Dose escalation of tolinapant (ASTX660) in combination with standard radical chemoradiotherapy in cervical cancer : a study protocol for a phase 1b TiTE-CRM clinical trial (CRAIN) in UK secondary care centres.

BACKGROUND: Cervical cancer is the fourth most common cancer in women, with an estimated 342,000 deaths worldwide in 2020. Current standard of care in the UK for locally advanced cervical cancer is concurrent chemoradiotherapy with weekly cisplatin, yet 5-year overall survival rates are only 65% with a distant relapse rate of 50%. Inhibitors of Apoptosis Proteins (IAPs) are often overexpressed in cancer cells and associated with tumour progression and resistance to treatment. Tolinapant, developed by Astex Pharmaceuticals, is an IAP antagonist with an additional mechanism of action via down-regulation of NF-kB, an important regulator in cervical cancer. Preclinical studies performed using tolinapant in combination with cisplatin and radiotherapy showed inhibition of tumour growth and enhanced survival. There is therefore a strong rationale to combine tolinapant with chemoradiotherapy (CRT). METHODS: CRAIN is a phase Ib open-label, dose escalation study to characterise the safety, tolerability and initial evidence for clinical activity of tolinapant when administered in combination with cisplatin based CRT. Up to 42 patients with newly diagnosed cervix cancer will be recruited from six UK secondary care sites. The number of participants and the duration of the trial will depend on toxicities observed and dose escalation decisions, utilising a TiTE-CRM statistical design. Treatment will constist of standard of care CRT with 45 Gy external beam radiotherapy given in 25 daily fractions over 5 weeks with weekly cisplatin 40mg/m2. This is followed by brachytherapy for which common schedules will be 28 Gy in 4 fractions high-dose-rate or 34 Gy in 2 fractions pulsed-dose-rate. Tolinapant will be administered in fixed dose capsules taken orally daily for seven consecutive days as an outpatient on alternate weeks (weeks 1, 3, 5) during chemoradiation. Dose levels for tolinapant which will be assessed are: 60 mg; 90 mg (starting level); 120 mg; 150 mg; 180 mg. Escalation will be guided by emerging safety data and decisions by the Safety Review Committee. DISCUSSION: If this trial determines a recommended phase II dose and shows tolinapant to be safe and effective in combination with CRT, it would warrant future phase trials. Ultimately, we hope to provide a synergistic treatment option for these patients to improve outcome. TRIAL REGISTRATIONS: EudraCT Number: 2021-006555-34 (issued 30th November 2021); ISRCTN18574865 (registered 30th August 2022).

Ozonated water as an irrigant in disinfecting root canal systems - a systematic review.

Aim To evaluate the efficacy of ozonated water as an irrigant in disinfection of the root canal system.Materials and methods This systematic review was conducted according to PRISMA guidelines and methodological studies were assessed through the Cochrane Risk of Bias tool. All studies on extracted human teeth using ozonated water were considered for the study, whereas ex vivo studies, studies on animal dentition and studies which were published in languages other than English were excluded from the study. The search was carried out on various databases such as PubMed, Google Scholar and ScienceDirect within the last 15 years. The assessment of quality of the studies was performed under the following: 1) size of sample; 2) control group; 3) standardisation of procedure; 4) statistical analysis performed; 5) risk of bias.Results There were a total of 154 study results, out of which duplicates and full-text analysis were excluded. A total of seven studies were included in the systematic review. The results in one study by Cardoso et al. showed ozonated water was better at reducing microbial counts, while two other studies demonstrated the difference in reducing microbial counts when comparing ozonated water against other irrigants. The remaining four studies concluded that ozonated water did not perform better as compared to the other irrigants such as sodium hypochlorite and chlorhexidine.Discussion It could be concluded that ozonated water is not a better disinfecting irrigant than sodium hypochlorite and chlorhexidine in the disinfection of the root canal system; however, it had an almost comparable level of disinfection.

Expression of an S phase-stabilized version of the CDK inhibitor Dacapo can alter endoreplication.

In developing organisms, divergence from the canonical cell division cycle is often necessary to ensure the proper growth, differentiation, and physiological function of a variety of tissues. An important example is endoreplication, in which endocycling cells alternate between G and S phase without intervening mitosis or cytokinesis, resulting in polyploidy. Although significantly different from the canonical cell cycle, endocycles use regulatory pathways that also function in diploid cells, particularly those involved in S phase entry and progression. A key S phase regulator is the Cyclin E-Cdk2 kinase, which must alternate between periods of high (S phase) and low (G phase) activity in order for endocycling cells to achieve repeated rounds of S phase and polyploidy. The mechanisms that drive these oscillations of Cyclin E-Cdk2 activity are not fully understood. Here, we show that the Drosophila Cyclin E-Cdk2 inhibitor Dacapo (Dap) is targeted for destruction during S phase via a PIP degron, contributing to oscillations of Dap protein accumulation during both mitotic cycles and endocycles. Expression of a PIP degron mutant Dap attenuates endocycle progression but does not obviously affect proliferating diploid cells. A mathematical model of the endocycle predicts that the rate of destruction of Dap during S phase modulates the endocycle by regulating the length of G phase. We propose from this model and our in vivo data that endo S phase-coupled destruction of Dap reduces the threshold of Cyclin E-Cdk2 activity necessary to trigger the subsequent G-S transition, thereby influencing endocycle oscillation frequency and the extent of polyploidy.

The Impact of the Gender on the Pulp Vitality Testing for the Various Types of the Conducting Media: An Original Research.

Introduction: To identify gender-based differences in pulpal sensory thresholds in human teeth utilizing various conducting media. Materials and Methods: The study involved 50 participants of both genders equally distributed. The maxillary central incisors were the teeth selected for the intervention. The three conducting media that were put to the test were Colgate Sensitive Pro-Relief Enamel Repair Toothpaste (CS), Himalaya herbals sensitivity toothpaste (HS), and Lignox 2% gel (LG). Subject's sensory threshold readings as well as the Visual analogue scale (VAS) scores were noted at the tiniest sensation they experienced. Following an ANOVA, a post hoc analysis was performed to confirm the significance between the three media. Results: Lox 2% Jelly significantly reduced sensory threshold values compared to the other conducting media (P < 0.001). Comparing the sensory threshold values of the sexes showed that men have greater values. Male and female readings differed significantly in the Lox 2% Jelly group (P = 0.021), whereas Colgate Sensitive Pro-Relief Enamel Repair Toothpaste, Himalaya herbals sensitivity toothpaste (P < 0.001) groups showed highly significant variances. All the three conducting media had a highly significant variance for the VAS scores. (P < 0.001). Conclusion: The conducting material used and gender affect the pulpal sensory thresholds to electric impulses produced by EPT.

First case of primary appendiceal tuberculosis presented as stump appendicitis.

Tuberculosis (TB) remains as a significant global public health issue, especially in developing and underdeveloped nations. Extrapulmonary TB comprises 20% of the TB cases; of which 34.4% were in the lymphatics, 25.2% pleural, followed by 12.8% gastrointestinal and 9.4% in the central nervous system. Ileocecal involvement is the most common among gastrointestinal TB. Although it can cause secondary damage to the appendix, primary type of appendicular TB is rare and can occur with no other signs of the disease. A high index of suspicion is necessary for early diagnosis and treatment of TB. Similarly, stump appendicitis (SA) is a rare and delayed complication of appendectomy. Here we report a case of primary appendicular TB in a patient presented to a multi-specialty hospital in Kerala, India, with SA.

Analysis of Advances in Research Trends in Robotic and Digital Dentistry: An Original Research.

Introduction: The world has been transformed after invention of robotics, digitalization, and artificial intelligence. Their application in the medical field is well recorded; however, their application in dentistry is still being recognized. Hence, in our study, we aimed to analyze the advances in research trends in the digital and the robotics specifically to the dental fields. Material and Methods: We conducted a search for articles that recorded the use of robots, digitalization, and artificial intelligence in dentistry, specifically in endodontics. We piloted a questionnaire study to evaluate the awareness and application of these technologies by the clinicians. The results are presented as various applications of these technologies and the number of the articles for various terminologies. The application of these technologies was compared between the clinicians using ANOVA, with P < 0.05 being significant. Results: We observed a significant difference between the clinicians regarding the application of these technologies and lower awareness was noted. None of the participants used these technologies in practice. Of the total 20 articles that we had finalized, we observed that these technologies helped in studying the various pathologies and structures that were unviewed previously, as well as treatments, prognosis, and outcomes. Conclusions: There is a low awareness of these advanced technologies and application in routine practice. These technologies show greater precision and accuracy. However, the application of these in daily clinical practice and the economy are to be evaluated.

Recurrent phaeohyphomycosis: a case report.

Phaeohyphomycoses are rare, opportunistic, fungal infections which are usually seen in immunocompromised individuals. We are reporting a case of a 40-year-old man with recurrent cutaneous phaeohyphomycosis, who did not have any clinical evidence of immunodeficiency, who presented with signs which resembled a malignancy of the skin.

Adenocarcinoma of the small bowel: a surgical dilemma.

Malignant tumors of the small intestine are among the rarest types of gastrointestinal cancers. Due to their infrequent occurrence and the multitude of tumor types (viz, adenocarcinomas, carcinoids, sarcomas, and lymphomas), not much is known about their natural history and presentation, and there is often delay in the diagnosis. Adenocarcinoma is the commonest histologic type of small bowel cancer. There are no prospective randomized trials that have elucidated the best diagnostic and therapeutic options for this rare condition. In this article, a case of adenocarcinoma of the jejunum presenting as an abdominal lump is presented, along with a review of the literature.

Characteristics of associated craniofacial trauma in patients with head injuries: An experience with 100 cases.

BACKGROUND: Facial fractures and concomitant cranial injuries carry the significant potential for mortality and neurological morbidity mainly in young adults. AIMS AND OBJECTIVES: To analyze the characteristics of head injuries and associated facial injuries, the management options and outcome following cranio-facial trauma. METHODS: This retrospective review was performed at Justice K. S. Hegde Charitable Hospital, and associated A. B. Shetty Memorial Institute of Dental sciences, Deralakatte, Mangalore. Following Ethical Committee approval, hospital charts and radiographs of 100 consecutive patients of cranio-facial trauma managed at the Department of Oral and Maxillofacial Surgery and Neurosurgery between January 2004 and December 2004 were reviewed. RESULTS: Majority of the patients were in the 2nd to 4th decade (79%) with a male to female ratio of -8.09:1. Road traffic accidents were the common cause of craniofacial trauma in present study (54%) followed by fall from height (30%). Loss of consciousness was the most common clinical symptom (62%) followed by headache (33%). Zygoma was the most commonly fractured facial bone 48.2% (alone 21.2%, in combination 27.2%). Majority of patients had mild head injury and managed conservatively in present series. Causes of surgical intervention for intracranial lesions were compound depressed fracture, contusion and intracranial hematoma. Operative indications for facial fractures were displaced facial bone fractures. Major causes of mortality were associated systemic injuries. CONCLUSION: Adult males are the most common victims in craniofacial trauma, and road traffic accidents were responsible for the majority. Most of the patients sustained mild head injuries and were managed conservatively. Open reduction and internal fixation with miniplates was used for displaced facial bone fractures.