Catheter-associated urinary tract infection by Pseudomonas aeruginosa progresses through acute and chronic phases of infection.

Healthcare-associated infections are major causes of complications that lead to extended hospital stays and significant medical costs. The use of medical devices, including catheters, increases the risk of bacterial colonization and infection through the presence of a foreign surface. Two outcomes are observed for catheterized patients: catheter-associated asymptomatic bacteriuria and catheter-associated urinary tract infection (CAUTI). However, the relationship between these two events remains unclear. To understand this relationship, we studied a murine model of Pseudomonas aeruginosa CAUTI. In this model, we also observe two outcomes in infected animals: acute symptoms that is associated with CAUTI and chronic colonization that is associated with asymptomatic bacteriuria. The timing of the acute outcome takes place in the first week of infection, whereas chronic colonization occurs in the second week of infection. We further showed that mutants lacking genes encoding type III secretion system (T3SS), T3SS effector proteins, T3SS injection pore, or T3SS transcriptional activation all fail to cause acute symptoms of CAUTI. Nonetheless, all mutants defective for T3SS colonized the catheter and bladders at levels similar to the parental strain. In contrast, through induction of the T3SS master regulator ExsA, all infected animals showed acute phenotypes with bacteremia. Our results demonstrated that the acute symptoms, which are analogous to CAUTI, and chronic colonization, which is analogous to asymptomatic bacteriuria, are independent events that require distinct bacterial virulence factors. Experimental delineation of asymptomatic bacteriuria and CAUTI informs different strategies for the treatment and intervention of device-associated infections.

Characterization of the Entner-Doudoroff pathway in Pseudomonas aeruginosa catheter-associated urinary tract infections.

Pseudomonas aeruginosa is an opportunistic nosocomial pathogen responsible for a subset of catheter-associated urinary tract infections (CAUTI). In a murine model of P. aeruginosa CAUTI, we previously demonstrated that urea within urine suppresses quorum sensing and induces the Entner-Doudoroff (E-D) pathway. The E-D pathway consists of the genes zwf, pgl, edd, and eda. Zwf and Pgl convert glucose-6-phosphate into 6-phosphogluconate. Edd hydrolyzes 6-phosphogluconate to 2-keto-3-deoxy-6-phosphogluconate (KDPG). Finally, Eda cleaves KDPG to glyceraldehyde-3-phosphate and pyruvate, which enters the citric acid cycle. Here, we generated in-frame E-D mutants in the strain PA14 and assessed their growth phenotypes on chemically defined and complex media. These E-D mutants have a growth defect when grown on glucose or gluconate as the sole carbon source, which is similar to results previously reported for PAO1 mutants lacking E-D genes. RNA-sequencing following short exposure to urine revealed minimal gene regulation differences compared to the wild type. In a murine CAUTI model, virulence testing of E-D mutants revealed that two mutants lacking zwf and pgl showed minor fitness defects. Infection with the ∆pgl strain exhibited a 20% increase in host survival, and the ∆zwf strain displayed decreased colonization of the catheter and kidneys. Consequently, our findings suggest that the E-D pathway in P. aeruginosa is dispensable in this model of CAUTI. IMPORTANCE Prior studies have shown that the Entner-Doudoroff pathway is up-regulated when Pseudomonas aeruginosa is grown in urine. Pseudomonads use the Entner-Doudoroff (E-D) pathway to metabolize glucose instead of glycolysis, which led us to ask whether this pathway is required for urinary tract infection. Here, single-deletion mutants of each gene in the pathway were tested for growth on chemically defined media with single-carbon sources as well as complex media. The effect of each mutant on global gene expression in laboratory media and urine was characterized. The virulence of these mutants in a murine model of catheter-associated urinary tract infection revealed that these mutants had similar levels of colonization indicating that glucose is not the primary carbon source utilized in the urinary tract.

What are the optimal pharmacokinetic/pharmacodynamic targets for ß-lactamase inhibitors? A systematic review.

BACKGROUND: Pharmacokinetic/pharmacodynamic (PK/PD) indices are widely used for the selection of optimum antibiotic doses. For ß-lactam antibiotics, fT>MIC, best relates antibiotic exposure to efficacy and is widely used to guide the dosing of ß-lactam/ß-lactamase inhibitor (BLI) combinations, often without considering any PK/PD exposure requirements for BLIs. OBJECTIVES: This systematic review aimed to describe the PK/PD exposure requirements of BLIs for optimal microbiological efficacy when used in combination with ß-lactam antibiotics. METHODS: Literature was searched online through PubMed, Embase, Web of Science, Scopus and Cochrane Library databases up to 5 June 2023. Studies that report the PK/PD index and threshold concentration of BLIs approved for clinical use were included. Narrative data synthesis was carried out to assimilate the available evidence. RESULTS: Twenty-three studies were included. The PK/PD index that described the efficacy of BLIs was fT>CT for tazobactam, avibactam and clavulanic acid and fAUC0-24/MIC for relebactam and vaborbactam. The optimal magnitude of the PK/PD index is variable for each BLI based on the companion ß-lactam antibiotics, type of bacteria and ß-lactamase enzyme gene transcription levels. CONCLUSIONS: The PK/PD index that describes the efficacy of BLIs and the exposure measure required for their efficacy is variable among inhibitors; as a result, it is difficult to make clear inference on what the optimum index is. Further PK/PD profiling of BLI, using preclinical infection models that simulate the anticipated mode(s) of clinical use, is warranted to streamline the exposure targets for use in the optimization of dosing regimens.

Accuracy of genomic prediction using multiple Atlantic salmon populations.

BACKGROUND: The accuracy of genomic prediction is partly determined by the size of the reference population. In Atlantic salmon breeding programs, four parallel populations often exist, thus offering the opportunity to increase the size of the reference set by combining these populations. By allowing a reduction in the number of records per population, multi-population prediction can potentially reduce cost and welfare issues related to the recording of traits, particularly for diseases. In this study, we evaluated the accuracy of multi- and across-population prediction of breeding values for resistance to amoebic gill disease (AGD) using all single nucleotide polymorphisms (SNPs) on a 55K chip or a selected subset of SNPs based on the signs of allele substitution effect estimates across populations, using both linear and nonlinear genomic prediction (GP) models in Atlantic salmon populations. In addition, we investigated genetic distance, genetic correlation estimated based on genomic relationships, and persistency of linkage disequilibrium (LD) phase across these populations. RESULTS: The genetic distance between populations ranged from 0.03 to 0.07, while the genetic correlation ranged from 0.19 to 0.99. Nonetheless, compared to within-population prediction, there was limited or no impact of combining populations for multi-population prediction across the various models used or when using the selected subset of SNPs. The estimates of across-population prediction accuracy were low and to some extent proportional to the genetic correlation estimates. The persistency of LD phase between adjacent markers across populations using all SNP data ranged from 0.51 to 0.65, indicating that LD is poorly conserved across the studied populations. CONCLUSIONS: Our results show that a high genetic correlation and a high genetic relationship between populations do not guarantee a higher prediction accuracy from multi-population genomic prediction in Atlantic salmon.

A Bicyclic Analog of the Linear Peptide Arodyn Is a Potent and Selective Kappa Opioid Receptor Antagonist.

Kappa opioid receptor (KOR) antagonists have potential therapeutic applications in the treatment of stress-induced relapse to substance abuse and mood disorders. The dynorphin A analog arodyn (Ac[Phe1,2,3,Arg4,D-Ala8]dynorphin A-(1-11)-NH2) exhibits potent and selective kappa opioid receptor antagonism. Multiple cyclizations in longer peptides, such as dynorphin and its analogs, can extend the conformational constraint to additional regions of the peptide beyond what is typically constrained by a single cyclization. Here, we report the design, synthesis, and pharmacological evaluation of a bicyclic arodyn analog with two constraints in the opioid peptide sequence. The peptide, designed based on structure-activity relationships of monocyclic arodyn analogs, was synthesized by solid-phase peptide synthesis and cyclized by sequential ring-closing metathesis (RCM) in the C- and N-terminal sequences. Molecular modeling studies suggest similar interactions of key aromatic and basic residues in the bicyclic peptide with KOR as found in the cryoEM structure of KOR-bound dynorphin, despite substantial differences in the backbone conformations of the two peptides. The bicyclic peptide's affinities at KOR and mu opioid receptors (MOR) were determined in radioligand binding assays, and its KOR antagonism was determined in the [35S]GTPγS assay in KOR-expressing cells. The bicyclic analog retains KOR affinity and selectivity (Ki = 26 nM, 97-fold selectivity over MOR) similar to arodyn and exhibits potent KOR antagonism in the dynorphin-stimulated [35S]GTPγS assay. This bicyclic peptide represents a promising advance in preparing cyclic opioid peptide ligands and opens avenues for the rational design of additional bicyclic opioid peptide analogs.

Incident Kaposi sarcoma during the expansion of antiretroviral therapy eligibility in Nigeria: a retrospective cohort study.

INTRODUCTION: The expansion of antiretroviral therapy (ART) eligibility could lead to earlier initiation of Human Immunodeficiency Virus (HIV) treatment and consequently reduce the risk of HIV-associated Kaposi Sarcoma (KS). We investigated the impact of changes in the Nigerian HIV treatment guidelines on KS incidence among adults enrolled in HIV care in Nigeria. METHODS: We analyzed data of adults who enrolled for HIV care from January 2006 to December 2016 at one of Nigeria's largest HIV treatment centers. Based on changes in HIV treatment guidelines, we classified 2006-2009 as the pre-expansion period and 2010-2016 as the post-expansion period. We used Kaplan Meier curves to compare the incidence of KS in the pre-expansion to the post-expansion period. We used Cox regression models to assess the hazard for incident KS between the two periods after adjusting for potential confounders. RESULTS: Among 14,479 patients with HIV, the overall KS incidence was 2.35; 95% CI 2.01-2.74/1,000 person-years. The incidence of KS decreased from 2.53 to 1.58 per 1,000 person-years from 2006 to 2009 to 2010-2016. In models adjusting for age, sex, CD4-T cell count, and ART use, the risk for KS remained lower in 2010-2016 compared to 2006-2009. In analyses restricted to time on ART, there was no significant difference in KS incidence between HIV patients who enrolled in 2006-2009 and 2010-2016 after adjusting for age, sex, and CD4 T-cell count. CONCLUSION: The expansion of ART eligibility was associated with a reduced incidence of HIV-associated KS among adults initiating HIV care in Jos, Nigeria. The reduction was likely driven by earlier enrollment for HIV care and ART initiation.

Hand hygiene practices in Caribbean and Latin American countries: An integrative review.

AIM AND OBJECTIVE: To explore what is known about knowledge, attitudes and beliefs that influence hand hygiene practices in in low- and middle-income Caribbean and Latin American countries. BACKGROUND: With the emergence of infectious diseases such as the recent COVID-19 pandemic, handwashing is key to preventing communicable diseases as they disproportionately affect populations in low-income countries. While hand hygiene is known to be the single most effective method for avoiding the transmission of infection, little is known about the beliefs and practices of individuals in these regions. METHODS: Following PRISMA 2020 Checklist, an integrative review of studies published from 2008-2020 was conducted (Preferred Reporting Items for Systematic Reviews and Meta-analyses). Whittemore and Knafl's method was used to review the literature. Six databases were searched, and the Johns Hopkins Evidence Based Rating Scale was used for study appraisal. RESULTS: The review yielded 18 studies conducted across Latin America. Poor handwashing practices are influenced by various factors including inadequate education and training, cultural beliefs, lack of resources and substandard government regulations. Communicable diseases and other diarrheal illnesses were highly prevalent, especially after a major disease outbreak. CONCLUSION: Future post-disaster campaigns aimed at improving hand hygiene and handwashing practices should focus on beliefs and attitudes to affect behaviour change since there was a higher disease susceptibility during those times. Barriers to proper hand hygiene include false attitudes such as, washing hands only after touching bodily fluids/patient contact or not washing hands at all after open defecation. RELEVANCE TO CLINICAL PRACTICE: Researchers working with populations in Latin America and the Caribbean should partner with local community health workers to improve compliance to recommended hand hygiene practices.

A Predictive Model of Adaptive Resistance to BRAF/MEK Inhibitors in Melanoma.

The adaptive acquisition of resistance to BRAF and MEK inhibitor-based therapy is a common feature of melanoma cells and contributes to poor patient treatment outcomes. Leveraging insights from a proteomic study and publicly available transcriptomic data, we evaluated the predictive capacity of a gene panel corresponding to proteins differentially abundant between treatment-sensitive and treatment-resistant cell lines, deciphering predictors of treatment resistance and potential resistance mechanisms to BRAF/MEK inhibitor therapy in patient biopsy samples. From our analysis, a 13-gene signature panel, in both test and validation datasets, could identify treatment-resistant or progressed melanoma cases with an accuracy and sensitivity of over 70%. The dysregulation of HMOX1, ICAM, MMP2, and SPARC defined a BRAF/MEK treatment-resistant landscape, with resistant cases showing a >2-fold risk of expression of these genes. Furthermore, we utilized a combination of functional enrichment- and gene expression-derived scores to model and identify pathways, such as HMOX1-mediated mitochondrial stress response, as potential key drivers of the emergence of a BRAF/MEK inhibitor-resistant state in melanoma cells. Overall, our results highlight the utility of these genes in predicting treatment outcomes and the underlying mechanisms that can be targeted to reduce the development of resistance to BRAF/MEK targeted therapy.

Factors influencing the implementation of TB screening among PLHIV in selected HIV clinics in Ghana: a qualitative study.

BACKGROUND: Decreasing the burden of Tuberculosis (TB) among PLHIV through TB screening is an effective intervention recommended by the World Health Organization (WHO). However, after over a decade of implementation in Ghana, the intervention does not realize the expected outcomes. It is also not well understood whether this lack of success is due to implementation barriers. Our study, therefore, sought to examine the factors influencing the implementation of the intervention among people living with HIV (PLHIV) attending HIV clinics at district hospitals in Ghana. METHODS: This was a qualitative study conducted from 6th to 31 May 2019 in three regions of Ghana. We conducted 17 in-depth interviews (IDIs - comprising two regional, six districts and nine facility TB/HIV coordinators) and eight focus group discussions (FGD - consisting of a total of 65 participants) with HIV care providers. The Consolidated Framework for Implementation Research (CFIR) guided the design of interview guides, data collection and analysis. All responses were digitally audio-recorded and transcribed verbatim for coding and analysis using the Framework Approach. Participants consented to the interview and recording. RESULTS: The main barriers to TB screening relate to the low commitment of the implementers to screen for TB and limited facility infrastructure for the screening activities. Facilitators of TB screening include (1) ease in TB screening, (2) good communication and referral channels, (3) effective goals and feedback mechanisms, (4) health workers recognizing the need for the intervention and (5) the role of chemical sellers. CONCLUSIONS: Key barriers and facilitators to the intervention are revealed. The study has shown that there is a need to increase HIV care providers and institutional commitment towards TB screening interventions. In addition, cost issues need to be assessed as they are drivers of sustainability. Our study also advances the field of implementation science through CFIR to better understand the factors influencing the implementation.

5'-UTR recruitment of the translation initiation factor eIF4GI or DAP5 drives cap-independent translation of a subset of human mRNAs.

During unfavorable conditions (e.g. tumor hypoxia or viral infection), canonical, cap-dependent mRNA translation is suppressed in human cells. Nonetheless, a subset of physiologically important mRNAs (e.g. hypoxia-inducible factor 1α [HIF-1α], fibroblast growth factor 9 [FGF-9], and p53) is still translated by an unknown, cap-independent mechanism. Additionally, expression levels of eukaryotic translation initiation factor 4GI (eIF4GI) and of its homolog, death-associated protein 5 (DAP5), are elevated. By examining the 5' UTRs of HIF-1α, FGF-9, and p53 mRNAs and using fluorescence anisotropy binding studies, luciferase reporter-based in vitro translation assays, and mutational analyses, we demonstrate here that eIF4GI and DAP5 specifically bind to the 5' UTRs of these cap-independently translated mRNAs. Surprisingly, we found that the eIF4E-binding domain of eIF4GI increases not only the binding affinity but also the selectivity among these mRNAs. We further demonstrate that the affinities of eIF4GI and DAP5 binding to these 5' UTRs correlate with the efficiency with which these factors drive cap-independent translation of these mRNAs. Integrating the results of our binding and translation assays, we conclude that eIF4GI or DAP5 is critical for recruitment of a specific subset of mRNAs to the ribosome, providing mechanistic insight into their cap-independent translation.

Flow-regulated endothelial glycocalyx determines metastatic cancer cell activity.

Cancer metastasis and secondary tumor initiation largely depend on circulating tumor cell (CTC) and vascular endothelial cell (EC) interactions by incompletely understood mechanisms. Endothelial glycocalyx (GCX) dysfunction may play a significant role in this process. GCX structure depends on vascular flow patterns, which are irregular in tumor environments. This work presents evidence that disturbed flow (DF) induces GCX degradation, leading to CTC homing to the endothelium, a first step in secondary tumor formation. A 2-fold greater attachment of CTCs to human ECs was found to occur under DF conditions, compared to uniform flow (UF) conditions. These results corresponded to an approximately 50% decrease in wheat germ agglutinin (WGA)-labeled components of the GCX under DF conditions, vs UF conditions, with undifferentiated levels of CTC-recruiting E-selectin under DF vs UF conditions. Confirming the role of the GCX, neuraminidase induced the degradation of WGA-labeled GCX under UF cell culture conditions or in Balb/C mice and led to an over 2-fold increase in CTC attachment to ECs or Balb/C mouse lungs, respectively, compared to untreated conditions. These experiments confirm that flow-induced GCX degradation can enable metastatic CTC arrest. This work, therefore, provides new insight into pathways of secondary tumor formation.

Combinatorial effects of trans-cinnamaldehyde with fluoride and chlorhexidine on Streptococcus mutans.

AIMS: The aim of this study was to investigate the effects of trans-cinnamaldehyde (TC) and its synergistic activity with chlorhexidine (CHX) and fluoride against Streptococcus mutans. METHODS AND RESULTS: Streptococcus mutans UA159 was treated with TC alone and in combination with CHX or sodium fluoride. The synergy profile was analysed using the Zero Interaction Potency model. TC showed strong synergism (synergy score of 21·697) with CHX, but additive effect (synergy score of 5·298) with fluoride. TC and the combinations were tested for acid production (glycolytic pH drop) and biofilm formation by S. mutans, and nitric oxide production in macrophages. TC significantly inhibited sucrose-dependent biofilm formation and acid production by S. mutans. Mechanistic studies were carried out by qRT-PCR-based transcriptomic studies which showed that TC acts by impairing genes related to metabolism, quorum sensing, bacteriocin expression, stress tolerance and biofilm formation. CONCLUSIONS: trans-Cinnamaldehyde potentiates CHX and sodium fluoride in inhibiting S. mutans biofilms and virulence through multiple mechanisms. This study sheds significant new light on the potential to develop TC as an anti-caries treatment. SIGNIFICANCE AND IMPACT OF THE STUDY: Oral diseases were classified as a 'silent epidemic' in the US Surgeon General's Report on Oral Health. Two decades later, >4 billion people are still affected worldwide by caries, having significant effects on the quality of life. There is an urgent need to develop novel compounds and strategies to combat dental caries. Here, we prove that TC downregulates multiple pathways and potentiates the CHX and fluoride to prevent S. mutans biofilms and virulence. This study sheds significant new light on the potential to develop TC in combination with CHX or fluoride as novel treatments to arrest dental caries.

Metabolic Cross-talk Between Human Bronchial Epithelial Cells and Internalized Staphylococcus aureus as a Driver for Infection.

Staphylococcus aureus is infamous for causing recurrent infections of the human respiratory tract. This is a consequence of its ability to adapt to different niches, including the intracellular milieu of lung epithelial cells. To understand the dynamic interplay between epithelial cells and the intracellular pathogen, we dissected their interactions over 4 days by mass spectrometry. Additionally, we investigated the dynamics of infection through live cell imaging, immunofluorescence and electron microscopy. The results highlight a major role of often overlooked temporal changes in the bacterial and host metabolism, triggered by fierce competition over limited resources. Remarkably, replicating bacteria reside predominantly within membrane-enclosed compartments and induce apoptosis of the host within ∼24 h post infection. Surviving infected host cells carry a subpopulation of non-replicating bacteria in the cytoplasm that persists. Altogether, we conclude that, besides the production of virulence factors by bacteria, it is the way in which intracellular resources are used, and how host and intracellular bacteria subsequently adapt to each other that determines the ultimate outcome of the infectious process.

Adherence of HIV clinics to guidelines for the delivery of TB screening among people living with HIV/AIDS in Ghana.

BACKGROUND: Tuberculosis screening of people living with HIV (PLHIV) - an intervention to reduce the burden of TB among PLHIV - is being implemented at HIV clinics in Ghana since 2007, but TB screening coverage remains low. Facility adherence to intervention guidelines may be a factor but is missing in implementation science literature. This study assesses the level of HIV clinic adherence to the guidelines and related facility characteristics in selected district hospitals in Ghana. METHODS: This cross-sectional study was conducted in all 27 district hospitals with HIV clinics, X-ray and geneXpert machines in Ghana. These hospitals are in 27 districts representing about 27% of the 100 district hospitals with HIV clinics in Ghana. A data collection tool with 18-items (maximum score of 29) was developed from the TB/HIV collaborative guidelines to assess facility adherence to four interrelated components of the TB screening programme as stated in the guidelines: intensive TB case-finding among PLHIV (ITCF), Isoniazid preventive therapy initiation (IPT), TB infection control (TIC), and programme review meetings (PRM). Data were collected through record review and interviews with 27 key informants from each hospital. Adherence scores per component were summed to determine an overall adherence score per facility and summarized using medians and converted to proportions. Facility characteristics were assessed and compared across facilities with high (above median) versus low (below median) overall adherence scores, using nonparametric test statistics. RESULTS: From the 27 key interviews and facility records reviewed, the median adherence scores for ITCF, IPT, TIC, and PRM components were 85.7% (IQR: 85.5-100.0), 0% (IQR: 0-66.7), 33.3% (IQR: 33.3-50.0), and 90.0% (IQR: 70.0-90.0), respectively. The overall median adherence score was 62.1% (IQR: 58.6-65.1), and 17 clinics (63%) with overall adherence score above the median were categorized as high adherence. Compared to low adherence facilities, high adherence facilities had statistically significant lower PLHIV clinic attendees per month (256 (IQR: 60-904) vs. 900 (IQR: 609-2622); p = 0.042), and lower HIV provider workloads (28.6 (IQR: 8.6-113) vs. 90 (IQR: 66.7-263.5); p = 0.046), and most had screening guidelines (76%, p < 0.01) and questionnaire (80%, p < 0.01) available on-site. CONCLUSION: PRM had highest score while the IPT component had the lowest score. Almost a third of the facilities implemented the TB screening programme activities with a high level of adherence to the guidelines. We suggest to ensure adherence to all four components, reducing staff workloads and making TB screening questionnaires and guidelines available on-site would increase facility adherence to the intervention and ultimately achieve intervention targets.

Health Effects of Overweight and Obesity in 195 Countries over 25 Years.

BACKGROUND: Although the rising pandemic of obesity has received major attention in many countries, the effects of this attention on trends and the disease burden of obesity remain uncertain. METHODS: We analyzed data from 68.5 million persons to assess the trends in the prevalence of overweight and obesity among children and adults between 1980 and 2015. Using the Global Burden of Disease study data and methods, we also quantified the burden of disease related to high body-mass index (BMI), according to age, sex, cause, and BMI in 195 countries between 1990 and 2015. RESULTS: In 2015, a total of 107.7 million children and 603.7 million adults were obese. Since 1980, the prevalence of obesity has doubled in more than 70 countries and has continuously increased in most other countries. Although the prevalence of obesity among children has been lower than that among adults, the rate of increase in childhood obesity in many countries has been greater than the rate of increase in adult obesity. High BMI accounted for 4.0 million deaths globally, nearly 40% of which occurred in persons who were not obese. More than two thirds of deaths related to high BMI were due to cardiovascular disease. The disease burden related to high BMI has increased since 1990; however, the rate of this increase has been attenuated owing to decreases in underlying rates of death from cardiovascular disease. CONCLUSIONS: The rapid increase in the prevalence and disease burden of elevated BMI highlights the need for continued focus on surveillance of BMI and identification, implementation, and evaluation of evidence-based interventions to address this problem. (Funded by the Bill and Melinda Gates Foundation.).

Inhibitors of dipeptidyl peptidase-4 as therapeutic agents for individuals with type 2 diabetes: a 25-year journey.

In the 25 years since the hypothesis was first described, therapeutic use of inhibitors of dipeptidyl peptidase-4 (DPP-4i) as a novel approach to the treatment of type 2 diabetes has become established widely, with several compounds now available to exemplify the class. Although the clinical profiles of members of the DPP-4i class have been reviewed extensively, the underlying pragmatic small molecular design and pharmaceutical properties of these agents have seldom been addressed in the context of establishment of the class as treatments for type 2 diabetes. Among the reasons contributing to the wide acceptance of DPP-4i as oral anti-hyperglycaemic therapy are: (i) the endocrine basis of their pharmacology; (ii) their chemical 'simplicity' and low molecular mass; (iii) their pharmacological selectivity for their target mechanism of action; (iv) the nature of physiologically relevant substrates for the enzyme; (v) their relative ease of formulation into tablets; (vi) their efficacy as glucose-lowering agents; (vii) their absorption, distribution, metabolism and elimination profiles; and (viii) their limited tolerability issues.

Optimized Ring Closing Metathesis Reaction Conditions To Suppress Desallyl Side Products in the Solid-Phase Synthesis of Cyclic Peptides Involving Tyrosine(O-allyl).

We are exploring constraining aromatic residues in the kappa opioid receptor selective antagonist arodyn (Ac[Phe1,2,3,Arg4,d-Ala8]dynorphin A(1-11)-NH2) by ring closing metathesis (RCM) involving tyrosine(O-allyl) (Tyr(All)), but desallyl products limited the yields of the desired cyclic peptide. The model dipeptide Fmoc-Tyr(All)-Tyr(All) was used to explore different reaction conditions, including the use of isomerization suppressants, to minimize formation of the desallyl products and enhance formation of the desired RCM product. Reaction conditions were identified that enhanced the RCM product yield while suppressing desallyl products using both second-generation Grubbs and second-generation Hoveyda-Grubbs catalysts. These optimized reaction conditions were then applied to the cyclization of a tripeptide and an arodyn analog resulting in ≥70% conversion to the desired cyclic peptides. These strategies should be applicable to RCM involving Tyr(All) and similar residues in peptide and peptidomimetic cyclizations performed on solid phase.

Strong-field control of H3 + production from methanol dications: Selecting between local and extended formation mechanisms.

Using the CD3OH isotopologue of methanol, the ratio of D2H+ to D3 + formation is manipulated by changing the characteristics of the intense femtosecond laser pulse. Detection of D2H+ indicates a formation process involving two hydrogen atoms from the methyl side of the molecule and a proton from the hydroxyl side, while detection of D3 + indicates local formation involving only the methyl group. Both mechanisms are thought to involve a neutral D2 moiety. An adaptive control strategy that employs image-based feedback to guide the learning algorithm results in an enhancement of the D2H+/D3 + ratio by a factor of approximately two. The optimized pulses have secondary structures 110-210 fs after the main pulse and result in photofragments that have different kinetic energy release distributions than those produced from near transform limited pulses. Systematic changes to the linear chirp and higher order dispersion terms of the laser pulse are compared to the results obtained with the optimized pulse shapes.

Syndecans in chronic inflammatory and autoimmune diseases: Pathological insights and therapeutic opportunities.

Syndecans (SDCs) are a family of heparan sulfate proteoglycans (HSPGs) glycoproteins ubiquitously expressed on the cell surfaces and extracellular matrix of all mammalian tissues. There are four mammalian syndecans, SDC-1 thorough 4, which play a critical role in cell adhesion, migration, proliferation, differentiation, and angiogenesis through independent and growth factor mediated signaling. An altered expression of SDCs is often observed in autoimmune disorders, cancer, HIV infection, and many other pathological conditions. SDCs modulate disease progression by interacting with a diverse array of ligands, receptors, and other proteins, including extracellular matrix, glycoproteins, integrins, morphogens, and various growth factors and chemokines, along with their receptors and kinases. Specifically, SDCs present on cell surface can bind directly to chemokines to enhance their binding to receptors, downstream signaling, and migration. Alternatively, SDCs can be cleaved and shed to mediate negative regulation of chemokine and growth factor signaling pathways and ligand sequestration. Importantly, SDC shedding may be a biomarker of inflammation, especially in chronic inflammatory diseases. While the current therapies for cancer and several autoimmune disorders have revolutionized treatment outcomes, understanding the pathophysiological role of SDCs and the use of HSPG mimetic or antagonists on cytokine signaling networks may uncover potentially novel targeted therapeutic approaches. This review mainly summarizes the current findings on the role of individual SDCs in disease processes, mechanisms through which SDCs mediate their biological functions, and the possibility of targeting SDCs as future potential therapeutic approaches.

Total Body Irradiation Is Safe and Similarly Effective as Chemotherapy-Only Conditioning in Autologous Stem Cell Transplantation for Mantle Cell Lymphoma.

Autologous stem cell transplant (ASCT) consolidation has become a standard approach for patients with mantle cell lymphoma (MCL), yet there is little consensus on the role of total body irradiation (TBI) as part of high-dose transplantation conditioning. We analyzed 75 consecutive patients with MCL who underwent ASCT at our institution between 2001 and 2011 with either TBI-based (n = 43) or carmustine, etoposide, cytarabine, melphalan (BEAM; n = 32) high-dose conditioning. Most patients (97%) had chemosensitive disease and underwent transplantation in first remission (89%). On univariate analysis, TBI conditioning was associated with a trend toward improved PFS (hazard ratio [HR], .53; 95% confidence interval [CI], .28-1.00; P = .052) and similar OS (HR, .59; 95% CI, .26-1.35; P = .21), with a median follow-up of 6.3 years in the TBI group and 6.6 years in the BEAM group. The 5-year PFS was 66% in the TBI group versus 52% in the BEAM group; OS was 82% versus 68%, respectively. However, on multivariate analysis, TBI-based conditioning was not significantly associated with PFS (HR, .57; 95% CI .24-1.34; P = .20), after controlling for age, disease status at ASCT, and receipt of post-transplantation rituximab maintenance. Likewise, early toxicity, nonrelapse mortality, and secondary malignancies were similar in the 2 groups. Our data suggest that both TBI and BEAM-based conditioning regimens remain viable conditioning options for patients with MCL undergoing ASCT.