Activation of the p53 pathway by small-molecule-induced MDM2 and MDMX dimerization

Activation of p53 tumor suppressor by antagonizing its negative regulator murine double minute (MDM)2 has been considered an attractive strategy for cancer therapy and several classes of p53-MDM2 binding inhibitors have been developed. However, these compounds do not inhibit the p53-MDMX interaction, and their effectiveness can be compromised in tumors overexpressing MDMX. Here, we identify small molecules that potently block p53 binding with both MDM2 and MDMX by inhibitor-driven homo- and/or heterodimerization of MDM2 and MDMX proteins. Structural studies revealed that the inhibitors bind into and occlude the p53 pockets of MDM2 and MDMX by inducing the formation of dimeric protein complexes kept together by a dimeric small-molecule core. This mode of action effectively stabilized p53 and activated p53 signaling in cancer cells, leading to cell cycle arrest and apoptosis. Dual MDM2/MDMX antagonists restored p53 apoptotic activity in the presence of high levels of MDMX and may offer a more effective therapeutic modality for MDMX-overexpressing cancers.     

Rhino/enteroviruses in hospitalized children: A comparison to influenza viruses

BackgroundThe relative impact of human rhino/enteroviruses (HRV/EV) compared to influenza viruses on hospitalized children is unknown.ObjectivesThis retrospective study compared the epidemiology and clinical characteristics of hospitalized patients with HRV/EV to patients hospitalized with influenza virus.Study designRespiratory specimens from hospitalized children submitted between January 1, 2009 and December 31, 2009 to Children's Hospital Colorado Virology Laboratory in Aurora, CO were tested by a commercial multiplex PCR for 16 respiratory viruses and subtypes. Patients with specimens positive for HRV/EV or influenza virus without bacterial or viral co-infection were selected for retrospective chart review.ResultsOf the 2299 patients with specimens tested during the study period, 427 (18.6%) were singly positive for HRV/EV and 202 (8.8%) for influenza virus (p < 0.01). Children with HRV/EV were more likely to present with increased work of breathing (67.9% vs. 52.5%, p < 0.01) with crackles (36.3% vs. 23.3%, p < 0.01) and wheezing (41.7% vs. 22.8%, p < 0.01) noted on exam. Children hospitalized with HRV/EV had a shorter median length of stay (2 days vs. 3 days, p < 0.01), duration of fever (1 days vs. 3 days, p < 0.01), and duration of hypoxemia (2 days vs. 3 days, p < 0.01) than children with influenza virus. Similar percentages of children with HRV/EV and influenza virus were admitted to the PICU and required positive pressure ventilation. There were no deaths in children hospitalized with HRV/EV, whereas 6 children with influenza virus expired.ConclusionsHRV/EVs are common pathogens in hospitalized children associated with serious lower respiratory tract disease and significant morbidity, similar to influenza viruses.     

Greater Arch Injuries

Dislocations and fracture dislocations of carpal bones are uncommon injuries which invariably poses challenges in the management. Perilunate fracture dislocations are the combination of ligamentous and osseous injury that involve the “greater arc” of the perilunate associated instability. Despite their severity, these injuries often go unrecognized in the emergency department leading to delayed diagnosis and treatment. A Prospective study was done from June 2008 to December 2013 in 15 cases of complex wrist injuries which included of greater arch injuries, perilunate fracture dislocation and one dorsal dislocation of Scaphoid. 10 cases of perilunate fracture dislocation underwent open reduction and internal fixation with Herbert screw and k-wire, 4 cases of greater arch injury underwent closed reduction and kwire fixation and one case of neglected dorsal dislocation underwent proximal row carpectomy. One patient had Sudecks osteodystrophy 1 had Scaphoid nonunion and 6 had median nerve compression. Overall outcome according to Mayo wrist score was 53 % excellent, 33 % good and 14 % fair. Greater arch injuries are difficult to treat because injuries to many ligaments are involved and failure to recognize early leads to persistent pain, disability and early onset of arthritis. Prompt recognition requires CT scan and MRI. Management requires reduction and multiple K-Wiring according to merits of the case.     

Oral Verrucous Hyperplasia: A Case Report

Oral verrucous hyperplasia is a whitish or pinkinsh elevated pre malignant lesion which occurs rarely. Its is also considered to be an early form of verrucous carcinoma. We have reported a case of verrucous hyperplasia which was diagnosed and treated with buccal fat pad as graft.     

Ethnomedical value of Cissampelos pareira extract in experimentally induced diarrhoea

The antidiarrhoeal activity of the ethanolic extract of Cissampelos pareira (Menispermaceae) roots was assessed on experimental animals. The hydroethanolic extract (25-100 mg dry extract kg(-1) body mass, p.o.) exhibited a dose dependent decrease in the total number of faecal droppings (control 65, reduced to 26-46) and 29.2-60.0% inhibition in castor oil-induced diarrhoea. Further, C. pareira produced a significant (p < 0.01) and dose dependent reduction in intestinal fluids accumulation (26.0-59.0%). The extract showed a greater inhibitory effect on the concentration of Na+ (20.0 and 34.5%) than on the concentration of K+ (6.7 and 9.4%). The extract also reduced dose dependently the gastrointestinal transit from 46.4 and 38.7%, equivalent to 53.6 and 61.3%. However, C. pareira significantly reduced the lipid peroxidation and inhibited the decrease in antioxidant enzyme levels (superoxide dismutase and catalase) on prior administration to castor oil-induced fluid accumulation. The extract of C. pareira had no effect on normal defecation at 25 mg kg(-1) in mice. However, 50 and 100 mg kg(-1) inhibited defecation by 100% in the initial 2 h and the activity was reduced to 40.0 and 73.0%, respectively, in the third hour.     

Peripheral ossifying fibroma: A clinical report

The gingiva is often the site of localized growths that are considered to be reactive rather than neoplastic in nature. Many of these lesions are difficult to be identified clinically and can be identified as specific entity only on the basis of typical and consistent histomorphology. Peripheral ossifying fibroma is one such reactive lesion. It has been described with various synonyms and is believed to arise from the periodontal ligament comprising about 9% of all gingival growths. The size of the lesion is usually small, located mainly in the anterior maxilla with a higher predilection for females, and it is more common in the second decade of life. A clinical report of a 12-year-old girl with a large peripheral ossifying fibroma in the posterior maxilla showing significant growth and interference with occlusion is presented.     

Supracondylar skeletal traction and open interlocking nailing for neglected fracture of the shaft of femur – Retrospective study

BackgroundNeglected trauma is a common problem faced by Orthopaedic surgeons practicing in developing countries. Nothing much in English literature is available regarding the practical difficulties and guidelines for treating neglected trauma of long bones.MethodsIn our institution from November 2003 to October 2009 we treated 25 cases of neglected fracture of shaft of femur. Patients underwent either of three types of management protocols depending upon the preoperative manual traction radiographs. The fracture was fixed with open interlocking nail. Primary bone grafting and bone shortening procedures were not performed in any of the patient.ResultsThe fractures united in all patients at an average duration of 17 weeks. Two patients had limb length discrepancy.ConclusionCareful preoperative evaluation is mandatory for good results. Preoperative skeletal traction and two stage surgical procedure may be required to avoid limb length discrepancy and neurovascular complication.     

Hypofractionated accelerated radiotherapy (HART) with concurrent and adjuvant temozolomide in newly diagnosed glioblastoma: a phase II randomized trial (HART-GBM trial)

Introduction

Maximal safe surgical resection followed by adjuvant chemoradiation has been standard for newly diagnosed glioblastoma multiforme (GBM). Hypofractionated accelerated radiotherapy (HART) has the potential to improve outcome as it reduces the overall treatment time and increases the biological effective dose.

Methods

Between October 2011 and July 2017, a total of 89 newly diagnosed GBM patients were randomized to conventional fractionated radiotherapy (CRT) or HART. Radiotherapy was delivered in all patients with a three-dimensional conformal radiotherapy technique in CRT arm (60 Gy in 30 fractions over 6 weeks @ 2 Gy/per fraction) or simultaneous integrated boost intensity modulated radiotherapy in HART arm (60 Gy in 20 fractions over 4 weeks @ 3 Gy/per fraction to high-risk planning target volume (PTV) and 50 Gy in 20 fractions over 4 weeks @ 2.5 Gy/per fraction to low-risk PTV). The primary endpoint of the trial was overall survival (OS).

Results

After a median follow-up of 11.4 months (Range: 2.9–42.5 months), 26 patients died and 39 patients had progression of the disease. Median OS for the entire cohort was 23.4 months. Median OS in the CRT and HART arms were 18.07 months (95% CI 14.52-NR) and 25.18 months (95% CI 12.89-NR) respectively, p?=?0.3. Median progression free survival (PFS) for the entire cohort was 13.5 months (Range: 11.7–15.7 months). In multivariate analysis patients younger than 40 years of age, patients with a gross total resection of tumor and a mutated IDH-1 had significantly better OS. PFS was significantly better for patients with a gross total resection of tumor and a mutated IDH-1. All patients included in the trial completed the planned course of radiation. Only two patients required hospital admission for features of raised intracranial tension. One patient in the HART arm required treatment interruption.

Conclusion

HART is comparable to CRT in terms of survival outcome. HART arm had no excess treatment interruption and minimal toxicity. Dose escalation, reduction in overall treatment time, is the advantages with use of HART.