysis was conducted, exploring the effect of verbal reports on SD outcomes. Results: 517 (256 intervention) clinic visits were audio-recorded. General discussion of problematic SxQOL was similar in both groups. Control group patients reported a median 75% of problematic SxQOL using any specific coached statement compared to a median 85% in the intervention group (p = .0009). The median report index of coached statements was 0.25 for the control group and 0.31 for the intervention group (p = 0.008). Fatigue, pain and physical function issues were reported significantly more often in the intervention group (all p < .05). Clinicians' verbalized responses did not differ between groups. Patients' verbal reports did not mediate final SD outcomes (p = .41). Conclusions: Adding electronically-delivered, self-care instructions and communication coaching to ESRA-C promoted specific patient descriptions of problematic SxQOL issues compared with ESRA-C assessment alone. However, clinician verbal responses were no different and subsequent symptom distress group differences were not mediated by the patients' reports. Trial registration NCT00852852; 26 Feb 200

Perinatal outcome in pregnancies complicated with oligohydramnios at term

Background: AFI of less than or equal to five cm is considered oligohydramnios. Various approaches, such as NST, acoustic stimulation, and foetal Doppler velocimetry, are useful in assessing foetal well-being and identifying pregnancies at risk of postnatal complications. The goal of this study was to learn about the negative perinatal outcomes in pregnant women who had oligohydramnios at term and to assess the efficacy of AFI in predicting foetal distress and caesarean delivery.Methods: A retrospective and comparative study of singleton pregnancies outcomes in 60 women diagnosed with oligohydramnios by USG after 37 weeks of pregnancy, compared to 60 women who did not have oligohydramnios and were matched for other factors. Some criteria for inclusion and exclusion were utilised. The data was analysed using statistical criteria such as mean, standard deviation, and chi square test sensitivity, specificity, PPV, and NPV.Results: The occurrence of non-reactive and re-active NST patterns differed significantly between the two groups. In comparison to women with AFI >5 cm, women with AFI 5cm have a higher rate of labour induction. LBW (2.5 kg) was more common in women with oligohydramnios, and LSCS rates were higher in oligohydramnios-complicated pregnancies.Conclusions: After 37 weeks of pregnancy, an AFI of less than 5 cm is a sign of poor perinatal outcome. AFI can be used in conjunction with other foetal monitoring techniques. AFI is a useful screening test for predicting foetal distress during labour that necessitates a caesarean section

Clinicopathological and functional significance of RECQL1 helicase in sporadic breast cancers

RECQL1, a key member of the RecQ family of DNA helicases, is required for DNA replication and DNA repair. Two recent studies have shown that germline RECQL1 mutations are associated with increased breast cancer susceptibility. Whether altered RECQL1 expression has clinicopathologic significance in sporadic breast cancers is unknown. We evaluated RECQL1 at the transcriptomic level (METABRIC cohort, n = 1,977) and at the protein level [cohort 1, n = 897; cohort 2, n = 252; cohort 3 (BRCA germline deficient), n = 74]. In RECQL1-depleted breast cancer cells, we investigated anthracycline sensitivity. High RECQL1 mRNA was associated with intClust.3 (P = 0.026), which is characterized by low genomic instability. On the other hand, low RECQL1 mRNA was linked to intClust.8 [luminal A estrogen receptor–positive (ER+) subgroup; P = 0.0455] and intClust.9 (luminal B ER+ subgroup; P = 0.0346) molecular phenotypes. Low RECQL1 expression was associated with shorter breast cancer–specific survival (P = 0.001). At the protein level, low nuclear RECQL1 level was associated with larger tumor size, lymph node positivity, high tumor grade, high mitotic index, pleomorphism, dedifferentiation, ER negativity, and HER-2 overexpression (P < 0.05). In ER+ tumors that received endocrine therapy, low RECQL1 was associated with poor survival (P = 0.008). However, in ER− tumors that received anthracycline-based chemotherapy, high RECQL1 was associated with poor survival (P = 0.048). In RECQL1-depleted breast cancer cell lines, we confirmed doxorubicin sensitivity, which was associated with DNA double-strand breaks accumulation, S-phase cell-cycle arrest, and apoptosis. We conclude that RECQL1 has prognostic and predictive significance in breast cancers