Metformin Enhances Cisplatin-Induced Apoptosis and Prevents Resistance to Cisplatin in Co-mutated KRAS/LKB1 NSCLC

Introduction

We hypothesized that activating KRAS mutations and inactivation of the liver kinase B1 (LKB1) oncosuppressor can cooperate to sustain NSCLC aggressiveness. We also hypothesized that the growth advantage of KRAS/LKB1 co-mutated tumors could be balanced by higher sensitivity to metabolic stress conditions, such as metformin treatment, thus revealing new strategies to target this aggressive NSCLC subtype.

Induction chemotherapy followed by simultaneous hyperfractionated radiochemotherapy in advanced head and neck cancer

Purpose

To evaluate the feasibility of induction chemotherapy followed by concomitant chemotherapy and hyperfractionated irradiation in locally advanced, inoperable head and neck cancer.

Methods

A pilot study was undertaken comprising 3 cycles of cisplatinum (100 mg/m², day 1) and 5-fluorouracil (1000 mg/m² in continuous intravenous infusion over the first 120 h) followed by bifractionated radiotherapy applied to tumor/involved lymph nodes up to the dose of 74.4 Gy given in 2 fractions of 1.2 Gy daily for 5 days a week combined with concomitant weekly cisplatinum infusion (50 mg/m²).

Results

Six patients were enrolled in the study. All of them completed the protocol therapy. Severe mucositis and myelotoxicity were the most common acute side effects observed in all and in 5 of the patients, respectively. Acute toxicity required interruption of concomitant chemotherapy in 5 cases and in 2 interruption of radiotherapy was necessary. Opioid analgesic parenteral therapy was administered in 4 patients. Three of them had to be hospitalized. One patient experienced cerebral stroke 1 day after the completion of therapy and died 7 days later. Due to high acute toxicity, patient accrual was terminated after 6 patients. At the mean follow-up of 17 months, 4 patients are alive, 3 of them are free of disease and in 1 local progression has been diagnosed.

Conclusions

High acute toxicity of induction cisplatinum and 5-fluorouracil followed by concomitant cisplatinum and hyperfractionated irradiation calls for less toxic treatment schedules in locally advanced inoperable head and neck cancer.     

Effects of Chlamydia trachomatis infection on the expression of natural killer (NK) cell ligands and susceptibility to NK cell lysis

Natural killer (NK) cells are an important component of the immediate immune response to infections, including infection by intracellular bacteria. We have investigated recognition of Chlamydia trachomatis (CT) by NK cells and show that these cells are activated to produce interferon (IFN)-gamma when peripheral blood mononuclear cells (PBMC) are stimulated with CT organisms. Furthermore, infection of epithelial cell lines with CT renders them susceptible to lysis by human NK cells. Susceptibility was observed 18-24 h following infection and required protein synthesis by the infecting chlamydiae, but not by the host cell; heat or UV inactivated chlamydiae did not induce susceptibility to NK cell lysis. CT infection was also shown to decrease the expression of classical and non-classical major histocompatibility complex (MHC) molecules on infected cells, thus allowing recognition by NK cells when combined with an activating signal. A candidate activating signal is MICA/B, which was shown to be expressed constitutively on epithelial cells.     

Degradation and cell culture studies on block copolymers prepared by ring opening polymerization of epsilon-caprolactone in the presence of poly(ethylene glycol)

Poly(epsilon-caprolactone) (PCL) and its block copolymers with poly(ethylene glycol) (PEG) were prepared by ring-opening polymerization of epsilon-caprolactone in the presence of ethylene glycol or PEG, using zinc metal as catalyst. The resulting polymers were characterized by various analytical techniques such as (1)H NMR, SEC, DSC, IR, X-ray, ESEM, and CZE. PCL/PEG copolymers with long PCL chains presented the same crystalline structure as PCL homopolymer, whereas PEG-bearing short PCL blocks retained the crystalline structure of PEG and exhibited an amphiphilic behavior in aqueous solutions. Degradation of PCL and PCL/PEG diblock and triblock copolymers was realized in a 0.13 M, pH 7.4 phosphate buffer at 37 degrees C. The results indicated that the copolymers exhibited higher hydrophilicity and degradability compared with the PCL homopolymer. Large amounts of PEG were released from the bulk after 60 weeks' degradation. In vitro cell culture studies were conducted on scaffolds manufactured via solid free form fabrication by using primary human and rat bone marrow derived stromal cells (hMSC, rMSC). Light, scanning electron, and confocal laser microscopy, as well as immunocytochemistry, showed cell attachment, proliferation, and extracellular matrix production on the surface, as well as inside the scaffold architecture. Copolymers showed better performance in the cell culture studies than the PCL homopolymer.     

Oral health–related food selectivity among French independently living elders

Impaired oral conditions are described as influencing food intake behaviour and contributing to poor nutritional status in elderly persons. In order to evaluate the influence of age and oral factors on food choice among independently living elderly, we investigated food selectivity and oral health status in elders (aged over 65 years) and in younger people (aged between 35 and 64 years). Food selective behaviour was appraised by using a food selectivity questionnaire based on traditional French dishes. A stepwise binary logistic regression analysis was done to sequentially identify age and oral conditions associated with oral discomfort–related food avoidance. Occlusal status and oral health–related quality of life contributed to food choice. Risk of oral discomfort–related food avoidance was significantly increased in people with fewer than seven occlusal functional units (OFUs) and with Geriatric Oral Health Assessment Index summary scores (GOHAI-ADD) indicating poor and average oral health–related quality of life (P < .05). Age was never a significant factor of food selective behaviour. The present data support the impact of occlusal status and oral health–related quality of life on food behaviour. Specific attention should be given in maintaining or restoring good oral conditions throughout the lifespan, especially occluding teeth.