Molecular and Genetic Medicine

Various microorganisms e.g., bacteria, fungi and higher organism e.g., plant during their metabolism produces both primary and secondary metabolites, needed for their survival and defense. Often these secondary metabolites are being used in drug discovery. The genes for the enzymes of these secondary metabolic pathways are generally grouped together as biosynthetic gene clusters (BGCs) and hidden away in organism’s genome. Genome mining of the unexplored microbes, medicinal plants, and underexplored human microbiota with emerging genomics research involving next-generation sequencing technology along with bioinformatics tools like anti-SMASH (antibiotics and Secondary Metabolite Analysis Shell), planti-SMASH, may help in finding many BGCs and subsequently in the discovery of many new drugs in future.

Carfilzomib is an irreversible proteasome inhibitor (PI), first approved in 2012 for treatment of relapsed refractory multiple myeloma (RRMM). The real-world use of carfilzomib in treatment of RRMM is important to assess. The objectives of this study are to evaluate the real-world outcome in overall response rates (ORR), progression-free survival (PFS), and adverse drug events (ADEs), including cardiotoxicity and nephrotoxicity for RRMM patients treated with carfilzomib. We retrospectively analyzed the charts of patients with a diagnosis of MM treated with carfilzomib between January 2013 and December 2018. Demographics, cytogenetics, fluorescence in situ hybridization (FISH), and treatment history were collected. Sixty-six patients fit the study criteria, with median age of 65 years (range 48 - 84). Using the Revised International Staging System (R-ISS), 7 (10.6%) patients were stage I, 28 (42.4%) stage II, and 31 (47.0%) stage III. Cytogenetics showed 33 (48.5%) were high risk. Eight (12.12%) patients were pretreated with more than 4 treatment lines and 27 (40.95) had an autologous stem cell transplant (ASCT) prior to carfilzomib. Prior treatments included lenalidomide, bortezomib, and cyclophosphamide-based regimens. The ORR was 77.2%, with 4 (6.2%) complete responses (CR). Ten patients (15%) received ASCT after carfilzomib for progression of disease (POD). The majority with POD received daratumumab (40%) or pomalidomide (46%). Grade 2 hypertension was noted in 9 (13.6%) patients, acute renal failure (ARF) in 11 (16.7%) and heart failure (HF) in 12 (18.2%). The median PFS on Carfilzomib was 6.96 months. This study showed carfilzomib improved PFS in patients with RRMM; however, there is increased risk for cardiac and renal toxicity, greater than previously reported in the literature. This study reinforces the importance for oncologists to be aware of these toxicities. Astute awareness, early monitoring, and prevention may favorably impact outcomes with use of carfilzomib.

Oral cancers are heterogeneous group of tumors in topography (they can be localized at on the lips, tongue, upper and lower gums, hard and soft palates, floor of mouth, retromolar region, or inside of cheek), histologic forms (that can be carcinoma, sarcoma, lymphoma, melanoma or cylindroma) and clinical outcomes (good or poor prognosis). However, more than 50% of these cancer phenotypes express a mutation at TP53 gene while in the other 50% of cases; the TP53 protein pathway is often partially inactivated. In cancerous tissues, particularly in oral squamous cells, the loss of function at TP53 gene is associated with three molecular causes: (1) The genotoxic effect of risk factors such as alcohol abuse, tobacco smoking or betel nut chewing, (2) The inhibitory effect of the TP53 antagonist genes such as MDM2, or (3) The action of oncoproteins of high-risk human papillomavirus (HPV). This paper attempts firstly to make an exhaustive review of TP53 gene signalling pathways in normal and stressed cells, and secondly to describe in oral cancers the genetic events that occur at different steps of carcinogenesis after a loss of function in TP53 encoded protein.

Purpose: To assess the agreement between 123I-metaiodobenzylguanidine or [123I]-I-mIBG and Whole Body Magnetic Resonance Imaging with diffusion-weighted whole-body imaging with background body signal suppression (WB MRI-DWIBS) in High and Intermediate risk Neuroblastoma, a retrospective review was performed on [123I]-I-mIBG and DWIBS paired scans acquired at diagnosis, response-to-therapy, after-surgery, off therapy and after relapse with systemic involvement, and osteo-bone marrow metastatic load was evaluated for each of them.

Methods: 80 paired [123I]-I-mIBG and DWIBS scans were acquired for 31 patients between June 2009 and June 2019 within 30 days and without intercurrent therapy. SIOPEN Semi-quantitative Scoring Systems for NB with 12 body sections was applied at whole body MIBG and WB MRI-DWIBS acquired to evaluate the skeletal disease extent. In each case thoracic-abdominal SPECT was used to confirm or exclude doubtful scintigraphic alterations. We evaluated specificity, sensitivity, overall accuracy, positive predictive value (PPV) and negative predictive value (NPV) of WB MRI-DWIBS respect [123I]-I-mIBG scintigraphy considered as gold standard. The inverse theoretical statistic exercise was performed for [123I]-I-mIBG respect DWIBS results.

Results: DWIBS and [123I]-I-mIBG images were concordant in 890 out of the 960 analyzed segments, with high agreement between the two techniques (Kendal=0.85 P < 0.0001 and Chi 536.5975 P < 0.0001). Considering [123I]-I-mIBG as gold standard, WB MRI-DWIBS overall accuracy was 93%, sensitivity 78%, specificity 95%, PPV 77% and NPV 96%. Otherwise, on the theoretical statistic exercise, [123I]-I-mIBG overall accuracy was 93%; sensitivity 77%; specificity 97%; VPP 78%; VPN 95%, respect DWIBS. [123I]-I-mIBG and WB MRI-DWIBS SIOPEN scoring resulted superimposable (Rho Spearman=0.88, P < 0.0001).

Conclusion: DWIBS and [123I]-I-mIBG images showed a very high concordance: a first validation of SIOPEN Scoring System seems possible on the basis of these data. WB MRI may represent an alternative in weak-avid MIBG tumors and for follow up assessment. A multimodal imaging protocol is proposed for High and Intermediate Risk protocols.