Clinico-radiological features of intracranial atherosclerosis-related large vessel occlusion prior to endovascular treatment.

The identification of large vessel occlusion with underlying intracranial atherosclerotic disease (ICAS-LVO) before endovascular treatment (EVT) continues to be a challenge. We aimed to analyze baseline clinical-radiological features associated with ICAS-LVO that could lead to a prompt identification. We performed a retrospective cross-sectional study of consecutive patients with stroke treated with EVT from January 2020 to April 2022. We included anterior LVO involving intracranial internal carotid artery and middle cerebral artery. We analyzed baseline clinical and radiological variables associated with ICAS-LVO and evaluated the diagnostic value of a multivariate logistic regression model to identify ICAS-LVO before EVT. ICAS-LVO was defined as presence of angiographic residual stenosis or a trend to re-occlusion during EVT procedure. A total of 338 patients were included in the study. Of them, 28 patients (8.3%) presented with ICAS-LVO. After adjusting for confounders, absence of atrial fibrillation (OR 9.33, 95% CI 1.11-78.42; p = 0.040), lower hypoperfusion intensity ratio (HIR [Tmax > 10 s/Tmax > 6 s ratio], (OR 0.69, 95% CI 0.50-0.95; p = 0.025), symptomatic intracranial artery calcification (IAC, OR .15, 95% CI 1.64-26.42, p = 0.006), a more proximal occlusion (ICA, MCA-M1: OR 4.00, 95% CI 1.23-13.03; p = 0.021), and smoking (OR 2.91, 95% CI 1.08-7.90; p = 0.035) were associated with ICAS-LVO. The clinico-radiological model showed an overall well capability to identify ICAS-LVO (AUC = 0.88, 95% CI 0.83-0.94; p < 0.001). In conclusion, a combination of clinical and radiological features available before EVT can help to identify an ICAS-LVO. This approach could be useful to perform a rapid assessment of underlying etiology and suggest specific pathophysiology-based measures. Prospective studies are needed to validate these findings in other populations.

Methods for Using Race and Ethnicity in Prediction Models for Lung Cancer Screening Eligibility.

Importance: Using race and ethnicity in clinical prediction models can reduce or inadvertently increase racial and ethnic disparities in medical decisions. Objective: To compare eligibility for lung cancer screening in a contemporary representative US population by refitting the life-years gained from screening-computed tomography (LYFS-CT) model to exclude race and ethnicity vs a counterfactual eligibility approach that recalculates life expectancy for racial and ethnic minority individuals using the same covariates but substitutes White race and uses the higher predicted life expectancy, ensuring that historically underserved groups are not penalized. Design, Setting, and Participants: The 2 submodels composing LYFS-CT NoRace were refit and externally validated without race and ethnicity: the lung cancer death submodel in participants of a large clinical trial (recruited 1993-2001; followed up until December 31, 2009) who ever smoked (n = 39 180) and the all-cause mortality submodel in the National Health Interview Survey (NHIS) 1997-2001 participants aged 40 to 80 years who ever smoked (n = 74 842, followed up until December 31, 2006). Screening eligibility was examined in NHIS 2015-2018 participants aged 50 to 80 years who ever smoked. Data were analyzed from June 2021 to September 2022. Exposure: Including and removing race and ethnicity (African American, Asian American, Hispanic American, White) in each LYFS-CT submodel. Main Outcomes and Measures: By race and ethnicity: calibration of the LYFS-CT NoRace model and the counterfactual approach (ratio of expected to observed [E/O] outcomes), US individuals eligible for screening, predicted days of life gained from screening by LYFS-CT. Results: The NHIS 2015-2018 included 25 601 individuals aged 50 to 80 years who ever smoked (2769 African American, 649 Asian American, 1855 Hispanic American, and 20 328 White individuals). Removing race and ethnicity from the submodels underestimated lung cancer death risk (expected/observed [E/O], 0.72; 95% CI, 0.52-1.00) and all-cause mortality (E/O, 0.90; 95% CI, 0.86-0.94) in African American individuals. It also overestimated mortality in Hispanic American (E/O, 1.08, 95% CI, 1.00-1.16) and Asian American individuals (E/O, 1.14, 95% CI, 1.01-1.30). Consequently, the LYFS-CT NoRace model increased Hispanic American and Asian American eligibility by 108% and 73%, respectively, while reducing African American eligibility by 39%. Using LYFS-CT with the counterfactual all-cause mortality model better maintained calibration across groups and increased African American eligibility by 13% without reducing eligibility for Hispanic American and Asian American individuals. Conclusions and Relevance: In this study, removing race and ethnicity miscalibrated LYFS-CT submodels and substantially reduced African American eligibility for lung cancer screening. Under counterfactual eligibility, no one became ineligible, and African American eligibility increased, demonstrating the potential for maintaining model accuracy while reducing disparities.

Sequential Treatment With Bacillus Calmette-Güerin (BCG) and Mitomycin C Administered With Electromotive Drug Administration (EMDA) in Patients With High-Risk Nonmuscle Invasive Bladder Cancer After BCG Failure.

BACKGROUND: Nowadays, there is no standard non-surgical treatment for patients with nonmuscle invasive bladder cancer (NMIBC) in whom Bacillus Calmette-Güerin (BCG) therapy has failed. OBJECTIVES: To assess the clinical and oncological outcomes of sequential treatment with Bacillus Calmette-Guerin (BCG) and Mitomycin C (MMC) administered with Electromotive Drug Administration (EMDA) in patients with high-risk NMIBC who fail BCG immunotherapy. MATERIAL AND METHODS: We retrospectively studied patients with NMIBC who failed BCG and received alternating BCG and Mitomycin C with EMDA between 2010 and 2020. Treatment schedule consisted in an induction therapy with 6 instillations (BCG, BCG, MMC + EMDA, BCG, BCG, MMC + EMDA) and a 1-year maintenance. Complete response (CR) was defined as the absence of high-grade (HG) recurrences during follow-up, and progression was defined as the occurrence of muscle invasive or metastatic disease. CR rate was estimated at 3, 6, 12, and 24 months. Progression rate and toxicity were also assessed. RESULTS: Twenty-two patients were included with a median age of 73 years. Fifty percent of tumors were single, 90% were smaller than 1.5cm, 40% were GII (HG) and 40% were Ta. CR rate was 95.5%, 81% and 70% at 3 and 6 months, 12 months and 24 months, respectively. With a median follow-up of 28.8 months, 6 patients (27%) presented HG recurrence and only 1 patient (4.5%) progressed and ended in cystectomy. This patient died due to metastatic disease. Treatment was well tolerated and 22% of the patients presented adverse effects, being dysuria the most frequent one. CONCLUSION: Sequential treatment with BCG and Mitomycin C with EMDA achieved good responses and low toxicity in selected patients who did not respond to BCG. Only 1 patient ended in cystectomy and died due to metastatic disease, therefore, cystectomy was avoided in most cases.

Growth Developmental Defects of Mitochondrial Iron Transporter 1 and 2 Mutants in Arabidopsis in Iron Sufficient Conditions.

Iron is the most abundant micronutrient in plant mitochondria, and it has a crucial role in biochemical reactions involving electron transfer. It has been described in Oryza sativa that Mitochondrial Iron Transporter (MIT) is an essential gene and that knockdown mutant rice plants have a decreased amount of iron in their mitochondria, strongly suggesting that OsMIT is involved in mitochondrial iron uptake. In Arabidopsis thaliana, two genes encode MIT homologues. In this study, we analyzed different AtMIT1 and AtMIT2 mutant alleles, and no phenotypic defects were observed in individual mutant plants grown in normal conditions, confirming that neither AtMIT1 nor AtMIT2 are individually essential. When we generated crosses between the Atmit1 and Atmit2 alleles, we were able to isolate homozygous double mutant plants. Interestingly, homozygous double mutant plants were obtained only when mutant alleles of Atmit2 with the T-DNA insertion in the intron region were used for crossings, and in these cases, a correctly spliced AtMIT2 mRNA was generated, although at a low level. Atmit1 Atmit2 double homozygous mutant plants, knockout for AtMIT1 and knockdown for AtMIT2, were grown and characterized in iron-sufficient conditions. Pleiotropic developmental defects were observed, including abnormal seeds, an increased number of cotyledons, a slow growth rate, pinoid stems, defects in flower structures, and reduced seed set. A RNA-Seq study was performed, and we could identify more than 760 genes differentially expressed in Atmit1 Atmit2. Our results show that Atmit1 Atmit2 double homozygous mutant plants misregulate genes involved in iron transport, coumarin metabolism, hormone metabolism, root development, and stress-related response. The phenotypes observed, such as pinoid stems and fused cotyledons, in Atmit1 Atmit2 double homozygous mutant plants may suggest defects in auxin homeostasis. Unexpectedly, we observed a possible phenomenon of T-DNA suppression in the next generation of Atmit1 Atmit2 double homozygous mutant plants, correlating with increased splicing of the AtMIT2 intron containing the T-DNA and the suppression of the phenotypes observed in the first generation of the double mutant plants. In these plants with a suppressed phenotype, no differences were observed in the oxygen consumption rate of isolated mitochondria; however, the molecular analysis of gene expression markers, AOX1a, UPOX, and MSM1, for mitochondrial and oxidative stress showed that these plants express a degree of mitochondrial perturbation. Finally, we could establish by a targeted proteomic analysis that a protein level of 30% of MIT2, in the absence of MIT1, is enough for normal plant growth under iron-sufficient conditions.

Cell-Free DNA Dynamic Concentration and Other Variables Are Predictors of Early Progression after Chimeric Antigen Receptor T Cell Therapy in Patients with Diffuse Large B Cell Lymphoma.

We propose a novel biomarker that can identify patients at high risk of early progression after chimeric antigen receptor (CAR) T cell therapy. Calculation of cell-free DNA (cfDNA) with a pre-apheresis (PA) and pre-lymphodepletion (PL) sample allows monitoring of tumor dynamics (∆cfDNA). In the present study, ∆cfDNA and other biomarkers and clinical variables were evaluated in 58 patients with relapsed/refractory diffuse large B cell lymphoma (DLBCL). ∆cfDNA (>11 ng/mL plasma; P =.003), C-reactive protein (CRP) PL (>1.06 mg/dL; P = .004), lactate dehydrogenase (LDH) PL (>304; P = .006), disease status PL (progressive disease; P = .035) and sex (male; P = .016) were highly correlated with 1 month progression. After adjusting for ∆cfDNA, CRP PL, and LDH PL, disease status PL, and sex, ∆cfDNA remained associated with 1-month progression after CAR T cell infusion.

To drain or not to drain in uro-oncological robotic surgery? A systematic review and meta-analysis.

INTRODUCTION: The aim of this study was to compare the perioperative outcomes of routine drainage insertion vs. no drainage in patients undergoing robot-assisted radical prostatectomy (RARP), robot-assisted partial nephrectomy (RAPN), and robot-assisted radical cystectomy (RARC). EVIDENCE ACQUISITION: A literature search was conducted through April 2022 using PubMed/Medline, Embase, and Web of Science databases. Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guidelines were followed to identify eligible studies. EVIDENCE SYNTHESIS: Eleven studies comprising 8447 RARPs and 1890 RAPNs met our inclusion criteria. Our search strategy did not identify any studies within the RARC framework. In RARP, patients without postoperative drainage had lower rate of postoperative ileus (OR 0.53, 95% CI: 0.38 to 0.74; P<0.001) and similar low-grade (Clavien 1-2, P=0.41) and high-grade (Clavien ≥3; P=0.85) complications, urinary leakage (P=0.07), pelvic hematoma (P=0.35), symptomatic lymphocele (P=0.13), fever (P=0.25), incisional hernia (P=0.31), reintervention (P=0.57), length of hospital stay (P=0.22), and readmission (P=0.74) compared with routinely drained patients. In RAPN, patients without postoperative drainage had shorter length of hospital stay (mean difference: -0.84 days, 95% CI: -1.06 to -0.63; P<0.001) and similar low-grade (P=0.94) and high-grade (P=0.31) complications, urinary leakage (P=0.49), hemorrhage (P=0.39), reintervention (P=0.69), and readmission (P=0.20) compared with routinely drained patients. CONCLUSIONS: In our study, patients without drainage had similar perioperative course to patients with prophylactic drain insertion after RARP and RAPN. Omission of drain insertion was associated with a lower rate of postoperative ileus for RARP and a shorter hospital stay for RAPN. In the era of robotic surgery, routine drain placement is no longer indicated in unselected patients.

Supervivencia extendida con pembrolizumab en un paciente con cáncer de pulmón no microcítico estadio IV: Reporte de caso / Extendedsurvival with pembrolizumab in a patient with stage IV non-small cell lung cancer:A case report

Introducción:La inmunoterapia con pembrolizumab ha mejorado el pronóstico del cáncer de pulmón metastásico. En el presente caso se presenta la supervivencia extendidad y evolución de un paciente específico.Caso clínico:Hombre de 66 años, fumador. Diagnosticado de masa pulmonar en lóbulo infe-rior izquierdo de dimensiones 9 x 8 cm, con metástasis supra e infratentoriales intraaxiliares. Taller diagnóstico: Establecida como neoplasia de pulmón en estadio IVc, se comprobó el estado de PDL1 que positivo en un 80 % de la muestra de masa pulmonar. Debuta con me-tástasis cerebrales.Evolución: Se inció inmunoterapia con Pembrolizumab, el cual se mantubo hasta la presencia de un efecto secundario atribuido al pembrolizumab, cumpliendo 30meses de supervivencia hasta el cierre de esta observación no se reportó la muerte del paciente.Conclusiones:En el presente reporte, la determinación del biomarcador histológico PDL1 po-sitivo en cáncer de pulmón ayudo a prescribir un tratamiento con inmunoterpia dirigida, lo que demostró aumentar la supervivencia más allá que el tratamiento convencional con quimiote-rapia

Introduction: Immunotherapy with pembrolizumab has improved the prognosis of metastatic lung cancer. A specific patient's extended survival and evolution is presented in the present case.Clinical case: 66-year-old man, smoker. Diagnosed with a lung mass in the left lower lobe measuring 9 x 8 cm, with supra and infratentorial intra-axial metastases.Diagnostic workshop: To establisha stage IVc lung neoplasm, 80% of the lung mass sample was confirmed to be positive for PDL1.Evolution: Immunotherapy was started with Pembrolizumab, which was maintained until the presence of a side effect attributed to pembrolizumab, completing 30 months of survival until the closure of this observation, the patient's death was not reported.Conclusions: In the present report, the determination of the positive histological biomarker PDL1 in lung cancer helped prescribe treatment with targeted immunotherapy, which was shown to increase survival beyond conventional treatment with chemotherapy

Intestinal anti-tissue transglutaminase IgA deposits as a complementary method for the diagnostic evaluation of celiac disease in patients with low-grade histological lesions.

Evaluating the usefulness of intestinal anti-transglutaminase IgA (anti-TG2 IgA) deposits detection as a complementary or decision-supporting tool in the diagnosis of celiac disease (CD) in patients with low degree of enteropathy. Small intestinal biopsies (SIB) were performed from 2008 to 2017 in patients on suspicion of CD (positive CD serology and/or symptoms) referred to our Pediatric Gastroenterology Unit. We determined anti-TG2 IgA deposits by using double immunofluorescence in all the patients in whom Marsh 0 or Marsh 1 was detected in the conventional histological study and in a random selection of patients with clearly positive serology and histological Marsh 2-3 lesion. Seventy-five pediatric patients were split into three groups according to the final diagnosis: (i) 13 children with a Marsh 0 or 1, negative CD serology and final non-CD diagnosis; none presented intestinal anti-TG2 IgA deposits; (ii) 15 potential CD cases (Marsh 0 or 1 and CD-associated antibodies), detecting anti-TG2 IgA deposits in 12; on follow-up, another biopsy performed in 11/15 showed villi atrophy in seven and a Marsh 2 lesion in two of them, patients being finally diagnosed as CD cases; and (iii) 47 children with Marsh 2-3 histological lesion and final CD diagnosis; all of them had intestinal anti-TG2 IgA deposits. Anti-TG2 deposits are a useful complementary tool for CD diagnosis in pediatric population with digestive pathologies suggestive of CD. It is especially helpful in those with low-grade lesion, in which anti-TG2 deposits are predictive of the development of more severe lesions on follow-up.

Medidas de salud pública en instituciones de protección a la infancia y la adolescencia en dos departamentos de Colombia durante la pandemia de COVID-19 / Public health measures during the COVID-19 pandemic in institutions for the protection of children and adolescents in two departments in Colombia / Medidas de saúde pública em instituições de proteção de crianças e adolescentes em dois departamentos da Colômbia durante a pandemia de COVID-19

RESUMEN Objetivo. Analizar los procesos facilitadores y obstaculizadores y los efectos de la implementación de las medidas de salud pública no farmacológicas para la prevención de la COVID-19 en los centros de protección de la infancia y la adolescencia de dos departamentos (Antioquia y la Guajira) de Colombia durante el período 2020-2021. Métodos. Estudio de métodos mixtos con un diseño paralelo convergente en 13 internados de protección de la infancia y adolescencia de Colombia (11 en Antioquia y 2 en La Guajira). Se aplicó un cuestionario a 145 niñas, niños y adolescentes y 23 entrevistas a mediadores de la implementación de las medidas del sistema nacional de bienestar familiar. Resultados. Las medidas de salud pública no farmacológicas implementadas no difieren por departamento; las más complejas para aplicar fueron el distanciamiento físico y la restricción de las visitas familiares. Conclusiones. En los centros de protección de la infancia y la adolescencia de Antioquia y la Guajira, las medidas de salud pública no farmacológicas contribuyeron a mitigar la propagación del virus en entornos considerados de riesgo.

ABSTRACT Objective. Analyze facilitating processes, obstacles, and effects of the implementation of non-pharmacological public health measures for the prevention of COVID-19 in child and adolescent protection centers in two departments (Antioquia and La Guajira) in Colombia during the period 2020-2021. Methods. Mixed methods study with a convergent parallel design in 13 residential child/adolescent protection facilities in Colombia (11 in Antioquia and two in La Guajira). A questionnaire was given to 145 children and adolescents, and 23 interviews were held with persons responsible for the implementation of measures in the national family welfare system. Results. The implemented non-pharmacological public health measures did not differ by department; the most complex to implement were physical distancing and restriction of family visits. Conclusions. In centers for the protection of children and adolescents in Antioquia and La Guajira, non-pharmacological public health measures helped mitigate the spread of the virus in environments considered at-risk.

RESUMO Objetivo. Analisar os processos que facilitam e dificultam a implementação de medidas não farmacológicas de saúde pública para a prevenção da COVID-19 em centros de proteção de crianças e adolescentes em dois departamentos (Antioquia e La Guajira) da Colômbia, e os efeitos de tal implementação, durante o período 2020-2021. Métodos. Estudo de métodos mistos com delineamento paralelo convergente em 13 internatos para a proteção de crianças e adolescentes na Colômbia (11 em Antioquia e 2 em La Guajira). Foi aplicado um questionário a 145 crianças e adolescentes, e foram realizadas 23 entrevistas com os responsáveis pela implementação das medidas do sistema nacional de bem-estar familiar. Resultados. As medidas não farmacológicas de saúde pública implementadas não diferiram por departamento. As mais complexas de serem aplicadas foram o distanciamento físico e a restrição de visitas familiares. Conclusões. Nos centros de proteção de crianças e adolescentes de Antioquia e La Guajira, medidas não farmacológicas de saúde pública contribuíram para mitigar a propagação do vírus em ambientes considerados de risco.

The Long-Term Study of Urinary Biomarkers of Renal Injury in Spontaneously Hypertensive Rats.

BACKGROUND: The age-related increase in blood pressure in spontaneously hypertensive rats (SHRs) is associated to cardiac hypertrophy, heart failure, and renal injury. Here, we investigated for the first time the urinary enzymatic activities of glutamil aminopeptidase (GluAp), alanyl aminopeptidase (AlaAp), dipeptidyl peptidase-4 (DPP4), and Klotho urinary levels, proteins that are strongly expressed in the kidney, as early biomarkers of renal injury in SHRs. METHODS: Male SHR and Wistar Kyoto (WKY) rats were studied from 2 to 8 months old. Systolic blood pressure (SBP), the heart rate (HR), metabolic variables, and urinary markers were measured monthly. At the end of the study, a histopathological evaluation of the kidney was performed. RESULTS: Kidneys of SHR did not develop signs of relevant histopathological changes, but showed increased glomerular area and cellularity. Plasma creatinine was decreased, and creatinine clearance was augmented in SHR at the end of the study. Urinary excretion of Klotho was higher in SHR at 5 and 8 months old, whereas plasma Klotho levels were similar to WKY. GluAp, AlaAp, and DPP4 urinary activities were increased in SHR throughout the time-course study. A positive correlation between glomerular area and cellularity with creatinine clearance was observed. Urinary GluAp, AlaAp, DPP4, and Klotho showed positive correlations with SBP. CONCLUSIONS: GluAp, AlaAp, DPP4, and Klotho in the urine are useful tools for the evaluation of renal damage at early stages, before the whole histopathological and biochemical manifestations of renal disease are established. Moreover, these observations may represent a novel and noninvasive diagnostic approach to assess the evolution of kidney function in hypertension and other chronic diseases.

[Sarcomatoid carcinoma of the nasal cavity: a case report and review of the literature]. / Carcinoma sarcomatoide de fosa nasal: a propósito de un caso y revisión de la literatura.

Spindle cell carcinoma of the nasal cavity is a rare variant of squamous cell carcinoma. We report a case of a 50 year-old male presenting with a polypoid mass in the left nasal cavity. Histologically, the tumor was biphasic, composed of non-keratinizing squamous nests and a sarcomatoid stroma with positivity for CKAE1-AE3. Metastatic ipsilateral lymph nodes were present and the patient underwent radical neck dissection, followed by adjuvant radiotherapy and cisplatin. Two years after diagnosis the patient is free of disease.

Sentinel Lymph Node Biopsy in Breast Cancer with 99mTc-Tilmanocept: A Multicenter Study on Real-Life Use of a Novel Tracer.

99mTc-tilmanocept is a novel radiopharmaceutical for sentinel lymph node (SLN) biopsy in breast cancer. Our aim was to describe results with 99mTc-tilmanocept in a heterogeneous group of breast cancer patients scheduled for SLN biopsy. Methods: Radiotracer preparation followed the manufacturer's indications. Local protocols for SLN detection within 9 participant centers were not changed for the entire duration of the study. In total, 344 patients with T1-T4, N0-N2 breast cancer (352 lesions) were included. Superficial (intradermal or periareolar) or deep (peritumoral or intratumoral) injections were performed. The doses were adjusted depending on the scheduled time for surgery. Results: Lymphoscintigraphy was able to depict at least 1 SLN in 339 of 352 breast lesions (96.3%), and the intraoperative SLN detection rate reached 97.2%. On univariable analysis, SLN detection rates did not differ by age, clinical T or N stage, tumor location, histologic subtype, or prior neoadjuvant therapy. Lymphoscintigraphy showed higher SLN detection in patients with a normal weight (body mass index < 25) than in those who were overweight or obese (body mass index ≥ 25), at 99.2% versus 94.6%, respectively (P = 0.031). The proportion of patients with preoperative lymphoscintigraphic detection or excised SLNs was higher with superficial than deep injections. Reinjected cases were significantly lower when superficial injection was chosen first (P < 0.001). Injection site and the tumor markers human epidermal growth factor receptor 2 and estrogen receptor had an impact on preoperative SLN visualization and intraoperative localization. In 80 cases, SLN biopsy resulted in a positive lymph node. During a mean follow-up of 19 mo, no axillary recurrences were observed. Conclusion: Whatever the protocol, 99mTc-tilmanocept showed good results in a heterogeneous breast cancer population, although the best results were achieved when a superficial injection was chosen.

Bacillus thuringiensis Cry1Ab Domain III ß-16 Is Involved in Binding to Prohibitin, Which Correlates with Toxicity against Helicoverpa armigera (Lepidoptera: Noctuidae).

Helicoverpa armigera is a major insect pest of several crops worldwide. This insect is susceptible to some Bacillus thuringiensis (Bt) Cry insecticidal proteins expressed in transgenic crops or used in biopesticides. Previously, we identified H. armigera prohibitin (HaPHB) as a Cry1Ac-binding protein. Here, we further analyzed the potential role of PHB as a Cry toxin receptor in comparison to cadherin (CAD), well recognized as a Cry1Ac receptor. HaPHB-2 midgut protein and HaCAD toxin-binding region (TBR) fragment from H. armigera were expressed in Escherichia coli cells, and binding assays with different Cry1 toxins were performed. We demonstrated that Cry1Ab, Cry1Ac, and Cry1Fa toxins bound to HaPHB-2 in a manner similar to that seen with HaCAD-TBR. Different Cry1Ab mutant toxins located in domain II (Cry1AbF371A and Cry1AbG439D) or domain III (Cry1AbL511A and Cry1AbN514A), which were previously characterized and found to be affected in receptor binding, were analyzed regarding their binding interaction with HaPHB-2 and toxicity against H. armigera One ß-16 mutant (Cry1AbN514A) showed increased binding to HaPHB-2 that correlated with 6-fold-higher toxicity against H. armigera, whereas the other ß-16 mutant (Cry1AbL511A) was affected in binding to HaPHB-2 and lost toxicity against H. armigera Our data indicate that ß-16 from domain III of Cry1Ab is involved in interactions with HaPHB-2 and in toxicity. This report identifies a region of Cry1Ab involved in binding to HaPHB-2 from a Lepidoptera insect, suggesting that this protein may participate as a novel receptor in the mechanism of action of the Cry1 toxins in H. armigeraIMPORTANCEHelicoverpa armigera is a polyphagous pest that feeds on important crops worldwide. This insect pest is sensitive to different Cry1 toxins from Bacillus thuringiensis In this study, we analyzed the potential role of PHB-2 as a Cry1 toxin receptor in comparison to CAD. We show that different Cry1 toxins bound to HaPHB-2 and HaCAD-TBR similarly and identify ß-16 from domain III of Cry1Ab as a binding region involved in the interaction with HaPHB-2 and in toxicity. This report characterized HaPHB-Cry1 binding interaction, providing novel insights into potential target sites for improving Cry1 toxicity against H. armigera.

Intraoperative radiotherapy in early breast cancer: observational comparison with whole breast radiotherapy. / Radioterapia intraoperatoria en cáncer de mama precoz: análisis observacional frente a radioterapia externa.

INTRODUCTION: In early breast cancer (EBC), a single dose of intraoperative radiotherapy (IORT) might be an option to standard whole breast radiotherapy (WBRT). However, there is no consensus about its use and clinical results. AIM: to analyse the morbidity and oncological outcomes of IORT as monotherapy in EBC. METHODS: A single centre observational analytic study was performed. A prospective IORT cohort (2015-17) and a retrospective WBRT cohort (2012-17) were selected following the same criteria: ≥ 45 y.o., invasive ductal carcinoma or variants, radiological tumour size ≤ 3 cm, positive oestrogenic receptors, negative HER2, cN0; exclusion criteria: lymphovascular invasion, multicentricity/multifocality, BRCA mutation and neoadjuvant therapy. Clinical, histological, surgical, oncological characteristics and complications were collected. RESULTS: A total of 425 cases were selected: 217 in IORT cohort and 208 in WBRT cohort. Average age in IORT and WBRT groups was 67±9.5 and 64.8 ± 9.9 y.o. respectively (p = 0.01). ASA 3 risk score patients were 17.7% in IORT and 24 cases in WBRT (p = 0.027). There were no differences in histological results or tumoral stage. Average follow up was 24.4 ± 8 months in IORT and 50.5 ± 18 months in WBRT (p < 0.001). No differences were detected in local recurrence, metastases or mortality. Complications that required reintervention or hospitalization were similar in both groups. A total of 3 and 14 cases developed early severe dermatitis in IORT and WBRT groups respectively (p = 0.01). CONCLUSION: IORT as monotherapy in selected patients with EBC stands for an alternative option versus WBRT. It seems especially useful in advanced-age patients with severe comorbidities. IORT associates lesser early severe dermatitis.

Rearrangement of N-Terminal α-Helices of Bacillus thuringiensis Cry1Ab Toxin Essential for Oligomer Assembly and Toxicity.

Cry proteins produced by Bacillus thuringiensis are pore-forming toxins that disrupt the membrane integrity of insect midgut cells. The structure of such pore is unknown, but it has been shown that domain I is responsible for oligomerization, membrane insertion and pore formation activity. Specifically, it was proposed that some N-terminal α-helices are lost, leading to conformational changes that trigger oligomerization. We designed a series of mutants to further analyze the molecular rearrangements at the N-terminal region of Cry1Ab toxin that lead to oligomer assembly. For this purpose, we introduced Cys residues at specific positions within α-helices of domain I for their specific labeling with extrinsic fluorophores to perform Föster resonance energy transfer analysis to fluorescent labeled Lys residues located in Domains II-III, or for disulfide bridges formation to restrict mobility of conformational changes. Our data support that helix α-1 of domain I is cleaved out and swings away from the toxin core upon binding with Manduca sexta brush border membrane vesicles. That movement of helix α-2b is also required for the conformational changes involved in oligomerization. These observations are consistent with a model proposing that helices α-2b and α-3 form an extended helix α-3 necessary for oligomer assembly of Cry toxins.

Aminopeptidases in Cardiovascular and Renal Function. Role as Predictive Renal Injury Biomarkers.

Aminopeptidases (APs) are metalloenzymes that hydrolyze peptides and polypeptides by scission of the N-terminus amino acid and that also participate in the intracellular final digestion of proteins. APs play an important role in protein maturation, signal transduction, and cell-cycle control, among other processes. These enzymes are especially relevant in the control of cardiovascular and renal functions. APs participate in the regulation of the systemic and local renin-angiotensin system and also modulate the activity of neuropeptides, kinins, immunomodulatory peptides, and cytokines, even contributing to cholesterol uptake and angiogenesis. This review focuses on the role of four key APs, aspartyl-, alanyl-, glutamyl-, and leucyl-cystinyl-aminopeptidases, in the control of blood pressure (BP) and renal function and on their association with different cardiovascular and renal diseases. In this context, the effects of AP inhibitors are analyzed as therapeutic tools for BP control and renal diseases. Their role as urinary biomarkers of renal injury is also explored. The enzymatic activities of urinary APs, which act as hydrolyzing peptides on the luminal surface of the renal tubule, have emerged as early predictive renal injury biomarkers in both acute and chronic renal nephropathies, including those induced by nephrotoxic agents, obesity, hypertension, or diabetes. Hence, the analysis of urinary AP appears to be a promising diagnostic and prognostic approach to renal disease in both research and clinical settings.

Eficacia y seguridad clínica del itolizumab en fase de inducción en pacientes con psoriasis grave / Efficacy and clinical safety of Itolizumab in the induction phase in patients with severe psoriasis

Introducción: La psoriasis, enfermedad inflamatoria sistémica de la piel, tiene consecuencias adversas serias para el bienestar físico, mental y social de las personas; sus tratamientos son costosos y con marcados efectos adversos. El itolizumab, anticuerpo monoclonal anti CD6 humanizado, actúa como inmunomodulador de las células T y desempeña un importante papel en su patogénesis. Objetivo: Evaluar la eficacia y la seguridad clínica del itolizumab en 80 pacientes con psoriasis vulgar grave. Métodos: Se realizó un programa de uso clínico expandido, promovido por el Centro de Inmunología Molecular. La respuesta clínica se midió por el índice de gravedad y área de afectación de psoriasis, y para la eficacia se conjugaron estos elementos con los de seguridad, mediante un análisis clínico complementario de los datos generados durante la fase de inducción. Se emplearon como medidas de resumen los números absolutos, el porciento, el promedio y estadísticas de asociación: las pruebas de correlación de de Pearson, de Friedman y la prueba de Lambda. Resultados: El análisis del área de afectación de psoriasis arrojó un rápido y sostenido descenso de sus valores; prevalecieron los eventos adversos relacionados con la administración del producto en investigación, de aparición inmediata, ligeros, muy probables y no serios. Conclusiones: El itolizumab es seguro y eficaz en el 96 por ciento de los pacientes psoriásicos graves durante los esquemas de inducción(AU)

Introduction: Psoriasis, systemic inflammatory skin disease, has serious adverse consequences for the physical, mental and social well-being of people; its treatments are expensive and with marked adverse effects. Itolizumab, a humanized anti-CD6 monoclonal antibody, acts as an immunomodulator of T cells and plays an important role in its pathogenesis. Objective: To evaluate the efficacy and clinical safety of itolizumab in 80 patients with severe psoriasis vulgaris. Methods: An expanded clinical use program was carried out, promoted by the Molecular Immunology Center. The clinical response was measured by the severity index and area of psoriasis involvement and for effectiveness these elements were combined with safety, through a complementary clinical analysis of the data generated during the induction phase. Absolute numbers, percent and average and association statistics such as Pearson's correlation tests or Lambda's test were used as summary measures. Results: The area of psoriasis involvement analysis showed a rapid and sustained decrease in its values; adverse events related to the administration of the product under investigation prevailed, light onset, very probable and not serious. Conclusions: Itolizumab is safe and effective in 96 percent of severe psoriatic patients during the induction phase(AU)

Usefulness of monitoring antitumor necrosis factor serum levels during the induction phase in patients with Crohn's disease.

AIMS: The aims of this study were (a) to know the kinetics of antitumor necrosis factor (TNF) drug serum levels during the induction phase in patients with Crohn's disease; (b) to identify variables associated with these levels; and (c) to assess the relation between these levels and short-term effectiveness in Crohn's disease patients. METHODS: Patients with Crohn's disease naïve to anti-TNF treatment were prospectively included. Remission was defined as a Crohn's disease activity index (CDAI) score <150 after 14 weeks of treatment. Blood samples were obtained at baseline and at weeks 4, 8, and 14. Adalimumab and infliximab levels were measured, receiver operating characteristic (ROC) curves were constructed, and the area under the ROC curve was calculated. RESULTS: One-hundred fifty patients with Crohn's disease were included, 79 (53%) received infliximab and 71 (47%) had CDAI > 150 at study entry. At week 14, 52 out of 71 patients with CDAI > 150 at baseline (73%) had clinical remission. There were no differences in infliximab levels between patients with and without remission (8 vs. 9.1 µg/mL, P > 0.05) or with and without response (7 vs. 11 µg/mL, P > 0.05) at week 14. There was a trend to higher levels of adalimumab concentration in responders in comparison with nonresponders (13 vs. 6.7 µg/mL, P = 0.05) and in patients who achieved remission in comparison with nonremitters (13.5 vs. 8.4 µg/mL, P = 0.06). In the multivariate analysis, no variable was predictive of short-term remission, including infliximab and adalimumab serum levels. CONCLUSION: Determining anti-TNF serum levels during the induction phase is not useful for predicting short-term remission in patients with Crohn's disease.

Functional rare variants influence the clinical response to anti-TNF therapy in Crohn's disease.

BACKGROUND: The effect of low-frequency functional variation on anti-tumor necrosis factor alpha (TNF) response in Crohn's disease (CD) patients remains unexplored. The objective of this study was to investigate the impact of functional rare variants in clinical response to anti-TNF therapy in CD. METHODS: CD anti-TNF naïve patients starting anti-TNF treatment due to active disease [Crohn's Disease Activity Index (CDAI > 150)] were included. The whole genome was sequenced using the Illumina Hiseq4000 platform. Clinical response was defined as a CDAI score <150 at week 14 of anti-TNF treatment. Low-frequency variants were annotated and classified according to their damaging potential. The whole genome of CD patients was screened to identify homozygous loss-of-function (LoF) variants. The TNF signaling pathway was tested for overabundance of damaging variants using the SKAT-O method. Functional implication of the associated rare variation was evaluated using cell-type epigenetic enrichment analyses. RESULTS: A total of 41 consecutive CD patients were included; 3250 functional rare variants were identified (2682 damaging and 568 LoF variants). Two homozygous LoF mutations were found in HLA-B and HLA-DRB1 genes associated with lack of response and remission, respectively. Genome-wide LoF variants were enriched in epigenetic marks specific for the gastrointestinal tissue (colon, p = 4.11e-4; duodenum, p = 0.011). The burden of damaging variation in the TNF signaling pathway was associated with response to anti-TNF therapy (p = 0.016); damaging variants were enriched in epigenetic marks from CD8+ (p = 6.01e-4) and CD4+ (p = 0.032) T cells. CONCLUSIONS: Functional rare variants are involved in the response to anti-TNF therapy in CD. Cell-type enrichment analysis suggests that the gut mucosa and CD8+ T cells are the main mediators of this response.

[Mucin-producing urothelial type prostatic adenocarcinoma with signet ring cells and increased Ca 19.9 and Cea. Case report and literature review.] / Adenocarcinoma mucinoso de próstata tipo urotelial con células en anillo de sello y elevación del Ca 19.9 y Cea. Revisión de la literatura a propósito de un caso.

OBJECTIVE: Primary Mucin-producing Urothelial-type Adenocarcinoma of Prostate is extremely infrequent. The presence of signet ring cells is exceptional, more atypical in its mucinous variant. Anatomopathological and immunohistochemical study play a key role. METHODS: Bibliographic review and case report of a 66-year-old man with Ca 19.9 and CEA elevation, and normal PSA levels, associated with lower urinary tract symptoms (mucosuria, hesitancy and hematuria). He was diagnosed with mucin-producing urothelial- type adenocarcinoma of the prostate with signet ring cells by transrectal prostate biopsy after multiparametic MRI. RESULTS: We found 23 cases described in our review. No case diagnosed following an elevation of Ca 19.9 was found in the literature. In our case, after diagnosis, he was treated with retropubic radical prostatectomy and bilateral ilio-obturator lymph node dissection, with subsequent normalization of tumor markers; however, he presented secondary pulmonary involvement and pelvic tumor progression despite chemotherapy treatment. CONCLUSIONS: The elevation of associated tumor markers (Ca 19.9, CEA) is extraordinary. There is no treatment algorithm, however surgery (radical prostatectomy) with or without adjuvant chemotherapy treatment represents an alternative in its therapeutic management.

OBJETIVO: El adenocarcinoma primario de próstata de tipo urotelial es extremadamente infrecuente. La presencia de células en anillo de sello es excepcional, siendo más atípica aún en su variante mucinosa. Su estudio anatomopatológico e inmunohistoquímico juegan un papel fundamental.MÉTODOS: Revisión de la literatura a propósito del caso de un varón de 66 años con elevación de Ca 19.9 y CEA, y niveles de PSA normales, asociado a sintomatología del tracto urinario inferior (mucosuria, estranguria y hematuria) diagnosticado mediante biopsia prostática transrectal tras RMN multiparamétrica de un adenocarcinoma mucinoso de próstata tipo urotelial con células en anillo de sello. RESULTADOS: En la revisión efectuada se han encontrado descritos 23 casos. No se ha encontrado en la literatura ningún caso diagnosticado a raíz de una elevación del Ca 19.9. En nuestro caso, tras el diagnóstico fue tratado mediante prostatectomía radical retropúbica con linfadenectomía ilio-obturatriz bilateral, con normalización posterior de los marcadores tumorales; sin embargo, presentó afectación secundaria pulmonar y progresión tumoral pélvica a pesar de tratamiento quimioterápico. CONCLUSIONES: La elevación de marcadores tumorales asociada (Ca 19.9, CEA) es extraordinaria en este tipo de tumores. No existe un algoritmo de tratamiento, sin embargo la cirugía (prostatectomía radical) con o sin tratamiento adyuvante quimioterápico representa una alternativa en su manejo terapéutico.