Advancing Biological Understanding and Therapeutics Discovery with Small-Molecule Probes.

Small-molecule probes can illuminate biological processes and aid in the assessment of emerging therapeutic targets by perturbing biological systems in a manner distinct from other experimental approaches. Despite the tremendous promise of chemical tools for investigating biology and disease, small-molecule probes were unavailable for most targets and pathways as recently as a decade ago. In 2005, the NIH launched the decade-long Molecular Libraries Program with the intent of innovating in and broadening access to small-molecule science. This Perspective describes how novel small-molecule probes identified through the program are enabling the exploration of biological pathways and therapeutic hypotheses not otherwise testable. These experiences illustrate how small-molecule probes can help bridge the chasm between biological research and the development of medicines but also highlight the need to innovate the science of therapeutic discovery.

Prediction of adolescent weight status by machine learning: a population-based study.

BACKGROUND: Adolescent weight problems have become a growing public health concern, making early prediction of non-normal weight status crucial for effective prevention. However, few temporal prediction tools for adolescent four weight status have been developed. This study aimed to predict the short- and long-term weight status of Hong Kong adolescents and assess the importance of predictors. METHODS: A population-based retrospective cohort study of adolescents was conducted using data from a territory-wide voluntary annual health assessment service provided by the Department of Health in Hong Kong. Using diet habits, physical activity, psychological well-being, and demographics, we generated six prediction models for successive weight status (normal, overweight, obese and underweight) using multiclass Decision Tree, Random Forest, k-Nearest Neighbor, eXtreme gradient boosting, support vector machine, logistic regression. Model performance was evaluated by multiple standard classifier metrics and the overall accuracy. Predictors' importance was assessed using Shapley values. RESULTS: 442,898 Primary 4 (P4, Grade 4 in the US) and 344,186 in Primary 6 (P6, Grade 6 in the US) students, with followed up until their Secondary 6 (Grade 12 in the US) during the academic years 1995/96 to 2014/15 were included. The XG Boosts model consistently outperformed all other model in predicting the long-term weight status at S6 from P4 or P6. It achieved an overall accuracy of 0.72 or 0.74, a micro-averaging AUC of 0.92 or 0.93, and a macro-averaging AUC of 0.83 or 0.86, respectively. XG Boost also demonstrated accurate predictions for each predicted weight status, surpassing the AUC values obtained by other models. Weight, height, sex, age, frequency and hours of aerobic exercise were consistently the most important predictors for both cohorts. CONCLUSIONS: The machine learning approaches accurately predict adolescent weight status in both short- and long-term. The developed multiclass model that utilizing easy-assessed variables enables accurate long-term prediction on weight status, which can be used by adolescents and parents for self-prediction when applied in health care system. The interpretable models may help to provide the early and individualized interventions suggestions for adolescents with weight problems particularly.

Effectiveness of distance learning for preclinical periodontal education.

INTRODUCTION: This study aimed to investigate the effectiveness of distance learning (DL) for the second-year periodontics course compared to classroom learning (CL). MATERIALS AND METHODS: DL for Class A (n1 = 126) and CL for Class B (n2 = 133) were implemented. The same instructors recorded or delivered the same lectures in the two learning modules during the second-year periodontics course. Classes A and B took the same final examinations (a total % score of 200). General linear model (GLM) and ordinal logistic regression (OLR) analyses were conducted after considering individual first-year final % scores as a covariate to test if the second-year final % scores and the distributions of letter grades were significantly different between Class A and B. RESULTS: The mean second-year final % score of the DL group (166.4) was significantly higher than that of the CL group (160.8) (independent t-test, p = .019). However, in GLM, the first-year final % scores significantly affected the second-year scores (p = .016); the second-year final % scores between the two groups were not significantly different (p = .268) after considering the individual first-year scores. In OLR, there was no difference in the likelihood of getting lower grades in the second-year course between the two groups (odds ratio = 1.6; 95% confidence interval = [0.95, 2.72], p = .078) after considering the first-year final % scores. CONCLUSION: Within the limitations of the study, the DL for preclinical periodontics resulted in comparable student learning outcomes when compared to the traditional CL.

An Optimized Dihydrodibenzothiazepine Lead Compound (SBI-0797750) as a Potent and Selective Inhibitor of Plasmodium falciparum and P. vivax Glucose 6-Phosphate Dehydrogenase 6-Phosphogluconolactonase.

In Plasmodium, the first two and rate-limiting enzymes of the pentose phosphate pathway, glucose 6-phosphate dehydrogenase (G6PD) and the 6-phosphogluconolactonase, are bifunctionally fused to a unique enzyme named GluPho, differing structurally and mechanistically from the respective human orthologs. Consistent with the enzyme's essentiality for malaria parasite proliferation and propagation, human G6PD deficiency has immense impact on protection against severe malaria, making PfGluPho an attractive antimalarial drug target. Herein we report on the optimized lead compound N-(((2R,4S)-1-cyclobutyl-4-hydroxypyrrolidin-2-yl)methyl)-6-fluoro-4-methyl-11-oxo-10,11-dihydrodibenzo[b,f][1,4]thiazepine-8-carboxamide (SBI-0797750), a potent and fully selective PfGluPho inhibitor with robust nanomolar activity against recombinant PfGluPho, PvG6PD, and P. falciparum blood-stage parasites. Mode-of-action studies have confirmed that SBI-0797750 disturbs the cytosolic glutathione-dependent redox potential, as well as the cytosolic and mitochondrial H2O2 homeostasis of P. falciparum blood stages, at low nanomolar concentrations. Moreover, SBI-0797750 does not harm red blood cell (RBC) integrity and phagocytosis and thus does not promote anemia. SBI-0797750 is therefore a very promising antimalarial lead compound.

Skipping Breakfast and Eating Breakfast Away From Home Were Prospectively Associated With Emotional and Behavioral Problems in 115,217 Chinese Adolescents.

BACKGROUND: Breakfast is deemed the most important meal of the day. We examined the prospective associations of breakfast habits with emotional/behavioral problems in adolescents and potential effect modification. METHODS: 115,217 Primary 6 students (United States Grade 6; mean age, 11.9; standard deviation [SD], 0.59 years) who attended the Student Health Service of Department of Health in Hong Kong in 2004/05, 2006/07, 2008/09 were followed till Secondary 6 (United States Grade 12). Emotional/behavioral problems were biennially examined using Youth Self-Report since Secondary 2 (United States Grade 8). Lifestyles were biennially examined using standardized questionnaires since Primary 6. Prospective associations of breakfast habit with emotional/behavioral problems and potential effect modification were examined using generalized estimating equations. RESULTS: Compared with eating breakfast at home, eating breakfast away from home was significantly associated with total emotional/behavioral problems and seven syndromes, including withdrawal, somatic complaints, anxiety/depression, thought problems, attention problems, delinquent behaviors, and aggressive behaviors (adjusted odds ratios [AORs] 1.22-2.04), while skipping breakfast showed stronger associations with the above problems and social problems (AORs 1.34-2.29). Stronger associations were observed in younger students for total and attention problems (P < 0.03) and in those with lower weight status for delinquent behaviors (P = 0.005). CONCLUSION: Eating breakfast away from home and especially skipping breakfast were prospectively associated with adolescent emotional/behavioral problems. The associations weakened with increasing age for total emotional/behavioral and attention problems, and weakened with higher weight status for delinquent behaviors, highlighting the vulnerability of younger and underweight children. If the associations are causal, increasing home breakfast may reduce adolescent emotional/behavioral problems and benefit psychosocial health.

Late-onset or chronic overweight/obesity predicts low self-esteem in early adolescence: a longitudinal cohort study.

BACKGROUND: How weight status changes with time may affect self-esteem was seldom studied. We identified the distinct trajectories of overweight/obesity over age and assessed their associations with different domains of self-esteem in Hong Kong Chinese children. METHODS: Territory-wide longitudinal data of 48,558 children (girls: 50.0%; 6.3 ± 0.51 years) studying Primary 1 in the academic cohorts of 1995/96 and 1996/97 followed till Primary 6 were obtained from the Student Health Service of Hong Kong. Weight was annually measured and categorized as underweight/normal and overweight/obese and self-esteem was measured in Primary 6. Distinct trajectories of weight status were first identified using growth mixture modeling and their associations with low self-esteem were assessed by logistic regression. RESULTS: Four distinct overweight/obesity trajectories were identified: never (76.8%), late-onset (8.1%), early-onset (4.2%) and chronic (10.9%) overweight/obesity. Compared with children who were never overweight/obese, more of those in the late-onset or chronic overweight/obesity group showed low self-esteem and specific domains including general, social and academic/school-related (adjusted odds ratios: 1.20 - 1.43, all P < 0.001) except parent/home-related self-esteem (P = 0.36), whereas children being in the early-onset overweight/obesity group showed no significant difference (P ≥ 0.53) except a lower risk of low social self-esteem (adjusted odds ratio = 0.82, P = 0.03). CONCLUSIONS: Late-onset or chronic overweight/obesity predicted low general, social and academic/school-related self-esteem. Children who successfully reduced weight may have equal levels of self-esteem or even better social self-esteem than those being always underweight/normal weight. Overweight/obese children had a vulnerability to self-esteem in non-domestic environments.

Knowledge and Attitudes of Potential Community Health Worker Employers: Findings from the State of Arkansas, USA.

Community health workers (CHWs) are critical to health equity efforts, but sustaining CHW programs is challenging. Understanding stakeholders' knowledge and attitudes about CHWs can inform strategies to advance this important workforce. The authors implemented an online survey of potential CHW employers to learn their perceptions of CHWs' roles, outcomes, and abilities to affect important health outcomes, and of key issues that affect CHW employment. The survey was disseminated statewide to a diverse group of stakeholders working in healthcare in Arkansas. A total of 151 surveys were collected and included in the analysis. The organizations represented by respondents primarily included state and local agencies and clinics, followed by healthcare systems. The main professional roles of survey respondents were administrators and clinicians, followed by healthcare staff. Over 90% of respondents agreed that CHWs have the ability to conduct community outreach, serve as a liaison, navigate health systems, provide coaching support, and participate in care coordination. Over 90% of healthcare administrators, clinicians, and policymakers agreed that standardized training and a clear definition of role and scope of practice are important to CHW employment. However, almost two-thirds of respondents' organizations were not employing CHWs, adding to previous research which has primarily focused on CHW employers' attitudes. Understanding and addressing attitudes of those who lack experience with CHWs can help to identify actions needed to promote and increase adoption of CHWs. The authors share how they are using these data to engage stakeholders in decision-making and adoption of CHWs in their state.

Development of a Robust High-Throughput Screening Platform for Inhibitors of the Striatal-Enriched Tyrosine Phosphatase (STEP).

Many human diseases are the result of abnormal expression or activation of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs). Not surprisingly, more than 30 tyrosine kinase inhibitors (TKIs) are currently in clinical use and provide unique treatment options for many patients. PTPs on the other hand have long been regarded as "undruggable" and only recently have gained increased attention in drug discovery. Striatal-enriched tyrosine phosphatase (STEP) is a neuron-specific PTP that is overactive in Alzheimer's disease (AD) and other neurodegenerative and neuropsychiatric disorders, including Parkinson's disease, schizophrenia, and fragile X syndrome. An emergent model suggests that the increase in STEP activity interferes with synaptic function and contributes to the characteristic cognitive and behavioral deficits present in these diseases. Prior efforts to generate STEP inhibitors with properties that warrant clinical development have largely failed. To identify novel STEP inhibitor scaffolds, we developed a biophysical, label-free high-throughput screening (HTS) platform based on the protein thermal shift (PTS) technology. In contrast to conventional HTS using STEP enzymatic assays, we found the PTS platform highly robust and capable of identifying true hits with confirmed STEP inhibitory activity and selectivity. This new platform promises to greatly advance STEP drug discovery and should be applicable to other PTP targets.

Both HIV-Infected and Uninfected Cells Express TRAILshort, Which Confers TRAIL Resistance upon Bystander Cells within the Microenvironment.

TNF-related apoptosis-inducing ligand (TRAIL) was initially described to induce apoptosis of tumor cells and/or virally infected cells, although sparing normal cells, and has been implicated in the pathogenesis of HIV disease. We previously identified TRAILshort, a TRAIL splice variant, in HIV-infected patients and characterized it as being a dominant negative ligand to subvert TRAIL-mediated killing. Herein, using single-cell genomics we demonstrate that TRAILshort is produced by HIV-infected cells, as well as by uninfected bystander cells, and that the dominant stimulus which induces TRAILshort production are type I IFNs and TLR7, TLR8, and TLR9 agonists. TRAILshort has a short t1/2 by virtue of containing a PEST domain, which targets the protein toward the ubiquitin proteasome pathway for degradation. Further we show that TRAILshort binds preferentially to TRAIL receptors 1 and 2 with significantly reduced interaction with the decoy TRAIL receptors 3 and 4. Recombinant TRAILshort is sufficient to protect cells against TRAIL-induced killing, whereas immunodepletion of TRAILshort with a specific Ab restores TRAIL sensitivity. Importantly we show that TRAILshort is shed in microvesicles into the cellular microenvironment and therefore confers TRAIL resistance not only on the cell which produces it, but also upon neighboring bystander cells. These results establish a novel paradigm for understanding and overcoming TRAIL resistance, in particular how HIV-infected cells escape immune elimination by the TRAIL:TRAILshort receptor axis.

Capzimin is a potent and specific inhibitor of proteasome isopeptidase Rpn11.

The proteasome is a vital cellular machine that maintains protein homeostasis, which is of particular importance in multiple myeloma and possibly other cancers. Targeting of proteasome 20S peptidase activity with bortezomib and carfilzomib has been widely used to treat myeloma. However, not all patients respond to these compounds, and those who do eventually suffer relapse. Therefore, there is an urgent and unmet need to develop new drugs that target proteostasis through different mechanisms. We identified quinoline-8-thiol (8TQ) as a first-in-class inhibitor of the proteasome 19S subunit Rpn11. A derivative of 8TQ, capzimin, shows >5-fold selectivity for Rpn11 over the related JAMM proteases and >2 logs selectivity over several other metalloenzymes. Capzimin stabilized proteasome substrates, induced an unfolded protein response, and blocked proliferation of cancer cells, including those resistant to bortezomib. Proteomic analysis revealed that capzimin stabilized a subset of polyubiquitinated substrates. Identification of capzimin offers an alternative path to develop proteasome inhibitors for cancer therapy.

Diabetes reversal by inhibition of the low-molecular-weight tyrosine phosphatase.

Obesity-associated insulin resistance plays a central role in type 2 diabetes. As such, tyrosine phosphatases that dephosphorylate the insulin receptor (IR) are potential therapeutic targets. The low-molecular-weight protein tyrosine phosphatase (LMPTP) is a proposed IR phosphatase, yet its role in insulin signaling in vivo has not been defined. Here we show that global and liver-specific LMPTP deletion protects mice from high-fat diet-induced diabetes without affecting body weight. To examine the role of the catalytic activity of LMPTP, we developed a small-molecule inhibitor with a novel uncompetitive mechanism, a unique binding site at the opening of the catalytic pocket, and an exquisite selectivity over other phosphatases. This inhibitor is orally bioavailable, and it increases liver IR phosphorylation in vivo and reverses high-fat diet-induced diabetes. Our findings suggest that LMPTP is a key promoter of insulin resistance and that LMPTP inhibitors would be beneficial for treating type 2 diabetes.

Increasing socioeconomic disparities in sedentary behaviors in Chinese children.

BACKGROUND: Sedentary behaviors are prevalent in Chinese children, however, the studies on their trends and socioeconomic disparities are scarce. We examined the time trends of daily television (TV) viewing and video game playing and the associated socioeconomic factors in Chinese children in Hong Kong, the most developed and westernized city in China. METHODS: In a panel data study involving 538,300 primary four and 510,294 primary six students from 1999/2000 to 2008/09, data on socioeconomic status, sedentary behaviors (TV viewing and video game playing) and other lifestyle habits were collected using a self-administered questionnaire. Trends in sedentary behaviors over time were assessed. Their socioeconomic disparities were examined by interactions in generalized estimating equations with the adjustment for weight status and extracurricular physical activities. RESULTS: The age and sex-standardized prevalence of ≥2 h daily TV viewing decreased from 51.4% (95% confidence interval [CI] 51.1-51.8%) in 1999/2000 to 43.8% (95% CI 43.4-44.2%) in 2008/09 (P for trend < 0.001), whereas that of ≥1 h daily video game playing increased from 8.2% (95% CI 7.9-8.4%) to 22.4% (95% CI 22.0-22.7%). Both sedentary behaviors were more prevalent in boys than girls, but the disparities decreased over time (Ratio of odds ratio [ROR] = 0.996 and 0.924 for TV viewing and video game playing, respectively). In contrast, both sedentary behaviors were increasingly more prevalent in children whose parents had lower education levels or non-managerial/professional occupations (ROR 1.006-1.082). CONCLUSIONS: Children in lower socioeconomic families in Hong Kong were increasingly at risk of having sedentary behaviors over years and thus deserve more attention. Effective strategies targeting children and/or their parents of lower socioeconomic status are needed to reduce sedentary behaviors.

TGR5 contributes to hepatic cystogenesis in rodents with polycystic liver diseases through cyclic adenosine monophosphate/Gαs signaling.

Hepatic cystogenesis in polycystic liver disease is associated with increased levels of cyclic adenosine monophosphate (cAMP) in cholangiocytes lining liver cysts. Takeda G protein receptor 5 (TGR5), a G protein-coupled bile acid receptor, is linked to cAMP and expressed in cholangiocytes. Therefore, we hypothesized that TGR5 might contribute to disease progression. We examined expression of TGR5 and Gα proteins in cultured cholangiocytes and in livers of animal models and humans with polycystic liver disease. In vitro, we assessed cholangiocyte proliferation, cAMP levels, and cyst growth in response to (1) TGR5 agonists (taurolithocholic acid, oleanolic acid [OA], and two synthetic compounds), (2) a novel TGR5 antagonist (m-tolyl 5-chloro-2-[ethylsulfonyl] pyrimidine-4-carboxylate [SBI-115]), and (3) a combination of SBI-115 and pasireotide, a somatostatin receptor analogue. In vivo, we examined hepatic cystogenesis in OA-treated polycystic kidney rats and after genetic elimination of TGR5 in double mutant TGR5-/- ;Pkhd1del2/del2 mice. Compared to control, expression of TGR5 and Gαs (but not Gαi and Gαq ) proteins was increased 2-fold to 3-fold in cystic cholangiocytes in vitro and in vivo. In vitro, TGR5 stimulation enhanced cAMP production, cell proliferation, and cyst growth by ∼40%; these effects were abolished after TGR5 reduction by short hairpin RNA. OA increased cystogenesis in polycystic kidney rats by 35%; in contrast, hepatic cystic areas were decreased by 45% in TGR5-deficient TGR5-/- ;Pkhd1del2/del2 mice. TGR5 expression and its colocalization with Gαs were increased ∼2-fold upon OA treatment. Levels of cAMP, cell proliferation, and cyst growth in vitro were decreased by ∼30% in cystic cholangiocytes after treatment with SBI-115 alone and by ∼50% when SBI-115 was combined with pasireotide. CONCLUSION: TGR5 contributes to hepatic cystogenesis by increasing cAMP and enhancing cholangiocyte proliferation; our data suggest that a TGR5 antagonist alone or concurrently with somatostatin receptor agonists represents a potential therapeutic approach in polycystic liver disease. (Hepatology 2017;66:1197-1218).

Evaluation of potential antiplatelet effects of CSL112 (Apolipoprotein A-I [Human]) in patients with atherosclerosis: results from a phase 2a study.

CSL112 (Apolipoprotein A-I [Human]), an infusible, plasma-derived apolipoprotein A-I, is being developed to reduce cardiovascular events following acute myocardial infarction (AMI). A predecessor compound (CSL111) demonstrated a potential antiplatelet effect. A phase 2a multicentre, randomised, single-ascending dose study in patients with stable atherosclerotic disease receiving dual antiplatelet therapy (DAPT) assessed the potential additive effects of CSL112 administration on platelet function and increase bleeding risk in the subacute period after AMI. Patients (n = 44) on aspirin (75-325 mg/day) and either clopidogrel (75 mg/day, n = 37) or prasugrel (10 mg/day, n = 7) for > 30 days alongside standard-of-care therapy were randomised to a single dose of placebo or CSL112: 1.7, 3.4, or 6.8 g. Light transmission aggregometry was used to assess platelet aggregation in response to 2 mM arachidonic acid, 5 and 20 µM adenosine diphosphate, and 4 µg/mL collagen, pre-dose (baseline) and up to 48 h post-dosing. Compared to placebo, CSL112 had no clinically meaningful time- or dose-dependent effects on maximum platelet aggregation in response to any agonist, by either dose or renal function subgroup (p > 0.05). Coagulation parameters showed little variation over time or between treatment groups (p > 0.05). CSL112, when co-administered with standard DAPT, did not significantly influence platelet aggregation in response to agonists and is, therefore, not expected to significantly increase bleeding risk when administered with antiplatelet therapies.

Childhood Obesity and Physical Activity-Friendly School Environments.

OBJECTIVE: Childhood obesity may be related to school environment, but previous studies often focused on food environment only. This study aimed to examine the relationship between school physical activity environment and childhood obesity. STUDY DESIGN: This is a cross-sectional study with multilevel data collected on school physical activity environment using teacher questionnaires, students' growth, and obesity status from electronic health records, and neighborhood socioeconomic status from census data. RESULTS: This study included 208 280 students (6-18 years of age) from 438 schools (45% of Hong Kong). Prevalence of obesity was 5.0%. After controlling for socioeconomic status and intraschool correlation, robust Poisson regression revealed a reduced obesity risk associated with higher teachers' perceived physical activity benefits (risk ratio 0.96, 95% CI 0.94-0.99, P = .02), physical activity teaching experience (0.93, 0.91-0.96, P < .001), school campus size (0.93, 0.87-0.99, P = .02), physical activity ethos (0.91, 0.88-0.94, P < .001), number of physical activity programs (0.93, 0.90-0.96, P < .001), and physical activity facilities (0.87, 0.84-0.90, P < .001). Students in schools with at least 3 physical activity-friendly environmental factors (11.7%) had a much lower risk of obesity (0.68, 0.62-0.75, P < .001) than those without (23.7%). CONCLUSIONS: A physical activity-friendly school environment is associated with lower risk of obesity. School physical activity environment should be considered in future epidemiologic and intervention studies.

Dual-specificity phosphatase 3 deficiency or inhibition limits platelet activation and arterial thrombosis.

BACKGROUND: A limitation of current antiplatelet therapies is their inability to separate thrombotic events from bleeding occurrences. A better understanding of the molecular mechanisms leading to platelet activation is important for the development of improved therapies. Recently, protein tyrosine phosphatases have emerged as critical regulators of platelet function. METHODS AND RESULTS: This is the first report implicating the dual-specificity phosphatase 3 (DUSP3) in platelet signaling and thrombosis. This phosphatase is highly expressed in human and mouse platelets. Platelets from DUSP3-deficient mice displayed a selective impairment of aggregation and granule secretion mediated by the collagen receptor glycoprotein VI and the C-type lectin-like receptor 2. DUSP3-deficient mice were more resistant to collagen- and epinephrine-induced thromboembolism compared with wild-type mice and showed severely impaired thrombus formation on ferric chloride-induced carotid artery injury. Intriguingly, bleeding times were not altered in DUSP3-deficient mice. At the molecular level, DUSP3 deficiency impaired Syk tyrosine phosphorylation, subsequently reducing phosphorylation of phospholipase Cγ2 and calcium fluxes. To investigate DUSP3 function in human platelets, a novel small-molecule inhibitor of DUSP3 was developed. This compound specifically inhibited collagen- and C-type lectin-like receptor 2-induced human platelet aggregation, thereby phenocopying the effect of DUSP3 deficiency in murine cells. CONCLUSIONS: DUSP3 plays a selective and essential role in collagen- and C-type lectin-like receptor 2-mediated platelet activation and thrombus formation in vivo. Inhibition of DUSP3 may prove therapeutic for arterial thrombosis. This is the first time a protein tyrosine phosphatase, implicated in platelet signaling, has been targeted with a small-molecule drug.

New p32/gC1qR Ligands for Targeted Tumor Drug Delivery.

Cell surface p32, the target of LyP-1 homing peptide, is upregulated in tumors and atherosclerotic plaques and has been widely used as a receptor for systemic delivery of payloads. Here, we identified an improved LyP-1-mimicking peptide (TT1, CKRGARSTC). We used this peptide in a fluorescence polarization-based high-throughput screening of a 50,000-compound chemical library and identified a panel of compounds that bind p32 with low micromolar affinity. Among the hits identified in the screen, two compounds were shown to specifically bind to p32 in multiple assays. One of these compounds was chosen for an in vivo study. Nanoparticles surface-functionalized with this compound specifically adhered to surfaces coated with recombinant p32 and, when injected intravenously, homed to p32-expressing breast tumors in mice. This compound provides a lead for the development of p32-targeted affinity ligands that circumvent some of the limitations of peptide-based probes in guided drug delivery.

A retrospective study of outcomes of device-associated osteomyelitis treated with daptomycin.

BACKGROUND: Daptomycin appears well tolerated and effective for osteomyelitis treatment. However, limited data exist regarding daptomycin use for treatment of device-associated osteomyelitis (DAO). METHODS: We used a retrospective, observational database (Cubicin® Outcomes Registry and Experience [CORE® 2007-2009]) that assessed patients treated with daptomycin to evaluate the characteristics of patients with DAO, outcomes after daptomycin treatment, and safety of daptomycin in this setting. Information from 54 institutions for patients with prosthetic joint infection (PJI) and other hardware-associated osteomyelitis (OHAO) who received daptomycin from January 2007 to December 2008 with follow-up data in 2009 was collected using a standardized data collection form. RESULTS: Eighty-two patients receiving daptomycin were identified in CORE 2007-2009; 48 patients (59 %) had follow-up data. Sixty-seven percent of patients had received a previous antibiotic. Surgical intervention was similar between the 2 groups: PJI, 22 of 27 (82 %) and OHAO, 17 of 21 (81 %). However, device removal or replacement was more frequent in the PJI patients (17 of 27, 63 %) than in the OHAO patients (8 of 21, 38 %). Clinical success was reported in 22 of 27 (82 %; 95 % confidence interval [CI], 62-94 %) patients with PJI and 18 of 21 (86 %; 95 % CI, 64-97 %) patients with OHAO at follow-up (13-402 days). Adverse events occurred in 8 of 50 (16 %) patients in the safety population and did not differ by daptomycin dose. CONCLUSION: Daptomycin appeared effective and well tolerated in patients with DAO, including PJI or OHAO.

Antibody-based imaging strategies for cancer.

Although mainly developed for preclinical research and therapeutic use, antibodies have high antigen specificity, which can be used as a courier to selectively deliver a diagnostic probe or therapeutic agent to cancer. It is generally accepted that the optimal antigen for imaging will depend on both the expression in the tumor relative to normal tissue and the homogeneity of expression throughout the tumor mass and between patients. For the purpose of diagnostic imaging, novel antibodies can be developed to target antigens for disease detection, or current FDA-approved antibodies can be repurposed with the covalent addition of an imaging probe. Reuse of therapeutic antibodies for diagnostic purposes reduces translational costs since the safety profile of the antibody is well defined and the agent is already available under conditions suitable for human use. In this review, we will explore a wide range of antibodies and imaging modalities that are being translated to the clinic for cancer identification and surgical treatment.

Dynamic contrast-enhanced MRI evaluates the early response of human head and neck tumor xenografts following anti-EMMPRIN therapy with cisplatin or irradiation.

PURPOSE: To assess the early therapeutic effects of anti-EMMPRIN (extracellular matrix metalloprotease inducer) antibody with/without cisplatin or X-ray radiation in head and neck cancer mouse models using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). MATERIALS AND METHODS: Mice bearing SCC1 (or OSC19) tumor xenografts were treated with anti-EMMPRIN antibody, radiation, cisplatin, or anti-EMMPRIN antibody plus cisplatin (or radiation) for a week (n = 4-5 per group). DCE-MRI was carried out on a 9.4T small animal MR scanner on days 0, 3, and 7, and K(trans) values were averaged in a 0.5-mm-thick peripheral tumor region. Ki67 and CD31 staining were implemented for all tumors after imaging. RESULTS: The K(trans) changes of SCC1 and OSC19 tumors treated with anti-EMMPRIN antibody for 3 days were -18 ± 8% and 4 ± 7%, respectively, which were significantly lower than those of control groups (39 ± 5% and 45 ± 7%; P = 0.0025 and 0.0220, respectively). When cisplatin was added, those were -42 ± 9% and -44 ± 9%, respectively, and with radiation, -45 ± 9% and -27 ± 10%, respectively, which were also significantly lower than those of control groups (P < 0.0001 for all four comparisons). In the eight groups untreated (served as control) or treated with anti-EMMPRIN antibody with/without cisplatin or radiation, the mean K(trans) change for 3 days was significantly correlated with the mean tumor volume change for 7 days (r = 0.74, P = 0.0346), Ki67-expressing cell density (r = 0.96, P = 0.0001), and CD31 density (r = 0.84, P = 0.0084). CONCLUSION: DCE-MRI might be utilized to assess the early therapeutic effects of anti-EMMPRIN antibody with/without chemotherapy or radiotherapy in head and neck cancer.