Retrospective exploratory analysis of VEGF polymorphisms in the prediction of benefit from first-line FOLFIRI plus bevacizumab in metastatic colorectal cancer

<p>Abstract</p> <p>Background</p> <p>Molecular predictors of bevacizumab efficacy in colorectal cancer have not been identified yet. Specific <it>VEGF </it>polymorphisms may affect gene transcription and therefore indirectly influence the efficacy of bevacizumab.</p> <p>Methods</p> <p>Genomic DNA of 111 consecutive metastatic colorectal cancer patients treated with first-line FOLFIRI plus bevacizumab was obtained from blood samples. <it>VEGF </it>-2578 C/A, -1498 C/T, + 405 C/G, + 936 C/T polymorphisms were analyzed by means of PCR-RFLP. DNA samples from 107 patients treated with FOLFIRI alone served as historical control group. The relation of <it>VEGF </it>polymorphisms with PFS, evaluated through Kaplan-Meier method and log-rank test, was the primary end-point. An interaction test with a Cox model has been performed in order to demonstrate the heterogeneity of the effect of <it>VEGF </it>-1498 C/T polymorphism between bevacizumab-and control group.</p> <p>Results</p> <p>In the bevacizumab-group median PFS and OS of patients carrying <it>VEGF </it>-1498 C/C, C/T and T/T allelic variants were, respectively, 12.8, 10.5, 7.5 months (p = 0.0046, log-rank test) and 27.3, 20.5, 18.6 months (p = 0.038, log-rank test). <it>VEGF </it>-1498 T/T genotype was associated with shorter PFS (HR = 2.13, [1.41-5.10], p = 0.0027). In the control group no significant association of <it>VEGF </it>-1498 C/T allelic variants and PFS or OS was found. Interaction between <it>VEGF </it>-1498 C/T variants and treatment effect suggested that the relation of <it>VEGF </it>-1498 T/T genotype with shorter PFS was caused by the effect of bevacizumab (p = 0.011). Other investigated polymorphisms did not affect the outcome.</p> <p>Conclusions</p> <p>These data suggest a possible role for <it>VEGF </it>-1498 C/T variants in predicting the efficacy of bevacizumab in the up-front treatment of metastatic colorectal cancer patients. A molecular tool for selecting subjects candidate to benefit from the anti-VEGF could be important for clinical practice. The retrospective and exploratory design of the present study, coupled with the non-randomized nature of the comparison between treated and untreated patients, imply that these results should be considered as hypothesis generators. A prospective validating trial is currently ongoing.</p

Retrospective exploratory analysis of VEGF polymorphisms in the prediction of benefit from first-line FOLFIRI plus bevacizumab in metastatic colorectal cancer

<p>Abstract</p> <p>Background</p> <p>Molecular predictors of bevacizumab efficacy in colorectal cancer have not been identified yet. Specific <it>VEGF </it>polymorphisms may affect gene transcription and therefore indirectly influence the efficacy of bevacizumab.</p> <p>Methods</p> <p>Genomic DNA of 111 consecutive metastatic colorectal cancer patients treated with first-line FOLFIRI plus bevacizumab was obtained from blood samples. <it>VEGF </it>-2578 C/A, -1498 C/T, + 405 C/G, + 936 C/T polymorphisms were analyzed by means of PCR-RFLP. DNA samples from 107 patients treated with FOLFIRI alone served as historical control group. The relation of <it>VEGF </it>polymorphisms with PFS, evaluated through Kaplan-Meier method and log-rank test, was the primary end-point. An interaction test with a Cox model has been performed in order to demonstrate the heterogeneity of the effect of <it>VEGF </it>-1498 C/T polymorphism between bevacizumab-and control group.</p> <p>Results</p> <p>In the bevacizumab-group median PFS and OS of patients carrying <it>VEGF </it>-1498 C/C, C/T and T/T allelic variants were, respectively, 12.8, 10.5, 7.5 months (p = 0.0046, log-rank test) and 27.3, 20.5, 18.6 months (p = 0.038, log-rank test). <it>VEGF </it>-1498 T/T genotype was associated with shorter PFS (HR = 2.13, [1.41-5.10], p = 0.0027). In the control group no significant association of <it>VEGF </it>-1498 C/T allelic variants and PFS or OS was found. Interaction between <it>VEGF </it>-1498 C/T variants and treatment effect suggested that the relation of <it>VEGF </it>-1498 T/T genotype with shorter PFS was caused by the effect of bevacizumab (p = 0.011). Other investigated polymorphisms did not affect the outcome.</p> <p>Conclusions</p> <p>These data suggest a possible role for <it>VEGF </it>-1498 C/T variants in predicting the efficacy of bevacizumab in the up-front treatment of metastatic colorectal cancer patients. A molecular tool for selecting subjects candidate to benefit from the anti-VEGF could be important for clinical practice. The retrospective and exploratory design of the present study, coupled with the non-randomized nature of the comparison between treated and untreated patients, imply that these results should be considered as hypothesis generators. A prospective validating trial is currently ongoing.</p

Metal release from stainless steel electrodes of a PEF treatment chamber: Effects of electrical parameters and food composition

The effects of electrical parameters (field strength E, total specific energy inputWT and pulse frequency) and product composition on the release of the main metallic elements (Fe, Cr, Ni and Mn) of stainless steel (type 316L) electrodes of a continuous flow parallel plate PEF chamber into the treatmentmedium were investigated. Experiments were carried out by subjecting two different buffer solutions (McIlvaine and Trizma-HCl) with the same values of pH (7) and electrical conductivity (ó=2 mS/cm) to PEF treatments (mono-polar exponential decay pulses, lasting 3.1 ìs) at different intensities (E = 12–21–31 kV/cm, WT = 20–60–100 J/mL) and flow rates (2–3–4L/h). The results showed that, for each field strength applied, the concentration ofmetallic elements increased upon increasing the total specific energy input. At constant total energy input, it was noticed that the metal concentration decreased upon increasing the field strength applied. These results were mainly attributed to the key role played by the pulse frequency in the charging process of the double layer capacitors at the electrode–solution interface. Moreover, it was shown that the amount of metal released from the electrodes markedly depended on the presence of halides in the composition of the processed product

Recovery of lycopene from industrially derived tomato processing byproducts by pulsed electric fields-assisted extraction

The influence of pulsed electric fields (PEF) pre-treatment at different field strength (E = 1–5 kV/cm) and energy input (WT = 5–10 kJ/kg) on the recovery yield of lycopene in either acetone or ethyl lactate from industrial tomato peels residues, was investigated. The rate of lycopene extraction in both solvents decreased with time and was predicted rather satisfactorily (R2 = 0.96–0.99) by the Peleg's model. Micrograph of tomato peels showed that PEF induced size reduction and separation between the plant cells likely due to pore formation and leakage of intracellular matter. Coherently, PEF treatment (5 kV/cm, 5 kJ/kg) significantly enhanced the extraction rate (27–37%), the lycopene yields (12–18%) and the antioxidant power (18.0–18.2%) in either acetone and ethyl lactate extracts, as compared with untreated samples. However, acetone gave the highest lycopene yield. HPLC analyses revealed that all-trans lycopene was the main carotenoid extracted and no degradation/ isomerization phenomena occurred. The results obtained in this work suggest that the application of PEF prior to solid-liquid extraction with environmentally friendly solvents could represent a sustainable approach for the valorization of industrial tomato peels residues

Effect of pulsed electric fields – assisted extraction on anti-inflammatory and cytotoxic activity of brown rice bioactive compounds

The bioactive compounds of brown rice exhibit many beneficial health effects, ranging from antioxidant to cytotoxic activities. Pulsed Electric Field (PEF) pretreatment can significantly enhance their extraction, through the induction of the electro-permeabilization of the cell membranes. This paper aims to demonstrate that PEF-assisted extraction of brown rice enables not only enhanced yields of antioxidant compounds, such as γ-oryzanol, polyphenols and phenolic acids, and of saturated and unsaturated fatty acids, but also increased cytotoxic effects on cancer cells. Initially, the PEF-assisted extraction conditions have been defined by the assessment of the cell permeabilization index via impedance measurements and the DPPH antioxidant activity. Subsequently, the biological effects of PEF have been evaluated on the cytotoxicity and anti-inflammatory properties against human colon cancer cell line HT29. The results show that PEF-assisted extraction, enhancing the yield of bioactive compounds, with respect to untreated extracts, significantly promotes their antioxidant activity, which is correlated with an increased HT29 cells cytotoxicity. In addition, PEF extracts of brown rice substantially inhibit also gene expression and interleukin production in colon cancer cells, suggesting their exploitation as natural anti-inflammatory agents. The integration of PEF pretreatment in the solvent extraction process of bioactives from brown rice appears, therefore, as a promising practice to significantly enhance their biological activity

PEF assisted extraction of valuable compounds from microalgae C. vulgaris

In recent years the cultivation and exploitation of Microalgae biomass has stimulated intensive research due both to its high productivity, when compared to agriculturally grown biomass, and the large relative content of more than 50% of valuable cell components, like lipids, proteins, polysaccharides, antioxidants, vitamins and pigments (Goettel et al., 2013; Luengo et al., 2014). However, the extraction of these compounds is limited by the mass transfer of these compounds through cell membranes. In this frame, thanks to the reduction of the resistances to mass transfer due to the induced permeabilization of plant cells, Pulsed Electric Field (PEF) technology can be used as a pre-treatment of concentrated microalgae suspension in order to enhance the extraction yield of valuable compounds (such as antioxidants and colorants) from the inner parts of the cells(Mahnič-Kalamiza et al., 2014). In this work the effect of different PEF treatment intensity on the extraction of valuable compound from microalgae Chlorella Vulgaris was investigated. Culture of C. vulgaris strain inoculated in TAP-medium, were cultivated in batch 26 L photo-bioreactor. Growth conditions were monitored by OD measurements at 750 nm. The algae were harvested after 18-24 days and concentrated up to a final biomass concentration of about 40-50 gdw/kgsus. PEF experiments of different intensities (E=27-35 kV/cm, and WT=50-100- 150 kJ/kg) were carried out in a laboratory scale continuous flow unit. Determinations of time-conductivity profile as well as quantification of dry matter, protein content, total polyphenolics (TP), and antioxidant activity (AA) of the supernatant were performed. Results showed a higher increase of the electrical conductivity of PEF treated suspension, when compared to the untreated sample. Moreover, the PEF treatment increased the dry matter content as well as the amount of proteins released into the supernatant from inside the algae cells. Additionally, increments of total phenolics and antioxidant activity were also detected. The results obtained from this study demonstrate the potential of PEF for improving extraction of compounds of interest from the microalgae C. vulgaris

Treatment of latent tuberculosis infection in incarcerated people: a systematic review

Background: The estimated number of people deprived of liberty is increasing, with 11.55 million incarcerated globally in 2021. Transmission of Mycobacterium tuberculosis strains is facilitated in over-crowded, poorly ventilated settings, such as jails and penitentiaries. Moreover, inmates may show in-dividual risk factors for the development of tuberculosis disease. Treatment regimens for latent tuber-culosis infection (LTBI) may require up to 9 months of drug exposure and are characterized by adverse events (AE) and low completion rates.Objectives: To describe current scientific evidence on feasibility, acceptability, and completion rate of LTBI treatment in prison or correctional institutes.Data sources: Articles were retrieved from MEDLINE/PubMed, no time restriction was applied.Study eligibility criteria: Human retrospective and prospective studies published on LTBI treatment in incarcerated populations were included.Assessment of risk of bias: Bias assessment plots and Egger weighted regression test were used to determine the risk of bias. Methods of data synthesis: Absolute and relative frequencies were assessed for qualitative data. Pooled proportion of included study groups and 95% confidence interval estimates, weighted for sample sizes, were illustrated in forest plots. I2 indicator association were used for true variability and overall variation. Fixed and random-effects models were chosen depending on the estimated between-study heterogeneity.Results: Of the 11 selected studies, only 1 was conducted in a high tuberculosis incidence country. Overall, completion rates ranged from 26% to 100% across the included studies. Reason for the discon-tinuation of treatment were transfer to other facilities, release, or loss to follow-up (range, 0-74%), incidence of AEs (range, 0-18%), and refusal or withdrawal from treatment (range, 0-16%). Conclusions: Implementation of short-course regimens in prisons should be considered given the low incidence of AEs observed; however, inmates consistently refused to complete LTBI treatment, thus underlining the need for improvement in retention in care. Tommaso Matucci, Clin Microbiol Infect 2023;29:714 &amp; COPY; 2023 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved

Thyroid function in childhood obesity: Which comes first?

The paper describes the clinical conditions and Thyroid function in obese children. In particular it is discussed the clinical association of these two conditions and the reciprocal impact

Interplay between Nox2 Activity and Platelet Activation in Patients with Sepsis and Septic Shock: A Prospective Study

Background. Although preclinical studies highlighted the potential role of NADPH oxidase (NOX) in sepsis, only few studies evaluated the oxidative stress in patients with sepsis and septic shock. The objective of the study is to appraise the oxidative stress status and platelet function in patients with sepsis and septic shock compared to healthy controls. Methods and Results. Patients with sepsis or septic shock admitted to the hospital Policlinico Umberto I (Sapienza University, Rome) underwent a blood sample collection within 1 hour from admission. Platelet aggregation, serum thromboxane B2 (TxB2), soluble NOX2-derived peptides (sNox2-dp), and hydrogen peroxide breakdown activity (HBA) were measured and compared to those of healthy volunteers. Overall, 33 patients were enrolled; of these, 20 (60.6%) had sepsis and 13 (39.4%) septic shock. Compared to healthy controls (n=10, age 67.8±3.2, male 50%), patients with sepsis and septic shock had higher platelet aggregation (49% (IQR 45-55), 60% (55.75-67.25), and 73% (IQR 69-80), respectively, p<0.001), higher serum TxB2 (77.5 (56.5-86.25), 122.5 (114-131.5), and 210 (195-230) pmol/L, respectively, p<0.001), higher sNox2-dp (10 (7.75-12), 19.5 (17.25-21), and 33 (29.5-39) pg/mL, respectively, p<0.001), and lower HBA (75% (67.25-81.5), 50% (45-54.75), and 27% (21.5-32.5), respectively, p<0.001). Although not statistically significant, a trend in higher levels of serum TxB2 and sNox2-dp in patients who died was observed. Conclusions. Patients with septic shock exhibit higher Nox2 activity and platelet activation than patients with sepsis. These insights joined to better knowledge of these mechanisms could guide the identification of future prognostic biomarkers and new therapeutic strategies in the scenario of septic shock