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This paper outlines the protocol for the deployment of a cloud-based universal medical image repository system. The proposal aims not only at the deployment but also at the automatic expansion of the platform, incorporating Artificial Intelligence (AI) for the analysis of medical image examinations. The methodology encompasses efficient data management through a universal database, along with the deployment of various AI models designed to assist in diagnostic decision-making. By presenting this protocol, the goal is to overcome technical challenges and issues that impact all phases of the workflow, from data management to the deployment of AI models in the healthcare sector. These challenges include ethical considerations, compliance with legal regulations, establishing user trust, and ensuring data security. The system has been deployed, with a tested and validated proof of concept, possessing the capability to receive thousands of images daily and to sustain the ongoing deployment of new AI models to expedite the analysis process in medical image exams., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Pacheco et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

This paper presents an artificial intelligence-based classification model for the detection of pulmonary embolism in computed tomography angiography. The proposed model, developed from public data and validated on a large dataset from a tertiary hospital, uses a two-dimensional approach that integrates temporal series to classify each slice of the examination and make predictions at both slice and examination levels. The training process consists of two stages: first using a convolutional neural network InceptionResNet V2 and then a recurrent neural network long short-term memory model. This approach achieved an accuracy of 93% at the slice level and 77% at the examination level. External validation using a hospital dataset resulted in a precision of 86% for positive pulmonary embolism cases and 69% for negative pulmonary embolism cases. Notably, the model excels in excluding pulmonary embolism, achieving a precision of 73% and a recall of 82%, emphasizing its clinical value in reducing unnecessary interventions. In addition, the diverse demographic distribution in the validation dataset strengthens the model's generalizability. Overall, this model offers promising potential for accurate detection and exclusion of pulmonary embolism, potentially streamlining diagnosis and improving patient outcomes., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Silva et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Missed and delayed diagnoses of Hansen's disease (HD) are making the battle against it even more complex, increasing its transmission and significantly impacting those affected and their families. This strains public health systems and raises the risk of lifelong impairments and disabilities. Worryingly, the three countries most affected by HD witnessed a growth in new cases in 2022, jeopardizing the World Health Organization's targets to interrupt transmission. Artificial intelligence (AI) can help address these challenges by offering the potential for rapid case detection, customized treatment, and solutions for accessibility challenges-especially in regions with a shortage of trained healthcare professionals. This perspective article explores how AI can significantly impact the clinical management of HD, focusing on therapeutic strategies. AI can help classify cases, ensure multidrug therapy compliance, monitor geographical treatment coverage, and detect adverse drug reactions and antimicrobial resistance. In addition, AI can assist in the early detection of nerve damage, which aids in disability prevention and planning rehabilitation. Incorporating AI into mental health counseling is also a promising contribution to combating the stigma associated with HD. By revolutionizing therapeutic approaches, AI offers a holistic solution to reduce the burden of HD and improve patient outcomes., Competing Interests: PD, BF, BO, SL, and RL are currently involved in a project financed by the Program of Support for the Institutional Development of the Unified Health System (PROADI-SUS) in collaboration with Hospital Israelita Albert Einstein. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Deps, Yotsu, Furriel, de Oliveira, de Lima and Loureiro.)

Competing Interests: Declaration of Competing Interest The authors have no competing interest to declare.

Background: Traditional health care systems face long-standing challenges, including patient diversity, geographical disparities, and financial constraints. The emergence of artificial intelligence (AI) in health care offers solutions to these challenges. AI, a multidisciplinary field, enhances clinical decision-making. However, imbalanced AI models may enhance health disparities., Objective: This systematic review aims to investigate the economic performance and equity impact of AI in diagnostic imaging for skin, neurological, and pulmonary diseases. The research question is "To what extent does the use of AI in imaging exams for diagnosing skin, neurological, and pulmonary diseases result in improved economic outcomes, and does it promote equity in health care systems?", Methods: The study is a systematic review of economic and equity evaluations following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) and CHEERS (Consolidated Health Economic Evaluation Reporting Standards) guidelines. Eligibility criteria include articles reporting on economic evaluations or equity considerations related to AI-based diagnostic imaging for specified diseases. Data will be collected from PubMed, Embase, Scopus, Web of Science, and reference lists. Data quality and transferability will be assessed according to CHEC (Consensus on Health Economic Criteria), EPHPP (Effective Public Health Practice Project), and Welte checklists., Results: This systematic review began in March 2023. The literature search identified 9,526 publications and, after full-text screening, 9 publications were included in the study. We plan to submit a manuscript to a peer-reviewed journal once it is finalized, with an expected completion date in January 2024., Conclusions: AI in diagnostic imaging offers potential benefits but also raises concerns about equity and economic impact. Bias in algorithms and disparities in access may hinder equitable outcomes. Evaluating the economic viability of AI applications is essential for resource allocation and affordability. Policy makers and health care stakeholders can benefit from this review's insights to make informed decisions. Limitations, including study variability and publication bias, will be considered in the analysis. This systematic review will provide valuable insights into the economic and equity implications of AI in diagnostic imaging. It aims to inform evidence-based decision-making and contribute to more efficient and equitable health care systems., International Registered Report Identifier (irrid): DERR1-10.2196/48544., (©Giulia Osório Santana, Rodrigo de Macedo Couto, Rafael Maffei Loureiro, Brunna Carolinne Rocha Silva Furriel, Edna Terezinha Rother, Joselisa Péres Queiroz de Paiva, Lucas Reis Correia. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 28.12.2023.)

Competing Interests: The authors disclose no conflicts of interest.

To characterize maxillofacial, otorhinolaryngological and oral manifestations of Hansen's disease (HD), we conducted a cross-sectional study in 21 current patients attending the Unidade Básica de Saúde de Jardim América, Espírito Santo, Brazil and 16 former patients resident at Pedro Fontes Hospital using data from computed tomography imaging, rhinoscopy, and oroscopy. Maxillofacial characteristics were compared with 37 controls. Differences in bone alterations across the three groups were determined mainly by severe resorption/atrophy being more frequent in former HD patients, with severe resorption/atrophy of the anterior alveolar process of maxilla in 50.0% (8/16) of former patients, 28.6% (6/21) of current patients and 10.8% (4/37) of controls and of nasal bones and aperture in 31.3% (5/16) of former patients compared with 0/21 current patients and two controls. There were no substantial differences in otorhinolaryngological and oroscopic findings between the two patient groups. HD patients had more tooth loss than the age-matched control group. Maxillofacial, otorhinolaryngological and oroscopic finding scores were strongly correlated only in current HD patients. Correlation between otorhinolaryngological and maxillofacial scores suggests that protocols for HD patient assessment and follow-up could include otorhinolaryngological evaluation, with radiological imaging where necessary, subject to replication of our findings in a larger study., (© 2022. The Author(s).)

Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interest.

Background More than four million people today live with Hansen's disease, and 200,000 new cases are diagnosed every year. Lifetime effects of Hansen's disease manifest as changes to bones of the face, hands and feet, resulting in physical impairment, secondary complications and facial changes that can be detrimental to quality of life, particularly among the elderly. Aims This study aimed to perform a detailed characterization of rhinomaxillary syndrome and its clinical manifestations in older persons treated in the past for Hansen's disease. Methods This was a cross-sectional study to characterize rhinomaxillary syndrome among older persons (age 60+ years) resident at Pedro Fontes Hospital, Cariacica, Espírito Santo, Brazil. Computed tomography images were examined with three-dimensional reconstructions to assess alterations to maxillofacial bones according to criteria for radiological rhinomaxillary syndrome. Participants were examined to assess facial alterations according to criteria for clinical rhinomaxillary syndrome. Results Rhinomaxillary syndrome was investigated in 16 participants (ten females and six males), median age 70 (range 60-89) years, age at diagnosis 20 (6-43) years and time since diagnosis 46 (26-70) years. Four participants fully met radiological rhinomaxillary syndrome criteria, four partially. All participants with full radiological rhinomaxillary syndrome presented with facial changes which met criteria for clinical rhinomaxillary syndrome, including "saddle nose" (loss of nasal dorsal height and shortened length of nose, due to cartilaginous and/or bone collapse), concave middle third of the face with sunken nose, maxillary retrognathia and inverted upper lip. Limitations Clinical histories were incomplete for some participants because records were lost at the hospital over time. Conclusion Until Hansen's disease is eliminated from endemic countries, persons affected will continue to present with rhinomaxillofacial alterations caused by Mycobacterium leprae infection. Clinical protocols for assessment and long-term care need to include otorhinolaryngological evaluation, mainly to prevent secondary complications. When rhinomaxillofacial bone changes are suspected, this evaluation should be supported by computed tomography imaging, if available.

Orthognathic surgery is the standard procedure to correct congenital, developmental, or acquired dentofacial deformities. The maxillomandibular relationship corrected by orthognathic surgery can improve facial esthetics, masticatory function, articulation, and breathing. The most common types of osteotomies include the combination of Le Fort I osteotomy, bilateral sagittal split mandibular ramus osteotomy, and genioplasty. High-resolution low-dose computed tomography is useful for evaluating the facial skeleton and soft tissues after surgery as well as for depicting a variety of possible complications. This article reviews the postoperative imaging findings of the most common orthognathic surgeries and their potential complications on multidetector-row computed tomography., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

This study reported the case of a healthy male in his 40s who presented with a 3-month history of frontal headache and post-nasal drip, which did not improve with oral antibiotics. One month prior to the onset of the symptoms, he underwent a nasopharyngeal swab testing for SARS-CoV-2 (which yielded a negative result) for a history of malaise and cough. The patient claimed that the swab insertion into the nasal cavity was particularly painful on the left side. Sinus computed tomography (CT) scan showed deformity of the left middle nasal turbinate with occlusion of the osteomeatal complex, resulting in ethmoid silent sinus syndrome. This study makes a significant contribution to the literature because nasopharyngeal, midturbinate and anterior nasal swabs have been recommended as initial diagnostic specimen collection methods by the US Centers for Disease Control and Prevention (CDC) for the coronavirus disease 2019. These methods require introducing an instrument into the nasal cavity, potentially leading to adverse effects due to the delicate and complex nasal anatomy. However, complications related to swab testing for respiratory pathogens have not yet been fully discussed in the literature., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Competing Interests: The authors have declared that no competing interests exist.

We aim to characterize patients with Gomez-López-Hernández syndrome (GLHS) clinically and to investigate them molecularly. A clinical protocol, including a morphological and neuropsychological assessment, was applied to 13 patients with GLHS. Single-nucleotide polymorphism (SNP) array and whole-exome sequencing were undertaken; magnetic resonance imaging was performed in 12 patients, including high-resolution, heavily T2-weighted sequences (HRT2) in 6 patients to analyze the trigeminal nerves. All patients presented alopecia; two did not present rhombencephalosynapsis (RES); trigeminal anesthesia was present in 5 of the 11 patients (45.4%); brachycephaly/brachyturricephaly and mid-face retrusion were found in 84.6 and 92.3% of the patients, respectively. One patient had intellectual disability. HRT2 sequences showed trigeminal nerve hypoplasia in four of the six patients; all four had clinical signs of trigeminal anesthesia. No common candidate gene was found to explain GLHS phenotype. RES does not seem to be an obligatory finding in respect of GLHS diagnosis. We propose that a diagnosis of GLHS should be considered in patients with at least two of the following criteria: focal non-scarring alopecia, rhombencephalosynapsis, craniofacial anomalies (brachyturrycephaly, brachycephaly or mid-face retrusion), trigeminal anesthesia or anatomic abnormalities of the trigeminal nerve. Studies focusing on germline whole genome sequencing or DNA and/or RNA sequencing of the alopecia tissue may be the next step for the better understanding of GLHS etiology., (© 2020 Wiley Periodicals LLC.)

The Zika virus (ZIKV) attracted attention due to one striking characteristic: the ability to cross the placental barrier and infect the fetus, possibly causing severe neurodevelopmental disruptions included in the Congenital Zika Syndrome (CZS). Few years after the epidemic, the CZS incidence has begun to decline. However, how ZIKV causes a diversity of outcomes is far from being understood. This is probably driven by a chain of complex events that relies on the interaction between ZIKV and environmental and physiological variables. In this review, we address open questions that might lead to an ill-defined diagnosis of CZS. This inaccuracy underestimates a large spectrum of apparent normocephalic cases that remain underdiagnosed, comprising several subtle brain abnormalities frequently masked by a normal head circumference. Therefore, new models using neuroimaging and artificial intelligence are needed to improve our understanding of the neurobiology of ZIKV and its true impact in neurodevelopment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Moura, Ferreira, Loureiro, de Paiva, Rosa-Ribeiro, Amaro, Soares and Machado.)

Objective: To analyze computed tomography scans of paranasal sinuses of a series of patients with coronavirus disease 2019, and correlate the findings with the disease., Methods: Computed tomography scans of 95 adult patients who underwent a polymerase chain reaction test for severe acute respiratory syndrome coronavirus 2 were analyzed. Clinical data were obtained from patients' records and telephone calls. Paranasal sinus opacification was graded and compared according to severe acute respiratory syndrome coronavirus 2 positivity., Results: Of the patients 28 (29.5%) tested positive for severe acute respiratory syndrome coronavirus 2 (median age 52 [range 26-95] years) and 67 were negative (median age 50 [range 18-95] years). Mucosal thickening was present in 97.4% of maxillary sinuses, 80% of anterior ethmoid air cells, 75.3% of posterior ethmoid air cells, 74.7% of frontal sinuses, and 66.3% of sphenoid sinuses. Minimal or mild mucosal thickening (score 1)and normally aerated sinuses (score 0) corresponded to 71.4% and 21.3% of all paranasal sinuses, respectively. The mean score of each paranasal sinus among severe acute respiratory syndrome coronavirus 2 positive and negative patients was 0.85±0.27 and 0.87±0.38, respectively (p=0.74). Median paranasal sinus opacification score among severe acute respiratory syndrome coronavirus 2 positive patients was 9 (interquartile range 8-10) compared to 9 (interquartile range 5-10) in negative patients (p=0.89). There was no difference in mean score adjusted for age and sex. Nasal congestion was more frequent in severe acute respiratory syndrome coronavirus 2 positive than negative patients (p=0.05)., Conclusion: Severe acute respiratory syndrome coronavirus 2 infection was associated with patient recall of nasal congestion, but showed no correlation with opacification of paranasal sinuses.

Third molars may be associated with a wide range of pathologic conditions, including mechanical, inflammatory, infectious, cystic, neoplastic, and iatrogenic. Diagnosis of third molar-related conditions can be challenging for radiologists who lack experience in dental imaging. Appropriate imaging evaluation can help practicing radiologists arrive at correct diagnoses, thus improving patient care. This review discusses the imaging findings of various conditions related to third molars, highlighting relevant anatomy and cross-sectional imaging techniques. In addition, key imaging findings of complications of third molar extraction are presented., (© 2020 by American Journal of Neuroradiology.)

The pharmaceutical industry is one of the most competitive sectors in Europe and has a strong presence in many European Union (EU) countries. The mutual recognition agreement (MRA) for inspections of medicines manufacturers between the United States (US) Food and Drug Administration (FDA) and the EU started by the end of 2017 and gradually extended to all EU member states (MSs) in July 2019. We quantified the number of FDA and EU good manufacturing practice (GMP) inspections carried out in each other's territory between 2009 and 2018. The five EU MSs with the largest number of FDA inspections were Germany, followed by Italy, France, the United Kingdom (UK), and Spain. All of them, with the exception of Germany, were included in the group of the first eight EU MSs recognized by the FDA in the context of the MRA. In 2018, these five EU MSs were within the top 10 EU exporters of pharmaceutical products to the US. Four of these five EU MSs (Italy, Germany, France, and the UK) accounted for 53.4% of the total pharmaceutical production in the EU in 2018. We also studied the type of manufacturing operations covered by the manufacturer's authorizations issued by each EU MS for the manufacturers within its territory. We verified a high prevalence of conventional technology versus complex technology manufacturing for many EU countries. Going forward, this unbalance should be addressed at a national and EU level. Supporting for instance (bio)pharmaceutical manufacturing through pharma policy initiatives, especially for EU countries with a lower level of innovation and technological development, would promote the pharmaceutical manufacturing sustainability and competitiveness of these countries. The full implementation of the MRA between the US FDA and the EU can make it faster and less costly for both sides to bring medicines to the market, improving future competitiveness of the EU and the US pharmaceutical industry., (© PDA, Inc. 2020.)

Dental disease is a frequent finding on head and neck images, especially in the context of emergencies, and can be a challenge for radiologists who are inexperienced with findings of dental trauma or disease. Dental abnormalities can be subtle and therefore must be included in the systematic approach to these images. Although dedicated dental images are not acquired in most emergency cases, the teeth are included on many different images of the head and neck, and their initial evaluation seldom requires a specific protocol. The high prevalence of craniofacial trauma, sinus infection, and maxillomandibular procedures, among other conditions, frequently requires interpretation of dental images in daily emergency practice. The imaging findings can be categorized into infection, trauma, and complications of procedures, although sometimes these categories can overlap. Such categories can help the radiologist decide which imaging protocol and dynamic maneuvers should be used and are also useful when reading images and proposing differential diagnoses. Familiarity with the imaging findings of dental emergencies improves the radiologist's diagnostic confidence and role in guiding patient care, avoiding progression to life-threatening conditions, and reducing aesthetic problems, dental loss, and related conditions. Information about the imaging protocols is provided, the relevant anatomy of the teeth and related structures is reviewed, and the key imaging findings of dental emergencies are presented. © RSNA, 2019.

Technical advances in magnetic resonance imaging have allowed to accurately detect and grade endolymphatic space distension in Ménière disease; this was only possible in post-mortem histological studies until a few years ago. Magnetic resonance imaging rules out other causes of vertigo and hearing loss, and is able to evaluate the cochlear and vestibular compartments of the endolymphatic space using a dedicated protocol.

Early lead compounds in this gamma secretase modulator series were found to potently inhibit CYP3A4 and other human CYP isoforms increasing their risk of causing drug-drug-interactions (DDIs). Using structure-activity relationships and CYP3A4 structural information, analogs were developed that minimized this DDI potential. Three of these new analogs were further characterized by rat PK, rat PK/PD and rat exploratory toxicity studies resulting in selection of SPI-1865 (14) as a preclinical development candidate., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Both leprosy and human immunodeficiency virus (HIV) are infectious diseases, and are an important global health problem. Patients with leprosy who are co-infected with HIV seem to be at higher risk of developing leprosy reactions., Aim: To examine the histological features of leprosy in patients with HIV and leprosy co-infection, particularly to determine whether the typical leprosy histopathology is present in skin biopsies, and to assess the histological features of leprosy reactions in co-infected patients., Methods: This was a matched cohort study with 11 co-infected patients and 31 HIV-negative patients with leprosy. A structured protocol for skin-biopsy evaluation was followed, focusing on inflammation of the skin and dermal nerves., Results: Of the 11 HIV-positive patients, 7 (63%) had borderline tuberculoid (BT) leprosy and 5 (70%) of these 7 patients had developed a type 1 reaction. The lesions in these patients were immunologically active, with 100% of biopsies having evidence of compact granulomas, 90% evidence of oedema and 30% evidence of necrosis., Conclusions: In this study, patients co-infected with HIV and M. leprae had the typical histological lesions of leprosy. There was evidence of immune activation in patients who received combination antiretroviral therapy, and these patients had BT leprosy and leprosy-upgrading reactions., (© 2013 British Association of Dermatologists.)

Introduction: Modulation of the gamma-secretase enzyme, which reduces the production of the amyloidogenic Aβ42 peptide while sparing the production of other Aβ species, is a promising therapeutic approach for the treatment of Alzheimer's disease. Satori has identified a unique class of small molecule gamma-secretase modulators (GSMs) capable of decreasing Aβ42 levels in cellular and rodent model systems. The compound class exhibits potency in the nM range in vitro and is selective for lowering Aβ42 and Aβ38 while sparing Aβ40 and total Aβ levels. In vivo, a compound from the series, SPI-1865, demonstrates similar pharmacology in wild-type CD1 mice, Tg2576 mice and Sprague Dawley rats., Methods: Animals were orally administered either a single dose of SPI-1865 or dosed for multiple days. Aβ levels were measured using a sensitive plate-based ELISA system (MSD) and brain and plasma exposure of drug were assessed by LC/MS/MS., Results: In wild-type mice using either dosing regimen, brain Aβ42 and Aβ38 levels were decreased upon treatment with SPI-1865 and little to no statistically meaningful effect on Aβ40 was observed, reflecting the changes observed in vitro. In rats, brain Aβ levels were examined and similar to the mouse studies, brain Aβ42 and Aβ38 were lowered. Comparable changes were also observed in the Tg2576 mice, where Aβ levels were measured in brain as well as plasma and CSF., Conclusions: Taken together, these data indicate that SPI-1865 is orally bioavailable, brain penetrant, and effective at lowering Aβ42 in a dose responsive manner. With this unique profile, the class of compounds represented by SPI-1865 may be a promising new therapy for Alzheimer's disease.

γ-Secretase modulators (GSM), which reduce amyloidogenic Aβ(42) production while maintaining total Aβ levels, and Notch-sparing γ-secretase inhibitors (GSIs) are promising therapies for the treatment of Alzheimer's Disease (AD). To have a safety margin for therapeutic use, GSMs and GSIs need to allow Notch intracellular domain (NICD) production, while preventing neurotoxic Aβ peptide production. Typically, GSI and GSM effects on these substrates are determined using two different cell lines, one for the measurement of enzyme activity against each substrate. However, predicting selectivity for different substrates across cell systems may reduce the reliability of such ratios such that the in vitro data are not useful for predicting in vivo safety margins. This is especially concerning since the IC(50)'s of some GSIs vary depending upon the level of APP expression in a cell line. To circumvent this problem, we utilized the SUP-T1 cell line which expresses a truncated Notch receptor fragment that does not need sheddase cleavage to be a γ-secretase substrate. When combined with a sensitive method of measuring Aβ production, this assay system allows both substrates to be measured simultaneously, reducing the potential to calculate imprecise selectivity margins. To demonstrate the value of this system, known GSIs and GSMs were examined in the SUP-T1 dual substrate assay. IC(50)'s were determined for both substrates and the in vitro selectivity margin was calculated. These data suggest using a single cell line is a more accurate prediction of the fold difference between NICD inhibition and Aβ(42) lowering for therapeutically promising GSIs and GSMs., (Copyright © 2012 Elsevier B.V. All rights reserved.)

A series of triterpene-based γ-secretase modulators is optimized. An acetate present at the C24 position of the natural product was replaced with either carbamates or ethers to provide compounds with better metabolic stability. With one of those pharmacophores in place at C24, morpholines or carbamates were installed at the C3 position to refine the physicochemical properties of the analogues. This strategy gave compounds with low clearance and good distribution into the central nervous system (CNS) of CD-1 mice. Two of these compounds, 100 and 120, were tested for a pharmacodynamic effect in the strain and lowered brain Aβ42 levels.

The discovery of a new series of γ-secretase modulators is disclosed. Starting from a triterpene glycoside γ-secretase modulator that gave a very low brain-to-plasma ratio, initial SAR and optimization involved replacement of a pendant sugar with a series of morpholines. This modification led to two compounds with significantly improved central nervous system (CNS) exposure.

The Amyloid Hypothesis states that the cascade of events associated with Alzheimer's disease (AD)-formation of amyloid plaques, neurofibrillary tangles, synaptic loss, neurodegeneration, and cognitive decline-are triggered by Aβ peptide dysregulation (Kakuda et al., 2006, Sato et al., 2003, Qi-Takahara et al., 2005). Since γ-secretase is critical for Aβ production, many in the biopharmaceutical community focused on γ-secretase as a target for therapeutic approaches for Alzheimer's disease. However, pharmacological approaches to control γ-secretase activity are challenging because the enzyme has multiple, physiologically critical protein substrates. To lower amyloidogenic Aβ peptides without affecting other γ-secretase substrates, the epsilon (ε) cleavage that is essential for the activity of many substrates must be preserved. Small molecule modulators of γ-secretase activity have been discovered that spare the ε cleavage of APP and other substrates while decreasing the production of Aβ(42). Multiple chemical classes of γ-secretase modulators have been identified which differ in the pattern of Aβ peptides produced. Ideally, modulators will allow the ε cleavage of all substrates while shifting APP cleavage from Aβ(42) and other highly amyloidogenic Aβ peptides to shorter and less neurotoxic forms of the peptides without altering the total Aβ pool. Here, we compare chemically distinct modulators for effects on APP processing and in vivo activity.

Fusion of 4-nitrophenol and acetamide in a 1:1 molar ratio gives the title product, C6H5NO3.C2H5NO, (III), which has the character of a pure covalently bonded compound, having a high sharp melting point. Complex (III) (m.p. 371.9-372.9 K) can be recrystallized from various solvents and forms eutectics with either acetamide or 4-nitrophenol. Similar fusion of mixtures of acetamide and 2-nitrophenol yields no complex similar to (III) and mixtures of acetamide and 3-nitrophenol produce only a weak low-melting complex. The significance of this study lies in its demonstration, via graph set analysis, that some of the patterns found individually in crystalline acetamide or 4-nitrophenol have been preserved in crystals of complex (III), while several higher order graph sets are produced in (III) due to new hydrogen bonds involving the nitro group. In particular, large hydrogen-bonded rings are formed together with helical chains.

Vascular endothelial growth factor (VEGF) is a potent stimulator of angiogenesis. Although many positive regulators of VEGF have been identified, relatively little is known regarding the negative regulation of VEGF expression. We identified a zinc finger transcription factor, ZNF24, that may repress VEGF transcription. An inverse correlation between expression of VEGF and ZNF24 was observed in a series of independent studies. ZNF24 was up-regulated in angiogenic tumor nodules where VEGF expression is significantly decreased compared with preangiogenic nodules. In human breast carcinoma cells cultured under normoxic conditions, ZNF24 levels were significantly up-regulated whereas VEGF levels were low. In contrast, VEGF was significantly increased in hypoxic cells whereas ZNF24 was down-regulated. The same inverse correlation between ZNF24 and VEGF was also observed in 70% of matched cDNA pairs of normal and malignant tissues from human colon and breast biopsies. Overexpression of ZNF24 resulted in a significant down-regulation of VEGF, whereas silencing of ZNF24 with small interfering RNA led to increased VEGF expression. Cotransfection of ZNF24 and a VEGF promoter luciferase reporter construct in MDA-MB-231 cells resulted in a significant decrease in VEGF promoter activity. Taken together, these data suggest that ZNF24 is involved in negative regulation of VEGF and may represent a novel repressor of VEGF transcription.

Vascular endothelial growth factor (VEGF) is critical for vascularization of tissues, including tumors, making it an attractive target for controlling angiogenesis. An important first step towards the goal of effectively blocking tumor angiogenesis is to understand the relationships among tumor-promoting molecules. Whereas little is known about developmental regulation of VEGF, pathological regulation of VEGF during disease states and tumorigenesis is better understood. This review focuses on transcriptional regulation of VEGF expression in cancer. Understanding how VEGF is regulated in tumors cells may provide the basis for future treatments that target both the tumor and its vascular supply.

The angiogenic molecule, vascular endothelial growth factor (VEGF), is a critical regulator of normal and pathologic angiogenesis. ErbB2, an epidermal growth factor receptor family member whose overexpression in mammary tumors is correlated with poor patient prognosis, has been implicated as a positive modulator of VEGF expression. Mammary tumor cells overexpressing ErbB2 (NAFA cells) and a normal mouse mammary cell line (HC11) transfected with ErbB2 expression vectors were used to study the effects of ErbB2 overexpression on VEGF regulation. We found that ErbB2 overexpression led to an increase in endogenous VEGF mRNA as well as ErbB3 protein levels in HC11 cells. Additionally, we determined that ErbB2 overexpression-mediated upregulation of VEGF involves at least two distinct promoter elements, one previously identified as the hypoxia responsive element and the other the core promoter region (-161 to -51bp), which is specifically controlled via two adjacent SP1 binding sites (-80 to -60bp).

The vasculature forms during development via two processes, vasculogenesis and angiogenesis, in which vessels form de novo from angioblast precursors or as sprouts from pre-existing vessels, respectively. A common and critical aspect of both processes is vascular morphogenesis, which includes branching of endothelial cell cords and lumen formation. Although ample evidence support the central role of vascular endothelial growth factor (VEGF) in both vasculogenesis and angiogenesis, the role of VEGF in vascular morphogenesis is unclear and little is known about the regulation of vascular morphogenesis, in general. We have used the in vitro vessel differentiation system of embryonic stem (ES) cell-derived cystic embryonic bodies (CEB) as a model for studying VEGF-mediated vessel formation. Whereas CEB formed from wild-type ES cells make well-formed vessel-like structures, CEB derived from VEGF-null ES cells contain PECAM-1-positive endothelial cells, but these cells do not participate in vascular morphogenesis. Using gene expression microarray analysis to compare gene expression in these two systems, we have been able to identify many genes and novel ESTs that are downstream of VEGF function, and which may be involved in VEGF-mediated vascular morphogenesis including caveolin-1 and HEY-1. These results support using the CEB model, in combination with gene knockout ES cells, for studying vascular morphogenesis.