Calcium inhibits promotion by hot dog of 1,2‐dimethylhydrazine‐induced mucin‐depleted foci in rat colon

Epidemiology suggests that processed meat is associated with colorectal cancer risk, but few experimental studies support this association. We have shown that a model of cured meat made in a pilot workshop promotes preneoplastic lesions, mucin‐depleted foci (MDF) in the colon of rats. This study had two aims: to check if real store‐bought processed meats also promote MDF, and to test if calcium carbonate, which suppresses heme‐induced promotion, can suppress promotion by processed meat. A 14‐day study was done to test the effect of nine purchased cured meats on fecal and urinary biomarkers associated with heme‐induced carcinogenesis promotion. Fecal water from rats given hot dog or fermented raw dry sausage was particularly cytotoxic. These two cured meats were thus given to rats pretreated with 1,2‐dimethylhydrazine, to evaluate their effect on colorectal carcinogenesis. After a 100‐days feeding period, fecal apparent total N‐nitroso compounds (ATNC) were assayed and colons were scored for MDF. Hot dog diet increased fecal ATNC and the number of MDF per colon compared with the no‐meat control diet (3.0 ± 1.7 vs. 1.2 ± 1.4, p < 0.05). In a third study, addition of calcium carbonate (150 µmol/g) to the hot dog diet decreased the number of MDF/colon and fecal ATNC compared with the hot dog diet without calcium carbonate (1.2 ± 1.1 vs. 2.3 ± 1.4, respectively, p < 0.05). This is the first experimental evidence that a widely consumed processed meat promotes colon carcinogenesis in rats. It also shows that dietary prevention of this detrimental effect is possible.     

Acetyltransferases (HATs) as Targets for Neurological Therapeutics

The acetylation of histone and non-histone proteins controls a great deal of cellular functions, thereby affecting the entire organism, including the brain. Acetylation modifications are mediated through histone acetyltransferases (HAT) and deacetylases (HDAC), and the balance of these enzymes regulates neuronal homeostasis, maintaining the pre-existing acetyl marks responsible for the global chromatin structure, as well as regulating specific dynamic acetyl marks that respond to changes and facilitate neurons to encode and strengthen long-term events in the brain circuitry (e.g., memory formation). Unfortunately, the dysfunction of these finely-tuned regulations might lead to pathological conditions, and the deregulation of the HAT/HDAC balance has been implicated in neurological disorders. During the last decade, research has focused on HDAC inhibitors that induce a histone hyperacetylated state to compensate acetylation deficits. The use of these inhibitors as a therapeutic option was efficient in several animal models of neurological disorders. The elaboration of new cell-permeant HAT activators opens a new era of research on acetylation regulation. Although pathological animal models have not been tested yet, HAT activator molecules have already proven to be beneficial in ameliorating brain functions associated with learning and memory, and adult neurogenesis in wild-type animals. Thus, HAT activator molecules contribute to an exciting area of research.     

Seek and destroy: improving PK/PD profiles of anticancer agents with nanoparticles

Introduction: The Pharmacokinetics/pharmacodynamics (PK/PD) relationships with cytotoxics are usually based on a steepening concentration–effect relationship; the greater the drug amount, the greater the effect. The Maximum Tolerated Dose paradigm, finding the balance between efficacy, while keeping toxicities at their manageable level, has been the rule of thumb for the last 50-years. Developing nanodrugs is an appealing strategy to help broaden this therapeutic window. The fact that efficacy and toxicity with cytotoxics are intricately linked is primarily due to the complete lack of specificity toward the tumor tissue during their distribution phase. Because nanoparticles are expected to better target tumor tissue while sparing healthy cells, accumulating large amounts of cytotoxics in tumors could be achieved in a safer way.

Areas covered: This review aims at presenting how nanodrugs present unique features leading to reconsidering PK/PD relationships of anticancer agents.

Expert commentary: The constant interplay between carrier PK, interactions with cancer cells, payload release, payload PK, target expression and target engagement, makes picturing the exact PK/PD relationships of nanodrugs particularly challenging. However, those improved PK/PD relationships now make the once contradictory higher efficacy and lower toxicities requirement an achievable goal in cancer patients.     

Concomitant administration of live attenuated Japanese encephalitis chimeric virus vaccine (JE-CV) and measles,mumps, rubella (MMR) vaccine: Randomized study in toddlers in Taiwan

Background

Japanese encephalitis (JE) is the most important cause of viral encephalitis in Asia.

Methods

In this randomized, open-label, multicenter trial in 550 children aged 12 to 18 months in Taiwan, children received one dose of JE-CV and one dose of MMR vaccine. Vaccines were either administered separately 6 weeks apart (Groups ‘JE-CV’ and ‘MMR’, named after which vaccine was given first), or concomitantly (Group ‘Co-Ad’). JE neutralizing antibody titers were assessed using PRNT₅₀. MMR antibody levels were determined by ELISA.

Results

All groups had low seroprotection/seropositivity rates (<10%) before vaccination for all antigens. Forty two days after vaccination, on either Study Day 42 or 84, seroconversion rates for all antigens were high in all groups, irrespective of the order of vaccinations. Seroconversion for JE ranged from 96.9% in Group Co-Ad on D42 to 100% in Group MMR. Non-inferiority was demonstrated for all analyses as the lower bound of the 95% CI of the difference in seroconversion rates between groups was above the pre-defined limit of −10.0%. The immune responses remained high for all antigens and well above the level of protection 12 months after vaccination in all groups. There were no safety concerns.

Conclusions

JE-CV is safe and induces a strong protective immune response which persists over 1 year when co-administered with MMR vaccine.     

Partial cricotracheal resection for pediatric subglottic stenosis: long-term outcome in 57 patients

OBJECTIVE: We sought to assess the long-term outcome of 57 pediatric patients who underwent partial cricotracheal resection for subglottic stenosis. METHODS: Eighty-one pediatric partial cricotracheal resections were performed in our tertiary care institution between 1978 and 2004. Fifty-seven patients had a minimal follow-up time of 1 year and were included in this study. Evaluation was based on the last laryngotracheal endoscopy, the responses to a questionnaire, and a retrospective review of the patient's data. The following parameters were analyzed: decannulation rates, breathing, voice quality, and deglutition. RESULTS: A single-stage partial cricotracheal resection was performed in 38 patients, and a double-stage procedure was performed in 19 patients. Sixteen patients underwent an extended partial cricotracheal resection (ie, partial cricotracheal resection combined with another open procedure). At a median follow-up time of 5.1 years, the decannulation rates after a single- or double-stage procedure were 97.4% and 95%, respectively. Two patients remained tracheotomy dependent. One patient had moderate exertional dyspnea, and all other patients had no exertional dyspnea. Voice quality was found to improve after surgical intervention for 1 +/- 1.34 grade dysphonia (P < .0001) according to the adapted GRBAS grading system (Grade, Roughness, Breathiness, Asthenia, and Strain). CONCLUSIONS: Partial cricotracheal resection provides good results for grades III and IV subglottic stenosis as primary or salvage operations. The procedure has no deleterious effects on laryngeal growth and function. The quality of voice significantly improves after surgical intervention but largely depends on the preoperative condition.     

Follicular adenoma in a juxtathyroidal thyroglossal duct cyst with papillary carcinoma in the adjacent thyroid gland

This patient presented with a neck mass diagnosed as a papillary thyroid carcinoma by fine-needle aspiration. Preoperative computed tomography revealed a papillary carcinoma within a juxtathyroidal thyroglossal duct cyst. After surgery, the initial diagnosis was papillary thyroid carcinoma. After correlation with the computed tomography, the diagnosis was revised to a papillary thyroid carcinoma plus a follicular adenoma in a juxtathyroidal thyroglossal duct cyst. This case demonstrates the need for close clinical and radiographic correlation in such a complex case.