Analysis of the Mental Foramen and Inferior Alveolar Canal pattern based on CBCT data

The mental foramen is located in a position where certain dental procedures may cause inadvertent damage to the mental nerve and lead to disorders of sensory functions such as altered sensa¬tion, complete numbness, and neuropathic pain, which are uncommon but severe treatment complications with significant medico-legal implications. Hence thorough knowledge of its anatomical relation to its surrounding structures is critical while undertaking dental procedures. To investigate the size, shape, and position of the mental foramen (MF), its distance from adjacent teeth and mandibular borders, and the pattern of the inferior alveolar canal using CBCT in the Indian subpopulation. This was a retrospective, cross-sectional study The study evaluated 310 CBCT scans (179 males, 131 females) in axial, sagittal, and coronal planes. CBCT scans were evaluated, mapped and measured for all the parameters listed above based on age and sex. Data were analyzed using ANOVA, independent‘t-test, and chi-square test. The size of MF is independent of age and sex; the most frequent shape of MF was Type III (round); location was below the apex of the second premolar (p>0.05). The distance of MF from the nearest root apex decreased with an increase in age and more in females than males (p>0.05). Inferior Alveolar Nerve Canal (IAC) pattern was perpendicular, and linear patterns of exit at MF were more common than anterior loops in all age groups

Novel Allosteric Mechanism of Dual p53/MDM2 and p53/MDM4 Inhibition by a Small Molecule

Restoration of the p53 tumor suppressor for personalised cancer therapy is a promising treatment strategy. However, several high-affinity MDM2 inhibitors have shown substantial side effects in clinical trials. Thus, elucidation of the molecular mechanisms of action of p53 reactivating molecules with alternative functional principle is of the utmost importance. Here, we report a discovery of a novel allosteric mechanism of p53 reactivation through targeting the p53 N-terminus which promotes inhibition of both p53/MDM2 (murine double minute 2) and p53/MDM4 interactions. Using biochemical assays and molecular docking, we identified the binding site of two p53 reactivating molecules, RITA (reactivation of p53 and induction of tumor cell apoptosis) and protoporphyrin IX (PpIX). Ion mobility-mass spectrometry revealed that the binding of RITA to serine 33 and serine 37 is responsible for inducing the allosteric shift in p53, which shields the MDM2 binding residues of p53 and prevents its interactions with MDM2 and MDM4. Our results point to an alternative mechanism of blocking p53 interaction with MDM2 and MDM4 and may pave the way for the development of novel allosteric inhibitors of p53/MDM2 and p53/MDM4 interactions

Novel allosteric mechanism of p53 activation by small molecules for targeted anticancer therapy

Given the immense significance of p53 restoration for anti-cancer therapy and that p53-activating molecules are in clinical trials, elucidation of the mechanisms of action of p53-activating molecules is of the utmost importance. Here we report a discovery of a novel allosteric modulation of p53 by small molecules, which is an unexpected turn in the p53 story. We identified a structural element involved in allosteric regulation of p53, whose targeting by small molecules RITA, PpIX and licofelone blocks the binding of two p53 inhibitors, MDM2 and MDMX, thereby restoring p53 function. Deletion and mutation analysis followed by molecular modeling and its thorough validation, identified the key p53 residues S33 and S37 targeted by RITA and PpIX. We propose that the binding of small molecules to the identified site in p53 induces a conformational trap preventing p53 from the interaction with MDM2 and MDMX. These results point to a high potential of allosteric activators as targeted drugs. Our study provides a basis for the development of therapeutics with a novel mechanism of action, thus extending the p53 pharmacopeia

Novel Allosteric Mechanism of Dual p53/MDM2 and p53/MDM4 Inhibition by a Small Molecule

Restoration of the p53 tumor suppressor for personalised cancer therapy is a promising treatment strategy. However, several high-affinity MDM2 inhibitors have shown substantial side effects in clinical trials. Thus, elucidation of the molecular mechanisms of action of p53 reactivating molecules with alternative functional principle is of the utmost importance. Here, we report a discovery of a novel allosteric mechanism of p53 reactivation through targeting the p53 N-terminus which promotes inhibition of both p53/MDM2 (murine double minute 2) and p53/MDM4 interactions. Using biochemical assays and molecular docking, we identified the binding site of two p53 reactivating molecules, RITA (reactivation of p53 and induction of tumor cell apoptosis) and protoporphyrin IX (PpIX). Ion mobility-mass spectrometry revealed that the binding of RITA to serine 33 and serine 37 is responsible for inducing the allosteric shift in p53, which shields the MDM2 binding residues of p53 and prevents its interactions with MDM2 and MDM4. Our results point to an alternative mechanism of blocking p53 interaction with MDM2 and MDM4 and may pave the way for the development of novel allosteric inhibitors of p53/MDM2 and p53/MDM4 interactions

Evaluation of Liver Transplantation Among Advanced Age Recipients in a Large Multicenter U. S. Cohort

Purpose: The proportion of adults \u3e70 years (y) listed for liver transplant (LT) in the U. S. is rising. Outcomes in this growing population are limited to small, single-center cohorts or national database studies that lack granularity. We aimed to better characterize outcomes in LT recipients \u3e70y in a large multicenter cohort. Methods: All primaty LT recipients (LTR) \u3e65y~who underwent LT from 2010-16 at 13 centers were included. For LTRs \u3e70y, survival was estimated using Kaplan-Meier methods; other outcomes were assessed within ly post-LT and compared toLTRs\u3c70y. Results: Of 179 LTRs \u3e70y, median was age 71y (range 70-78), 64% were male. and 770/c Caucasian. Leading indications for LT were NASH (27%), alcohol (11%). HCV (17%). 52% had HCC, of which 63% had MELD exceptions. Median laboratory MELDNa at LT was 19 (IQR 13-26), and median allocation MELD was 22 (IQR16-29). Comorbidities included diabetes (39%), congestive heart failure (8%), cerebrovascular disease (6%), chronic pulmonaty disease (11%), renal disease (38%). and osteoporosis/osteopenia (42%). The median donor age was 48y (33-62); 8% were donations after cardiac death, 10% living donation LT, and 6% SLK During LT, 1. 70/0 received induction with a T-cell depleting agent compared to 9% of LTRs \u3c70y in the cohort. At discharge, 77% were on calcineurin inhibitors and 73% on steroids vs 85% and 84% respectively, of LTRs \u3c70y. Within ly post-LT, graft rejection occurred in 18% and biliary strictures in 26%. Cardiovascular complications occurred in 25% (12% afib, 3% MI, 8% stroke and 9% heart failure), delirium in 16% and seizures in 3%. Viral, bacterial and fungal infections occurred ly post-LT in 17% 39% and 7% respectively. Solid organ cancers ly post-LT occurred in 10% with recurrent HCC (40/0) and lung cancer (2%) being the most common; this is compared to 4% in the cohort \u3c70y (p=0. 002). One-year and three-year patient survival was 89% and 76% respectively, vs 90% and 84% in \u3c70y. Conclusions: In a large US multicenter cohort, ly and 3y survival in LTRs \u3e70y were acceptable. De novo solid organ cancers within ly post-LT occurred in 10% of LTRs \u3e70y, more frequently than in those \u3c70y. Our data provide further understanding of the comorbidities experienced in advanced age LTRs and lay the foundation for improved selection and management of older LTRs