Expression and activity of CYP2E1 in circulating lymphocytes are not altered in diabetic individuals

Cytochrome P4502E1 (CYP2E1) plays an important role in ROS production thus favouring accelerated membrane lipid peroxidation. This isoform is strongly expressed in the liver but it can be also found in lymphocytes. As such, lymphocyte may provide a non-invasive accessible pool for screening CYP2E1 expression in man. We have, therefore, analysed CYP2E1 expression and activity in lymphocyte microsomes from 12 healthy controls, 11 type 1 and 12 type 2 diabetic subjects by using Western blot and enzymatic activities. Immunoblotting did not show difference among CYP2E1 protein bands in controls, type 1 and type 2 diabetics. To assess CYP2E1 activity we used the 7-ethoxy-4-trifluoromethylcoumarin (7-EFC), as a fluorescent substrate. The rate of deethylation of 7-EFC from controls did not differ from type 1 and type 2 diabetic subjects. The lack of any difference in CYP2E1 activity also was confirmed by the NADPH-dependent microsomal lipid peroxidation CCL4-induced assay showing similar peroxidation rates among controls and diabetic subjects. The results show that CYP2E1 expression/activity in lymphocytes is not enhanced in diabetes.     

Involvement of the cannabimimetic compound, N-palmitoyl-ethanolamine, in inflammatory and neuropathic conditions: Review of the available pre-clinical data, and first human studies

The endogenous cannabimimetic compound, and anandamide analogue, N-palmitoyl-ethanolamine (PEA), was shown to exert potent anti-inflammatory and analgesic effects in experimental models of visceral, neuropathic and inflammatory pain by acting via several possible mechanisms. However, only scant data have been reported on the regulation of PEA levels during pathological conditions in animals or, particularly, humans. We review the current literature on PEA and report the results of three separate studies indicating that its concentrations are significantly increased during three different inflammatory and neuropathic conditions, two of which have been assessed in humans, and one in a mouse model. In patients affected with chronic low back pain, blood PEA levels were not significantly different from those of healthy volunteers, but were significantly and differentially increased (1.6-fold, P<0.01, N = 10 per group) 30 min following an osteopathic manipulative treatment. In the second study, the paw skin levels of PEA in mice with streptozotocin-induced diabetic neuropathic pain were found to be significantly higher (1.5-fold, P<0.005, N = 5) than those of control mice. In the third study, colonic PEA levels in biopsies from patients with ulcerative colitis were found to be 1.8-fold higher (P<0.05, N = 8–10) than those in healthy subjects. These heterogeneous data, together with previous findings reviewed here, substantiate the hypothesis that PEA is an endogenous mediator whose levels are increased following neuroinflammatory or neuropathic conditions in both animals and humans, possibly to exert a local anti-inflammatory and analgesic action.     

Metronomic chemotherapy combined with bevacizumab and erlotinib in patients with metastatic HER2-negative breast cancer: clinical and biological activity

BackgroundThe object of this study was to evaluate the safety and efficacy of metronomic chemotherapy in combination with bevacizumab and erlotinib in patients with HER2-negative (HER2^?) metastatic breast cancer (MBC) and poor hormone receptor expression.Patients and MethodsPatients with untreated MBC were candidates to receive metronomic oral capecitabine (500 mg thrice daily) and cyclophosphamide (50 mg daily) plus bevacizumab (15 mg/kg every 3 weeks) and erlotinib (100 mg daily).ResultsOf 24 patients assessable for response, we observed 1 complete response (CR, 4%), 14 partial responses (58%), 5 patients with stable disease greater than 9 weeks' duration (SD, 21%), and 1 patient (4%) with early progression of disease. The overall clinical benefit (CB) (CR + partial response + SD > 24 weeks) was 75% (95% confidence interval [CI], 53%-90%). Median time to progression was 43 weeks (95% CI, 21-69). Patients with low levels of circulating endothelial progenitors (CEPs) at baseline had a significantly improved progression-free survival (PFS). Toxicity was generally mild. Grade 3 toxicity included diarrhea (n = 1), thrombosis (n = 1), and hypertension (n = 2). Grade 2 adverse events included diarrhea (n = 5), hand-foot syndrome (n = 13), and hypertension (n = 4).ConclusionTreatment with metronomic chemotherapy in combination with bevacizumab and erlotinib was effective in HER2^?, estrogen receptor (ER)- and progesterone receptor (PR)-poor advanced breast cancer.     

Evaluation of therapeutic modalities in the control of Hodgkin's disease

The results achieved in three different studies carried out on patients affected by Hodgkin's disease are discussed. In study No. 1, 58 patients with pathological Stage I-II were treated with only a "Mantle" field irradiation. The complete remission (CR) rate was 98% with an actuarial overall survival of 90%, and a median of follow-up of 80 months. Thirty-one percent of patients relapsed. In study No. 2, 42 patients were randomly allocated to receive only MOPP chemotherapy versus extended field irradiation; CR rate was 68 and 95%, respectively (p less than 0.05). The overall survival rate was 100% in the radiotherapy group and 82% in the MOPP group. No relapses have been observed in patients treated with MOPP. In study No. 3, 218 patients affected by advanced Stage HD were randomly treated with 6 cycles of MOPP chemotherapy versus 6 cycles of ABVD chemotherapy. In the MOPP group the CR rate, the relapse-free survival rate (RFS), and overall survival (OS) rates at 60 months were 77, 68, and 76% respectively, whereas, in the ABVD group the CR, the RFS, and OS rates at 60 months were 75, 77 and 80% respectively, (p less than 0.05). These data and statistical comparisons are analyzed.     

Preoperative Chemoradiation for Extraperitoneal T3 Rectal Cancer: Acute Toxicity, Tumor Response, and Sphincter Preservation

Purpose: To evaluate whether or not an intermediate dose of preoperative external radiation therapy intensified by systemic chemotherapy could improve the tumor response, sphincter preservation, and tumor control.

Methods and Materials: Between March 1990 and December 1995, 83 consecutive patients with resectable extraperitoneal adenocarcinoma of the rectum were treated with preoperative chemoradiation: bolus i.v. mitomycin C (MMC), 10 mg/m², Day 1 plus 24-h continuous infusion i.v. 5-fluorouracil (5FU) 1000 mg/m², Days 1–4, and concurrent external beam radiotherapy (37.8 Gy). All but 2 patients had T3 disease. Surgery was performed 4–6 weeks after the end of chemoradiation.

Results: Total Grade 3–4 acute toxicity during chemoradiation was observed in 11 (13%) patients: hematological Grade 3 toxicity was recorded in 8 (10%) patients, and Grade 4 toxicity was recorded in 2 (2%) patients. Grade 3 diarrhea was seen in 2 (2%) patients. No patient had major skin or urological acute toxicity. Two patients had no surgery: 1 died before surgery from septic complications after Grade 4 hematological toxicity; 1 refused surgery and is still alive after 6 years. There was no postoperative mortality and the overall perioperative morbidity rate was 25%. The analysis of tumor response involved 81 patients. Overall, 9% [7] of 81 patients had a complete pathologic response. Comparing the stage at the diagnostic workup with the pathologic stage, tumor downstaging was observed in 46 (57%) patients. We had 7 (9%) pT0, 5 (6%) pT1, 33 (41%) pT2, and 36 (44%) pT3. Nodal status downstaging was detected in 46 patients (57%). No evidence of nodal involvement was observed in 59 patients (73%). The incidence of tumor response was affected significantly by the number of quarters of rectal circumference involved (p = 0.03) and, marginally, by the length of the tumor (p = 0.09). The distance between the lower pole of the tumor and the anorectal ring had no influence. Of the patients, 63 (78%) had a sphincter-saving surgical procedure. In 12 (44%) of 27 patients candidate for an APR, the sphincter was preserved, as it was in 19 (95%) of 20 probable candidates. Lengthening of the distance between the anorectal ring and the lower pole of the tumor > 20 mm was observed in 21 patients (26%). Of 63 patients, 4 (6%) had moderate soilage after the sphincter-saving procedure.

Conclusion: Preoperative combined modality therapy seems to afford some potential advantages in nonrandomized trials: patients are able to tolerate higher chemotherapy doses and they experience a lower acute toxicity. Tumor downstaging and resectability rates are high; sphincter preservation is feasible. Larger T3 tumors remained less influenced by this treatment; thus, taking into account the low toxicity rate recorded, a more aggressive schedule should be applied in these resectable tumors.     

Nosocomial outbreak by NDM-1-producing Klebsiella pneumoniae highly resistant to cefiderocol,Florence, Italy,August 2021 to June 2022

A nosocomial outbreak by cefiderocol (FDC)-resistant NDM-1-producing Klebsiella pneumoniae (NDM-Kp) occurred in a large tertiary care hospital from August 2021–June 2022 in Florence, Italy, an area where NDM-Kp strains have become endemic. Retrospective analysis of NDM-Kp from cases observed in January 2021–June 2022 revealed that 21/52 were FDC-resistant. The outbreak was mostly sustained by clonal expansion of a mutant with inactivated cirA siderophore receptor gene, which exhibited high-level resistance to FDC (MIC ≥ 32 mg/L) and spread independently of FDC exposure.     

Time of Dietary Energy and Nutrient Intake and Body Mass Index in Children: Compositional Data Analysis from the Childhood Obesity Project (CHOP) Trial

Meal timing is suggested to influence the obesity risk in children. Our aim was to analyse the effect of energy and nutrient distributions at eating occasions (EO), including breakfast, lunch, supper, and snacks, on the BMI z-score (zBMI) during childhood in 729 healthy children. BMI and three-day dietary protocols were obtained at 3, 4, 5, 6, and 8 years of age, and dietary data were analysed as the percentage of the mean total energy intake (TEI; %E). Intakes at EOs were transformed via an isometric log–ratio transformation and added as exposure variables to linear mixed-effects models. Stratified analyses by country and recategorization of EOs by adding intake from snacks to respective meals for further analyses were performed. The exclusion of subjects with less than three observations and the exclusion of subjects who skipped one EO or consumed 5% energy or less at one EO were examined in sensitivity analyses. Around 23% of the children were overweight at a given time point. Overweight and normal-weight children showed different distributions of dietary intakes over the day; overweight children consumed higher intakes at lunch and lower intakes of snacks. However, no significant effects of timing of EOs on zBMI were found in regression analyses.     

Instant in situ formation of a polymer film at the water–oil interface

The water–oil interface is an environment that is often found in many contexts of the natural sciences and technological arenas. This interface has always been considered a special environment as it is rich in different phenomena, thus stimulating numerous studies aimed at understanding the abundance of physico-chemical problems that occur there. The intense research activity and the intriguing results that emerged from these investigations have inspired scientists to consider the water–oil interface even as a suitable setting for bottom-up nanofabrication processes, such as molecular self-assembly, or fabrication of nanofilms or nano-devices. On the other hand, biphasic liquid separation is a key enabling technology in many applications, including water treatment for environmental problems. Here we show for the first time an instant nanofabrication strategy of a thin film of biopolymer at the water–oil interface. The polymer film is fabricated in situ, simply by injecting a drop of polymer solution at the interface. Furthermore, we demonstrate that with an appropriate multiple drop delivery it is also possible to quickly produce a large area film (up to 150 cm²). The film inherently separates the two liquids, thus forming a separation layer between them and remains stable at the interface for a long time. Furthermore, we demonstrate the fabrication with different oils, thus suggesting potential exploitation in different fields (e.g. food, pollution, biotechnology). We believe that the new strategy fabrication could inspire different uses and promote applications among the many scenarios already explored or to be studied in the future at this special interface environment.

A completely new method for easy and quick formation of a thin polymer film at the special setting of a stratified oil/water interface. Morphological SEM and quantitative full-field characterization have been reported using digital holography.