Fecal microbiota transplantation to improve efficacy of immune checkpoint inhibitors in renal cell carcinoma (TACITO trial)

Background: Renal cell carcinoma (RCC) is the 6° most common cancer in men and the 8° in women in the USA. In Italy RCC incidence was 11,500 new cases in 2017, while mortality was 3,371 cases in 2015. Increasing evidence suggests that response to immune checkpoint inhibitors (ICIs), a novel treatment for advanced RCC (aRCC) and other epithelial tumors, can be influenced by the patient gut microbiota. Fecal microbiota transplantation (FMT) is a novel treatment option aimed to restore healthy gut microbiota, and is the most effective therapy for recurrent C. difficile infection. Preliminary nonrandomized findings show that FMT is able to improve efficacy of ICIs in patients with advanced melanoma. The aim of this study is to evaluate, through a double-blinded placebo-controlled randomized clinical trial, the efficacy of targeted FMT (from donors who are responding to ICIs) in improving response rates to ICIs in subjects with aRCC. Methods: 50 patients who are about to receive, or have started by <8 weeks, pembrolizumab + axitinib as first-line therapy for aRCC will be enrolled. Exclusion criteria include major comorbidities, concomitant GI or autoimmune disorders, or HIV, HBV, HCV infection, continuative corticosteroid therapy, previous treatment with systemic immune-suppressants or immune-modulatory drugs, antibiotic therapy within 4 weeks prior to enrollment. Stool samples and clinical data will be collected at baseline. Then, patients will be randomized to donor FMT or placebo FMT. They will receive the first infusion by colonoscopy and then oral frozen fecal or placebo capsules (8 capsules t.i.d.) 90 and 180 days after the first FMT. Stool donors will be searched among long-term (>12 months) responders to ICIs, and will be selected by following protocols recommended by international guidelines. Patients in the FMT group will always receive feces from the same donor throughout the three fecal transplants. Frozen fecal batches and frozen fecal capsules will be manufactured according to international guidelines. Patients will be followed-up 7, 15, 30, 90, 180, 270, and 360 days after randomization for clinical evaluation and collection of stool samples. Patients will also undergo radiological assessment at 90, 180, 270 and 360 days after randomization. Microbiome analysis will be performed with shotgun metagenomics. The primary endpoint is the progression-free survival (PFS) at 12 months. Secondary endpoints are: objective response rate at 12 months; overall survival at 12 months; adverse events after FMT; microbiome changes after FMT. Sample size calculation was based on the hypothesis that FMT can improve the 1-year PFS rate from 60% (reported 1-year PFS for SOC) to 80% wen associated to SOC. Clinical trial information: NCT04758507

ART in Europe, 2016 : results generated from European registries by ESHRE

STUDY QUESTION: What are the reported data on cycles in ART, IUI and fertility preservation (FP) interventions in 2016 as compared to previous years, as well as the main trends over the years? SUMMARY ANSWER: The 20th ESHRE report on ART and IUI shows a progressive increase in reported treatment cycle numbers in Europe, with a decrease in the number of transfers with more than one embryo causing a reduction of multiple delivery rates (DR), as well as higher pregnancy rates and DR after frozen embryo replacement (FER) compared to fresh IVF and ICSI cycles, while the outcomes for IUI cycles remained stable. WHAT IS KNOWN ALREADY: Since 1997, ART aggregated data generated by national registries, clinics or professional societies have been collected, analysed by the European IVF-monitoring Consortium (EIM) and reported in 19 manuscripts published in Human Reproduction and Human Reproduction Open. STUDY DESIGN, SIZE, DURATION: Yearly collection of European medically assisted reproduction (MAR) data by EIM for ESHRE. The data on treatments performed between 1 January and 31 December 2016 in 40 European countries were provided by either National Registries or registries based on personal initiatives of medical associations and scientific organizations. PARTICIPANTS/MATERIALS, SETTING, METHODS: In all, 1347 clinics offering ART services in 40 countries reported a total of 918 159 treatment cycles, involving 156 002 with IVF, 407 222 with ICSI, 248 407 with FER, 27 069 with preimplantation genetic testing, 73 927 with egg donation (ED), 654 with IVM of oocytes and 4878 cycles with frozen oocyte replacement (FOR). European data on IUI using husband/partner’s semen (IUI-H) and donor semen (IUI-D) were reported from 1197 institutions offering IUI in 29 and 24 countries, respectively. A total of 162 948 treatments with IUI-H and 50 467 treatments with IUI-D were included. A total of 13 689 FP interventions from 11 countries including oocyte, ovarian tissue, semen and testicular tissue banking in pre-and postpubertal patients were reported. MAIN RESULTS AND THE ROLE OF CHANCE: In 20 countries (18 in 2015) with a total population of approximately 325 million inhabitants, in which all ART clinics reported to the registry, a total of 461 401 treatment cycles were performed, corresponding to a mean of 1410 cycles per million inhabitants (range 82–3088 per million inhabitants). In the 40 reporting countries, after IVF the clinical pregnancy rates (PR) per aspiration and per transfer in 2016 were similar to those observed in 2015 (28.0% and 34.8% vs 28.5% and 34.6%, respectively). After ICSI, the corresponding rates were also similar to those achieved in 2015 (25% and 33.2% vs 26.2% and 33.2%). After FER with own embryos, the PR per thawing is still on the rise, from 29.2% in 2015 to 30.9% in 2016. After ED, the PR per fresh embryo transfer was 49.4% (49.6% in 2015) and per FOR 43.6% (43.4% in 2015). In IVF and ICSI together, the trend towards the transfer of fewer embryos continues with the transfer of 1, 2, 3 and 4 embryos in 41.5%, 51.9%, 6.2% and 0.4% of all treatments, respectively (corresponding to 37.7%, 53.9%, 7.9% and 0.5% in 2015). This resulted in a proportion of singleton, twin and triplet DRs of 84.8%, 14.9% and 0.3%, respectively (compared to 83.1%, 16.5% and 0.4%, respectively in 2015). Treatments with FER in 2016 resulted in twin and triplet DR of 11.9% and 0.2%, respectively (vs 12.3% and 0.3% in 2015). After IUI, the DRs remained similar at 8.9% after IUI-H (7.8% in 2015) and at 12.4% after IUI-D (12.0% in 2015). Twin and triplet DRs after IUI-H were 8.8% and 0.3%, respectively (in 2015: 8.9% and 0.5%) and 7.7% and 0.4% after IUI-D (in 2015: 7.3% and 0.6%). The majority of FP interventions included the cryopreservation of ejaculated sperm (n¼7877 from 11 countries) and of oocytes (n¼4907 from eight countries). LIMITATIONS, REASONS FOR CAUTION: As the methods of data collection and levels of completeness of reported data vary among European countries, the results should be interpreted with caution. A number of countries failed to provide adequate data about the number of initiated cycles and deliveries. WIDER IMPLICATIONS OF THE FINDINGS: The 20th ESHRE report on ART and IUI shows a continuous increase of reported treatment numbers and MAR-derived livebirths in Europe. Being already the largest data collection on MAR in Europe, continuous efforts to stimulate data collection and reporting strive for future quality control of the data, transparency and vigilance in the field of reproductive medicine.The study has no external funding and all costs were covered by ESHRE.peer-reviewe

ART in Europe, 2017: results generated from European registries by ESHRE

© The Author(s) 2021. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.Study question: What are the data on ART and IUI cycles, and fertility preservation (FP) interventions reported in 2017 as compared to previous years, as well as the main trends over the years? Summary answer: The 21st ESHRE report on ART and IUI shows the continual increase in reported treatment cycle numbers in Europe, with a decrease in the proportion of transfers with more than one embryo causing an additional slight reduction of multiple delivery rates (DR) as well as higher pregnancy rates (PR) and DR after frozen embryo replacement (FER) compared to fresh IVF and ICSI cycles, while the number of IUI cycles increased and their outcomes remained stable. What is known already: Since 1997, ART aggregated data generated by national registries, clinics or professional societies have been gathered and analyzed by the European IVF-monitoring Consortium (EIM) and communicated in a total of 20 manuscripts published in Human Reproduction and Human Reproduction Open. Study design size duration: Data on European medically assisted reproduction (MAR) are collected by EIM for ESHRE on a yearly basis. The data on treatments performed between 1 January and 31 December 2017 in 39 European countries were provided by either National Registries or registries based on personal initiatives of medical associations and scientific organizations. Participants/materials setting methods: Overall, 1382 clinics offering ART services in 39 countries reported a total of 940 503 treatment cycles, including 165 379 with IVF, 391 379 with ICSI, 271 476 with FER, 37 303 with preimplantation genetic testing (PGT), 69 378 with egg donation (ED), 378 with IVM of oocytes, and 5210 cycles with frozen oocyte replacement (FOR). A total of 1273 institutions reported data on 207 196 IUI cycles using either husband/partner's semen (IUI-H; n = 155 794) or donor semen (IUI-D; n = 51 402) in 30 countries and 25 countries, respectively. Thirteen countries reported 18 888 interventions for FP, including oocyte, ovarian tissue, semen and testicular tissue banking in pre- and postpubertal patients. Main results and the role of chance: In 21 countries (20 in 2016) in which all ART clinics reported to the registry, 473 733 treatment cycles were registered for a total population of approximately 330 million inhabitants, allowing a best-estimate of a mean of 1435 cycles performed per million inhabitants (range: 723-3286).Amongst the 39 reporting countries, the clinical PR per aspiration and per transfer in 2017 were similar to those observed in 2016 (26.8% and 34.6% vs 28.0% and 34.8%, respectively). After ICSI the corresponding rates were also similar to those achieved in 2016 (24% and 33.5% vs 25% and 33.2% in 2016). When freeze all cycles were removed, the clinical PRs per aspiration were 30.8% and 27.5% for IVF and ICSI, respectively.After FER with embryos originating from own eggs the PR per thawing was 30.2%, which is comparable to 30.9% in 2016, and with embryos originating from donated eggs it was 41.1% (41% in 2016). After ED the PR per fresh embryo transfer was 49.2% (49.4% in 2016) and per FOR 43.3% (43.6% in 2016).In IVF and ICSI together, the trend towards the transfer of fewer embryos continues with the transfer of 1, 2, 3 and ≥4 embryos in 46.0%, 49.2%, 4.5% and in 0.3% of all treatments, respectively (corresponding to 41.5%, 51.9%. 6.2% and 0.4% in 2016). This resulted in a reduced proportion of twin DRs of 14.2% (14.9% in 2016) and stable triplet DR of 0.3%. Treatments with FER in 2017 resulted in a twin and triplet DR of 11.2% and 0.2%, respectively (vs 11.9% and 0.2% in 2016).After IUI, the DRs remained similar at 8.7% after IUI-H (8.9% in 2016) and at 12.4% after IUI-D (12.4.0% in 2016). Twin and triplet DRs after IUI-H were 8.1% and 0.3%, respectively (in 2016: 8.8% and 0.3%) and 6.9% and 0.2% after IUI-D (in 2016: 7.7% and 0.4%). Amongst 18 888 FP interventions in 13 countries, cryopreservation of ejaculated sperm (n = 11 112 vs 7877 from 11 countries in 2016) and of oocytes (n = 6588 vs 4907 from eight countries in 2016) were the most frequently reported. Limitations reasons for caution: As the methods of data collection and levels of reporting vary amongst European countries, interpretation of results should remain cautious. Some countries were unable to deliver data about the number of initiated cycles and deliveries. Wider implications of the findings: The 21st ESHRE report on ART, IUI and FP interventions shows a continuous increase of reported treatment numbers and MAR-derived livebirths in Europe. Being already the largest data collection on MAR in Europe, efforts should continue to optimize data collection and reporting with the perspective of improved quality control, transparency and vigilance in the field of reproductive medicine. Study funding/competing interests: The study has received no external funding and all costs are covered by ESHRE. There are no competing interests.info:eu-repo/semantics/publishedVersio

Effects of seeding date and seeding rate on yield, proximate composition and total tannins content of two Kabuli chickpea cultivars

Experiments were conducted in open field to assess the effect of seeding season and density on the yield, the chemical composition and the accumulation of total tannins in grains of two chickpea (Cicer arietinum L.) cultivars (Pascià and Sultano). Environmental conditions and genetic factors considerably affected grain yield, nutrient and total tannins content of chickpea seeds, giving a considerable range in its qualitative characteristics. Results confirmed cultivar selection as a central factor when a late autumn-early winter sowing is performed. In effect, a more marked resistance to Ascochyta blight (AB) of Sultano, allowed better agronomic performances when favourable-to-AB climatic conditions occur. Winter sowing appeared to be the best choice in the Mediterranean environment when cultivating to maximise the grain yield (+19%). Spring sowing improved crude protein (+10%) and crude fibre (+8%) content, whereas it did not significantly affect the accumulation of anti-nutrients compounds such as total tannins. The most appropriate seeding rate was 70 seeds m–2, considering that plant density had relatively little effect on the parameters studied

INTERAÇÕES FÁRMACO-RECEPTOR: APLICAÇÕES DE TÉCNICAS COMPUTACIONAIS EM AULA PRÁTICA SOBRE A EVOLUÇÃO DOS INIBIDORES DA ENZIMA CONVERSORA DE ANGIOTENSINA

Teaching classes and events regarding the molecular aspects of drug-receptor interactions is not an easy task. The ligand stereochemistry and the spatial arrangement of the macromolecular targets highly increase the complexity of the process. In this context, the use of alternative and more playful approaches could allow students to gain a more thorough understanding of this important topic in medicinal chemistry. Herein, we describe a practical teaching approach that uses computational strategies as a tool for drug-receptor interaction studies performed for angiotencsin converting enzyme inhibitors (ACEi). Firstly, the students learn how to find the crystallographic structure (enzyme-ligand complex). Then, they proceed to the treatment of crude crystallographic data. Thereafter, they learn how to analyze the positioning of the drug on the active site of the enzyme, looking for regions related to the molecular recognition. At the end of the study, students can summarize the molecular requirements for the interaction and the structure-activity relationships of the studied drugs

Sowing date and seeding rate affect bioactive compound contents of chickpea grains

© 2019 by the authors. Licensee MDPI, Basel, Switzerland. Chickpea grains may represent an alternative to soybean meals and energetic concentrates in animal feeding, as their nutritional value can help to increase the sustainability of livestock systems. Unfortunately, the presence of bioactive compounds with anti-nutritional effects can prevent its direct use, especially in mono-gastrics. It is known that the synthesis of these compounds depends on genetic expression, which is also influenced by growth conditions. The objective of this two-year study was to assess the effect of sowing date (winter versus spring) and seeding rate (70 versus 110 seeds m−2) on the accumulation of soluble carbohydrates, α-galactosides, trypsin inhibitors, and inositol phosphates in the grains of two Kabuli cultivars, in the Mediterranean climate. The results showed that seeds collected from winter sowing contained more trypsin inhibitors than those seeded in spring (+4%, on average), reaching values between 16.1 and 18.6 TIU mg protein−1. The seeding rate affects only the α-galactosides content, which increases (+9%) at lower densities (70 seeds m−2). These findings suggest that agronomic management can be used to modulate the content of some anti-nutritional factors in the seeds, even though the genetic characteristics and phenotypic expression, in relation to the climatic conditions, seem to deeply affect the content of all the bioactive compounds investigated.7s

UNDERSTANDING THE CHEMICAL PROCESS RELATED TO THE BIOACTIVATION OF SIMVASTATIN THROUGH EXPERIMENTAL AND IN SILICO

Cholesterol is a lipid which in high concentration can be an important risk factor for coronary diseases and atherosclerotic lesions. This lipid presents an endogenous biosynthesis that involves several steps; one of them is modulated by the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase). HMG-CoA reductase is inhibited by statins, such as simvastatin, in order to reduce seric become active. The structure of simvastatin has a lactone ring that undergoes enzymatic hydrolysis giving the 3,5-dihydroxy-heptanoate metabolite. This group is essential for simvastatin antilipemic activity, but significantly increases their water solubility. Make students understand the influence of chemical groups and organic functions on physicochemical properties and pharmacokinetic profiles of drugs, as simvastatin, is not an easy task. In this context, combine practical strategies and theoretical presentations of the concepts involved on drug biotransformation certainly could improve the teaching learning process. This manuscript correlates organic strategies and in silico techniques throught simvastatin hydrolysis followed by comparative ClogP measurement. This approach intends to allow students to have contact with a cross-platform and multidisciplinary learning, making it ludic, easier and more interesting than theoretical classes

The potential role of spineless safflower (Carthamus tinctorius L. var. inermis) as fodder crop in central Italy

The present study aimed at assessing how nitrogen (N) fertilization affects nutritional characteristics of spineless safflower grown under Mediterranean conditions and evaluating a 2-days wilting treatment on moisture reduction and pH before ensiling. Spineless safflower, sown in November 2008, was grown in 3 m x 18 m plot (45 plants m-2). A randomized complete block design (RCBD) one cultivar x four N-fertilization levels (N0=0 kg/ha, land allocation, N1=35 kg/ha, N2=70 kg/ha, N3=105 kg ha-1) (3 replicates each level) was adopted. At mowing (May 2009, before blooming) the crop biomass production was recorded. Wilted plant material for each plot was collected and pH was measured. Dried and ground samples (1 mm mesh) were analyzed for crude protein (CP), lipids (EE), crude fibre (CFom), neutral detergent fibre (aNDFom), acid detergent fibre (ADF), lignin (ADL) and ash (ASH) content. All data were analyzed by ANOVA and difference among means was assessed significant at P<0.05. Biomass production showed a nitrogen-dose relationship [from N0=1.80±0.29 to N3=2.71±0.20 t ha-1 dry matter (DM), P<0.01]. N-fertilization significantly affected the CP content, with the highest values (17.52±0.26% DM) observed for the N3 fertilization level. The other nutritional characteristics (EE: 1.36±0.23% DM; CFom: 41.70±3.65% DM; aNDFom: 44,6±2.71% DM; ASH: 12.74±0.74% DM) were not or only slightly affected (ADF: 34.15±2.14%; ADL: 9.53±2.35) (P<0.05) by the N-fertilization. After the 2-day wilting treatment, the highest pH (5.99±0.08) was found for N2 treatment, while the lowest one (5.85±0.06) was recorded for the N0 level (P<0.01). The wilting treatment gave a sufficient moisture reduction, allowing satisfactory preservation of safflower by ensiling. Spineless safflower shows an interesting potential to be grown for ruminants feeding purposes in Mediterranean area. N-fertilization plays an important role as far as productivity of safflower and its CP content are concerned. Further studies are in progress to fully characterize safflower as fresh and preserved forage resource for crop-livestock production systems in central Italy

HLA-DQB1 typing of north east Italian IDDM patients using amplified DNA, oligonucleotide probes and a rapid DNA-enzyme immunoassay (DEIA)

We report on HLA-DQB1 typing in IDDM patients of north east Italian region using an enzymatic method based on the detection of hybridization reaction between PCR amplified DNA from whole blood and allele specific oligonucleotides by an antibody directed against double stranded DNA (DNA-enzyme immunoassay or DEIA). The method is reliable, simple and sensitive as the classical radioactive method with the advantage of using a universal non radioactive detection reagent. Nineteen families, each including one subject with juvenile insulin-dependent diabetes mellitus (IDDM) were analyzed. A strong association between absence of an aspartic acid (Asp) in position 57 of DQB1 beta chain in homozygous conditions and susceptibility to IDDM was found. In contrast with some previous observations, however, no significant association was found between Asp/non-Asp heterozygous genotype and IDDM. No patients were found with an homozygous Asp/Asp genotype, known to be protective in caucasoid population. Of particular interest was the DQB1 allelic distribution in our population sample. The non-Asp allele most frequently found in IDDM subjects was the DQB1 0201 allele and this finding was statistically significant (Pc value &lt; 0.05, relative risk = 5.01). No significant association was found for any other allele including the DQB1 0302 (Pc value = not significant although with relative risk = 3.28) previously reported as the most frequent allele in IDDM caucasoid patients

Concurrent Nivolumab and Metformin in Diabetic Cancer Patients: Is It Safe and More Active?

Background/aim: Recent evidence suggests potential synergistic antitumor effects of the combination of programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) immune checkpoint inhibitors with the oral hypoglycemic agent metformin. The aim of this study was to investigate the safety and activity of metformin combined with nivolumab in diabetic cancer patients. Patients and methods: Patients with advanced melanoma, renal cell carcinoma or lung cancer receiving nivolumab with concurrent diabetes treated with metformin were retrospectively collected. The primary endpoint was the safety of nivolumab plus metformin combination. Results: We collected 40 patients with solid tumors who received metformin for concomitant diabetes and nivolumab as anticancer therapy in four Italian Hospitals. The concomitant use of nivolumab and metformin was well tolerated; adverse events (AEs) of any grade occurred in 75% of patients (mainly fatigue, pruritus, rash, and asthenia). Grade 3 AEs occurred only in 20% of cases; no grade 4 AEs were observed. A statistically significant correlation was found between higher doses of metformin (&gt;1,000 mg daily) and longer progression-free survival (p=0.021), overall survival (p=0.037) and higher overall response rate. Conclusion: The combination of nivolumab and metformin was safe and might have an antitumor activity, supporting further investigations on the synergistic antitumor effect of this combination