Ingestible light source for intragastric antibacterial phototherapy: a device safety study on a minipig model.

Helicobacter pylori gastric infections are among the most diffused worldwide, suffering from a rising rate of antibiotic resistance. In this context, some of the authors have previously designed an ingestible device in the form of a luminous capsule to perform antibacterial photodynamic inactivation in the stomach. In this study, the light-emitting capsules were tested to verify the safety of use prior to perform clinical efficacy studies. First, laboratory tests measured the capsule temperature while in function and verified its chemical resistance in conditions mimicking the gastric and gut environments. Second, safety tests in a healthy minipig model were designed and completed, to verify both the capsule integrity and the absence of side effects, associated with its illumination and transit throughout the gastrointestinal tract. To this aim, a capsule administration protocol was defined considering a total of 6 animals with n = 2 treated with 8 capsules, n = 2 treated with 16 capsules and n = 2 controls with no capsule administration. Endoscopies were performed in sedated conditions before-after every capsule administration. Biopsies were taken from the corpus and antrum regions, while the gastric cavity temperature was monitored during illumination. The bench tests confirmed a very good chemical resistance and a moderate (about 3 °C) heating of the capsules. The animal trials showed no significant effects on the gastric wall tissues, both visually and histologically, accompanied with overall good animal tolerance to the treatment. The integrity of the administered capsules was verified as well. These encouraging results pose the basis for the definition of successive trials at the clinical level.

Photon- and Singlet-Oxygen-Induced Cis-Trans Isomerization of the Water-Soluble Carotenoid Crocin.

Studying the cis-trans isomerization process in crocin (CR), one of the few water-soluble carotenoids extracted from saffron, is important to better understand the physiological role of cis-carotenoids in vivo and their potential as antioxidants in therapeutic applications. For that, cis-trans isomerization of both methanol- and water-dissolved CR was induced by light or thermally generated singlet oxygen (1O2). The kinetics of molecular concentrations were monitored by both high-performance liquid chromatography (HPLC) and non-destructive spectrophotometric methods. These last made it possible to simultaneously follow the cis-trans isomerization, the possible bleaching of compounds and the amount of thermally generated 1O2. Our results were in accordance with a comprehensive model where the cis-trans isomerization occurs as relaxation from the triplet state of all-trans- or 13-cis-CR, whatever is the way to populate the CR triplet state, either by photon or 1O2 energy transfer. The process is much more (1.9 to 10-fold) efficient from cis to trans than vice versa. In H2O, a 1O2-induced bleaching effect on the starting CR was not negligible. However, the CR "flip-flop" isomerization reaction could still occur, suggesting that this process can represent an efficient mechanism for quenching of reactive oxygen species (ROS) in vivo, with a limited need of carotenoid regeneration.

The Effects of Peripubertal THC Exposure in Neurodevelopmental Rat Models of Psychopathology.

Adolescent exposure to cannabinoids as a postnatal environmental insult may increase the risk of psychosis in subjects exposed to perinatal insult, as suggested by the two-hit hypothesis of schizophrenia. Here, we hypothesized that peripubertal Δ9-tetrahydrocannabinol (aTHC) may affect the impact of prenatal methylazoxymethanol acetate (MAM) or perinatal THC (pTHC) exposure in adult rats. We found that MAM and pTHC-exposed rats, when compared to the control group (CNT), were characterized by adult phenotype relevant to schizophrenia, including social withdrawal and cognitive impairment, as revealed by social interaction test and novel object recognition test, respectively. At the molecular level, we observed an increase in cannabinoid CB1 receptor (Cnr1) and/or dopamine D2/D3 receptor (Drd2, Drd3) gene expression in the prefrontal cortex of adult MAM or pTHC-exposed rats, which we attributed to changes in DNA methylation at key regulatory gene regions. Interestingly, aTHC treatment significantly impaired social behavior, but not cognitive performance in CNT groups. In pTHC rats, aTHC did not exacerbate the altered phenotype nor dopaminergic signaling, while it reversed cognitive deficit in MAM rats by modulating Drd2 and Drd3 gene expression. In conclusion, our results suggest that the effects of peripubertal THC exposure may depend on individual differences related to dopaminergic neurotransmission.

Aerosol-based antimicrobial photoinactivation in the lungs: an action spectrum study.

Chronic lung infections are among the most diffused human infections, being often associated with multidrug-resistant bacteria. In this framework, the European project "Light4Lungs" aims at synthesizing and testing an inhalable light source to control lung infections by antimicrobial photoinactivation (aPDI), addressing endogenous photosensitizers only (porphyrins) in the representative case of S. aureus and P. aeruginosa. In the search for the best emission characteristics for the aerosolized light source, this work defines and calculates the photo-killing action spectrum for lung aPDI in the exemplary case of cystic fibrosis. This was obtained by applying a semi-theoretical modelling with Monte Carlo simulations, according to previously published methodology related to stomach infections and applied to the infected trachea, bronchi, bronchioles and alveoli. In each of these regions, the two low and high oxygen concentration cases were considered to account for the variability of in vivo conditions, together with the presence of endogenous porphyrins and other relevant absorbers/diffusers inside the illuminated biofilm/mucous layer. Furthermore, an a priori method to obtain the "best illumination wavelengths" was defined, starting from maximizing porphyrin and light absorption at any depth. The obtained action spectrum is peaked at 394 nm and mostly follows porphyrin extinction coefficient behavior. This is confirmed by the results from the best illumination wavelengths, which reinforces the robustness of our approach. These results can offer important indications for the synthesis of the aerosolized light source and definition of its most effective emission spectrum, suggesting a flexible platform to be considered in further applications.

Ascariasis in a 75-year-old man with small bowel volvulus: a case report.

BACKGROUND: Ascaris lumbricoides and Ascaris suum are the most common soil-transmitted helminths of humans and pigs, respectively. The zoonotic potential of A. suum has been a matter of debate for decades. This study was aimed to present a case of human ascariasis caused by A. suum in southern Italy. CASE PRESENTATION: A 75-year-old man presented to the department of surgery in Avellino (southern Italy) complaining of abdominal pain and vomiting. Physical examination revealed bloating and abdominal tenderness. A computed tomography scan showed air-fluid levels and small bowel distension. During exploratory laparotomy a small bowel volvulus with mesenteritis was evident and surprisingly an intraluminal worm was detected. The worm was removed with a small enterotomy and identified as an adult female of A. suum based on morphological and molecular analysis. Faecal examination revealed the presence of unfertilized Ascaris eggs with an intensity of 16 eggs per gram (EPG) of faeces. The patient was treated with mebendanzole 100 mg twice a day for 3 days. The post-operative course was regular with re-alimentation after 3 days and discharge after 12 days. CONCLUSIONS: This report shows as A. suum can function as a relevant agent of human zoonosis. Therefore, in patients with bowel obstruction with no evident aetiology a helminthic infestation should be considered for an accurate diagnosis, especially in patients living in rural areas.

Influence of Trace Elements on Neurodegenerative Diseases of The Eye-The Glaucoma Model.

Glaucoma is a heterogeneous group of chronic neurodegenerative disorders characterized by a relatively selective, progressive damage to the retinal ganglion cells (RGCs) and their axons, which leads to axon loss and visual field alterations. To date, many studies have shown the role of various elements, mainly metals, in maintaining the balance of prooxidative and antioxidative processes, regulation of fluid and ion flow through cell membranes of the ocular tissues. Based on the earlier and current research results, their relationship with the development and progression of glaucoma seems obvious and is increasingly appreciated. In this review, we aimed to summarize the current evidence on the role of trace elements in the pathogenesis and prevention of glaucomatous diseases. Special attention is also paid to the genetic background associated with glaucoma-related abnormalities of physiological processes that regulate or involve the ions of elements considered as trace elements necessary for the functioning of the cells.

Lipid Nanoparticles Traverse Non-Corneal Path to Reach the Posterior Eye Segment: In Vivo Evidence.

Lipid-based nanocarriers (LNs) have made it possible to prolong corneal residence time and improve the ocular bioavailability of ophthalmic drugs. In order to investigate how the LNs interact with the ocular mucosa and reach the posterior eye segment, we have formulated lipid nanocarriers that were designed to bear a traceable fluorescent probe in the present work. The chosen fluorescent probe was obtained by a conjugation reaction between fluoresceinamine and the solid lipid excipient stearic acid, forming a chemically synthesized adduct (ODAF, N-(3',6'-dihydroxy-3-oxospiro [isobenzofuran-1(3H),9'-[9H] xanthen]-5-yl)-octadecanamide). The novel formulation (LN-ODAF) has been formulated and characterized in terms of its technological parameters (polydispersity index, mean particle size and zeta potential), while an in vivo study was carried out to assess the ability of LN-ODAF to diffuse through different ocular compartments. LN-ODAF were in nanometric range (112.7 nm ± 0.4), showing a good homogeneity and long-term stability. A TEM (transmission electron microscopy) study corroborated these results of characterization. In vivo results pointed out that after ocular instillation, LN ODAF were concentrated in the cornea (two hours), while at a longer time (from the second hour to the eighth hour), the fluorescent signals extended gradually towards the back of the eye. From the results obtained, LN-ODAF demonstrated a potential use of lipid-based nanoparticles as efficient carriers of an active pharmaceutical ingredient (API) involved in the management of retinal diseases.

Accuracy and trending ability of hemoglobin measurement by the Pulse CO-Oximeter during vascular surgery.

Real time information of Hb concentration can guide a tailored patient blood management. The study investigates the accuracy, precision and trending ability of the Pulse CO-Oximeter (SpHb) and blood gas analyzer in measuring the Hb concentration, compared to hematological analysis, in surgery at high risk of hemorrhage. We performed an observational study, involving 48 patients undergoing abdominal aortic open surgery. The primary endpoints of the study were to compare the accuracy in measuring the Hb concentration using non-invasive method (Masimo rainbow SET® Radical 7 Pulse CO-Oximetry™) compared to the values provided by invasive conventional blood gas analyzer and hematological analysis. The secondary endpoint was to compare the differences between the baseline and the final value of the Hb after surgery (Δ-values), as well as the trending ability. Bias (precision) for the SpHb was 1.63 g/dL (± 0.05) with 95% limits of agreement between 0.85 and + 2.4 g/dL, while for the blood gas analyzer was 0.69 g/dL (± 0.04) with 95% limits of agreement between 0.07 and 1.3 g/dL. Δ-values values were not statistically different from the reference values of ΔHb obtained with the hematological analysis. Trending ability was good for both Pulse CO-Oximeter and blood gas analysis. Our results have shown that the SpHb is not precise enough to replace an invasive approach, but the trending ability of SpHb is accurate and may provide important information on the changes in hemoglobin concentration to guide blood management.

Curcumin prevents high glucose damage in retinal pigment epithelial cells through ERK1/2-mediated activation of the Nrf2/HO-1 pathway.

To study the effects of curcumin on human retinal pigment epithelial (RPE) cells exposed to high glucose (HG) insult, we performed in vitro studies on RPE cells cultured both in normal and HG conditions to assess the effects of curcumin on the cell viability, nuclear factor erythroid 2-related factor 2 (Nrf2) expression, HO-1 activity, and ERK1/2 expression. RPE cells exposed to HG insult were treated with curcumin. The cell viability, apoptosis, HO-1 activity, ERK, and Nrf2 expression were evaluated. The data indicated that treatment with curcumin caused a significant decrease in terms of apoptosis. Further, curcumin was able to induce HO-1 expression via Nrf2 activation and counteracts the damage elicited by HG. The present study demonstrated that curcumin provides protection against HG-induced damage in RPE cells through the activation of Nrf2/HO-1 signaling that involves the ERK pathway, suggesting that curcumin may have therapeutic value in the treatment of diabetic retinopathy.

Anesthetic Preconditioning as Endogenous Neuroprotection in Glaucoma.

Blindness in glaucoma is the result of death of Retinal Ganglion Cells (RGCs) and their axons. RGC death is generally preceded by a stage of reversible dysfunction and structural remodeling. Current treatments aimed at reducing intraocular pressure (IOP) are ineffective or incompletely effective in management of the disease. IOP-independent neuroprotection or neuroprotection as adjuvant to IOP lowering in glaucoma remains a challenge as effective agents without side effects have not been identified yet. We show in DBA/2J mice with spontaneous IOP elevation and glaucoma that the lifespan of functional RGCs can be extended by preconditioning RGCs with retrobulbar lidocaine in one eye at four months of age that temporary blocks RGC axonal transport. The contralateral, PBS-injected eye served as control. Lidocaine-induced impairment of axonal transport to superior colliculi was assessed by intravitreal injection of cholera toxin B. Long-term (nine months) effect of lidocaine were assessed on RGC electrical responsiveness (PERG), IOP, expression of relevant protein (BDNF, TrkB, PSD95, GFAP, Synaptophysin, and GAPDH) and RGC density. While lidocaine treatment did not alter the age-related increase of IOP, TrkB expression was elevated, GFAP expression was decreased, RGC survival was improved by 35%, and PERG function was preserved. Results suggest that the lifespan of functional RGCs in mouse glaucoma can be extended by preconditioning RGCs in early stages of the disease using a minimally invasive treatment with retrobulbar lidocaine, a common ophthalmologic procedure. Lidocaine is inexpensive, safe and is approved by Food and Drug Administration (FDA) to be administered intravenously.

Two-stage Turnbull-Cutait pull-through coloanal anastomosis versus coloanal anastomosis with protective loop ileostomy for low rectal cancer. Protocol for a randomized controlled trial (Turnbull-BCN).

PURPOSE: The aim of this study was to determine whether patients that underwent ultra-low rectal resection for cancer can benefit from the recently reintroduced two-stage Turnbull-Cutait abdominoperineal pull-through procedure. METHODS: Patients with low rectal tumors undergoing radical sphincter-sparing resection are eligible for inclusion in a randomized multicenter study. Whether two-stage Turnbull-Cutait coloanal anastomosis provides significant benefits over hand-sewn coloanal anastomosis and associated lateral ileostomy in terms of postoperative morbidity is the primary endpoint. In addition, the study aims to assess secondary endpoints such as quality of life, fecal incontinence, and locoregional recurrence of the neoplasm. Patients with adenocarcinoma of the lower rectum diagnosed by rigid proctoscopy, with histological confirmation of malignancy, and who are candidates of rectal removal and coloanal anastomosis will be included in a randomized controlled and multicenter trial. Postoperative morbidity is defined as complications that occur within 30 days of the data of the second surgical procedure of the last patient included in the trial. Patients will be followed for a minimum period of 3 years. CONCLUSIONS: The two-stage Turnbull-Cutait coloanal anastomosis may constitute an effective surgical alternative in the current approach to the treatment of low rectal cancer without the need of a temporary loop colostomy, preventing the wide range of complications related to stoma surgery. TRIAL REGISTRATION: This trial is registered at clinicaltrials.gov (trial number: NCT01766661). This trial is registered in January 10, 2013.

Transanal Inspection and Management of Low Colorectal Anastomosis Performed With a New Technique: the TICRANT Study.

BACKGROUND: Anastomotic leakage is one of the most serious complications after rectal cancer surgery. METHOD: A prospective multicenter interventional study to assess a newly described technique of creating the colorectal and coloanal anastomosis. The primary outcome was to access the safety and efficacy of this technique in the reduction of anastomotic leak. RESULT: Fifty-three patients with rectal cancer who underwent low or ultra-low anterior resection were included in the study. There were 35 males and 18 females, with a median age of 68 years (range = 49-89 years). The median tumor distance from the anal verge was 8 cm (range = 4-12 cm), and the median body mass index was 24 kg/m2 (range = 20-35 kg/m2). Thirty patients underwent open, 16 laparoscopic, and 7 robotic surgeries. Multiple firing (2-charges) was required in 30 patients to obtain a complete rectal division. Forty-five patients had colorectal anastomosis, and 8 patients had coloanal anastomosis. The protective ileostomy was created in 40 patients at the time of initial surgery. There was no mortality in the first 30 days postoperatively, and only 10 (19%) patients developed complications. There were 3 anastomotic leakages (6%); 2 of them were subclinical with ileostomy created at initial operation and both were treated conservatively with transanal drainage and intravenous antibiotics. One patient required reoperation and ileostomy. The median length of hospital stay was 10 days (range = 4-20 days). CONCLUSION: Our technique is a safe and efficient method of creation of colorectal anastomosis. It is also a universal method that can be used in open, laparoscopic, and robotic surgeries.

A randomized phase 3 study on the optimization of the combination of bevacizumab with FOLFOX/OXXEL in the treatment of patients with metastatic colorectal cancer-OBELICS (Optimization of BEvacizumab scheduLIng within Chemotherapy Scheme).

BACKGROUND: Despite the improvements in diagnosis and treatment, colorectal cancer (CRC) is the second cause of cancer deaths in both sexes. Therefore, research in this field remains of great interest. The approval of bevacizumab, a humanized anti-vascular endothelial growth factor (VEGF) monoclonal antibody, in combination with a fluoropyrimidine-based chemotherapy in the treatment of metastatic CRC has changed the oncology practice in this disease. However, the efficacy of bevacizumab-based treatment, has thus far been rather modest. Efforts are ongoing to understand the better way to combine bevacizumab and chemotherapy, and to identify valid predictive biomarkers of benefit to avoid unnecessary and costly therapy to nonresponder patients. The BRANCH study in high-risk locally advanced rectal cancer patients showed that varying bevacizumab schedule may impact on the feasibility and efficacy of chemo-radiotherapy. METHODS/DESIGN: OBELICS is a multicentre, open-label, randomised phase 3 trial comparing in mCRC patients two treatment arms (1:1): standard concomitant administration of bevacizumab with chemotherapy (mFOLFOX/OXXEL regimen) vs experimental sequential bevacizumab given 4 days before chemotherapy, as first or second treatment line. Primary end point is the objective response rate (ORR) measured according to RECIST criteria. A sample size of 230 patients was calculated allowing reliable assessment in all plausible first-second line case-mix conditions, with a 80% statistical power and 2-sided alpha error of 0.05. Secondary endpoints are progression free-survival (PFS), overall survival (OS), toxicity and quality of life. The evaluation of the potential predictive role of several circulating biomarkers (circulating endothelial cells and progenitors, VEGF and VEGF-R SNPs, cytokines, microRNAs, free circulating DNA) as well as the value of the early [(18)F]-Fluorodeoxyglucose positron emission tomography (FDG-PET) response, are the objectives of the traslational project. DISCUSSION: Overall this study could optimize bevacizumab scheduling in combination with chemotherapy in mCRC patients. Moreover, correlative studies could improve the knowledge of the mechanisms by which bevacizumab enhance chemotherapy effect and could identify early predictors of response. EudraCT Number: 2011-004997-27 TRIAL REGISTRATION: ClinicalTrials.gove number, NCT01718873.

Surgery has a key role for quality assurance of colorectal cancer screening programs: impact of the third level multidisciplinary team on lymph nodal staging.

PURPOSE: From 2011 to 2013 in the area of the Naples 3 public health district (ASL-NA3), a colorectal cancer screening program (CCSP) was developed. In order to stress the need of quality assurance procedures for surgery and pathology, a third level oncologic pathway was added and set up at a referral colorectal cancer center (RC). Lymph nodal (LN) harvesting, as a process indicator, and nodal positivity were adopted for an interim analysis. METHODS: The program was implemented by a series of audit meetings and a double type of multidisciplinary team (MDT): "horizontal" and "vertical." Three hundred and forty colorectal cancer (CRC) patients underwent surgery: 119 chose to be operated at the RC (Gr In), 65 were operated at 22 district hospitals (DH) (Gr Out), and 156 symptomatic not screened patients were operated at the RC (Gr Sym). RESULTS: Statistical analysis revealed differences between Gr In and Gr Out colon groups both for LN harvesting (median of 26 and 11, respectively, P = 0.0001), and for nodal positivity after the first screening round (34.78 and 19.45%, respectively, P = 0.0169). Results were all the more significant in a subset analysis on early T stage colon subgroups (In vs Out) both for LN harvesting (P < 0.0001) and nodal positivity (P < 0.0001). CONCLUSION: xSignificant differences between RC and DHs were found, particularly for early-stage CRC patients. LN harvesting should be considered as a surrogate marker of quality assurance for at least screening hospitals for "minimum best" standard of care. This should lead to set up a third level in any CCSP.

Phase 1/2 study of valproic acid and short-course radiotherapy plus capecitabine as preoperative treatment in low-moderate risk rectal cancer-V-shoRT-R3 (Valproic acid--short Radiotherapy--rectum 3rd trial).

BACKGROUND: Locally advanced rectal cancer (LARC) is a heterogeneous group of tumors where a risk-adapted therapeutic strategy is needed. Short-course radiotherapy (SCRT) is a more convenient option for LARC patients than preoperative long-course RT plus capecitabine. Histone-deacetylase inhibitors (HDACi) have shown activity in combination with RT and chemotherapy in the treatment of solid tumors. Valproic acid (VPA) is an anti-epileptic drug with HDACi and anticancer activity. In preclinical studies, our group showed that the addition of HDACi, including VPA, to capecitabine produces synergistic antitumour effects by up-regulating thymidine phosphorylase (TP), the key enzyme converting capecitabine to 5-FU, and by downregulating thymidylate synthase (TS), the 5-FU target. METHODS/DESIGN: Two parallel phase-1 studies will assess the safety of preoperative SCRT (5 fractions each of 5 Gy, on days 1 to 5) combined with (a) capecitabine alone (increasing dose levels: 500-825 mg/m2/bid), on days 1-21, or (b) capecitabine as above plus VPA (oral daily day -14 to 21, with an intra-patient titration for a target serum level of 50-100 microg/ml) followed by surgery 8 weeks after the end of SCRT, in low-moderate risk RC patients. Also, a randomized phase-2 study will be performed to explore whether the addition of VPA and/or capecitabine to preoperative SCRT might increase pathologic complete tumor regression (TRG1) rate. A sample size of 86 patients (21-22/arm) was calculated under the hypothesis that the addition of capecitabine or VPA to SCRT can improve the TRG1 rate from 5% to 20%, with one-sided alpha = 0.10 and 80% power.Several biomarkers will be evaluated comparing normal mucosa with tumor (TP, TS, VEGF, RAD51, XRCC1, Histones/proteins acetylation, HDAC isoforms) and on blood samples (polymorphisms of DPD, TS, XRCC1, GSTP1, RAD51 and XRCC3, circulating endothelial and progenitors cells; PBMCs-Histones/proteins acetylation). Tumor metabolism will be measured by 18FDG-PET at baseline and 15 days after the beginning of SCRT. DISCUSSION: This project aims to improve the efficacy of preoperative treatment of LARC and to decrease the inconvenience and the cost of standard long-course RT. Correlative studies could identify both prognostic and predictive biomarkers and could add new insight in the mechanism of interaction between VPA, capecitabine and RT.EudraCT Number: 2012-002831-28. TRIAL REGISTRATION: ClinicalTrials.gov number, NCT01898104.

Clinical competence in the surgery of rectal cancer: the Italian Consensus Conference.

BACKGROUND AND AIM: The literature continues to emphasize the advantages of treating patients in "high volume" units by "expert" surgeons, but there is no agreed definition of what is meant by either term. In September 2012, a Consensus Conference on Clinical Competence was organized in Rome as part of the meeting of the National Congress of Italian Surgery (I Congresso Nazionale della Chirurgia Italiana: Unità e valore della chirurgia italiana). The aims were to provide a definition of "expert surgeon" and "high-volume facility" in rectal cancer surgery and to assess their influence on patient outcome. METHOD: An Organizing Committee (OC), a Scientific Committee (SC), a Group of Experts (E) and a Panel/Jury (P) were set up for the conduct of the Consensus Conference. Review of the literature focused on three main questions including training, "measuring" of quality and to what extent hospital and surgeon volume affects sphincter-preserving procedures, local recurrence, 30-day morbidity and mortality, survival, function, choice of laparoscopic approach and the choice of transanal endoscopic microsurgery (TEM). RESULTS AND CONCLUSION: The difficulties encountered in defining competence in rectal surgery arise from the great heterogeneity of the parameters described in the literature to quantify it. Acquisition of data is difficult as many articles were published many years ago. Even with a focus on surgeon and hospital volume, it is difficult to define their role owing to the variability and the quality of the relevant studies.

In vitro assessment of antibody-conjugated gold nanorods for systemic injections.

BACKGROUND: The interest for gold nanorods in biomedical optics is driven by their intense absorbance of near infrared light, their biocompatibility and their potential to reach tumors after systemic administration. Examples of applications include the photoacoustic imaging and the photothermal ablation of cancer. In spite of great current efforts, the selective delivery of gold nanorods to tumors through the bloodstream remains a formidable challenge. Their bio-conjugation with targeting units, and in particular with antibodies, is perceived as a hopeful solution, but the complexity of living organisms complicates the identification of possible obstacles along the way to tumors. RESULTS: Here, we present a new model of gold nanorods conjugated with anti-cancer antigen 125 (CA125) antibodies, which exhibit high specificity for ovarian cancer cells. We implement a battery of tests in vitro, in order to simulate major nuisances and predict the feasibility of these particles for intravenous injections. We show that parameters like the competition of free CA125 in the bloodstream, which could saturate the probe before arriving at the tumors, the matrix effect and the interference with erythrocytes and phagocytes are uncritical. CONCLUSIONS: Although some deterioration is detectable, anti-CA125-conjugated gold nanorods retain their functional features after interaction with blood tissue and so represent a powerful candidate to hit ovarian cancer cells.

Resveratrol and vascular health: evidence from clinical studies and mechanisms of actions related to its metabolites produced by gut microbiota.

Cardiovascular diseases are among the leading causes of mortality worldwide, with dietary factors being the main risk contributors. Diets rich in bioactive compounds, such as (poly)phenols, have been shown to potentially exert positive effects on vascular health. Among them, resveratrol has gained particular attention due to its potential antioxidant and anti-inflammatory action. Nevertheless, the results in humans are conflicting possibly due to interindividual different responses. The gut microbiota, a complex microbial community that inhabits the gastrointestinal tract, has been called out as potentially responsible for modulating the biological activities of phenolic metabolites in humans. The present review aims to summarize the main findings from clinical trials on the effects of resveratrol interventions on endothelial and vascular outcomes and review potential mechanisms interesting the role of gut microbiota on the metabolism of this molecule and its cardioprotective metabolites. The findings from randomized controlled trials show contrasting results on the effects of resveratrol supplementation and vascular biomarkers without dose-dependent effect. In particular, studies in which resveratrol was integrated using food sources, i.e., red wine, reported significant effects although the resveratrol content was, on average, much lower compared to tablet supplementation, while other studies with often extreme resveratrol supplementation resulted in null findings. The results from experimental studies suggest that resveratrol exerts cardioprotective effects through the modulation of various antioxidant, anti-inflammatory, and anti-hypertensive pathways, and microbiota composition. Recent studies on resveratrol-derived metabolites, such as piceatannol, have demonstrated its effects on biomarkers of vascular health. Moreover, resveratrol itself has been shown to improve the gut microbiota composition toward an anti-inflammatory profile. Considering the contrasting findings from clinical studies, future research exploring the bidirectional link between resveratrol metabolism and gut microbiota as well as the mediating effect of gut microbiota in resveratrol effect on cardiovascular health is warranted.

Isoflavones Effects on Vascular and Endothelial Outcomes: How Is the Gut Microbiota Involved?

Isoflavones are a group of (poly)phenols, also defined as phytoestrogens, with chemical structures comparable with estrogen, that exert weak estrogenic effects. These phytochemical compounds have been targeted for their proven antioxidant and protective effects. Recognizing the increasing prevalence of cardiovascular diseases (CVD), there is a growing interest in understanding the potential cardiovascular benefits associated with these phytochemical compounds. Gut microbiota may play a key role in mediating the effects of isoflavones on vascular and endothelial functions, as it is directly implicated in isoflavones metabolism. The findings from randomized clinical trials indicate that isoflavone supplementation may exert putative effects on vascular biomarkers among healthy individuals, but not among patients affected by cardiometabolic disorders. These results might be explained by the enzymatic transformation to which isoflavones are subjected by the gut microbiota, suggesting that a diverse composition of the microbiota may determine the diverse bioavailability of these compounds. Specifically, the conversion of isoflavones in equol-a microbiota-derived metabolite-seems to differ between individuals. Further studies are needed to clarify the intricate molecular mechanisms behind these contrasting results.

Dendritic cells with lymphocyte-stimulating activity differentiate from human CD133 positive precursors.

CD133 is a hallmark of primitive myeloid progenitors. We have addressed whether human cord blood cells selected for CD133 can generate dendritic cells, and Langerhans cells in particular, in conditions that promote that generation from CD34(+) progenitors. Transforming growth factor-ß1 (TGF-ß1) and anti-TGF-ß1 antibody, respectively, were added in some experiments. With TGF-ß, monocytoid cells were recognized after 7 days. Immunophenotypically immature dendritic cells were present at day 14. After 4 more days, the cells expressed CD54, CD80, CD83, and CD86 and were potent stimulators in mixed lymphocyte reaction; part of the cells expressed CD1a and langerin, but not Birbeck granules. Without TGF-ß, only a small fraction of cells acquired a dendritic shape and expressed the maturation-related antigens, and lymphocytes were poorly stimulated. With anti-TGF-ß, the cell growth was greatly hampered, CD54 and langerin were never expressed, and lymphocytes were stimulated weakly. In conclusion, CD133(+) progenitors can give rise in vitro, through definite steps, to mature, immunostimulatory dendritic cells with molecular features of Langerhans cells, although without Birbeck granules. Addition of TGF-ß1 helps to stimulate cell growth and promotes the acquisition of mature immunophenotypical and functional features. Neither langerin nor Birbeck granules proved indispensable for lymphocyte stimulation.