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OBJECTIVES: The 2- to 6-page print journal article has been the standard for 200 years, yet this format severely limits the amount of detailed information that can be conveyed. The World Wide Web provides a low-cost option for posting extended text and supplementary information. It also can enhance the experience of journal editors, reviewers, readers, and authors through added functionality (eg, online submission and peer review, postpublication critique, and e-mail notification of table of contents.) Our aim was to characterize ways that journals were using the World Wide Web in 2005 and note changes since 2003. METHODS: We analyzed the Web sites of 138 high-impact print journals in 3 ways. First, we compared the print and Web versions of March 2003 and 2005 issues of 28 journals (20 of which were randomly selected from the 138) to determine how often articles were published Web only and how often print articles were augmented by Web-only supplements. Second, we examined what functions were offered by each journal Web site. Third, for journals that offered Web pages for reader commentary about each article, we analyzed the number of comments and characterized these comments. RESULTS: Fifty-six articles (7%) in 5 journals were Web only. Thirteen of the 28 journals had no supplementary online content. By 2005, several journals were including Web-only supplements in >20% of their papers. Supplementary methods, tables, and figures predominated. The use of supplementary material increased by 5% from 2% to 7% in the 20-journal random sample from 2003 to 2005. Web sites had similar functionality with an emphasis on linking each article to related material and e-mailing readers about activity related to each article. There was little evidence of journals using the Web to provide readers an interactive experience with the data or with each other. Seventeen of the 138 journals offered rapid-response pages. Only 18% of eligible articles had any comments after 5 months. CONCLUSIONS: Journal Web sites offer similar functionality. The use of online-only articles and online-only supplements is increasing. [ABSTRACT FROM AUTHOR]

Background: The Great Mekong Subregion has attained a major decline in malaria cases and fatalities over the last years, but residual transmission hotspots remain, supposedly fueled by forest workers and migrant populations. This study aimed to: (i) characterize the fine-scale mobility of forest-goers and understand links between their daily movement patterns and malaria transmission, using parasites detection via real time polymerase chain reaction (RT PCR) and the individual exposure to Anopheles bites by quantification of anti-Anopheles saliva antibodies via enzyme-linked immunosorbent assay; (ii) assess the concordance of questionnaires and Global Positioning System (GPS) data loggers for measuring mobility., Methods: Two 28 day follow-ups during dry and rainy seasons, including a GPS tracking, questionnaires and health examinations, were performed on male forest goers representing the population at highest risk of infection. Their time spent in different land use categories and demographic data were analyzed in order to understand the risk factors driving malaria in the study area., Results: Malaria risk varied with village forest cover and at a resolution of only a few kilometers: participants from villages outside the forest had the highest malaria prevalence compared to participants from forest fringe's villages. The time spent in a specific environment did not modulate the risk of malaria, in particular the time spent in forest was not associated with a higher probability to detect malaria among forest-goers. The levels of antibody response to Anopheles salivary peptide among participants were significantly higher during the rainy season, in accordance with Anopheles mosquito density variation, but was not affected by sociodemographic and mobility factors. The agreement between GPS and self-reported data was only 61.9% in reporting each kind of visited environment., Conclusions: In a context of residual malaria transmission which was mainly depicted by P. vivax asymptomatic infections, the implementation of questionnaires, GPS data-loggers and quantification of anti-saliva Anopheles antibodies on the high-risk group were not powerful enough to detect malaria risk factors associated with different mobility behaviours or time spent in various environments. The joint implementation of GPS trackers and questionnaires allowed to highlight the limitations of both methodologies and the benefits of using them together. New detection and follow-up strategies are still called for., (© 2024. The Author(s).)

Precision nanomedicine can be employed as an alternative to chemo- or radiotherapy to overcome challenges associated with the often narrow therapeutic window of traditional treatment approaches, while safely inducing effective, targeted antitumor responses. Herein, we report the formulation of a therapeutic nanocomposite comprising a hyaluronic acid (HA)-coated gold nanoframework (AuNF) delivery system and encapsulated IT848, a small molecule with potent antilymphoma and -myeloma properties that targets the transcriptional activity of nuclear factor kappa B (NF-κB). The porous AuNFs fabricated via a liposome-templated approach were loaded with IT848 and surface-functionalized with HA to formulate the nanotherapeutics that were able to efficiently deliver the payload with high specificity to myeloma and lymphoma cell lines in vitro. In vivo studies characterized biodistribution, pharmacokinetics, and safety of HA-AuNFs, and we demonstrated superior efficacy of HA-AuNF-formulated IT848 vs free IT848 in lymphoma mouse models. Both in vitro and in vivo results affirm that the AuNF system can be adopted for targeted cancer therapy, improving the drug safety profile, and enhancing its efficacy with minimal dosing. HA-AuNF-formulated IT848 therefore has strong potential for clinical translation.

Multiple myeloma is a plasma cell malignancy that is still largely incurable, despite considerable progress in recent years. NF-κB is a well-established therapeutic target in multiple myeloma, but none of the currently available treatment options offer direct, specific pharmacologic targeting of NF-κB transcriptional activity. Thus, we designed a novel direct NF-κB inhibitor (IT848) as a drug candidate with strong potential for clinical translation and conducted comprehensive in vitro and in vivo mechanistic studies in multiple myeloma cell lines, primary multiple myeloma cells, xenograft models, and immunocompetent mouse models of multiple myeloma. Here, we show that IT848 inhibits NF-κB activity through inhibition of DNA binding of all five NF-κB subunits. IT848 treatment of multiple myeloma cell lines and patient samples inhibited proliferation and induced caspase-dependent and independent apoptosis. In addition to direct NF-κB inhibitory effects, IT848 treatment altered the redox homeostasis of multiple myeloma cells through depletion of the reduced glutathione pool, selectively inducing oxidative stress in multiple myeloma but not in healthy cells. Multiple myeloma xenograft studies confirmed the efficacy of IT848 as single agent and in combination with bortezomib. Furthermore, IT848 significantly improved survival when combined with programmed death protein 1 inhibition, and correlative immune studies revealed that this clinical benefit was associated with suppression of regulatory T-cell infiltration of the bone marrow microenvironment. In conclusion, IT848 is a potent direct NF-κB inhibitor and inducer of oxidative stress specifically in tumor cells, displaying significant activity against multiple myeloma cells in vitro and in vivo, both as monotherapy as well as in combination with bortezomib or immune checkpoint blockade., (©2022 American Association for Cancer Research.)

Improved control of Plasmodium vivax malaria can be achieved with the discovery of new antimalarials with radical cure efficacy, including prevention of relapse caused by hypnozoites residing in the liver of patients. We screened several compound libraries against P. vivax liver stages, including 1565 compounds against mature hypnozoites, resulting in one drug-like and several probe-like hits useful for investigating hypnozoite biology. Primaquine and tafenoquine, administered in combination with chloroquine, are currently the only FDA-approved antimalarials for radical cure, yet their activity against mature P. vivax hypnozoites has not yet been demonstrated in vitro. By developing an extended assay, we show both drugs are individually hypnozonticidal and made more potent when partnered with chloroquine, similar to clinically relevant combinations. Post-hoc analyses of screening data revealed excellent performance of ionophore controls and the high quality of single point assays, demonstrating a platform able to support screening of greater compound numbers. A comparison of P. vivax liver stage activity data with that of the P. cynomolgi blood, P. falciparum blood, and P. berghei liver stages reveals overlap in schizonticidal but not hypnozonticidal activity, indicating that the delivery of new radical curative agents killing P. vivax hypnozoites requires an independent and focused drug development test cascade., (© 2021. The Author(s).)

Child undernutrition in Cambodia is a persistent public health problem requiring low-cost and scalable solutions. Rising cellphone use in low-resource settings represents an opportunity to replace in-person counselling visits with phone calls; however, questions remain on relative effectiveness. Our objective was to evaluate the impact of two options for delivering a World Vision infant and young child feeding (IYCF) counselling programme: (1) traditional Positive Deviance/Hearth (PDH) programme with in-person visits or (2) PDH with Interactive Voice Calling (PDH-IVC) which integrates phone calls to replace 62.5% of face-to-face interaction between caregivers and volunteers, compared to the standard of care (SOC). We conducted a longitudinal cluster-randomised controlled trial in 361 children 6-23 months. We used an adjusted difference-in-difference approach using baseline, midline (3 months) and endline (12 months) surveys to evaluate the impact on child growth among the three groups. At baseline, nearly a third of children were underweight, and over half were food insecure. At midline the PDH group and the PDH-IVC groups had improved weight-for-age z-scores (0.13 DID, p = 0.011; 0.13 DID, p = 0.02, respectively) and weight-for-height z-score (0.16 DID, p = 0.038; 0.24 DID, p = 0.002), relative to SOC. There were no differences in child height-for-age z-scores. At endline, the impact was sustained only in the PDH-IVC group for weight-for-age z-score (0.14 DID, p = 0.049), and the prevalence of underweight declined by 12.8 percentage points (p = 0.036), relative to SOC. Integration of phone-based IYCF counselling is a potentially promising solution to reduce the burden of in-person visits; however, the modest improvements suggest the need to combine it with other strategies to improve child nutrition., (© 2021 World Vision International. Maternal & Child Nutrition published by John Wiley & Sons Ltd.)

This study provides the first investigation of the physical traits, pasting properties and volatile compounds of Cambodian rice cultivars, including traditional, improved, and improved traditional varieties, allowing for their differentiation as high and low quality rice. Analysis of the grain quality traits illustrates interesting features of traditional varieties and correlations between traits that assist with understanding texture. Untargeted profiling of volatile compounds shows that high quality fragrant varieties not only contain 2-acetyl-1-pyrroline but also several other compounds, including aldehydes, alcohols and 2-alkylfurans that contribute to overall aroma. Moreover, low odour threshold volatile compounds, which can be derived from the oxidation of unsaturated fatty acids, were more abundant in the fragrant varieties. The percentage area of both oleic and linoleic acid were found to be significantly different among the rice varieties tested. Such findings suggest that unsaturated fatty acids in milled rice contribute to rice fragrance, and thereby to overall quality., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

IT-901 is a novel and selective NF-κB inhibitor with promising activity in pre-clinical models. Here we show that treatment of chronic lymphocytic leukemia cells (CLL) with IT-901 effectively interrupts NF-κB transcriptional activity. CLL cells exposed to the drug display elevated mitochondrial reactive oxygen species, which damage mitochondria, limit oxidative phosphorylation and ATP production, and activate intrinsic apoptosis. Inhibition of NF-κB signaling in stromal and myeloid cells, both tumor-supportive elements, fails to induce apoptosis, but impairs NF-κB-driven expression of molecules involved in cell-cell contacts and immune responses, essential elements in creating a pro-leukemic niche. The consequence is that accessory cells do not protect CLL cells from IT-901-induced apoptosis. In this context, IT-901 shows synergistic activity with ibrutinib, arguing in favor of combination strategies. IT-901 is also effective in primary cells from patients with Richter syndrome (RS). Its anti-tumor properties are confirmed in xenograft models of CLL and in RS patient-derived xenografts, with documented NF-κB inhibition and significant reduction of tumor burden. Together, these results provide pre-clinical proof of principle for IT-901 as a potential new drug in CLL and RS., (Copyright© Ferrata Storti Foundation.)

NF-κB plays a variety of roles in oncogenesis and immunity that may be beneficial for therapeutic targeting, but strategies to selectively inhibit NF-κB to exert antitumor activity have been elusive. Here, we describe IT-901, a bioactive naphthalenethiobarbiturate derivative that potently inhibits the NF-κB subunit c-Rel. IT-901 suppressed graft-versus-host disease while preserving graft-versus-lymphoma activity during allogeneic transplantation. Further preclinical assessment of IT-901 for the treatment of human B-cell lymphoma revealed antitumor properties in vitro and in vivo without restriction to NF-κB-dependent lymphoma. This nondiscriminatory, antilymphoma effect was attributed to modulation of the redox homeostasis in lymphoma cells resulting in oxidative stress. Moreover, NF-κB inhibition by IT-901 resulted in reduced stimulation of the oxidative stress response gene heme oxygenase-1, and we demonstrated that NF-κB inhibition exacerbated oxidative stress induction to inhibit growth of lymphoma cells. Notably, IT-901 did not elicit increased levels of reactive oxygen species in normal leukocytes, illustrating its cancer selective properties. Taken together, our results provide mechanistic insight and preclinical proof of concept for IT-901 as a novel therapeutic agent to treat human lymphoid tumors and ameliorate graft-versus-host disease., (©2016 American Association for Cancer Research.)

Preventing unfavorable GVHD without inducing broad suppression of the immune system presents a major challenge of allogeneic hematopoietic stem cell transplantation (allo-HSCT). We developed a novel strategy to ameliorate GVHD while preserving graft-versus-tumor (GVT) activity by small molecule-based inhibition of the NF-κB family member c-Rel. Underlying mechanisms included reduced alloactivation, defective gut homing, and impaired negative feedback on interleukin (IL)-2 production, resulting in optimal IL-2 levels, which, in the absence of competition by effector T cells, translated into expansion of regulatory T cells. c-Rel activity was dispensable for antigen-specific T-cell receptor (TCR) activation, allowing c-Rel-deficient T cells to display normal GVT activity. In addition, inhibition of c-Rel activity reduced alloactivation without compromising antigen-specific cytotoxicity of human T cells. Finally, we were able to demonstrate the feasibility and efficacy of systemic c-Rel inhibitor administration. Our findings validate c-Rel as a promising target for immunomodulatory therapy and demonstrate the feasibility and efficacy of pharmaceutical inhibition of c-Rel activity.

Continued reliance on the androgen receptor (AR) is now understood as a core mechanism in castration-resistant prostate cancer (CRPC), the most advanced form of this disease. While established and novel AR pathway-targeting agents display clinical efficacy in metastatic CRPC, dose-limiting side effects remain problematic for all current agents. In this study, we report the discovery and development of ARN-509, a competitive AR inhibitor that is fully antagonistic to AR overexpression, a common and important feature of CRPC. ARN-509 was optimized for inhibition of AR transcriptional activity and prostate cancer cell proliferation, pharmacokinetics, and in vivo efficacy. In contrast to bicalutamide, ARN-509 lacked significant agonist activity in preclinical models of CRPC. Moreover, ARN-509 lacked inducing activity for AR nuclear localization or DNA binding. In a clinically valid murine xenograft model of human CRPC, ARN-509 showed greater efficacy than MDV3100. Maximal therapeutic response in this model was achieved at 30 mg/kg/d of ARN-509, whereas the same response required 100 mg/kg/d of MDV3100 and higher steady-state plasma concentrations. Thus, ARN-509 exhibits characteristics predicting a higher therapeutic index with a greater potential to reach maximally efficacious doses in man than current AR antagonists. Our findings offer preclinical proof of principle for ARN-509 as a promising therapeutic in both castration-sensitive and castration-resistant forms of prostate cancer.

SAR studies on the quinolone carboxylic acid class of HIV-1 integrase inhibitors focused on improving the metabolic stability and led to the discovery of 27 and 38., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

A structure-activity relationship study was carried out on a series of thiohydantoins and their analogues 14 which led to the discovery of 92 (MDV3100) as the clinical candidate for the treatment of hormone refractory prostate cancer.

The Rel/NF-κB transcription factors have emerged as novel therapeutic targets for a variety of human diseases and pathological conditions, including inflammation, autoimmune diseases, cancer, ischemic injury, osteoporosis, transplant rejection and neurodegeneration. Several US FDA-approved drugs may, in part, attribute their therapeutic effects to the inhibition of the Rel/NF-κB pathway. Strategies for blocking the Rel/NF-κB signaling pathway have inspired the pharmaceutical industry to develop inhibitors for I-κB kinase, however, this article focuses instead on identifying natural compounds that directly target and inhibit DNA binding and transcription activity of Rel/NF-κB. These include compounds containing a quinone core, an α,β unsaturated carbonyl and a benzene diamine. By investigating the mechanisms of action of existing natural inhibitors, novel strategies and synthetic approaches can be devised that will facilitate the development of novel and selective Rel/NF-κB inhibitors with better safety profiles.

Metastatic prostate cancer is treated with drugs that antagonize androgen action, but most patients progress to a more aggressive form of the disease called castration-resistant prostate cancer, driven by elevated expression of the androgen receptor. Here we characterize the diarylthiohydantoins RD162 and MDV3100, two compounds optimized from a screen for nonsteroidal antiandrogens that retain activity in the setting of increased androgen receptor expression. Both compounds bind to the androgen receptor with greater relative affinity than the clinically used antiandrogen bicalutamide, reduce the efficiency of its nuclear translocation, and impair both DNA binding to androgen response elements and recruitment of coactivators. RD162 and MDV3100 are orally available and induce tumor regression in mouse models of castration-resistant human prostate cancer. Of the first 30 patients treated with MDV3100 in a Phase I/II clinical trial, 13 of 30 (43%) showed sustained declines (by >50%) in serum concentrations of prostate-specific antigen, a biomarker of prostate cancer. These compounds thus appear to be promising candidates for treatment of advanced prostate cancer.

The cystic fibrosis (CF) transmembrane conductance regulator (CFTR) plays a crucial role in mediating duodenal bicarbonate (HCO(3)(-)) secretion (DBS). Although impaired DBS is observed in CF mutant mice and in CF patients, which would predict increased ulcer susceptibility, duodenal injury is rarely observed in CF patients and is reduced in CF mutant mice. To explain this apparent paradox, we hypothesized that CFTR dysfunction increases cellular [HCO(3)(-)] and buffering power. To further test this hypothesis, we examined the effect of a novel, potent, and highly selective CFTR inhibitor, CFTR(inh)-172, on DBS and duodenal ulceration in rats. DBS was measured in situ using a standard loop perfusion model with a pH stat under isoflurane anesthesia. Duodenal ulcers were induced in rats by cysteamine with or without CFTR(inh)-172 pretreatment 1 h before cysteamine. Superfusion of CFTR(inh)-172 (0.1-10 microM) over the duodenal mucosa had no effect on basal DBS but at 10 microM inhibited acid-induced DBS, suggesting that its effect was limited to CFTR activation. Acid-induced DBS was abolished at 1 and 3 h and was reduced 24 h after treatment with CFTR(inh)-172, although basal DBS was increased at 24 h. CFTR(inh)-172 treatment had no effect on gastric acid or HCO(3)(-) secretion. Duodenal ulcers were observed 24 h after cysteamine treatment but were reduced in CFTR(inh)-172-pretreated rats. CFTR(inh)-172 acutely produces CFTR dysfunction in rodents for up to 24 h. CFTR inhibition reduces acid-induced DBS but also prevents duodenal ulcer formation, supporting our hypothesis that intracellular HCO(3)(-) may be an important protective mechanism for duodenal epithelial cells.

Study Objectives: We measure the interobserver reliability of the triage process, examine the effect of vital signs on the triage process, and provide a context for the prior observation of poor interobserver agreement between in-person and telephonic interviews., Methods: We performed a prospective observational study using a randomized crossover design at a university teaching hospital emergency department. Patients were eligible if they spoke English, were not presenting for a reevaluation, and were unlikely to be harmed by the delay created by a second triage interview. Every eligible patient underwent 2 independent, sequential, in-person ED intake interviews conducted by experienced ED triage nurses. After taking a history, each nurse chose 1 of 5 hypothetic triage designations (ED by 911, ED within 2 hours, see a physician within 8 hours, see a physician within 24 hours, or home care-see a physician in >24 hours) and, after being told the patient's vital signs, again selected a designation., Results: Three hundred sixty-three patients presented during the study period: 113 were ineligible, 34 were missed by the investigators, and 15 refused to participate. Nineteen nurses participated in the triage of the 201 study patients. Agreement between 2 in-person designations made without knowledge of vital signs was poor (percent agreement 53%; kappa=0.30; tau(b)=0.50). Knowledge of vital signs did not improve agreement (percent agreement 49%; kappa=0.25; tau(b)=0.45)., Conclusion: There was poor interobserver agreement between certified triage nurses using a 5-item triage scale designed for telephonic triage. These findings suggest that only a small portion of the poor interobserver agreement observed in a prior study of telephonic versus in-person triage can be attributed to the use of the telephone.

Federal guidelines for the treatment of acute low back pain were locally modified and made more specific. These guidelines were then programmed into a rule-based computer charting system which provides real-time advice regarding documentation, testing, treatment, and disposition of emergency department patients with this condition. In a time-series off-on experiment the system was shown to significantly improve documentation of the medical record and discharge instructions. There was little effect on the appropriateness of testing and treatment and the cost of care. These findings contrast with our previous experiment using a similar program for the care of health care workers exposed to body fluids. In that study both the appropriateness of care and the cost-effectiveness of care were substantially improved.