Taste Perception And Food Choices

OBJECTIVES: The extent to which variation in taste perception influences food preferences is, to date, controversial. Bitterness in food triggers an innate aversion that is responsible for dietary restriction in children. We investigated the association among genetic variations in bitter receptor TAS2R38 and food choices in healthy children in the Mediterranean area, to develop appropriate tools to evaluate the relation among genetic predisposition, dietary habits, and feeding disorders. The aims of the study were to get a first baseline picture of taste sensitivity in healthy adults and their children and to explore taste sensitivity in a preliminary sample of obese children and in samples affected by functional gastrointestinal diseases. METHODS: Individuals (98 children, 87 parents, 120 adults) were recruited from the general population in southern Italy. Bitterness sensitivity was assessed by means of a suprathreshold method with 6-propyl-2-thiouracil. Genomic DNA from saliva was used to genotype individuals for 3 polymorphisms of TAS2R38 receptor, A49P, A262 V, and V296I. Food intake was assessed by a food frequency questionnaire. RESULTS: Children's taste sensation differed from that of adults: we observed a higher frequency of supertasters among children even in the mother-child dyads with the same diplotypes. Among adults, supertaster status was related with proline-alanine-valine (taster allele) homozygous haplotype, whereas supertaster children were mainly heterozygous. Regarding the food choices, we found that a higher percentage of taster children avoided bitter vegetables or greens altogether compared with taster adults. Taster status was also associated with body mass index in boys. CONCLUSIONS: Greater sensitivity to 6-propyl-2-thiouracil predicts lower preferences for vegetables in children, showing an appreciable effect of the genetic predisposition on food choices. None of the obese boys was a supertaster

Reduction of T Lymphoma Cells and Immunological Invigoration in a Patient Concurrently Affected by Melanoma and Sezary Syndrome Treated With Nivolumab

Despite the recent availability of several new drugs in hemato-oncology, T-cell lymphomas are still incurable and PD-1 blockade could represent a therapeutic chance for selected patients affected by these malignancies, although further studies are required to understand the biological effects of anti-PD-1 mAbs on neoplastic T-cells and to identify biomarkers for predicting and/or monitoring patients' response to therapy. Sezary Syndrome (SS) represents a rare and aggressive variant of cutaneous T cell lymphoma (CTCL) with a life expectancy of less than 5 years, characterized by the co-presence of neoplastic lymphocytes mainly in the blood, lymph nodes and skin. In this study we analyzed longitudinal blood samples and lesional skin biopsies of a patient concurrently affected by SS and melanoma who underwent 22 nivolumab administrations. In blood, we observed a progressive reduction of SS cell number and a raise in the percentage of normal CD4+ and CD8+ T cells and NK cells over total leukocytes. Eight weeks from the start of nivolumab, these immune cell subsets showed an increase of Ki67 proliferation index that positively correlated with their PD-1 expression. Conversely, SS cells displayed a strong reduction of Ki67 positivity despite their high PD-1 expression. On skin biopsies we observed a marked reduction of SS cells which were no more detectable at the end of therapy. We also found an increase in the percentage of normal CD4+ T cells with a concomitant decrease of that of CD8+ and CD4+ CD8+ T cells, two cell subsets that, however, acquired a cytotoxic phenotype. In summary, our study demonstrated that nivolumab marked reduced SS tumor burden and invigorated immune responses in our patient. Our data also suggest, for the first time, that Ki67 expression in circulating neoplastic and immune cell subsets, as well as an enrichment in T cells with a cytotoxic phenotype in lesional skin could be valuable markers to assess early on treatment SS patients' response to PD-1 blockade, a therapeutic strategy under clinical investigation in CTCL (NCT03385226, NCT04118868)

Lentiviral haemopoietic stem/progenitor cell gene therapy for treatment of Wiskott-Aldrich syndrome: interim results of a non-randomised, open-label, phase 1/2 clinical study

Background Wiskott-Aldrich syndrome is a rare, life-threatening, X-linked primary immunodeficiency characterised by microthrombocytopenia, infections, eczema, autoimmunity, and malignant disease. Lentiviral vector-mediated haemopoietic stem/progenitor cell (HSPC) gene therapy is a potentially curative treatment that represents an alternative to allogeneic HSPC transplantation. Here, we report safety and efficacy data from an interim analysis of patients with severe Wiskott-Aldrich syndrome who received lentiviral vector-derived gene therapy. Methods We did a non-randomised, open-label, phase 1/2 clinical study in paediatric patients with severe Wiskott-Aldrich syndrome, defined by either WAS gene mutation or absent Wiskott-Aldrich syndrome protein (WASP) expression or a Zhu clinical score of 3 or higher. We included patients who had no HLA-identical sibling donor available or, for children younger than 5 years of age, no suitable 10/10 matched unrelated donor or 6/6 unrelated cord blood donor. After treatment with rituximab and a reduced-intensity conditioning regimen of busulfan and fludarabine, patients received one intravenous infusion of autologous CD34+ cells genetically modified with a lentiviral vector encoding for human WAS cDNA. The primary safety endpoints were safety of the conditioning regimen and safety of lentiviral gene transfer into HSPCs. The primary efficacy endpoints were overall survival, sustained engraftment of genetically corrected HSPCs, expression of vector-derived WASP, improved T-cell function, antigen-specific responses to vaccinations, and improved platelet count and mean platelet volume normalisation. This interim analysis was done when the first six patients treated had completed at least 3 years of follow-up. The planned analyses are presented for the intention-to-treat population. This trial is registered with ClinicalTrials.gov (number NCT01515462) and EudraCT (number 2009-017346-32). Findings Between April 20, 2010, and Feb 26, 2015, nine patients (all male) were enrolled of whom one was excluded after screening; the age range of the eight treated children was 1·1–12·4 years. At the time of the interim analysis (data cutoff April 29, 2016), median follow-up was 3·6 years (range 0·5–5·6). Overall survival was 100%. Engraftment of genetically corrected HSPCs was successful and sustained in all patients. The fraction of WASP-positive lymphocytes increased from a median of 3·9% (range 1·8–35·6) before gene therapy to 66·7% (55·7–98·6) at 12 months after gene therapy, whereas WASP-positive platelets increased from 19·1% (range 4·1–31·0) to 76·6% (53·1–98·4). Improvement of immune function was shown by normalisation of in-vitro T-cell function and successful discontinuation of immunoglobulin supplementation in seven patients with follow-up longer than 1 year, followed by positive antigen-specific response to vaccination. Severe infections fell from 2·38 (95% CI 1·44–3·72) per patient-year of observation (PYO) in the year before gene therapy to 0·31 (0·04–1·11) per PYO in the second year after gene therapy and 0·17 (0·00–0·93) per PYO in the third year after gene therapy. Before gene therapy, platelet counts were lower than 20 × 109 per L in seven of eight patients. At the last follow-up visit, the platelet count had increased to 20–50 × 109 per L in one patient, 50–100 × 109 per L in five patients, and more than 100 × 109 per L in two patients, which resulted in independence from platelet transfusions and absence of severe bleeding events. 27 serious adverse events in six patients occurred after gene therapy, 23 (85%) of which were infectious (pyrexia [five events in three patients], device-related infections, including one case of sepsis [four events in three patients], and gastroenteritis, including one case due to rotavirus [three events in two patients]); these occurred mainly in the first 6 months of follow-up. No adverse reactions to the investigational drug product and no abnormal clonal proliferation or leukaemia were reported after gene therapy. Interpretation Data from this study show that gene therapy provides a valuable treatment option for patients with severe Wiskott-Aldrich syndrome, particularly for those who do not have a suitable HSPC donor available

Identification of sixteen novel candidate genes for late onset Parkinson’s disease

Background Parkinson’s disease (PD) is a neurodegenerative movement disorder affecting 1–5% of the general population for which neither effective cure nor early diagnostic tools are available that could tackle the pathology in the early phase. Here we report a multi-stage procedure to identify candidate genes likely involved in the etiopathogenesis of PD. Methods The study includes a discovery stage based on the analysis of whole exome data from 26 dominant late onset PD families, a validation analysis performed on 1542 independent PD patients and 706 controls from different cohorts and the assessment of polygenic variants load in the Italian cohort (394 unrelated patients and 203 controls). Results Family-based approach identified 28 disrupting variants in 26 candidate genes for PD including PARK2, PINK1, DJ-1(PARK7), LRRK2, HTRA2, FBXO7, EIF4G1, DNAJC6, DNAJC13, SNCAIP, AIMP2, CHMP1A, GIPC1, HMOX2, HSPA8, IMMT, KIF21B, KIF24, MAN2C1, RHOT2, SLC25A39, SPTBN1, TMEM175, TOMM22, TVP23A and ZSCAN21. Sixteen of them have not been associated to PD before, were expressed in mesencephalon and were involved in pathways potentially deregulated in PD. Mutation analysis in independent cohorts disclosed a significant excess of highly deleterious variants in cases (p = 0.0001), supporting their role in PD. Moreover, we demonstrated that the co-inheritance of multiple rare variants (≥ 2) in the 26 genes may predict PD occurrence in about 20% of patients, both familial and sporadic cases, with high specificity (> 93%; p = 4.4 × 10− 5). Moreover, our data highlight the fact that the genetic landmarks of late onset PD does not systematically differ between sporadic and familial forms, especially in the case of small nuclear families and underline the importance of rare variants in the genetics of sporadic PD. Furthermore, patients carrying multiple rare variants showed higher risk of manifesting dyskinesia induced by levodopa treatment. Conclusions Besides confirming the extreme genetic heterogeneity of PD, these data provide novel insights into the genetic of the disease and may be relevant for its prediction, diagnosis and treatment

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

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Intraperitoneal drain placement and outcomes after elective colorectal surgery: international matched, prospective, cohort study

Despite current guidelines, intraperitoneal drain placement after elective colorectal surgery remains widespread. Drains were not associated with earlier detection of intraperitoneal collections, but were associated with prolonged hospital stay and increased risk of surgical-site infections.Background Many surgeons routinely place intraperitoneal drains after elective colorectal surgery. However, enhanced recovery after surgery guidelines recommend against their routine use owing to a lack of clear clinical benefit. This study aimed to describe international variation in intraperitoneal drain placement and the safety of this practice. Methods COMPASS (COMPlicAted intra-abdominal collectionS after colorectal Surgery) was a prospective, international, cohort study which enrolled consecutive adults undergoing elective colorectal surgery (February to March 2020). The primary outcome was the rate of intraperitoneal drain placement. Secondary outcomes included: rate and time to diagnosis of postoperative intraperitoneal collections; rate of surgical site infections (SSIs); time to discharge; and 30-day major postoperative complications (Clavien-Dindo grade at least III). After propensity score matching, multivariable logistic regression and Cox proportional hazards regression were used to estimate the independent association of the secondary outcomes with drain placement. Results Overall, 1805 patients from 22 countries were included (798 women, 44.2 per cent; median age 67.0 years). The drain insertion rate was 51.9 per cent (937 patients). After matching, drains were not associated with reduced rates (odds ratio (OR) 1.33, 95 per cent c.i. 0.79 to 2.23; P = 0.287) or earlier detection (hazard ratio (HR) 0.87, 0.33 to 2.31; P = 0.780) of collections. Although not associated with worse major postoperative complications (OR 1.09, 0.68 to 1.75; P = 0.709), drains were associated with delayed hospital discharge (HR 0.58, 0.52 to 0.66; P < 0.001) and an increased risk of SSIs (OR 2.47, 1.50 to 4.05; P < 0.001). Conclusion Intraperitoneal drain placement after elective colorectal surgery is not associated with earlier detection of postoperative collections, but prolongs hospital stay and increases SSI risk

CD164 identifies CD4+ T cells highly expressing genes associated with malignancy in Sézary syndrome: the Sézary signature genes, FCRL3, Tox, and miR-214

Sézary syndrome (SS), a leukemic variant of cutaneous T-cell lymphoma (CTCL), is associated with a significantly shorter life expectancy compared to skin-restricted mycosis fungoides. Early diagnosis of SS is, therefore, key to achieving enhanced therapeutic responses. However, the lack of a biomarker(s) highly specific for malignant CD4+ T cells in SS patients has been a serious obstacle in making an early diagnosis. We recently demonstrated the high expression of CD164 on CD4+ T cells from Sézary syndrome patients with a wide range of circulating tumor burdens. To further characterize CD164 as a potential biomarker for malignant CD4+ T cells, CD164+ and CD164-CD4+ T cells isolated from patients with high-circulating tumor burden, B2 stage, and medium/low tumor burden, B1-B0 stage, were assessed for the expression of genes reported to differentiate SS from normal controls, and associated with malignancy and poor prognosis. The expression of Sézary signature genes: T plastin, GATA-3, along with FCRL3, Tox, and miR-214, was significantly higher, whereas STAT-4 was lower, in CD164+ compared with CD164-CD4+ T cells. While Tox was highly expressed in both B2 and B1-B0 patients, the expression of Sézary signature genes, FCRL3, and miR-214 was associated predominantly with advanced B2 disease. High expression of CD164 mRNA and protein was also detected in skin from CTCL patients. CD164 was co-expressed with KIR3DL2 on circulating CD4+ T cells from high tumor burden SS patients, further providing strong support for CD164 as a disease relevant surface biomarker