Treatment of refractory/relapsed Diamond-Blackfan anaemia with eltrombopag.

Diamond-Blackfan anaemia (DBA) is a rare, inherited bone marrow failure syndrome with a ribosomal defect causing slowed globin chain production with normal haem synthesis, causing an overabundance of reactive iron/haem and erythroid-specific cellular toxicity. Eltrombopag, a non-peptide thrombopoietin receptor agonist, is a potent intracellular iron chelator and induced a robust durable response in an RPS19-mutated DBA patient on another trial. We hypothesized eltrombopag would improve RBC production in DBA patients. We conducted a single-centre, single-arm pilot study (NCT04269889) assessing safety and erythroid response of 6 months of daily, fixed-dose eltrombopag for DBA patients. Fifteen transfusion-dependent (every 3-5 weeks) patients (median age 18 [range 2-56]) were treated. One responder had sustained haemoglobin improvement and >50% reduction in RBC transfusion frequency. Of note, 7/15 (41%) patients required dose reductions or sustained discontinuation of eltrombopag due to asymptomatic thrombocytosis. Despite the low response rate, eltrombopag has now improved erythropoiesis in several patients with DBA with a favourable safety profile. Dosing restrictions due to thrombocytosis may cause insufficient iron chelation to decrease haem production and improve anaemia in most patients. Future work will focus on erythropoiesis dynamics in patients and use of haem synthesis inhibitors without an impact on other haematopoietic lineages.

Posttranslational Regulation of O(6)-Methylguanine-DNA Methyltransferase (MGMT) and New Opportunities for Treatment of Brain Cancers.

O(6)-Methylguanine-DNA-methyltransferase (MGMT) is an antimutagenic DNA repair protein highly expressed in human brain tumors. Because MGMT repairs the mutagenic, carcinogenic and cytotoxic O(6)-alkylguanine adducts, including those generated by the clinically used anticancer alkylating agents, it has emerged as a central and rational target for overcoming tumor resistance to alkylating agents. Although the pseudosubstrates for MGMT [O(6)-benzylguanine, O(6)-(4- bromothenyl)guanine] have gained attention as powerful and clinically-relevant inhibitors, bone marrow suppression due to excessive alkylation damage has diminished this strategy. Our laboratory has been working on various posttranslational modifications of MGMT that affect its protein stability, DNA repair activity and response to oxidative stress. While these modifications greatly impact the physiological regulation of MGMT, they also highlight the opportunities for inactivating DNA repair and new drug discovery in this specific area. This review briefly describes the newer aspects of MGMT posttranslational regulation by ubiquitination, sumoylation and glutathionylation and reveals how the reactivity of the active site Cys145 can be exploited for potent inhibition and depletion of MGMT by thiol-reacting drugs such as the disulfiram and various dithiocarbamate derivatives. The possible repurposing of these nontoxic and safe drugs for improved therapy of pediatric and adult brain tumors is discussed.

Design and synthesis of a C7-aryl piperlongumine derivative with potent antimicrotubule and mutant p53-reactivating properties.

Small molecules that can restore biological function to the p53 mutants found in human cancers have been highly sought to increase the anticancer efficacy. In efforts to generate hybrid anticancer drugs that can impact two or more targets simultaneously, we designed and developed piperlongumine (PL) derivatives with an aryl group inserted at the C-7 position. This insertion bestowed a combretastatin A4 (CA4, an established microtubule disruptor) like structure while retaining the piperlongumine configuration. The new compounds exhibited potent antiproliferative activities against eight cancer cell lines, in particular, were more cytotoxic against the SKBR-3 breast cancer cells which harbor a R175H mutation in p53 suppressor. KSS-9, a representative aryl PL chosen for further studies induced abundant ROS generation and protein glutathionylation. KSS-9 strongly disrupted the tubulin polymerization in vitro, destabilized the microtubules in cells and induced a potent G2/M cell cycle block. More interestingly, KSS-9 showed the ability to reactivate the p53 mutation and restore biological activity to the R175H mutant protein present in SKBR3 cells. Several procedures, including immunocytochemistry using conformation-specific antibodies for p53, immunoprecipitation combined with western blotting, electrophoretic shift mobility shift assays showed a reciprocal loss of mutant protein and generation of wild-type like protein. p53 reactivation was accompanied by the induction of the target genes, MDM2, p21cip1 and PUMA. Mechanistically, the redox-perturbation in cancer cells by the hybrid drug appears to underlie the p53 reactivation process. This anticancer drug approach merits further development.

Maternal periodontal disease and preterm birth: A case-control study.

BACKGROUND AND OBJECTIVE: Preterm birth (PTB) is an important issue in public health and is a major cause for infant mortality and morbidity. There is a growing consensus that systemic diseases elsewhere in the body may influence PTB. Recent studies have hypothesized that maternal periodontitis could be a high-risk factor for PTB. The aim of the present study was to investigate the relationship between maternal periodontitis on PTB. MATERIALS AND METHODS: Forty systemically healthy primiparous mothers aged 18-35 years were recruited for the study. Based on inclusion and exclusion criteria, they were categorized into PTB group as cases and full term birth group (FTB) as controls. PTB cases (n = 20) defined as spontaneous delivery before/<37 completed weeks of gestation. Controls (FTB) were normal births at or after 37 weeks of gestation. Data on periodontal status, pregnancy outcome variables, and information on other factors that may influence adverse pregnancy outcomes were collected within 2 days of labor. Data were subjected to Student's t-test and Pearson's correlation coefficient statistical analysis. RESULTS: Statistically significant difference with respect to the gestational period at the time of delivery and birth weight of the infants in (PTB) group (<0.001) compared to (FTB) group was observed. Overall, there was statistically significant poor periodontal status in the (PTB) group compared to (FTB) group. The statistical results also showed a positive correlation between gestational age and clinical parameters. CONCLUSION: An observable relationship was noticed between periodontitis and gestational age, and a positive correlation was found with respect to PTB and periodontitis. Further studies should be designed to establish periodontal disease as an independent risk factor for PTB/preterm low birth weight.

Aerosols how dangerous they are in clinical practice.

BACKGROUND AND OBJECTIVES: The purpose of the present study was to determine the microbial atmospheric contamination during initial periodontal treatment using a modern piezoelectric scaler and to evaluate the efficacy of two commercially available mouth rinses (0.2% Chlorhexidine mouth rinse and Listerine) in reducing bacterial contamination when used as a pre-procedural rinse, with and without high volume evacuation (Aerosol reduction device). MATERIALS AND METHODS: Subjects for the study were selected from the outpatient Department of Periodontics, Sri Siddhartha Dental College and Hospital, Tumkur, India. Total 60 patients were taken for the study and on the basis of inclusion and exclusion criteria's they were divided into three groups. The sampling was carried out in two stages before and after implementing a set protocol. Total duration of study was four months. MICROBIOLOGICAL EVALUATION: The samples (blood agar plates) were transported immediately to the Department of Microbiology, Sri Siddhartha Medical College, Tumkur for: Identification of microorganisms as per standard procedures (Gram stain, Biochemical Test, Species Identification).Counting the number of colonies formed on blood agar plates using colony counter unit. RESULTS: Out of all the three pre-procedural rinses 0.2% w/v Chlorhexidine is the best in reducing aerobic bacteria (CFU) followed by Listerine and then Water. CONCLUSION: The following conclusion was drawn that the use of pre-procedural rinses along with the use of high volume suction apparatus significantly reduced the aerosol contamination and hence chances of cross-infection in the dental units.

Central odontogenic fibroma.

Central odontogenic fibroma (COF), which has been categorized under the subheading of odontogenic tumors of ectomesenchyme, is such an uncommon neoplasm that much of its nature is left uncharted. COF is a rare tumor that accounts for 0.1% of all odontogenic tumors. Clinically, the lesion grows slowly and leads to cortical expansion. Radiologically, the lesion may be unilocular or multilocular. In some cases, it may be associated with root resorption or displacement. Histopathologically, the lesion is characterized by mature collagen fibers and numerous fibroblasts. A case of COF of the mandible in a male patient aged 49 years is described in this report. The patient showed no symptoms, no history of swelling discomfort or pain, and was unaware of the presence of the lesion. Orthopantomogram (OPG) showed generalized bone loss along with a unilocular radiolucent area, with a clear sclerotic lining and angular bone loss. Surgical enucleation of the lesion along with placement of osseo-graft, which is a bioresorbable demineralized bone matrix (DMBM), and platelet-rich fibrin was carried out in the defect site. Following surgery, patient was recalled for revaluation of the lesion; the surgical site showed good healing and an increase in bone height was seen.

Paramolar concrescence and periodontitis.

Concrescence is a developmental anomaly of dental hard tissues. It is a condition showing union of adjacent teeth by cementum. The concrescence leads to a loss of gingival architecture leading to the development of funnels, which may cause plaque accumulation thus, resulting in periodontal tissue destruction. There is a slight predilection for the mandible especially in the premolar area followed by the molar and anterior regions. Awareness of these developmental disturbances with proper diagnosis and treatment is very essential because it can compromise the periodontal attachment and can lead to the tooth loss. This article highlights the presence of a concrescence between mandibular second molar and the supernumerary fused teeth with their clinical and radiographic findings, along with its management.