A first-in-class, first-in-human, phase I trial of CIGB-552, a synthetic peptide targeting COMMD1 to inhibit the oncogenic activity of NF-κB in patients with advanced solid tumors.

CIGB-552 is a synthetic peptide that interacts with COMMD1 and upregulates its protein levels. The objectives of this phase I study were safety, pharmacokinetic profile, evaluation of the lymphocytes CD4+ and CD8+ and preliminary activity in patients with advanced tumors. A 3 + 3 dose-escalation design with seven dose levels was implemented. Patients were included until a grade 3 related adverse event occurred and the maximum tolerated dose was reached. The patients received subcutaneous administration of CIGB-552 three times per week for 2 weeks. Single-dose plasma pharmacokinetics was characterized at two dose levels, and tumor responses were classified by RECIST 1.1. Twenty-four patients received CIGB-552. Dose-limiting toxicity was associated with a transient grade 3 pruritic maculopapular rash at a dose of 7.0 mg. The maximum tolerated dose was defined as 4.7 mg. Ten patients were assessable for immunological status. Seven patients had significant changes in the ratio CD4/CD8 in response to CIGB-552 treatment; three patients did not modify the immunological status. Stable disease was observed in five patients, including two metastatic soft sarcomas. We conclude that CIGB-552 at dose 4.7 mg was well tolerated with no significant adverse events and appeared to provide some clinical benefits.

Identification of a novel antitumor peptide based on the screening of an Ala-library derived from the LALF(32-51) region.

Novel therapeutic peptides are increasingly making their way into clinical application. The cationic and amphipathic properties of certain peptides allow them to cross biological membranes in a non-disruptive way without apparent toxicity increasing drug bioavailability. By modifying the primary structure of the Limulus-derived LALF(32-51) peptide we designed a novel peptide, L-2, with antineoplastic effect and cell-penetrating capacity. Interestingly, L-2 induced cellular cytotoxicity in a variety of tumor cell lines and systemic injection into immunocompetent and nude mice bearing established solid tumor, resulted in substantial regression of the tumor mass and apoptosis. To isolate the gene transcripts specifically regulated by L-2 in tumor cells, we conducted suppressive subtractive hybridization (SSH) analysis and identified a set of genes involved in biological processes relevant to cancer biology. Our findings describe a novel peptide that modifies the gene expression of the tumor cells and exhibits antitumor effect in vivo, indicating that peptide L-2 is a potential candidate for anticancer therapy.

Electrophoretic techniques applied to the detection and analysis of the human microsatellite DG10s478.

Short nucleotide repetitions (STRs) are commonly used as genetic markers; thus their detection and analysis constitutes a very important tool for the mapping of genetic diseases, as well as for gathering information about genetic polymorphisms at the population level. STRs can be detected with agarose- or acrylamide-based electrophoretic techniques, followed by visualization of the DNA sample with ethidium bromide, silver nitrate, or fluorophore labeling. In this work, we analyzed genomic DNA from five individuals affected with type II diabetes mellitus (T2DM) and five controls (unaffected individuals) in order to know the most precise and reproducible technique for the analysis of the existing polymorphism in the STR DG10S478 of the TCF7L2 gene. The combination of PCR with labeling of the products with the CY5 fluorophore, followed by detection on an ALFexpress sequencer, offered the required resolution to detect the variability in this STR, based solely on size analysis. Our methodology offers similar accuracy and reproducibility at lower costs than existing methods based on the sequencing of PCR products, and is a faster alternative when applied to genotyping studies.

Utilidad de la resonancia magnética cardíaca en pacientes con distrofias neuromusculares (distrofia neuromuscular de Duchene/ Becker) / Usefulness of Cardiac Magnetic Resonance Imaging in Patients with Neuromuscular Dystrophies (Duchenne/Becker Muscular Dystrophy)

RESUMEN Introducción: La Resonancia Magnética Cardíaca (RMC) es cada vez más frecuentemente utilizada en pacientes con Distrofia Neuromuscular de Duchene y Becker (DMD y DMB). Por la capacidad de demostrar realce tardío con gadolinio (RTG), que identifica zonas de fibrosis de la pared media y subepicárdica, subendocárdica o global, y el cálculo de la fracción de eyección ventricular izquierda (FEVI), se considera el patrón oro en el diagnóstico y pronóstico de la afección cardíaca de estas distrofias. Objetivos: Determinar por medio de RMC la presencia de fibrosis cardíaca en pacientes con distrofia neuromuscular. Determinar el compromiso neuromuscular y cardiaco. Definir la evolución cardiovascular de estos pacientes Material y métodos: Se realizó un estudio descriptivo de corte transversal de 16 pacientes consecutivos desde marzo de 2021 a julio de 2022 en el Área de imagen cardiaca de CEMET (Centro Médico Tafi Viejo) y Diagnóstico Médico Dr. Gaya de la provincia de Tucumán. Resultados: Se evaluaron 16 pacientes, todos con diagnóstico confirmado de DMD/DMB por laboratorio, enzimas, y test genéticos. La edad promedio fue 19 años. Todos tenían estadio grave de la escala de Vignos y tratamiento neurológico. Todos tenían tratamiento con betabloqueantes o inhibidores de la enzima de conversión de la angiotensina. La RMC evidenció que 4 pacientes tenían deterioro grave de la FEVI (<35%); 8 pacientes tenían trastornos segmentarios o globales de la motilidad parietal del VI y en 12 se observó RTG, de distribución variable: difusa, mesocárdica, subendocárdica y subepicárdica. En 6 pacientes se observó miocardio no compacto y en 2 derrame pericárdico leve. Conclusión: La RMC debe ser incluida como método de cribaje para pacientes con distrofias neuromusculares. Su aporte para la estadificación clínica y terapéutica es de suma importancia.

ABSTRACT Introduction: Cardiac magnetic resonance imaging (CMR) is commonly used in patients with Duchene (DMD) and Becker (DMB) Neuromuscular Dystrophies. Late gadolinium enhancement (LGE) identifies areas of middle, subepicardial, or subendocardial wall fibrosis, and volumetric left ventricular ejection fraction (LVEF) is considered the gold standard in the diagnosis and prognosis of these dystrophies. Myocardial fibrosis occurs in patients with neuromuscular dystrophies. The purposes of our study were to determine the presence of cardiac fibrosis using CMR, to determine neuromuscular and cardiac involvement, and to evaluate the cardiovascular outcomes of these patients. Methods: A descriptive cross-sectional study of 16 consecutive patients was conducted from March 2021 to July 2022 in the Cardiac Imaging Service of Diagnóstico Médico and CEMET- Tucumán. Results: A total of 16 patients were evaluated, 100% of them with confirmed diagnosis of DMD/DMB by laboratory, enzymes and genetic tests. Mean age was 19 years. All patients had severe stage of the Vignos Scale and were under neurological treatment. All patients were also treated with beta-blockers or angiotensin-converting enzyme inhibitors. CMR revealed severe LVEF impairment <35% in 4 patients, segmental or global left ventricular (LV) wall motion disorders in 8 patients, and variable distribution pattern (diffuse, mesocardial, subendocardial and subepicardial patterns) of LGE in 12 patients. Non-compacted myocardium was observed in 6, and mild pericardial effusions in 2 patients. Conclusion: CMR should be included as a screening method in patients with neuromuscular dystrophies. Its contribution to clinical, echocardiographic and therapeutic staging is of utmost importance.

Assessment of IL-28: rs12979860 and rs8099917 Polymorphisms in a Cohort of Cuban Chronic HCV Genotype 1b Patients.

Hepatitis C virus (HCV) is a significant global public health problem with >185 million infections worldwide. A series of genome-wide association studies (GWAS) has identified IL-28B polymorphisms as a predictor of sustained virologic response (SVR), as well as spontaneous clearance in chronic HCV genotype 1 patients. The objective of this work was to evaluate the prevalence of IL-28B rs12979860 and rs8099917 polymorphisms in Cuban chronic HCV patients. The study cohort included 73 chronic HCV patients treated with concomitant administration of CIGB-230 and nonpegylated IFN-α plus ribavirin (non-pegIFN-α/R) antiviral therapy. The genotype distribution of IL-28B rs12979860CC, -CT, and -TT was 29, 41, and 30%, respectively, and the distribution for rs8099917TT, -TG, and -GG was 63, 31, and 5%, respectively. The allele frequencies for rs12979860C and -T alleles were 51 and 49%, respectively, and for rs8099917G and -T alleles, the values were 21 and 79%, respectively. SVR rates were 55, 42, and 35% for rs12979860CC, -CT, and -TT, respectively, and 52, 30, and 25% for rs8099917TT, -GT, and -GG, respectively. The combined assessment of both single nucleotide polymorphisms (SNPs) resulted in 3 major genotypes (rs12979860CC/rs8099917TT, rs12979860CT/rs8099917TT, and rs12979860CT/rs8099917GG) with a frequency of 30.1, 21.9, and 20.5%, respectively. In patients with heterozygous variant rs12979860CT, the additional genotyping of rs8099917 contributed to increase the SVR rate. It is concluded that in Cuban HCV-infected patients, the responder homogeneous variant rs8099917TT is the most frequent genotype. The simultaneous genotyping of 2 IL-28B SNPs could improve the prediction of SVR contributing to better therapeutic decisions and treatment management.

Use of a prospective space-time scan statistic to prioritize shigellosis case investigations in an urban jurisdiction.

OBJECTIVE: A prospective space-time scan statistic was applied to Chicago's 2002 shigellosis surveillance data to evaluate its utility in objectively describing clusters and assisting in the prioritization of investigations. METHODS: The prospective space-time module of SaTScan, a free software available online, was used to identify "live" clusters of disease, meaning cases that were current as of the date of the analysis and strongly associated in place and time. Fifty-two separate space-time analyses were run; one simulation for each week of 2002. Identified clusters were described in terms of space, time, risk factors reported by involved case-patients, and cases' links to venue-associated outbreaks. RESULTS: Twelve live clusters were detected at the p < 0.05 significance level: two single-household clusters and 10 community clusters. The community clusters ranged in size from 194 to 367 census tracts (median = 294), and in disease burden from 21 to 41 cases (median = 29). Geographically, all of the community clusters were located in the west-central part of the city and had a temporal span of 28 days. Within the 10 community clusters, 15 different day care centers were identified as potential exposure settings for case-patients or their close contacts. CONCLUSIONS: The prospective space-time scan statistic offers local health departments an objective way of describing clusters of shigellosis cases. The method used in this study could help prioritize the assignment and investigation of cases, particularly when overall shigellosis incidence exceeds expected numbers or when an agency's resources are stressed by other events, such as outbreaks.

Outbreak of catheter-associated Klebsiella oxytoca and Enterobacter cloacae bloodstream infections in an oncology chemotherapy center.

BACKGROUND: In March 2004, the Chicago Department of Public Health was notified of a cluster of bloodstream infections with Klebsiella oxytoca and Enterobacter cloacae at a chemotherapy center. Our purpose was to identify the source of the outbreak and prevent further cases. METHODS: The investigation included 103 oncology patients seen at an outpatient oncology chemotherapy center in Chicago during the 16 days before its closure. The outbreak investigation included case identification, retrospective cohort study, review of medical records, microbiologic testing of blood specimens, environmental cultures, and pulsed-field gel electrophoresis. The main outcome measure was infection with K oxytoca, E cloacae, or both, and the Mantel-Haenszel chi(2) test was used to assess risk of infection in relation to presence of central venous catheter. RESULTS: Among the 103 patients, risk of infection was associated with the presence of central venous catheter (relative risk undefined, P<.001). Twenty-seven patients had blood cultures that grew K oxytoca, E cloacae, or both, and all had central venous catheters that were flushed with isotonic sodium chloride solution at the clinic from February 17 through March 3, 2004. Isolates of K oxytoca and E cloacae were matched by pulsed-field gel electrophoresis to K oxytoca and E cloacae isolates obtained from multiple predrawn syringes and from the intravenous fluid and administration set in use in the clinic at the time of its closing. CONCLUSIONS: The injection of contaminated isotonic sodium chloride solution through the venous catheters of attendees at the clinic likely provided the opportunity for bloodstream infections in these 27 case patients. This outbreak highlights the need for continued emphasis on safe injection practices and suggests the need for guidelines and recommendations tailored to outpatient settings.

Arresting progressive atherosclerosis by immunization with an anti-glycosaminoglycan monoclonal antibody in apolipoprotein E-deficient mice.

Atherogenesis is associated with the early retention of low-density lipoproteins (LDL) in the arterial intima by interaction with glycosaminoglycan (GAG)-side chains of proteoglycans. Retained LDL undergo reactive oxygen species-mediated oxidation. Oxidized LDL trigger oxidative stress (OS) and inflammation, contributing to atherosclerosis development. Recently, we reported the preventive anti-atherogenic properties of the chimeric mouse/human monoclonal antibody (mAb) chP3R99-LALA, which were related to the induction of anti-chondroitin sulfate antibody response able to inhibit chondroitin sulfate dependent LDL-enhanced oxidation. In the present work, we aimed at further investigating the impact of chP3R99-LALA mAb vaccination on progressive atherosclerosis in apolipoprotein E-deficient mice (apoE(-/-)) fed with a high-fat high-cholesterol diet receiving 5 doses (50 µg) of the antibody subcutaneously, when ~5% of the aortic area was covered by lesions. Therapeutic immunization with chP3R99-LALA mAb halted atherosclerotic lesions progression. In addition, aortic OS was modulated, as shown by a significant (p<0.05) reduction of lipid and protein oxidation, preservation of antioxidant enzymes activity and reduced glutathione, together with a decrease of nitric oxide levels. chP3R99-LALA mAb immunization also regulated aortic NF-κB activation, diminishing the proinflammatory IL1-ß and TNF-α gene expression as well as the infiltration of macrophages into the arterial wall. The therapeutic immunization of apoE(-/-) with progressive atheromas and persistent hypercholesterolemia using chP3R99-LALA mAb arrested further development of lesions, accompanied by a decrease of aortic OS and NF-κB-regulated pro-inflammatory cytokine gene expression. These results contribute to broaden the potential use of this anti-GAG antibody-based immunotherapy as a novel approach to target atherosclerosis at different phases of progression.

Salmonella enterica serotype Uganda infection in New York City and Chicago.

Outbreaks associated with distinct strains of Salmonella enterica serotype Uganda, a rare serotype, occurred in New York City and Chicago during the summer of 2001. Both outbreaks were linked to eating ready-to-eat pork products. This serotype may emerge as a more frequent cause of human infections.

Emergence of pork carnitas as a cause of foodborne disease outbreaks in Chicago.

Carnitas are fried chunks of pork frequently served in Mexican-origin households, food service establishments, and social gatherings. During 1995-2002, carnitas emerged as the most frequently implicated vehicle of transmission in foodborne disease outbreaks in Chicago. Five (6%) of 90 foodborne disease outbreaks investigated and reported in Chicago during this period were linked to carnitas, and they accounted for 108 illnesses and 11 hospitalizations. The etiologic agent in four outbreaks was Salmonella, and these outbreaks accounted for 29% of the 14 Salmonella-associated foodborne disease outbreaks in Chicago during this period. Unsafe food handling practices that occurred after cooking were identified as contributing to multiple carnitas-associated outbreaks. Local health departments that serve significant Mexican-origin populations should be aware of carnitas as a potential source of foodborne disease, particularly salmonellosis.

Electrophoretic techniques applied to the detection and analysis of the human microsatellite DG10s478

Short nucleotide repetitions (STRs) are commonly used as genetic markers; thus their detection and analysis constitutes a very important tool for the mapping of genetic diseases, as well as for gathering information about genetic polymorphisms at the population level. STRs can be detected with agarose- or acrylamide-based electrophoretic techniques, followed by visualization of the DNA sample with ethidium bromide, silver nitrate, or fluorophore labeling. In this work, we analyzed genomic DNA from five individuals affected with type II diabetes mellitus (T2DM) and five controls (unaffected individuals) in order to know the most precise and reproducible technique for the analysis of the existing polymorphism in the STR DG10S478 of the TCF7L2 gene. The combination of PCR with labeling of the products with the CY5 fluorophore, followed by detection on an ALFexpress sequencer, offered the required resolution to detect the variability in this STR, based solely on size analysis. Our methodology offers similar accuracy and reproducibility at lower costs than existing methods based on the sequencing of PCR products, and is a faster alternative when applied to genotyping studie(AU)