Saliva is a reliable and practical source of germline DNA for genome-wide studies in chronic lymphocytic leukemia

High-throughput genomics requires tumor DNA matched to germline DNA, that cannot be easily obtained in the context of leukemia. Using chronic lymphocytic leukemia as a model, saliva DNA was frequently devoid of tumor DNA also during overt disease, and passed quality controls for SNP-array (77/102, 75.4%) and next generation sequencing (71/102, 69.6%). Compared to saliva, urine provides germline DNA of similar quality but in lower amounts. Saliva DNA was successfully run on SNP 6.0 arrays, and passed quality control call rate thresholds. On these bases, saliva represents a useful source of germline DNA for high-throughput genomic studies of hematologic neoplasia.     

N-Hydroxyindole-based inhibitors of lactate dehydrogenase against cancer cell proliferation

Current cancer research is being increasingly focused on the study of distinctive characters of tumour metabolism, resulting in a switch from oxidative phosphorylation to glycolysis (Warburg effect). Isoform 5 of human lactate dehydrogenase (hLDH5), which catalyzes the final step in the glycolytic cascade (pyruvate to lactate), constitutes a relatively new and untapped anti-cancer target. In this study, careful design and synthesis of a selected series of aryl-substituted N-hydroxyindole-2-carboxylates (NHIs) has led to several hLDH5-inhibitors, showing “first-in-class” potency and isoform selectivity. Enzyme kinetics studies indicated that these inhibitors exhibit a competitive mode of inhibition. Some representative examples were tested against two human pancreatic carcinoma cell lines, and displayed a good anti-proliferative activity, which was even more evident under hypoxic conditions.     

Acute strongyloidiasis in Italian tourists returning from Southeast Asia

Strongyloidiasis is a soil-transmitted helmithiasis with worldwide distribution. Contrary to chronic form, hyperinfestation and life-threatening dissemination, first (invasive) stages of the disease are not well characterized. This paper describes two cases of acute strongyloidiasis in travelers returning from Southeast Asia and highlights the need to take strongyloidiasis into account also among acute travel-related illnesses.     

Effect of AeroChamber Plus™ on the lung and systemic bioavailability of beclometasone dipropionate/formoterol pMDI

AIM

To assess the effect of AeroChamber Plus™ on lung deposition and systemic exposure to extra-fine beclometasone dipropionate (BDP)/formoterol (100/6 µg) pMDI (Foster®). The lung deposition of the components of the combination given with the pMDI was also evaluated using the charcoal block technique.

METHODS

Twelve healthy male volunteers received four inhalations of extra-fine BDP/formoterol (100/6 µg) using (i) pMDI alone, (ii) pMDI and AeroChamber Plus™ and (iii) pMDI and charcoal ingestion.

RESULTS

Compared with pMDI alone, use of AeroChamber Plus™ increased the peak plasma concentrations (C_max) of BDP (2822.3 ± 1449.9 vs. 5454.9 ± 3197.1 pg ml⁻¹), its active metabolite beclometasone 17-monopropionate (17-BMP) (771.6 ± 288.7 vs. 1138.9 ± 495.6 pg ml⁻¹) and formoterol (38.4 ± 17.8 vs. 54.7 ± 20.0 pg ml⁻¹). For 17-BMP and formoterol, the AUC(0,30 min), indicative of lung deposition, was increased in the AeroChamber Plus™ group by 41% and 45%, respectively. This increase was mainly observed in subjects with inadequate inhalation technique. However, use of AeroChamber Plus™ did not increase the total systemic exposure to 17-BMP and formoterol. Results after ingestion of charcoal confirmed that AUC(0,30 min) can be taken as an index of lung bioavailability and that more than 30% of the inhaled dose of extra-fine BDP/formoterol 100/6 µg was delivered to the lung using the pMDI alone.

CONCLUSIONS

The use of AeroChamber Plus™ optimizes the delivery of BDP and formoterol to the lung in subjects with inadequate inhalation technique. The total systemic exposure was not increased, supporting the safety of extra-fine BDP/formoterol pMDI with AeroChamber Plus™.     

Covalent inhibitors of fatty acid amide hydrolase: a rationale for the activity of piperidine and piperazine aryl ureas

Recently, covalent drugs have attracted great interest in the drug discovery community, with successful examples that have demonstrated their therapeutic effects. Here, we focus on the covalent inhibition of the fatty acid amide hydrolase (FAAH), which is a promising strategy in the treatment of pain and inflammation. Among the most recent and potent FAAH inhibitors (FAAHi), there are the cyclic piperidine and piperazine aryl ureas. FAAH hydrolyzes efficiently the amide bond of these compounds, forming a covalent enzyme-inhibitor adduct. To rationalize this experimental evidence, we performed an extensive computational analysis centered on piperidine-based PF750 (1) and piperazine-based JNJ1661010 (2), two potent lead compounds used to generate covalent inhibitors as clinical candidates. We found that FAAH induces a distortion of the amide bond of the piperidine and piperazine aryl ureas. Quantum mechanics/molecular mechanics ΔE(LUMO-HOMO) energies indicate that the observed enzyme-induced distortion of the amide bond favors the formation of a covalent FAAH-inhibitor adduct. These findings could help in the rational structure-based design of novel covalent FAAHi.     

Beyond anorexia -cachexia. Nutrition and modulation of cancer patients' metabolism: supplementary, complementary or alternative anti-neoplastic therapy?

Anorexia and muscle wasting are frequently observed in cancer patients and influence their clinical outcome. The better understanding of the mechanisms underlying behavioral changes and altered metabolism yielded to the development of specialized nutritional support, which enhances utilization of provided calories and proteins by counteracting some of the metabolic derangements occurring during tumor growth. Inflammation appears to be a key factor determining the cancer-associated biochemical abnormalities eventually leading to anorexia and cachexia. Interestingly, inflammation is also involved in carcinogenesis, cancer progression and metastasis by impairing immune surveillance, among other mechanisms. Therefore, nutritional interventions aiming at modulating inflammation to restore nutritional status may also result in improved response to pharmacological anti-cancer therapies. Recent clinical data show that supplementation with nutrients targeting inflammation and immune system increases response rate and survival in cancer patients. This suggests that nutrition therapy should be considered as an important adjuvant strategy in the multidimensional approach to cancer patients.     

JNK regulates APP cleavage and degradation in a model of Alzheimer's disease

Secretion of Amyloid-beta peptide (Aβ) circulating oligomers and their aggregate forms derived by processing of beta-amyloid precursor protein (APP) are a key event in Alzheimer's disease (AD).We show that phosphorylation of APP on threonine 668 may play a role in APP metabolism in H4-APP^sw cell line, a degenerative AD model. We proved that JNK plays a fundamental role in this phosphorylation since its specific inhibition, with the JNK inhibitor peptide (D-JNKI1), induced APP degradation and prevented APP phosphorylation at T668. This results in a significant drop of βAPPs, Aβ fragments and Aβ circulating oligomers. Moreover the D-JNKI1 treatment produced a switch in the APP metabolism, since the peptide reduced the rate of the amyloidogenic processing in favour of the non-amyloidogenic one. All together our results suggest an important link between APP metabolism and the JNK pathway and contribute to shed light on the molecular signalling pathway of this disease indicating JNK as an innovative target for AD therapy.     

3D-Conformal Versus Intensity-Modulated Postoperative Radiotherapy of Vaginal Vault: A Dosimetric Comparison

We evaluated a step-and-shoot IMRT plan in the postoperative irradiation of the vaginal vault compared with equispaced beam arrangements (3–5) 3D-radiotherapy (RT) optimized plans. Twelve patients were included in this analysis. Four plans for each patient were compared in terms of dose-volume histograms, homogeneity index (HI), and conformity index (CI): (1) 3 equispaced beam arrangement 3D-RT; (2) 4 equispaced beam arrangement 3D-RT; (3) 5 equispaced beam arrangement 3D-RT; (4) step-and-shoot IMRT technique. CI showed a good discrimination between the four plans. The mean scores of CI were 0.58 (range: 0.38–0.67) for the 3F-CRT plan, 0.58 (range: 0.41–0.66) for 4F-CRT, 0.62 (range: 0.43–0.68) for 5F-CRT and 0.69 (range: 0.58–0.78) for the IMRT plan. A significant improvement of the conformity was reached by the IMRT plan (p < 0.001 for all comparisons). As expected, the increment of 3D-CRT fields was associated with an improvement of target dose conformity and homogeneity; on the contrary, in the IMRT plans, a better conformity was associated to a worse target dose homogeneity. A significant reduction in terms of D_mean, V90%, V95%, V100% was recorded for rectal and bladder irradiation with the IMRT plan. Surprisingly, IMRT supplied a significant dose reduction also for rectum and bladder V30% and V50%. A significant dosimetric advantage of IMRT over 3D-RT in the adjuvant treatment of vaginal vault alone in terms of treatment conformity and rectum and bladder sparing is shown.     

Intra-articular benign bone lesions treated with Magnetic Resonance-guided Focused Ultrasound (MRgFUS): imaging follow-up and clinical results

Purpose of this study was to evaluate the employment of MRI-guided Focused Ultrasound (MRgFUS) for treatment of intra-articular benign bone lesions as alternative to surgery, and to monitor the success of the treatment on CT and MRI images. From March 2011 to August 2013, 14 intra-articular benign bone lesions were treated with MRgFUS. All patients were studied by CT and MR imaging. Pain was measured using the visual analogue scale (VAS) before and after treatment (6 and 12 months). All patients in our series demonstrated regression in painful symptomatology during screening. A significant drop in the mean VAS pain score (from 7.8 to 0.6) was observed at 12-month follow-up, and pain medication was no longer needed after treatment. No complications were observed. Three diagnostic imaging signs were found suggesting absence of biological activity and confirming the clinical findings: calcification of the treated lesion, lack of contrast enhancement and disappearance of bone oedema around the lesions. Conclusion: the employment of MRgFUS is safe and effective in the treatment of intra-articular benign bone lesions. The clinical outcome is satisfactory, and the success of the treatment is confirmed by diagnostic imaging.     

Current Trends in the Use of Bowel Preparation for Colorectal Surgery

Purpose of Review

This article reviews recent findings in the use of bowel preparation for preventing infectious complications after colorectal surgery.

Recent Findings

Whereas mechanical bowel preparation (MBP) was formerly used routinely in combination with prophylactic non-absorbable oral antibiotics (OAs) and prophylactic intravenous antibiotics, there was a trend toward omitting OAs in the 1990s and early 2000s. Since the mid-2000s, the use of MBP has declined given evidence of the limited role of MBP alone in preventing infectious complications. However, recent studies have demonstrated favorable outcomes after MBP when used in combination with OAs.

Summary

Results from recent studies have prompted surgeons to reexamine the appropriate regimen for preoperative bowel preparation. The principal question that should now be addressed by future research is whether OAs alone reduce surgical infectious complications after colorectal surgery.