Cross-protection and cross-neutralization capacity of ancestral and VOC-matched SARS-CoV-2 adenoviral vector-based vaccines.

COVID-19 vaccines were originally designed based on the ancestral Spike protein, but immune escape of emergent Variants of Concern (VOC) jeopardized their efficacy, warranting variant-proof vaccines. Here, we used preclinical rodent models to establish the cross-protective and cross-neutralizing capacity of adenoviral-vectored vaccines expressing VOC-matched Spike. CoroVaxG.3-D.FR, matched to Delta Plus Spike, displayed the highest levels of nAb to the matched VOC and mismatched variants. Cross-protection against viral infection in aged K18-hACE2 mice showed dramatic differences among the different vaccines. While Delta-targeted vaccines fully protected mice from a challenge with Gamma, a Gamma-based vaccine offered only partial protection to Delta challenge. Administration of CorovaxG.3-D.FR in a prime/boost regimen showed that a booster was able to increase the neutralizing capacity of the sera against all variants and fully protect aged K18-hACE2 mice against Omicron BA.1, as a BA.1-targeted vaccine did. The neutralizing capacity of the sera diminished in all cases against Omicron BA.2 and BA.5. Altogether, the data demonstrate that a booster with a vaccine based on an antigenically distant variant, such as Delta or BA.1, has the potential to protect from a wider range of SARS-CoV-2 lineages, although careful surveillance of breakthrough infections will help to evaluate combination vaccines targeting antigenically divergent variants yet to emerge.

The Nutrition in Early Life and Asthma (NELA) birth cohort study: Rationale, design, and methods.

BACKGROUND: Primary prevention strategies for asthma are lacking. Its inception probably starts in utero and/or during the early postnatal period as the developmental origins of health and disease (DOHaD) paradigm suggests. OBJECTIVES: The main objective of Nutrition in Early Life and Asthma (NELA) cohort study is to unravel whether the following factors contribute causally to the developmental origins of asthma: (1) maternal obesity/adiposity and foetal growth; (2) maternal and child nutrition; (3) outdoor air pollution; (4) endocrine disruptors; and (5) maternal psychological stress. Maternal and offspring biological samples are used to assess changes in offspring microbiome, immune system, epigenome and volatilome as potential mechanisms influencing disease susceptibility. POPULATION: Randomly selected pregnant women from three health areas of Murcia, a south-eastern Mediterranean region of Spain, who fulfilled the inclusion criteria were invited to participate at the time of the follow-up visit for routine foetal anatomy scan at 19-22 weeks of gestation, at the Maternal-Fetal Medicine Unit of the "Virgen de la Arrixaca" University Clinical Hospital over a 36-month period, from March 2015 to April 2018. DESIGN: Prospective, population-based, maternal-child, birth cohort study. METHODS: Questionnaires on exposures and outcome variables were administered to mothers at 20-24 gestation week; 32-36 gestation week; and delivery. Children were surveyed at birth, 3 and 18 months of age and currently at 5 years. Furthermore, physical examinations were performed; and different measurements and biological samples were obtained at these time points. PRELIMINARY RESULTS: Among the 1350 women invited to participate, 738 (54%) were finally enrolled in the study and 720 of their children were eligible at birth. The adherence was high with 612 children (83%) attending the 3 months' visit and 532 children (72%) attending the 18 months' visit. CONCLUSION: The NELA cohort will add original and unique knowledge to the developmental origins of asthma.

Neurorretinitis por Bartonella henselae en un adolescente / Bartonella henselae neuroretinitis in an adolescent

La neurorretinitis como manifestación de la enfermedad por arañazo de gato se presenta en el 1-2 % de los pacientes con afecciones oculares porBartonella henselae. Las manifestaciones oculares suelen suceder a las sistémicas, aunque pueden aparecer en ausencia de estas. La presencia de exudado macular en forma de estrella es característico y sugestivo de dicha infección. Se presenta el caso de un paciente de 14 años de edad, previamente sano, con disminución de la agudeza visual de 15 días de evolución, que ingresó por sospecha de neuritis óptica izquierda con edema de papila. El seguimiento oftalmológico reveló la aparición de la lesión característica en "estrella macular" que permitió arribar al diagnóstico de infección por B. henselae, confirmándose luego con serología positiva

Neurorretinitis as a manifestation of cat scratch disease occurs in 1-2 % of patients with Bartonella Henselae eye disease. Ocular manifestations tend to follow systemic ones, although they can appear in their absence. The presence of star-shaped macular exudate is characteristic and suggestive of this infection. We report a case of a 14-year-old healthy boy, with 15 days of decreased visual acuity, who was admitted for suspected left optic neuritis with papilledema. Ophthalmological examination revealed the characteristic "macular star" that led to the diagnosis of infection by Bartonella Henselae, later confirmed by positive serology.

Síndrome antifosfolipídico en pediatría: a propósito de un caso / The antiphospholipid antibody syndrome in pediatrics: a case repor

El síndrome antifosfolipídico (SAF) es infrecuente en la edad pediátrica (3 %) y se presenta como eventos trombóticos de lechos vasculares y/o abortos espontáneos, asociado a la presencia de anticuerpos antifosfolipídicos (aFL). Este síndrome puede ser primario o asociado a alguna enfermedad sistémica subyacente. Se presenta el caso de una niña de 12 años con hemiparesia faciobraquiocrural derecha y alteración en la marcha de aparición aguda, en la cual se confirma un accidente cerebrovascular (ACV) isquémico por trombosis de la arteria cerebral media asociado a aFL positivos (anticuerpo anticardiolipina, anticoagulante lúpico y anticuerpo anti-ß2-glicoproteína). Cumple con los criterios para realizar diagnóstico de síndrome antifosfolipídico. Luego de iniciar el tratamiento, la paciente evoluciona de manera favorable. Se trata de una patología infrecuente y de presentación variable, por lo que requiere un alto sentido de alerta por parte del equipo de salud para evitar retrasos en el diagnóstico y el tratamiento, y disminuir su morbimortalidad

Antiphospholipid syndrome (APS) is infrequent at pediatric age (3 %) and is characterized by venous or arterial thrombosis and/or spontaneous abortions. APS occurs either as a primary condition or in the setting of an underlying disease. This is a case of a 12-year-old girl with a right hemiparesis and acute disturbance in gait, in which an ischemic cerebrovascular accident (CVA) due to middle cerebral artery thrombosis associated with positive antiphospholipid antibodies is confirmed (anticardiolipin antibody, lupus anticoagulant and anti-ß2-glycoprotein antibody), fulfilling the criteria for the diagnosis of antiphospholipid syndrome . After starting treatment accordingly, the patient evolves favorably. As this pathology is infrequent and of variable presentation, it requires a high sense of alert from the health team to avoid delays in diagnosis and treatment

[Bartonella henselae neuroretinitis in an adolescent]. / Neurorretinitis por Bartonella henselae en un adolescente.

Neurorretinitis as a manifestation of cat scratch disease occurs in 1-2 % of patients with Bartonella Henselae eye disease. Ocular manifestations tend to follow systemic ones, although they can appear in their absence. The presence of star-shaped macular exudate is characteristic and suggestive of this infection. We report a case of a 14-year-old healthy boy, with 15 days of decreased visual acuity, who was admitted for suspected left optic neuritis with papilledema. Ophthalmological examination revealed the characteristic "macular star" that led to the diagnosis of infection by Bartonella Henselae, later confirmed by positive serology.

La neurorretinitis como manifestación de la enfermedad por arañazo de gato se presenta en el 1-2 % de los pacientes con afecciones oculares por Bartonella henselae. Las manifestaciones oculares suelen suceder a las sistémicas, aunque pueden aparecer en ausencia de estas. La presencia de exudado macular en forma de estrella es característico y sugestivo de dicha infección. Se presenta el caso de un paciente de 14 años de edad, previamente sano, con disminución de la agudeza visual de 15 días de evolución, que ingresó por sospecha de neuritis óptica izquierda con edema de papila. El seguimiento oftalmológico reveló la aparición de la lesión característica en "estrella macular" que permitió arribar al diagnóstico de infección por B. henselae, confirmándose luego con serología positiva.

[The antiphospholipid antibody syndrome in pediatrics: a case report]. / Síndrome antifosfolipídico en pediatría: a propósito de un caso.

Antiphospholipid syndrome (APS) is infrequent at pediatric age (3 %) and is characterized by venous or arterial thrombosis and/or spontaneous abortions. APS occurs either as a primary condition or in the setting of an underlying disease. This is a case of a 12-year-old girl with a right hemiparesis and acute disturbance in gait, in which an ischemic cerebrovascular accident (CVA) due to middle cerebral artery thrombosis associated with positive antiphospholipid antibodies is confirmed (anticardiolipin antibody, lupus anticoagulant and anti-ß2-glycoprotein antibody), fulfilling the criteria for the diagnosis of antiphospholipid syndrome. After starting treatment accordingly, the patient evolves favorably. As this pathology is infrequent and of variable presentation, it requires a high sense of alert from the health team to avoid delays in diagnosis and treatment.

El síndrome antifosfolipídico (SAF) es infrecuente en la edad pediátrica (3 %) y se presenta como eventos trombóticos de lechos vasculares y/o abortos espontáneos, asociado a la presencia de anticuerpos antifosfolipídicos (aFL). Este síndrome puede ser primario o asociado a alguna enfermedad sistémica subyacente. Se presenta el caso de una niña de 12 años con hemiparesia faciobraquiocrural derecha y alteración en la marcha de aparición aguda, en la cual se confirma un accidente cerebrovascular (ACV) isquémico por trombosis de la arteria cerebral media asociado a aFL positivos (anticuerpo anticardiolipina, anticoagulante lúpico y anticuerpo anti-ß2- glicoproteína). Cumple con los criterios para realizar diagnóstico de síndrome antifosfolipídico. Luego de iniciar el tratamiento, la paciente evoluciona de manera favorable. Se trata de una patología infrecuente y de presentación variable, por lo que requiere un alto sentido de alerta por parte del equipo de salud para evitar retrasos en el diagnóstico y el tratamiento, y disminuir su morbimortalidad.

Cardiólogo encuentra un caso de enfermedad de Fabry / Cardiologist finds a case with Fabry disease

Resumen En este reporte se llama la atención de los colegas ante la posibilidad de encontrar un caso de enfermedad de Fabry entre múltiples pacientes que consultan. Se exponen las condiciones clínicas de estos pacientes que los hacen únicos, a causa de una enfermedad huérfana. Es posible que muchas de estas condiciones clínicas hayan pasado inadvertidas y al no tenerlas presentes no se tenga un grado de sospecha que lleve al diagnóstico.

Abstract In this report is call the attention of our colleagues the possibility of finding a case of Fabry's disease within the multitude of patients in our practice. It is expose the clinical conditions of these patients which make them unique, due to a disease denominated as orphan. It is possible that many of these clinical conditions have gone unnoticed and by not having them present prevent/impide us from having a high degree of suspicion which would lead to a diagnosis.

Urban Retail Food Environments: Relative Availability and Prominence of Exhibition of Healthy vs. Unhealthy Foods at Supermarkets in Buenos Aires, Argentina.

There is growing evidence that the food environment can influence diets. The present study aimed to assess the relative availability and prominence of healthy foods (HF) versus unhealthy products (UP) in supermarkets in Buenos Aires, Argentina and to explore differences by retail characteristics and neighborhood income level. We conducted store audits in 32 randomly selected food retails. Food availability (presence/absence, ratio of cumulative linear shelf length for HF vs. UP) and prominence inside the store (location visibility) were measured based on the International Network for Food and Obesity/NCDs Research, Monitoring and Action Support (INFORMAS) protocol. On average, for every 1 m of shelf length for UP, there was about 25 cm of shelf length for HF (HF/UP ratio: 0.255, SD 0.130). UP were more frequently available in high-prominence store areas (31/32 retails) than HF (9/32 retails). Shelf length ratio differed across commercial chains (p = 0.0268), but not by store size or type. Retails in the lower-income neighborhoods had a lower HF/UP ratio than those in the higher-income neighborhoods (p = 0.0329). Availability of the selected HF was overcome largely by the UP, particularly in high prominence areas, and in neighborhoods with lower income level, which may pose an opportunity for public health interventions.

Human papillomavirus infection in anal intraepithelial lesions from HIV infected Cuban men.

BACKGROUND: An association between HPV infection and progression to anal squamous intraepithelial lesions (ASIL) has been established, specifically in high-risk populations such as HIV-infected men. In this population, anal cancer is one of the most common non-AIDS-defining malignancies. METHODS: A cross-sectional study to detect anal lesions and HPV infection was performed. Anal mucosa samples were collected from 56 HIV-infected men from Cuba. The cytological diagnosis was done according to Bethesda 2001 System. HPV DNA detection was determined by qPCR for six high-risk HPV types and end point PCR for low-risk HPV types (6 and 11). The end point PCR with nucleotide sequencing technique was achieved to detect other genotypes of HPV not included in the qPCR in those samples negative for HPV- 6 and 11 or negative for the six genotypes identified in the qPCR. RESULTS: Cytological diagnosis identified 53 of 56 (95%) men with abnormal anal cytology. Among those, 26% (14/53) had atypical squamous cells of undetermined significance (ASC-US), 4% (2/53) had atypical squamous cells of undetermined significance cannot exclude high-grade lesions (ASC-H), 64% (34/53) had low-grade squamous intraepithelial lesions (LSIL), and 6% (3/53) had high-grade squamous intraepithelial lesions (HSIL). HPV DNA was detected in 89% (50/56) of men and 79% had at least one of the high-risk HPV types. HPV- 16 was the most common genotype (52%), while HPV-18 was the most frequently detected genotype in men with HSIL. We found statistically significant differences in the HPV viral loads with respect to the cytology results (p = 0.0006) and that the practice of receptive anal sex was a risk factor for anal HPV infection (p = 0.032). CONCLUSION: This study shows a high prevalence of ASIL and high-risk HPV infections in the study group and is the first study showing the distribution of HPV genotypes in HIV infected Cuban men with abnormal anal cytology. This information may be of importance for local decision makers to improve prevention strategies, including the introduction of HPV vaccine in Cuba.

Occurrence of respiratory symptoms in persons with restrictive ventilatory impairment compared with persons with chronic obstructive pulmonary disease: The PLATINO study.

Patients with chronic obstructive pulmonary disease (COPD) usually complain of symptoms such as cough, sputum, wheezing, and dyspnea. Little is known about clinical symptoms in individuals with restrictive ventilatory impairment. The aim of this study was to compare the prevalence and type of respiratory symptoms in patients with COPD to those reported by individuals with restrictive ventilatory impairment in the Proyecto Latinoamericano de Investigacion en Obstruccion Pulmonar study. Between 2002 and 2004, individuals ≥40 years of age from five cities in Latin America performed pre and post-bronchodilator spirometry and had their respiratory symptoms recorded in a standardized questionnaire. Among the 5315 individuals evaluated, 260 (5.1%) had a restrictive spirometric diagnosis (forced vital capacity (FVC) < lower limit of normal (LLN) with forced expiratory volume in the first second to forced vital capacity ratio (FEV1/FVC) ≥ LLN; American Thoracic Society (ATS)/European Respiratory Society (ERS) 2005) and 610 (11.9%) were diagnosed with an obstructive pattern (FEV1/FVC < LLN; ATS/ERS 2005). Patients with mild restriction wheezed more ((30.8%) vs. (17.8%); p < 0.028). No difference was seen in dyspnea, cough, and sputum between the two groups after adjusting for severity stage. The health status scores for the short form 12 questionnaire were similar in restricted and obstructed patients for both physical (48.4 ± 9.4 vs. 48.3 ± 9.8) and mental (50.8 ± 10.6 vs. 50.0 ± 11.5) domains. Overall, respiratory symptoms are not frequently reported by patients with restricted and obstructed patterns as defined by spirometry. Wheezing was more frequent in patients with restricted pattern compared with those with obstructive ventilatory defect. However, the prevalence of cough, sputum production, and dyspnea are not different between the two groups when adjusted by the same severity stage.

Percepciones de investigadores e investigadoras en Antioquia sobre sus condiciones de salud y trabajo / Researchers´ perceptions on their health and working conditions in Antioquia, Colombia

Objetivo: analizar la percepción de mujeres y hombres dedicados a la investigación cietífica en Antioquia acerca de sus condiciones de salud y la relación con el trabajo. Metodología: estudio cualitativo a partir de entrevistas y revisión documental. Los participantes pertenecen a grupos de investigación clasificados por colciencias como A1, A y B, en instituciones públicas y privadas del departamento de Antioquia, Colombia. Resultados: la relación entre el trabajo y la salud de los investigadores(as) se percibe como una amalgama en la que se mezclan exigencias laborales, retos y satisfacciones individuales y colectivas. Se evidencia altas demandas de productividad intelectual; no hay correspondencia entre el tiempo que se invierte y el concetado en los planes de trabajo. En algunos momentos del proceso investigativo se superan los límites de las jornadas laborales, lo que genera malestar, dolencias físicas y estrés. Sin embargo, esta realidad se justifica por la pasión que para los participantes representa el hacer investigativo. Discusión: el contexto de exigencia que se plantea en el marco del Sistema Nacional deCiencia y Tecnología (SNCT), ha permitido la constitución de un campo en el que se ha normalizado en la vivencia cotidiana, la priorización de productividad intelectual sobre las condiciones de salud de los investigadores.

Objective: to analyze how male and female scientific researchers working at public and private universities in Antioquia (Colombia) perceive their health and working conditions. Methodology: a qualitative study conducted through interviews and a literature review. Participants belonged to research groups classified as A1, A, and B. according to the standerds issued by Colciencias (Colombia´s national Department of Science, Technology and Innovation). Results: researchers perceive the relationship between their work and health as a blend of work-related demands, challenges and personal and collective rewards. Demands on intellectual productivity are high; there is a mismatch between the actual time devoted to work and the time established in the work plans negotiated with the administration for every semester. In some points of the research process, these factors overload the daily work schedules, thus causing physical pain, stress, and malaise. Nevertheless, researchs find their work worthy because of the passion that research arouses in them . Discussion: The high demands defined within the framework of the National System for Science and Tecnology (Spanish acronym: SNCT) have created a field in wich intellectual productivity takes over the researchers´health conditions.

Six-minute walking distance in women with COPD.

BACKGROUND: The 6-minute walk distance (6MWD) has been useful in the evaluation of men with COPD. Little is known about 6MWD in women with the disease. OBJECTIVES: Using healthy women as a reference, to evaluate the factors that help determine 6MWD in women with COPD. To explore if the 350 meters threshold differentiates survival in women as it does in men. METHODS: Healthy women (n = 164) and with COPD (n = 223) were included in the study. Age, pack-years history, smoking status, comorbidities (Charlson Index), BMI, MRC dyspnea, spirometry and 6MWD were recorded in all participants and PaO(2) and IC/TLC in COPD women. The patients were prospectively followed and deaths registered. Factors predicting 6MWD were determined by multiple regression analysis. ROC analysis was used to calculate the best threshold value for the 6MWD with mortality as gold standard. Kaplan-Meier curves compared survival of patients that walked more or less than 350 m by age categories. RESULTS: The 6MWD is decreased in women with COPD. Values decrease with age and GOLD stages. Age, BMI, smoking status, comorbidities, MRC and FEV(1%) are statistical significant predictors of 6MWD. A 350 m cut-off value has a good sensitivity and specificity to predict (73% and 80% respectively) and differentiate survival (p < 0.001 for log rank comparisons) in these patients. CONCLUSIONS: In women with COPD, the 6MWD decreases with age and GOLD stages. A 350 m distance is a valid threshold to differentiate survival. Further studies in different settings should confirm our findings.

Prognostic assessment in COPD: health related quality of life and the BODE index.

RATIONALE: COPD is a debilitating disease with increasing mortality worldwide. The BODE index evaluates disease severity and the St George's Respiratory Questionnaire (SGRQ) measures health status. OBJECTIVE: To identify the relationship between BODE index and the SGRQ and to test the predictive value of both tools against survival. METHODS: Open cohort study of 1398 COPD patients (85% male) followed for up to 10 years. MEASUREMENTS AND MAIN RESULTS: At the time of the inclusion, clinical data, forced spirometry and 6 min walking distance were determined and BODE index and SGRQ were calculated. Vital status and cause of death were documented at the end of follow-up. RESULTS: The cohort's mean of FEV1% predicted was 46 ± 18%, BODE index was 3.6 ± 2.5, and SGRQ% total score was 49 ± 20. The SGRQ scores increased progressively as severity of COPD increased by BODE quartiles. The correlation between SGRQ and BODE index was good (r = 0.58, p < 0.0001). Both tests correlated with COPD survival (BODE = -0.4 vs. SGRQ = -0.20, p < 0.0001). The area under the curve (AUC) for the BODE index was 0.77 vs. 0.66 for the SGRQ % total score (p < 0.001). CONCLUSIONS: Health status as measured by SGRQ worsens with disease severity evaluated by the BODE index. Both tools predict mortality and provide complimentary information in the evaluation of patients with COPD.

Metronomic Cyclophosphamide and Methotrexate Chemotherapy Combined with 1E10 Anti-Idiotype Vaccine in Metastatic Breast Cancer.

The use of low doses of cytotoxic agents continuously for prolonged periods is an alternative for the treatment of patients with metastatic breast cancer who have developed resistance to conventional chemotherapy. The combination of metronomic chemotherapy with therapeutic vaccines might increase the efficacy of the treatment. Twenty one patients with metastatic breast cancer in progression and a Karnosky index ≥60%, were treated with metronomic chemotherapy (50 mg of cyclophospamide orally daily and 2.5 mg of methotrexate orally bi-daily), in combination with five bi-weekly subcutaneous injections of 1 mg of aluminum hydroxide-precipitated 1E10 anti-idiotype MAb (1E10-Alum), followed by reimmunizations every 28 days. Five patients achieved objective response, eight showed stable disease and eight had disease progression. Median time to progression was 9,8 months, while median overall survival time was 12,93 months. The median duration of the response (CR+PR+SD) was 18,43 months (12,20-24,10 months), being higher than 12 months in 76,9% of the patients. Overall toxicity was generally mild. Metronomic chemotherapy combined with 1E10-Alum vaccine immunotherapy might be a useful therapeutic option for the treatment of metastatic breast cancer due to its potential impact on survival and patient quality of live, low toxicity and advantages of the administration.

Prevalence of smoking and incidence of initiation in the Latin American adult population: the PLATINO study.

BACKGROUND: The PLATINO project was launched in 2002 in order to study the prevalence of chronic obstructive pulmonary disease (COPD) in Latin America. Because smoking is the main risk factor for COPD, detailed data on it were obtained. The aim of this paper was to evaluate the prevalence of smoking and incidence of initiation among middle-aged and older adults (40 years or older). Special emphasis was given to the association between smoking and schooling. METHODS: PLATINO is a multicenter study comprising five cross-sectional population-based surveys of approximately 1,000 individuals per site in Sao Paulo (Brazil), Santiago (Chile), Mexico City (Mexico), Montevideo (Uruguay) and Caracas (Venezuela). The outcome variable was smoking status (never, former or current). Current smokers were those who reported to smoke within the previous 30 days. Former smokers were those who reported to quit smoking more than 30 days before the survey. Using information on year of birth and age of smoking onset and quitting, a retrospective cohort analysis was carried out. Smoking prevalence at each period was defined as the number of subjects who started to smoke during the period plus those who were already smokers at the beginning of the period, divided by the total number of subjects. Incidence of smoking initiation was calculated as the number of subjects who started to smoke during the period divided by the number of non-smokers at its beginning. The independent variables included were sex, age and schooling. RESULTS: Non-response rates ranged from 11.1% to 26.8%. The prevalence of smoking ranged from 23.9% (95%CI 21.3; 26.6) in Sao Paulo to 38.5% (95%CI 35.7; 41.2) in Santiago. Males and middle-aged adults were more likely to smoke in all sites. After adjustment for age, schooling was not associated with smoking. Using retrospective cohort analysis, it was possible to detect that the highest prevalence of smoking is found between 20-29 years, while the highest incidence is found between 10-19 years. Age of smoking onset tended to decline over time among females. CONCLUSION: The prevalence of smoking varied considerably across sites, but was lower among countries with national anti-smoking campaigns.

Borderline personality disorder: a review and reformulation from evolutionary theory.

A number of authors have provided a useful evolutionary perspective on personality disorders, arguing that personality traits can be conceptualized in terms of evolutionary strategies. If we consider personality traits not as illnesses but as stable evolutionary strategies, the characteristic features of borderline personality disorder may respond to a behavioral pattern which, although deviating from the norm, would be in the service of survival of the species. Early environments involving factors such as childhood physical/sexual abuse may prove useful for explanation of personality traits based on gene-environment interaction, potentially providing a model for understanding borderline personality traits. We also review the question of whether personality traits exist in animals to also provide a translational perspective. We propose that certain traits in borderline personality disorder may derive from evolved mechanisms which in the short-term serve to help respond to adversity, but which when activated in an ongoing way prove maladaptive.

A novel A33 promoter-based conditionally replicative adenovirus suppresses tumor growth and eradicates hepatic metastases in human colon cancer models.

PURPOSE: A33 antigen is a membrane-bound protein expressed in intestinal epithelium that is overexpressed in 95% of primary and metastatic colorectal carcinomas but is absent in most epithelial tissues and tumor types. We hypothesized that A33 promoter might be useful in the design of a conditionally replicative adenovirus for the treatment of colorectal cancer (CRC). EXPERIMENTAL DESIGN: We cloned an A33 promoter fragment (A33Pr) that extends from -105 to +307 bp. Using luciferase activity as a reporter gene, we showed that A33Pr was active in CRC cell lines. We next constructed a conditionally replicative adenovirus named AV22EL where E1A was placed under the control of A33Pr. The tumor-specific oncolytic effect of AV22EL was investigated both in vitro and in vivo. RESULTS: AV22EL induced specific in vitro lysis of human CRC cell lines that expressed A33 and have negligible lytic capacity on cells that lacked or had minimal A33 expression, including normal human colonic cells. In vivo, a marked reduction of tumor growth and increased long-term survival rates were observed in nude mice xenografted with s.c. CRC tumors. Combination with 5-fluorouracil induced an additive effect in vitro with no toxic effects in vivo. Remarkably, AV22EL completely eliminated established hepatic metastases in >90% of mice and restored hepatic function according to biochemical parameters. Its systemic administration induced E1A expression only in the hepatic metastasis but not in normal organs. CONCLUSIONS: These data show that AV22EL is a stringently regulated and potent oncolytic agent for the treatment of CRC.

2-tert-Butylamino-4-chloro-6-ethylamino-1,3,5-triazine: a structure with Z' = 4 containing two different molecular conformations and two independent chains of hydrogen-bonded R(2)2(8) rings.

The title compound (trivial name terbutylazine), C(9)H(16)ClN(5), (I), crystallizes with Z' = 4 in the space group Pca2(1), and equal numbers of molecules adopt two different conformations for the ethylamine groups. The four independent molecules form two approximately enantiomorphic pairs. Eight independent N-H...N hydrogen bonds link the molecules into two independent chains of R(2)(2)(8) rings, in which the arrangement of the alkylamine substituents in the independent molecules precludes any further crystallographic symmetry. The significance of this study lies in its finding of two distinct molecular conformations within the structure and two distinct ways in which the molecules are organized into hydrogen-bonded chains, and in its comparison of the hydrogen-bonded structure of (I) with those of analogous 1,3,5-triazines and pyrimidines.

Phase II trial: concurrent radio-chemotherapy with weekly docetaxel for advanced squamous cell carcinoma of head and neck.

INTRODUCTION: Standard fractionation radiation therapy (RT) combined with concomitant chemotherapy (CT) based on cisplatin schemes is actually the standard treatment for locally advanced non-resectable squamous cell carcinoma of head and neck (SCCHN). The appearance of taxoids has introduced a new kind of treatment with high antitumoral power. The aim of this study is to add more information about the role of this new approach. MATERIALS AND METHODS: Twenty-six patients with locally advanced non-resectable SCCHN were recruited at six institutions in Spain, between January 2001 and January 2003. Docetaxel was administered weekly, for 6 weeks, concurrently with RT. RESULTS: The mean total delivered dose of RT was 70'2 Gy (range 64-74 Gy). The median and mean duration of time were 63 days and 61 days (range 49-103 days) respectively. After a median time control of 19 months (range 3.3-42.2 months), the response rate was 83.4%. The median time to local progression was 16.4 months (95% confidence interval [CI]=4.4-28.4 months). The median survival time was 26.9 months, with one- and two-year overall survival of 66.9% (95% CI=48.1-85.7%) and 57.5% (95% CI=37.3-77.7%) respectively. The median duration time response was 15.1 months (95% CI=3.7-26.5 months). The median time until treatment failure was 9.4 months (95% CI=4.7-14.1). Incidence of grade III-IV mucositis was 88%, neutropenia 72% and skin toxicity 92% (24% grade III-IV). The incidence of severe late toxicity (grade III and IV) due to RT/CT was 31.4%. CONCLUSIONS: Although therapeutics results are equivalent to cisplatin schemes of concurrent CT-RT, mucositis and cutaneous toxicity registered in this trial must be considered as limiting factors to application of this new approach.

Expression of a suicidal gene under control of the human secreted protein acidic and rich in cysteine (SPARC) promoter in tumor or stromal cells led to the inhibition of tumor cell growth.

The successful use of transcriptional targeting for cancer therapy depends on the activity of a given promoter inside the malignant cell. Because solid human tumors evolve as a "cross-talk" between the different cell types within the tumor, we hypothesized that targeting the entire tumor mass might have better therapeutic effect. Secreted protein acidic and rich in cysteine (SPARC) is a matricellular protein overexpressed in different human cancers malignant melanomas both in the malignant cells compartment as in the stromal one (fibroblasts and endothelial cells). We have shown that expression of the herpes simplex virus-thymidine kinase (TK) gene driven by the SPARC promoter in combination with ganciclovir inhibited human melanoma cell growth in monolayer as well as in multicellular spheroids. This inhibitory effect was observed both in homotypic spheroids composed of melanoma cells alone as well as in spheroids made of melanoma cells and stromal cells. Expression of the TK gene was also efficient to inhibit the in vivo tumor growth of established melanomas when TK was expressed either by the malignant cells themselves or by coadministered endothelial cells. Our data suggest that the use of therapeutic genes driven by SPARC promoter could be a valuable strategy for cancer therapy aiming to target all the cellular components of the tumor mass.