Phase I Study of Lenvatinib and Capecitabine with External Radiation Therapy in Locally Advanced Rectal Adenocarcinoma.

BACKGROUND: Neoadjuvant chemoradiation with fluoropyrimidine followed by surgery and adjuvant chemotherapy has been the standard treatment of locally advanced stages II and III rectal cancer for many years. There is a high risk for disease recurrence; therefore, optimizing chemoradiation strategies remains an unmet need. Based on a few studies, there is evidence of the synergistic effect of VEGF/PDGFR blockade with radiation. METHODS: In this phase I, dose-escalation and dose-expansion study, we studied 3 different dose levels of lenvatinib in combination with capecitabine-based chemoradiation for locally advanced rectal cancer. RESULTS: A total of 20 patients were enrolled, and 19 were eligible for assessment of efficacy. The combination was well tolerated, with an MTD of 24 mg lenvatinib. The downstaging rate for the cohort and the pCR was 84.2% and 37.8%, respectively. Blood-based protein biomarkers TSP-2, VEGF-R3, and VEGF correlated with NAR score and were also differentially expressed between response categories. The NAR, or neoadjuvant rectal score, encompasses cT clinical tumor stage, pT pathological tumor stage, and pN pathological nodal stage and provides a continuous variable for evaluating clinical trial outcomes. CONCLUSION: The combination of lenvatinib with capecitabine and radiation in locally advanced rectal cancer was found to be safe and tolerable, and potential blood-based biomarkers were identified. CLINICAL TRIAL REGISTRATION: NCT02935309.

Disruption of the ATXN1-CIC complex causes a spectrum of neurobehavioral phenotypes in mice and humans.

Gain-of-function mutations in some genes underlie neurodegenerative conditions, whereas loss-of-function mutations in the same genes have distinct phenotypes. This appears to be the case with the protein ataxin 1 (ATXN1), which forms a transcriptional repressor complex with capicua (CIC). Gain of function of the complex leads to neurodegeneration, but ATXN1-CIC is also essential for survival. We set out to understand the functions of the ATXN1-CIC complex in the developing forebrain and found that losing this complex results in hyperactivity, impaired learning and memory, and abnormal maturation and maintenance of upper-layer cortical neurons. We also found that CIC activity in the hypothalamus and medial amygdala modulates social interactions. Informed by these neurobehavioral features in mouse mutants, we identified five individuals with de novo heterozygous truncating mutations in CIC who share similar clinical features, including intellectual disability, attention deficit/hyperactivity disorder (ADHD), and autism spectrum disorder. Our study demonstrates that loss of ATXN1-CIC complexes causes a spectrum of neurobehavioral phenotypes.

Design, synthesis, and diversification of 3,5-substituted enone library.

This paper describes the synthesis of a 300 member library of 3,5-substituted enones. The synthesis starts with 6 different bromoenones that are accessed from the corresponding 1,3 diones. These bromides are then diversified by Suzuki coupling with a variety of aromatic and vinyl boronic acids. Additionally a small series of triazoles was synthesized by a Sonogashira coupling reaction dipolar cycloaddition sequence. The library was analyzed by principal component analysis to examine its diversity.

Testing the efficacy and toxicity of adenylyl cyclase inhibitors against enteric pathogens using in vitro and in vivo models of infection.

Enterotoxigenic Escherichia coli (ETEC) produces the ADP-ribosyltransferase toxin known as heat-labile enterotoxin (LT). In addition to the toxic effect of LT resulting in increases of cyclic AMP (cAMP) and disturbance of cellular metabolic processes, this toxin promotes bacterial adherence to intestinal epithelial cells (A. M. Johnson, R. S. Kaushik, D. H. Francis, J. M. Fleckenstein, and P. R. Hardwidge, J. Bacteriol. 191:178-186, 2009). Therefore, we hypothesized that the identification of a compound that inhibits the activity of the toxin would have a suppressive effect on the ETEC colonization capabilities. Using in vivo and in vitro approaches, we present evidence demonstrating that a fluorenone-based compound, DC5, which inhibits the accumulation of cAMP in intoxicated cultured cells, significantly decreases the colonization abilities of adenylyl cyclase toxin-producing bacteria, such as ETEC. These findings established that DC5 is a potent inhibitor both of toxin-induced cAMP accumulation and of ETEC adherence to epithelial cells. Thus, DC5 may be a promising compound for treatment of diarrhea caused by ETEC and other adenylyl cyclase toxin-producing bacteria.

Digital assessment of the reproductive tract versus colposcopy for directing biopsies in women with abnormal Pap smears.

OBJECTIVE: This study aimed to compare digital camera assessment of the reproductive tract (DART) to colposcopy for the evaluation of abnormal Pap smears. MATERIALS AND METHODS: Participants included 207 women with abnormal Pap smears. Colposcopy and DART were performed on each patient by separate examiners with the goal of lesion detection. Analysis was performed per patient and per biopsy. RESULTS: Patients had an average of 2.9 biopsies. Forty-two patients and 81 biopsies were positive for cervical intraepithelial neoplasia 2+. Both DART and colposcopy detected 41 (97.6%) of 42 patients (95% CI = 85.9%-99.9%). Digital camera assessment of the reproductive tract detected 66/81 (81.4%; CI = 70.7%-88.9%) and colposcopy detected 69/81 (85.2%; CI = 73.2%-92.4%) of biopsies that were cervical intraepithelial neoplasia 2+. CONCLUSIONS: Digital camera assessment of the reproductive tract detects high-grade lesions of the cervix with similar sensitivity to colposcopy. It holds great promise to expand cervical cancer precursor lesion detection in areas with limited resources.

Pyridopyrimidine derivatives as inhibitors of cyclic nucleotide synthesis: Application for treatment of diarrhea.

Acute secretory diarrhea induced by infection with enterotoxigenic strains of Escherichia coli involves binding of stable toxin (STa) to its receptor on the intestinal brush border, guanylyl cyclase type C (GC-C). Intracellular cGMP is elevated, inducing increase in chloride efflux and subsequent accumulation of fluid in the intestinal lumen. We have screened a library of compounds and identified a pyridopyrimidine derivatives {5-(3-bromophenyl)-1,3-dimethyl-5,11-dihydro-1H-indeno[2',1':5,6]pyrido[2,3-d]pyrimidine-2,4,6-trione; BPIPP} as an inhibitor of GC-C that can suppress STa-stimulated cGMP accumulation by decreasing GC-C activation in intact T84 human colorectal carcinoma cells. BPIPP inhibited stimulation of guanylyl cyclases, including types A and B and soluble isoform in various cells. BPIPP suppressed stimulation of adenylyl cyclase and significantly decreased the activities of adenylyl cyclase toxin of Bordetella pertussis and edema toxin of Bacillus anthracis. The effects of BPIPP on cyclic nucleotide synthesis were observed only in intact cells. The mechanism of BPIPP-dependent inhibition appears to be complex and indirect, possibly associated with phospholipase C and tyrosine-specific phosphorylation. BPIPP inhibited chloride-ion transport stimulated by activation of guanylyl or adenylyl cyclases and suppressed STa-induced fluid accumulation in an in vivo rabbit intestinal loop model. Thus, BPIPP may be a promising lead compound for treatment of diarrhea and other diseases.

Synthesis and screening of 3-substituted thioxanthen-9-one-10,10-dioxides.

This manuscript describes methods appropriate for the parallel synthesis of libraries based on the tricyclic thioxanthen-9-one-10,10-dioxide scaffold. The novel compounds were synthesized from previously reported 3-chlorothioxanthen-9-one-10,10-dioxide and commercially available 3-carboxylic acid thioxanthen-9-one-10,10-dioxide. The library members were screened for activity in a fluorescence polarization assay for inhibitors of BRCT domains of breast cancer gene 1 and in cell-based secreted alkaline phosphatase reported replicon system for activity against hepatitis C virus.

Participation of N-methyl-D-aspartate receptors on methylmercury-induced DNA damage in rat frontal cortex.

Methylmercury (MeHg) inhibits glutamate uptake by astrocytes, which can contribute to neuronal loss through excitotoxicity. We explored the extent at which this phenomenon is involved in MeHg-induced DNA damage in the rat cortex. MeHg amounts that increase extracellular glutamate (1.5, 7.5 and 15 nmol, according to previous reports) were stereotaxically injected in the frontal cortex of adult rats before DNA-damage determination by means of a quantitative TUNEL assay. After either 24 or 48 h, the cortex of all exposed animals showed significant increments of damaged DNA, compared with rats that only received sterile saline. In parallel experiments, we found that the administration of a non competitive NMDA receptor antagonist (MK-801, 10 mg/kg, i.p.) 1 h before MeHg injection, significantly reduced DNA damage. These results demonstrate that activation of NMDA receptors contributes importantly to MeHg neurotoxicity.

Brain cell karyotype of the phlebotomine sand fly Lutzomyia shannoni (Dyar) (Diptera: Psychodidae)

The brain cell karyotype of New World sand fly Lutzomyia shannoni was described. This species has four pairs of chromosomes, 2N=8, with one pair of heteromorphic chromosomes

Cultivos celulares primarios de Lutzomya shannoni (Diptera: psychodidae) y estudio cariológico preliminar de la especie / Primary cell cultures of Lutzomyia shannoni (Diptera: Psychodidae) and preliminar study karyotypes of the species

Con el propósito de obtener una línea celular de Lutzomya shannoni (Dyar) para estudios de susceptibilidad viral y mantenimiento de parásitos, se iniciaron cultivos celulares primarios de esta especie, vectora del virus de la estomatitis vesicular en los Estados Unidos y vectora sospechosa de leishmaniasis cutánea en la Américas. A partir de embriones y larvas neonatas del flebotomíneo, se realizaron explantes de tejidos embrionarios en el medio MM/VP12, suplementado con 20 por ciento de suero fetal bovino y una mezcla de antibiótico y antimicótico, los cuales fueron incubados a una temperatura promedio de 28§C, sin atmósfera de CO subíndice². El crecimiento celular comenzó en un período de 85 a 88 días después de efectuadas las siembras, mediante la presencia de vesículas compuestas de células epitelioides, flotando en le medio o adheridas a pequeños fragmentos de tejidos con células en división. Previa estimulación mecánica de los cultivos, se incrementó la proliferación celular a la semana siguiente de efectuado el procedimiento; sin embargo, el proceso mitótico de las células fue lento, similar al desarrollado con Lu. longipalpis, pero diferente a los cultivos celulares derivados de mosquitos. La formación de colonias individuales, dispersas en la superficie del frasco de cultivo, se observó a los 90 días de incubación, las cuales posteriormente evolucionaron a una monocapa semiconfluente. La morfología celular fue heterogénea con predominio de tipos epitelioides. Mediante la técnica de squash, se obtuvo el cariotipo de la especie, cuyo número diploide de cromosomas fue de 8, derivados de tejido cerebrales de larvas de IV estadio