Molecular mimicry of SARS-COV-2 antigens as a possible natural anti-cancer preventive immunization.

Background: In the present study we investigated whether peptides derived from the entire SARS-CoV-2 proteome share homology to TAAs (tumor-associated antigens) and cross-reactive CD8+ T cell can be elicited by the BNT162b2 preventive vaccine or the SARS-CoV-2 natural infection. Methods and results: Viral epitopes with high affinity (<100nM) to the HLA-A*02:01 allele were predicted. Shared and variant-specific epitopes were identified. Significant homologies in amino acidic sequence have been found between SARS-CoV-2 peptides and multiple TAAs, mainly associated with breast, liver, melanoma and colon cancers. The molecular mimicry of the viral epitopes and the TAAs was found in all viral proteins, mostly the Orf 1ab and the Spike, which is included in the BNT162b2 vaccine. Predicted structural similarities confirmed the sequence homology and comparable patterns of contact with both HLA and TCR α and ß chains were observed. CD8+ T cell clones cross-reactive with the paired peptides have been found by MHC class l-dextramer staining. Conclusions: Our results show for the first time that several SARS-COV-2 antigens are highly homologous to TAAs and cross-reactive T cells are identified in infected and BNT162b2 preventive vaccinated individuals. The implication would be that the SARS-Cov-2 pandemic could represent a natural preventive immunization for breast, liver, melanoma and colon cancers. In the coming years, real-world evidences will provide the final proof for such immunological experimental evidence. Moreover, such SARS-CoV-2 epitopes can be used to develop "multi-cancer" off-the-shelf preventive/therapeutic vaccine formulations, with higher antigenicity and immunogenicity than over-expressed tumor self-antigens, for the potential valuable benefit of thousands of cancer patients around the World.

Inclusions of Pesticides by ß-Cyclodextrin in Solution and Solid State: Chlorpropham, Monuron, and Propanil.

Persistence and degradation are important factors in determining the safe use of such synthetic products, and numerous studies have been addressed to develop pesticide remediation methods aimed at ameliorating these features. In this frame, the use of different cyclodextrins (CDs) molecules has attracted considerable attention due to their well-known non-toxic nature, limited environmental impact, and capability to reduce the environmental and health risks of pesticides. CDs appear to be a valuable tool for the elimination of pesticides from polluted areas as well as for better pesticide formulations that positively influence their hydrolysis or degradation. The present work investigates the interaction between ß-cyclodextrins and three commonly used pesticides (i.e., chlorpropham, monuron, and propanil) both in solution and in the solid state by means of UV-Vis, FT-IR, and X-ray powder diffractometry. We show that such interactions result in all three cases in the formation of inclusion complexes with a 1:1 stoichiometry and binding constants (Kb) of 369.9 M-1 for chlorpropham, 292.3 M-1 for monuron, and 298.3 M-1 for propanil. We also report the energy-minimized structures in silico for each complex. Our data expand and complement the available literature data in indicating CDs as a low-cost and very effective tool capable of modulating the properties that determine the environmental fate of pesticides.

High-Resolution Conformational Analysis of RGDechi-Derived Peptides Based on a Combination of NMR Spectroscopy and MD Simulations.

The crucial role of integrin in pathological processes such as tumor progression and metastasis formation has inspired intense efforts to design novel pharmaceutical agents modulating integrin functions in order to provide new tools for potential therapies. In the past decade, we have investigated the biological proprieties of the chimeric peptide RGDechi, containing a cyclic RGD motif linked to an echistatin C-terminal fragment, able to specifically recognize αvß3 without cross reacting with αvß5 and αIIbß3 integrin. Additionally, we have demonstrated using two RGDechi-derived peptides, called RGDechi1-14 and ψRGDechi, that chemical modifications introduced in the C-terminal part of the peptide alter or abolish the binding to the αvß3 integrin. Here, to shed light on the structural and dynamical determinants involved in the integrin recognition mechanism, we investigate the effects of the chemical modifications by exploring the conformational space sampled by RGDechi1-14 and ψRGDechi using an integrated natural-abundance NMR/MD approach. Our data demonstrate that the flexibility of the RGD-containing cycle is driven by the echistatin C-terminal region of the RGDechi peptide through a coupling mechanism between the N- and C-terminal regions.

[A narrative review on arteriovenous fistula for hemodialysis].

Vascular access is the lifeline for hemodialysis patients. Autologous artero-venous fistula (AVF) is still the most popular vascular access for hemodialysis even if declining during the last decades. Compared to central venous catheters and vascular grafts, AVF is characterized by a lower risk of infection and lower number of hospitalizations, and by a better quality of life, higher dialysis efficiency, and more prolonged life expectancy for patients. Since the year 1966 when the two surgeons Cimino and Brescia had the idea of connecting the forearm vein and artery for chronic dialysis, several data have accumulated on surgical procedures, positioning of AVF (distal vs proximal), time for the first use, monitoring and surveilling. All guidelines suggest that special care should be given by monitoring and surveilling AVF to avoid its failure or fatal closing. Attention should be paid to the patient's vasculature before surgery, through the "maturation" phase and chronic use. Indeed, AVF requires constant and careful care. The crucial role is played by the patient itself in cooperation with devoted clinical staff participated by skilled nurses, nephrologists, surgeons, radiologists, and sonographers. Literature on AVF is evaluated and guidelines suggestions reported as well as the data attained by the Accesso Vascolare per Emodialisi (AVE) project. This project aimed to evaluate the benefits of monitoring and surveilling, operated by a multidisciplinary team on dialysis adequacy, AVF longevity, and patient's mortality.

Bimodal antibody-titer decline following BNT162b2 mRNA anti-SARS-CoV-2 vaccination in healthcare workers of the INT - IRCCS "Fondazione Pascale" Cancer Center (Naples, Italy).

BACKGROUND: Both SARS-CoV-2 mRNA-based vaccines [BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna)] have shown high efficacy, with very modest side effects in limiting transmission of SARS-CoV-2 and in preventing the severe COVID-19 disease, characterized by a worrying high occupation of intensive care units (ICU), high frequency of intubation and ultimately high mortality rate. At the INT, in Naples, only the BNT162b2/Pfizer vaccine has been administered to cancer patients and healthcare professionals aged 16 and over. In the present study, the antibody response levels and their decline were monitored in an interval of 6-9 months after vaccine administration in the two different cohorts of workers of the INT - IRCCS "Fondazione Pascale" Cancer Center (Naples, Italy): the group of individuals previously infected with SARS-CoV-2 and vaccinated with a single dose; and that of individuals negative for previous exposure to SARS-CoV-2 vaccinated with two doses 21 days apart. METHODS: Specific anti-RBD (receptor-binding domain) titers against trimeric spike glycoprotein (S) of SARS-CoV-2 by Roche Elecsys Anti-SARS-CoV-2 S ECLIA immunoassay were determined in serum samples of 27 healthcare workers with a previously documented history of SARS-CoV-2 infection and 123 healthcare workers without, during antibody titers' monitoring. Moreover, geometric mean titers (GMT) and relative fold changes (FC) were calculated. RESULTS: Bimodal titer decline was observed in both previously infected and uninfected SARS-CoV-2 subjects. A first rapid decline was followed by a progressive slow decline in the 6/9 month-period before the further vaccine boost. The trend was explained by 2 different mathematical models, exponential and power function, the latter revealing as predictive of antibody titer decline either in infected or in not previously infected ones. The value of the prolonged lower vaccine titer was about 1 log below in the 6/9-month interval after the single dose for previously infected individuals with SARS-CoV-2 and the two doses for those not previously infected. The titer change, after the boost dose administration, on the other hand, was ≥ 1.5 FC higher than the titers at the 6/9-month time-points in both cohorts. A similar quantitative immune titer was observed in both cohorts 8 days after the last boost dose. The subsequent immunoresponse trend remains to be verified. DISCUSSION: The results show that a very rapid first decline, from the highest antibody peak, was followed by a very slow decline which ensured immune protection lasting more than 6 months. The apparent absence of adverse effects of the rapid decline on the vaccine's immune protective role has been related to a large majority of low avidity antibodies induced by current vaccines. High avidity antibodies with prolonged anti-transmission efficacy show a longer half-life and are lost over a longer interval period. The cellular immunity, capable of preventing severe clinical diseases, lasts much longer. The unbalanced dual activity (cellular vs humoral) while effective in limiting ICU pressure and overall mortality, does not protect against transmission of SARS-CoV-2, resulting in high circulation of the virus among unvaccinated subjects, including the younger population, and the continuous production of variants characterized by changes in transmissibility and pathogenicity. The high mutation rate, peculiar to the RNA virus, can however lead to a dual opposite results: selection of defective and less efficient viruses up to extinction; risk of more efficiently transmitted variants as the current omicron pandemic. CONCLUSIONS: In conclusion the current bimodal antibody-titer decline, following BNT162b2 mRNA anti-SARS-CoV-2 vaccination, needs a further extended analysis to verify the protective borderline levels of immunity and the optimal administration schedule of vaccine boosters. Our current results can contribute to such goal, besides a direct comparison of other FDA-approved and candidate vaccines.

Vaccination strategy and anti - SARS-CoV-2 S titers in healthcare workers of the INT - IRCCS "Fondazione Pascale" Cancer Center (Naples, Italy).

BACKGROUND: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection and the resulting disease, coronavirus disease 2019 (COVID-19), have spread to millions of people globally, requiring the development of billions of different vaccine doses. The SARS-CoV-2 spike mRNA vaccine (named BNT162b2/Pfizer), authorized by the FDA, has shown high efficacy in preventing SARS-CoV-2 infection after administration of two doses in individuals 16 years of age and older. In the present study, we retrospectively evaluated the differences in the SARS-CoV-2 humoral immune response after vaccine administration in the two different cohorts of workers at the INT - IRCCS "Fondazione Pascale" Cancer Center (Naples, Italy): previously infected to SARS-CoV-2 subjects and not infected to SARS-CoV-2 subjects. METHODS: We determined specific anti-RBD (receptor-binding domain) titers against trimeric spike glycoprotein (S) of SARS-CoV-2 by Roche Elecsys Anti-SARS-CoV-2 S immunoassay in serum samples of 35 healthcare workers with a previous documented history of SARS-CoV-2 infection and 158 healthcare workers without, after 1 and 2 doses of vaccine, respectively. Moreover, geometric mean titers and relative fold changes (FC) were calculated. RESULTS: Both previously infected and not infected to SARS-CoV-2 subjects developed significant immune responses to SARS-CoV-2 after the administration of 1 and 2 doses of vaccine, respectively. Anti-S antibody responses to the first dose of vaccine were significantly higher in previously SARS-CoV-2-infected subjects in comparison to titers of not infected subjects after the first as well as the second dose of vaccine. Fold changes for subjects previously infected to SARS-CoV-2 was very modest, given the high basal antibody titer, as well as the upper limit of 2500.0 BAU/mL imposed by the Roche methods. Conversely, for naïve subjects, mean fold change following the first dose was low ([Formula: see text] =1.6), reaching 3.8 FC in 72 subjects (45.6%) following the second dose. CONCLUSIONS: The results showed that, as early as the first dose, SARS-CoV-2-infected individuals developed a remarkable and statistically significant immune response in comparison to those who did not contract the virus previously, suggesting the possibility of administering only one dose in previously SARS-CoV-2-infected subjects. FC for previously infected subjects should not be taken into account for the generally high pre-vaccination values. Conversely, FC for not infected subjects, after the second dose, were = 3.8 in > 45.0% of vaccinees, and ≤ 3.1 in 19.0%, the latter showing a potential susceptibility to further SARS-CoV-2 infection.

Immunotherapy may protect cancer patients from SARS-CoV-2 infection: a single-center retrospective analysis.

Coronavirus disease 2019 (COVID-19) global pandemic has created unique challenges to healthcare systems throughout the world. Ensuring subjects' safety is mandatory especially in oncology, in consideration of cancer patients' particular frailty. We examined the proportion of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) IgM and/or IgG positive subjects in three different groups from Istituto Nazionale Tumori - IRCCS "Fondazione G. Pascale" in Naples (Campania region, Italy): cancer patients treated with Innovative Immunotherapy (Immune Checkpoint Inhibitors, ICIs), cancer patients undergoing standard Chemotherapies (CHTs) and healthcare providers. 9 out of 287 (3.1%) ICIs patients resulted positive, with a significant lower percentage in respect to CHTs patients (39 positive subjects out of 598, 6.5%) (p = 0.04). There was no statistically significant difference between ICIs cohort and healthcare providers, 48 out of 1050 resulting positive (4.6%). Performing a Propensity Score Matching based on gender and tumor stage, the effect of treatment on seropositivity was analyzed through a regression logistic model and the ICIs treatment resulted to be the only protective factor significantly (p = 0.03) associated with positivity (odds ratio-OR: 0.41; 95% confidence interval-CI 0.18-0.91). According to these preliminary data, ICIs would appear to be a protective factor against the onset of COVID-19 infection.

Characterization of the Mycobacterial MSMEG-3762/63 Efflux Pump in Mycobacterium smegmatis Drug Efflux.

Multi-drug resistant tuberculosis (MDR-TB) represents a major health problem worldwide. Drug efflux and the activity of efflux transporters likely play important roles in the development of drug-tolerant and drug-resistant mycobacterial phenotypes. This study is focused on the action of a mycobacterial efflux pump as a mechanism of drug resistance. Previous studies demonstrated up-regulation of the TetR-like transcriptional regulator MSMEG_3765 in Mycobacterium smegmatis and its ortholog Rv1685c in Mycobacterium tuberculosis (Mtb) in acid-nitrosative stress conditions. MSMEG-3765 regulates the expression of the MSMEG_3762/63/65 operon, and of the orthologous region in Mtb (Rv1687c/86c/85c). MSMEG-3762 and Rv1687c are annotated as ATP-binding proteins, while MSMEG-3763 and Rv1686c are annotated as trans-membrane polypeptides, defining an ABC efflux pump in both M. smegmatis and Mtb. The two putative efflux systems share a high percentage of identity. To examine the role of the putative efflux system MSMEG-3762/63, we constructed and characterized a MSMEG-3763 deletion mutant in M. smegmatis (∆MSMEG_3763). By comparative analysis of wild type, knockout, and complemented strains, together with structural modeling and molecular docking bioinformatics analyses of the MSMEG-3763 trans-membrane protein, we define the protein complex MSMEG-3762/63 as an efflux pump. Moreover, we demonstrate involvement of this pump in biofilm development and in the extrusion of rifampicin and ciprofloxacin (CIP), antimicrobial drugs used in first- and second-line anti-TB therapies.

Selective Targeting of αvß5 Integrin in HepG2 Cell Line by RGDechi15D Peptide.

Recently, the research community has become increasingly concerned with the receptor αvß5, a member of the well-known integrin family. Different ongoing studies have evidenced that αvß5 integrin regulates not only physiological processes but also a wide array of pathological events, suggesting the receptor as a valuable biomarker to specifically target for therapeutic/diagnostic purposes. Remarkably, in some tumors the involvement of the receptor in cell proliferation, tumor dissemination and angiogenesis is well-documented. In this scenario, the availability of a selective αvß5 antagonist without 'off-target' protein effects may improve survival rate in patients with highly aggressive tumors, such as hepatocellular carcinoma. We recently reported a cyclic peptide, RGDechi15D, obtained by structure-activity studies. To our knowledge it represents the first peptide-based molecule reported in the literature able to specifically bind αvß5 integrin and not cross react with αvß3. Here we demonstrated the ability of the peptide to diminish both adhesion and invasion of HepG2 cells, an in vitro model system for hepatocellular carcinoma, to reduce the cell proliferation through an apoptotic process, and to interfere with the PI3K pathway. The peptide, also decreases the formation of new vessels in endothelial cells. Taken together these results indicate that the peptide can be considered a promising molecule with properties suited to be assessed in the future for its validation as a selective therapeutic/diagnostic weapon in hepatocarcinoma.

Zinc Fingers.

Zinc finger (ZF) domains, that represent the majority of the DNA-binding motifs in eukaryotes, are involved in several processes ranging from RNA packaging to transcriptional activation, regulation of apoptosis, protein folding and assembly, and lipid binding. While their amino acid composition varies from one domain to the other, a shared feature is the coordination of a zinc ion, with a structural role, by a different combination of cysteines and histidines. The classical zinc finger domain (also called Cys2His2) that represents the most common class, uses two cysteines and two histidines to coordinate the metal ion, and forms a compact ßßα architecture consisting in a ß-sheet and an α-helix. GAG-knuckle resembles the classical ZF, treble clef and zinc ribbon are also well represented in the human genome. Zinc fingers are also present in prokaryotes. The first prokaryotic ZF domain found in the transcriptional regulator Ros protein was identified in Agrobacterium tumefaciens. It shows a Cys2His2 metal ion coordination sphere and folds in a domain significantly larger than its eukaryotic counterpart arranged in a ßßßαα topology. Interestingly, this domain does not strictly require the metal ion coordination to achieve the functional fold. Here, we report what is known on the main classes of eukaryotic and prokarotic ZFs, focusing our attention to the role of the metal ion, the folding mechanism, and the DNA binding. The hypothesis of a horizontal gene transfer from prokaryotes to eukaryotes is also discussed.

A potential prognostic marker in primitive lung neuroendocrine tumor: A case report.

BACKGROUND: The diagnosis and monitoring of primitive lung neuroendocrine tumors (lung pNETs) are usually performed by the measurement of serum chromogranin A (CgA) and urinary 5-hydroxyindolacetic acid (5-HIAA) levels. However, imaging techniques are necessary due to the poor diagnostic efficiency of the laboratory tests. METHODS: A total-body computed tomography and bone scintigraphy scans showed multiple hepatic and bone metastases of a 55-year-old man affected by well-differentiated lung pNETs without severe initial symptoms. After diagnosis, he started therapy and was monitored with serum, urinary markers, and imaging techniques. RESULTS: During follow-up, the urinary 5-HIAA levels did not significantly increase, while serum CgA and urinary para-hydroxyphenylacetic acid (pHPAA) levels (urinary organic acid physiologically present in the urines of healthy subjects) showed significant increases related to worsening clinical condition. CONCLUSIONS: The early increase in urinary pHPAA levels-usually not dosed in pNET patient monitoring-could be a promising prognostic marker.

Short- and Long-Term Evaluation of Renal Function after Radical Cystectomy and Cutaneous Ureterostomy in High-Risk Patients.

Deterioration of renal function has been reported after radical cystectomy (RC) with urinary diversion. We investigated renal function changes in elderly bladder cancer (BCa) patients who underwent RC with cutaneous ureterostomy (CU) urinary diversion. We performed a retrospective, observational study. BCa patients aged ≥75 with an American Society of Anesthesiologists (ASA) class greater than II were included. Glomerular filtration rate (GFR) was the main outcome measure. GFR values were recorded preoperatively, at discharge, at 6-month follow-up, and yearly up to 60 months. A total of 70 patients with a median age of 78.0 years were identified. Median preoperative GFR was 74.3 mL/min/1.73 m2 and declined significantly to 54.6 mL/min/1.73 m2 after 6 months (p < 0.001). A gradual GFR decline was observed thereafter, reaching a median value of 46.2 after 60 months. Preoperative GFR and acute kidney injury were significant predictors of fast deterioration of GFR and of 25% deterioration of GFR after 12 months. Elderly BCa patients with high comorbidity rates undergoing RC with CU should be carefully informed about the risk of GFR deterioration and the need for adequate monitoring.

Nissen fundoplication and dyspeptic symptoms: is the water load test useful?

BACKGROUND: The water load test is a simple, cheap and standardized method to evaluate gastric distension and gastric motility responses. We have previously shown that in patients with mild erosive or non-erosive esophagitis this test is frequently abnormal, suggesting an altered gastric function. The aim was to evaluate the water load test score before and after Nissen fundoplication in reflux patients. METHODS: Thirty-one patients (16 men, 15 women, mean age 46.5 y) were studied before and 3 months after Nissen fundoplication by stationary esophageal manometry, wireless Bravo pH system monitoring (48 hours), and water load test. A dyspepsia symptom questionnaire was also completed before and after surgery. Data were compared with those of 35 controls. RESULTS: All patients had pH-monitoring positive for pathological acid exposure and/or related-reflux symptoms in the absence of motility disorders. Basal symptoms scores were higher in patients compared to controls and improved after surgery, except than postprandial fullness, early satiation, and bloating, that were significantly increased. At baseline, all patients ingested significantly lower water volumes than controls, with a tendency to early onset of fullness and nausea, respectively. After surgery, the water volumes were significantly lower than presurgery. CONCLUSIONS: In patients with reflux-related symptoms, with or without esophagitis, the water load test is frequently abnormal, suggesting an altered gastric function. Nissen fundoplication is associated with a relatively higher incidence of bloating, epigastric pain and fullness. These preliminary data could explain the incomplete resolution of symptoms after surgery in some patients, and suggest the use of additional studies to explore the gastric function in presurgical evaluation.

Vitamin D in kidney transplant recipients
.

Kidney transplant recipients (KTRs) are susceptible to low levels of vitamin D, which may be responsible for mineral and bone metabolism disorders and play some role in the occurrence of cardiovascular, metabolic, immunologic, neoplastic, and infectious complications after kidney transplant. Kidney Disease Improving Global Outcomes (KDIGO) guidelines of the year 2017 recommended vitamin D supplementation in the first 12 months after transplant using the same treatment strategies for the general population. However, no recommendations are provided after the first 12 months due to a lack of sufficient data. This review analyses some studies that assessed the vitamin D status of KTRs and the effects of nutritional and active vitamin D supplementation on bone mineral density, cardiovascular disease, proteinuria, and graft function in KTRs.

Conformational studies of RGDechi peptide by natural-abundance NMR spectroscopy.

Integrins are heterodimeric cell-surface proteins that play important roles during developmental and pathological processes. Diverse human pathologies involve integrin adhesion including thrombotic diseases, inflammation, tumour progression, fibrosis, and infectious diseases. Although in the past decade, novel integrin-inhibitor drugs have been developed for integrin-based medical applications, the structural determinants modulating integrin-ligands recognition mechanisms are still poorly understood, reducing the number of integrin subtype exclusive antagonists. In this scenario, we have very recently showed, by means of chemical and biological assays, that a chimeric peptide (named RGDechi), containing a cyclic RGD motif linked to an echistatin C-terminal fragment, is able to interact with the components of integrin family with variable affinities, the highest for αv ß3. Here, in order to understand the mechanistic details driving the molecular recognition mechanism of αv ß3 by RGDechi, we have performed a detailed structural and dynamics characterization of the free peptide by natural abundance nuclear magnetic resonance (NMR) spectroscopy. Our data indicate that RGDechi presents in solution an heterogeneous conformational ensemble characterized by a more constrained and rigid pentacyclic ring and a largely unstructured acyclic region. Moreover, we propose that the molecular recognition of αv ß3 integrin by RGDechi occurs by a combination of conformational selection and induced fit mechanisms. Finally, our study indicates that a detailed NMR characterization, by means of natural abundance 15 N and 13 C, of a mostly unstructured bioactive peptide may provide the molecular basis to get essential structural insights into the binding mechanism to the biological partner.

Ligand-Based NMR Study of C-X-C Chemokine Receptor Type 4 (CXCR4)-Ligand Interactions on Living Cancer Cells.

Peptide-binding G protein-coupled receptors (GPCRs) are key effectors in numerous pathological and physiological pathways. The assessment of the receptor-bound conformation of a peptidic ligand within a membrane receptor such as a GPCR is of great impact for a rational drug design of more potent analogues. In this work, we applied multiple ligand-based nuclear magnetic resonance (NMR) methods to study the interaction of peptide heptamers, derived from the C-X-C Motif Chemokine 12 (CXCL12), and the C-X-C Chemokine Receptor Type 4 (CXCR4) on membranes of human T-Leukemia cells (CCRF-CEM cells). This study represents the first structural investigation reporting the receptor-bound conformation of a peptide to a GPCR directly on a living cell. The results obtained in the field of CXCL12/CXCR4 are proofs of concept, although important information for researchers dealing with the CXCR4 field arises. General application of the presented NMR methodologies is possible and surely may help to boost the development of new therapeutic agents targeting GPCRs.

A strategy to reduce inflammation and anemia treatment's related costs in dialysis patients.

This is a post-hoc analysis evaluating erythropoiesis stimulating agents' (ESA) related costs while using an additional ultrafilter (Estorclean PLUS) to produce ultrapure dialysis water located within the fluid pathway after the treatment with reverse osmosis and before the dialysis machine. Twenty-nine patients (19 treated with epoetin alfa and 10 with darboepoetin alfa) were included in the analysis. We showed to gain savings of 210 € per patient (35 € per patient each month) with epoetin alfa during the experimental period of 6 months, compared to the control period and of 545 € per patient (90 € per patient each month) with darboepoetin alfa. Estorclean PLUS had a cost of 600 € (25 € per month per each patient) and was used for 6 months. Intravenous iron therapy with sodium ferrigluconate had a cost of 0,545 €/62,5 mg. In conclusion, during the experimental period with the use of Estorclean, we obtained global savings of 11 € per patient per month with epoetin alfa and 30 € per patient per month with darboepoetin alfa to treat anemia in dialysis patients.

Chemical Modification for Proteolytic Stabilization of the Selective αvß3 Integrin RGDechi Peptide: in Vitro and in Vivo Activities on Malignant Melanoma Cells.

Herein, we report the synthesis and biological characterization of the new peptide ψRGDechi as the first step toward novel-targeted theranostics in melanoma. This pseudopeptide is designed from our previously reported RGDechi peptide, known to bind selectively αvß3 integrin, and differs for a modified amide bond at the main protease cleavage site. This chemical modification drastically reduces the enzymatic degradation in serum, compared to its parental peptide, resulting in an overall magnification of the biological activity on a highly expressing αvß3 human metastatic melanoma cell line. Selective inhibition of cell adhesion, wound healing, and invasion are demonstrated; near-infrared fluorescent ψRGDechi derivative is able to detect αvß3 integrin in human melanoma xenografts in a selective fashion. More, molecular docking studies confirm that ψRGDechi recognizes the receptor similarly to RGDechi. All these findings pave the way for the future employment of this novel peptide as promising targeting probe and therapeutic agent in melanoma disease.

Effectiveness of Switch to Erythropoiesis-Stimulating Agent (ESA) Biosimilars versus Maintenance of ESA Originators in the Real-Life Setting: Matched-Control Study in Hemodialysis Patients.

BACKGROUND: In hemodialysis (HD), switching from erythropoiesis-stimulating agent (ESA) originators to biosimilars is associated with the need for doses approximately 10% higher, according to industry-driven studies. OBJECTIVE: The aim of this study was to evaluate the efficacy on anemia control of switching from ESA originators to biosimilars in daily clinical practice. METHODS: We retrospectively selected consecutive HD patients receiving stable intravenous ESA doses, and who had not been transfused in the previous 6 months, from 12 non-profit Italian centers. Patients switched from originators to biosimilars (n = 163) were matched with those maintained on ESA originators (n = 163) using a propensity score approach. The study duration was 24 weeks, and the primary endpoint was the mean dose difference (MDD), defined as the difference between the switch and control groups of ESA dose changes during the study (time-weighted average ESA dose minus baseline ESA dose). RESULTS: Age (70 ± 13 years), male sex (63%), diabetes (29%), history of cardiovascular disease (40%), body weight (68 ± 14 kg), vascular access (86% arteriovenous fistula), hemoglobin [Hb] (11.2 ± 0.9 g/dL) and ESA dose (8504 ± 6370 IU/week) were similar in the two groups. Hb remained unchanged during the study in both groups. Conversely, ESA dose remained unchanged in the control group and progressively increased in the switch group from week 8 to 24. The time-weighted average of the ESA dose was higher in the switch group than in the control group (10,503 ± 7389 vs. 7981 ± 5858 IU/week; p = 0.001), leading to a significant MDD of 2423 IU/week (95% confidence interval [CI] 1615-3321), corresponding to a 39.6% (95% CI 24.7-54.6) higher dose of biosimilars compared with originators. The time-weighted average of Hb was 0.2 g/dL lower in the switch group, with a more frequent ESA hyporesponsiveness (14.7 vs. 2.5%). Iron parameters and other resistance factors remained unchanged. CONCLUSIONS: In stable dialysis patients, switching from ESA originators to biosimilars requires 40% higher doses to maintain anemia control.

Ultrapure dialysis water obtained with additional ultrafilter may reduce inflammation in patients on hemodialysis.

BACKGROUND: Patients on standard dialysis, in particular those on high-flux and high-efficiency dialysis, are exposed to hundreds of liters of dialysis-water per week. The quality of dialysis-water is a factor responsible for inflammation in dialysis patients. Inflammation is a potent trigger of atherosclerosis and a pathogenetic factor in anemia, increasing mortality and morbidity in dialysis patients. Current systems for water treatment do not completely eliminate bacteria and endotoxins. This prospective study tested whether improved dialysis-water purity by an additional ultrafilter can reduce inflammation and ameliorate hemoglobin levels, with a consequent reduction in erythropoietin-stimulating agents (ESA). METHODS: An ultrafilter, composed of two serially positioned devices with polysulfone membranes of 2.0 and 1.0 m2, respectively, was positioned within the fluid pathway before the dialysis machine. Prevalent dialysis patients were assigned either to continue dialysis with conventional dialysis-water (control phase) or to initiate dialysis sessions with improved dialysis-water purity (study phase). After 6 months, patients were crossed over. Total study duration was 1 year. Routine chemistry, bacterial count, endotoxin levels in dialysis-water as well as blood levels of pro- and anti-inflammatory cytokines, human serum amyloid A, C-reactive protein and fraction 5 of complement were measured. RESULTS: Thirty-two patients completed the study. Mean bacterial count was lower and endotoxin levels were absent in dialysis-water obtained with the ultrafilter. At the end of the study-phase, C-reactive protein and pro-inflammatory cytokines decreased while anti-inflammatory ones increased. Hemoglobin levels were improved with lower ESA doses. CONCLUSIONS: An additional ultrafilter improved dialysis-water purity, reduced levels of inflammation markers, ameliorated hemoglobin concentration with reduced ESA doses. These results remain speculative but they may generate studies to assess whether improved dialysis-water quality with an ultrafilter can reduce inflammation and improve survival of dialysis patients.