Understanding how combinatorial targeting of TLRs and TNFR family costimulatory members promote enhanced T cell responses

Introduction: Due to the ability of pathogen-associated molecular patters and tumor necrosis factor receptor (TNFR) family costimulatory agonists to boost T cell responses, studies have combined Toll-like receptor (TLR) ligands with TNFR family costimulatory receptor agonists to induce impressive and long-lasting T cell responses. Although some studies have determined how these combinatorial vaccines promote enhanced T cell responses, much remains unknown about the mechanism used by these combinations to promote synergistic T cell responses – especially in settings of infectious diseases or cancer.

Areas covered: In this review, we look in detail at the signaling pathways induced by combinatorial targeting of TLR and TNFR family costimulatory members that help them promote synergistic T cell responses. Understanding this can greatly aid the development of novel vaccine regimens that promote cellular immune responses, which is essential for treating certain infectious diseases and cancer.

Expert opinion: Vaccines against some infectious diseases as well as therapeutic cancer vaccines require cellular immunity. Therefore, we evaluate here how signaling pathways induced by TLR ligand and costimulatory agonist combinations promote enhanced T cell responses during immunization with model antigens, viral pathogens, or tumor antigens. Once pathways that drive these combinatorial vaccines to boost T cell activation are identified, they can be incorporated in vaccines designed to target pathogens or cancer.     

The benefit of cardioneuroablation to reduce syncope recurrence in vasovagal syncope patients: a case-control study

Journal of Interventional Cardiac Electrophysiology - Adequate and effective therapy for resistant vasovagal syncope patients is lacking and the benefit of cardioneuroablation (CNA) in this cohort...     

Montelukast versus Budesonide as a First Line Preventive Therapy in Mild Persistent Asthma in 2 to 18 y

Objectives

To compare the efficacy of oral Montelukast and inhaled Budesonide as a first line preventive therapy in mild persistent asthma in age group 2–18 y.

Methods

This prospective randomized controlled clinical study was conducted for 12 wk. Sixty patients of mild persistent asthma aged 2 to 18 y were randomly allocated to either oral Montelukast (n?=?60) or inhaled Budesonide (n?=?60) group. Outcomes measured were improvement in peak expiratory flow rate (PEFR), forced expiratory volume 1 s/forced vital capacity (FEV1/FVC), day time and night time symptoms and frequency of exacerbations and need to change medications.

Results

There was significant improvement in PEFR, FEV1/FVC, day time and night time symptoms and frequency of exacerbations in both groups. However, more significant improvement in FEV1/FVC (CI 95 %, p?=?0.029) and day time symptoms (CI 95 %, p?=?0.002) was seen in Budesonide group compared to Montelukast group.

Conclusions

The present study suggests that oral Montelukast is not inferior to Budesonide in treatment of mild persistent asthma in 2 to 18 y children in terms of control of symptoms and improvement in pulmonary function tests over a 12 wk period. However, there was more significant improvement in day time symptoms, more significant increase in FEV1/FVC ratio and less exacerbation in patients receiving Budesonide compared to those receiving Montelukast. However, side effects due to long term use of steroids such as growth stunting and bone osteopenia should also be considered before recommending. Trial registered at CTRI no. REF/2012/09/004035     

Pro-Regenerative Signaling after Acetaminophen-Induced Acute Liver Injury in Mice Identified Using a Novel Incremental Dose Model

Acetaminophen (APAP) overdose results in acute liver failure and has limited treatment options. Previous studies show that stimulating liver regeneration is critical for survival after APAP overdose, but the mechanisms remain unclear. In this study, we identified major signaling pathways involved in liver regeneration after APAP-induced acute liver injury using a novel incremental dose model. Liver injury and regeneration were studied in C57BL/6 mice treated with either 300 mg/kg (APAP300) or 600 mg/kg (APAP600) APAP. Mice treated with APAP300 developed extensive liver injury and robust liver regeneration. In contrast, APAP600-treated mice exhibited significant liver injury but substantial inhibition of liver regeneration, resulting in sustained injury and decreased survival. The inhibition of liver regeneration in the APAP600 group was associated with cell cycle arrest and decreased cyclin D1 expression. Several known regenerative pathways, including the IL-6/STAT-3 and epidermal growth factor receptor/c-Met/mitogen-activated protein kinase pathways, were activated, even at APAP600, where regeneration was inhibited. However, canonical Wnt/β-catenin and NF-κB pathways were activated only in APAP300-treated mice, where liver regeneration was stimulated. Furthermore, overexpression of a stable form of β-catenin, where serine 45 is mutated to aspartic acid, in mice resulted in improved liver regeneration after APAP overdose. Taken together, our incremental dose model has identified a differential role of several signaling pathways in liver regeneration after APAP overdose and highlighted canonical Wnt signaling as a potential target for regenerative therapies for APAP-induced acute liver failure.Acetaminophen (APAP) is one of the most widely used over-the-counter analgesic and antipyretic drugs in the world. APAP is safe at therapeutic doses, but overdose can cause acute liver failure (ALF). In fact, APAP overdose is associated with 56,000 emergency department visits and 26,000 hospitalizations every year in the United States.¹ The only pharmacological intervention, at present, is N-acetyl cysteine (precursor of glutathione), which is successful only if given within a few hours after APAP overdose.² An ultimate option is liver transplantation, which is complicated by issues such as donor availability, long-term immunosuppression, and exorbitant costs.³Previous studies suggest that liver regeneration after APAP overdose plays a critical role in determination of outcome of injury.^4–7 α-Feto protein, a marker of liver regeneration, was found to be associated with better survival rate in patients with APAP-induced ALF.⁴ Several other studies in animal models suggest that timely stimulation of liver regeneration, such as with stem cell factor⁶ and vascular endothelial growth factor,⁷ improves survival after APAP overdose in mice. These studies highlight stimulating liver regeneration in APAP-induced patients with ALF as a plausible therapeutic option. However, the mechanisms of liver regeneration after APAP-induced ALF are not well known. Although liver regeneration has been extensively studied in the past,⁸ most of the studies are on the basis of a partial hepatectomy (PHX) model, a mechanistically different model from APAP-induced ALF.Data on hepatotoxicants, in general, suggest that liver regeneration follows the principles of dose-response.⁹ Studies indicate that liver regeneration after toxic injury to liver increases proportionately to injury but only up to a threshold dose. Doses higher than the threshold dose actually inhibit liver regeneration, resulting in progression of injury to ALF and death.^9–11 These studies have suggested that at higher doses, regeneration is inhibited because of blockade in critical proregenerative signaling pathways.^9,11,12 On the basis of this principle, we developed a novel incremental dose model to delineate the mechanisms of liver regeneration after APAP-induced acute liver injury (ALI). We used two doses of APAP, a lower dose (300 mg/kg), after which liver regeneration is intact, and a higher dose (600 mg/kg), after which liver regeneration is inhibited. We performed a comprehensive analysis of several signaling pathways known to be involved in liver regeneration and identified pathways that are potentially important for liver regeneration after APAP-induced ALI; these pathways can be targeted therapeutically.     

An audit of histopathology reports of carcinoma endometrium: Experience from a tertiary referral center

Background:

The aim was to see, compliance to minimum data information in carcinoma endometrium reports, in a team of 13 pathologists, and also to analyze these parameters e.g. tumor size, type, grade, depth of myometrial invasion, lymph node yield, pTNM stage etc.

Materials and Methods:

Reports of 114 cases of carcinoma endometrium, that were operated in-house during the years 2008 to 2010 were analyzed from the files of the Pathology department of our hospital.

Results:

The median age was 58.04 years and median tumor size was 4 cm. Endometrioid adenocarcinoma was the most common type (82.5%), followed by malignant mixed Mullerian tumor (MMMT) (6.1%) and Serous carcinoma (3.5%). Grade 2 was the commonest tumor grade (42.1%). Less than half of myometrial invasion was seen in 50% of the cases and more than half of the myometrial invasion was seen in 46.5% of cases. (Information was not available in four cases). Parametrial involvement was seen in 5.3% cases. The pTNM stage was not mentioned in 71.9% reports. The median lymph node yield was 15.

Conclusion:

The compliance to adhere to and to provide minimum data information in carcinoma endometrium reports is generally good. Lymph node yield is reasonable. Mentioning of pTNM staging is to be done more meticulously. Use of proformas/checklists is recommended.KEY WORDS: Audit, endometrial carcinoma, histopathology report     

High-Resolution Analysis by Whole-Genome Sequencing of an International Lineage (Sequence Type 111) of Pseudomonas aeruginosa Associated with Metallo-Carbapenemases in the United Kingdom

Whole-genome sequencing (WGS) was carried out on 87 isolates of sequence type 111 (ST-111) of Pseudomonas aeruginosa collected between 2005 and 2014 from 65 patients and 12 environmental isolates from 24 hospital laboratories across the United Kingdom on an Illumina HiSeq instrument. Most isolates (73) carried VIM-2, but others carried IMP-1 or IMP-13 (5) or NDM-1 (1); one isolate had VIM-2 and IMP-18, and 7 carried no metallo-beta-lactamase (MBL) gene. Single nucleotide polymorphism analysis divided the isolates into distinct clusters; the NDM-1 isolate was an outlier, and the IMP isolates and 6/7 MBL-negative isolates clustered separately from the main set of 73 VIM-2 isolates. Within the VIM-2 set, there were at least 3 distinct clusters, including a tightly clustered set of isolates from 3 hospital laboratories consistent with an outbreak from a single introduction that was quickly brought under control and a much broader set dominated by isolates from a long-running outbreak in a London hospital likely seeded from an environmental source, requiring different control measures; isolates from 7 other hospital laboratories in London and southeast England were also included. Bayesian evolutionary analysis indicated that all the isolates shared a common ancestor dating back ∼50 years (1960s), with the main VIM-2 set separating approximately 20 to 30 years ago. Accessory gene profiling revealed blocks of genes associated with particular clusters, with some having high similarity (≥95%) to bacteriophage genes. WGS of widely found international lineages such as ST-111 provides the necessary resolution to inform epidemiological investigations and intervention policies.     

Histone modifications predispose genome regions to breakage and translocation

Chromosome translocations are well-established hallmarks of cancer cells and often occur at nonrandom sites in the genome. The molecular features that define recurrent chromosome breakpoints are largely unknown. Using a combination of bioinformatics, biochemical analysis, and cell-based assays, we identify here specific histone modifications as facilitators of chromosome breakage and translocations. We show enrichment of several histone modifications over clinically relevant translocation-prone genome regions. Experimental modulation of histone marks sensitizes genome regions to breakage by endonuclease challenge or irradiation and promotes formation of chromosome translocations of endogenous gene loci. Our results demonstrate that histone modifications predispose genome regions to chromosome breakage and translocations.