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Co-inhibitory immune receptors can contribute to T cell dysfunction in patients with cancer1,2. Blocking antibodies against cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death 1 (PD-1) partially reverse this effect and are becoming standard of care in an increasing number of malignancies3. However, many of the other axes by which tumours become inhospitable to T cells are not fully understood. Here we report that V-domain immunoglobulin suppressor of T cell activation (VISTA) engages and suppresses T cells selectively at acidic pH such as that found in tumour microenvironments. Multiple histidine residues along the rim of the VISTA extracellular domain mediate binding to the adhesion and co-inhibitory receptor P-selectin glycoprotein ligand-1 (PSGL-1). Antibodies engineered to selectively bind and block this interaction in acidic environments were sufficient to reverse VISTA-mediated immune suppression in vivo. These findings identify a mechanism by which VISTA may engender resistance to anti-tumour immune responses, as well as an unexpectedly determinative role for pH in immune co-receptor engagement. V-domain immunoglobulin suppressor of T cell activation (VISTA) selectively engages P-selectin glycoprotein ligand-1 (PSGL-1) and suppresses T cells at acidic pH similar to those in tumour microenvironments, thereby mediating resistance to anti-tumour immune responses.

The development of antibody therapeutics relies on animal models that accurately recapitulate disease biology. Syngeneic mouse models are increasingly used with new molecules to capture the biology of complex cancers and disease states, and to provide insight into the role of the immune system. The establishment of syngeneic mouse models requires the ability to generate surrogate mouse counterparts to antibodies designed for humans. In the field of bispecific antibodies, there remains a dearth of technologies available to generate native IgG-like mouse bispecific antibodies. Thus, we engineered a simple co-expression system for one-step purification of intact mouse IgG1 and IgG2a bispecific antibodies from any antibody pair. We demonstrated proof of concept with CD3/CD20 bispecific antibodies, which highlighted both the quality and efficacy of materials generated by this technology.

Which factors determine the current provision of supervised exercise in the UK?

Objectives Peripheral arterial disease most commonly presents as intermittent claudication (IC). Early evidence has suggested that extracorporeal shockwave therapy is efficacious in the short term for the management of intermittent claudication. The objective of this pilot trial was to evaluate the medium-term efficacy of this treatment. Methods This double-blind randomised placebo-controlled pilot trial randomised patients with unilateral intermittent claudication in a 1:1 fashion to receive extracorporeal shockwave therapy or a sham treatment for three sessions per week over three weeks. Primary outcomes were maximum walking distance and intermittent claudication distance using a fixed-load treadmill test. Secondary outcomes included pre- and post-exertional ankle-brachial pressure indices, safety and quality of life assessed using generic (SF36, EQ-5D-3L) and disease-specific (vascular quality of life) measures. All outcome measures were assessed at 12 months post-treatment. Results Thirty participants were included in the study (extracorporeal shockwave therapy, n = 15; sham, n = 15), with 26 followed up and analysed at 12 months (extracorporeal shockwave therapy, n = 13; sham, n = 13). Intragroup analysis demonstrated significant improvements in maximum walking distance, intermittent claudication distance and post-exertional ankle-brachial pressure indices ( p Conclusions These findings suggest that extracorporeal shockwave therapy is effective in improving walking distances at 12 months. Although this study provides important pilot data, a larger study is needed to corroborate these findings and to investigate the actions of this treatment. ISRCTN: NCT02652078.

Purpose Surgical arteriovenous fistula (AVF) or graft (AVG) is preferred to a central venous catheter for dialysis access. Surgical access may suffer thrombosis early after placement and systemic anticoagulation during surgical access formation may increase patency rates but would be expected to increase bleeding-related complications. A systematic review and meta-analysis of randomised controlled trials was conducted to examine the impact of systemic anticoagulation on access surgery perioperative bleeding and patency rates. Methods We included randomised controlled trials testing systemic anticoagulation during access formation versus a control group without systemic anticoagulation reporting bleeding complications and access patency. Medline, Embase, CENTRAL and CINAHL were searched up to March 2015. Risk of bias was assessed using the Cochrane risk of bias tool and the Jadad score. Meta-analysis was performed using Cochrane Revman® software. Results Searches identified 445 reports of which four randomised studies involving 411 participants were included. Three studies pertained to AVF only and one included both AVF and AVG. Systemic anticoagulation led to increased bleeding events in all access [four trials; risk ratio (RR) 7.18; confidence interval (CI), 2.41 to 21.38; pConclusions The use of intraoperative systemic anticoagulation during access formation is associated with a highly significant increased risk of bleeding-related complications. A significant improvement in AVF patency was seen, though not when AVF and AVG were analysed together.

Background Intermittent claudication (IC) is a common and debilitating symptom of peripheral arterial disease and is associated with a significant reduction in a sufferer's quality of life. Guidelines recommend a supervised exercise program (SEP) as the primary treatment option; however, anecdotally there is a low participation rate for exercise in this group of patients. We undertook a systematic review of the uptake and adherence rates to SEPs for individuals with IC. Methods The MEDLINE, Embase, and PubMed databases were searched up to January 2015 for terms related to supervised exercise in peripheral arterial disease. The review had 3 aims: first, to establish the rates of uptake to SEPs, second, the rates of adherence to programs, and finally to determine the reasons reported for poor uptake and adherence. Separate inclusion and/or exclusion criteria were applied in selecting reports for each aim of the review. Results Only 23 of the 53 potentially eligible articles for uptake analysis identified on literature searches reported any details of screened patients ( n = 7,517) with only 24.2% of patients subsequently recruited to SEPs. Forty-five percent of screen failures had no reason for exclusion reported. Sixty-seven articles with 4,012 patients were included for analysis of SEP adherence. Overall, 75.1% of patients reportedly completed an SEP; however, only one article defined a minimal attendance required for SEP completion. Overall, 54.1% of incomplete adherence was due to patient withdrawal and no reason for incomplete adherence was reported for 16% of cases. Conclusions Reporting of SEP trials was poor with regard to the numbers of subjects screened and reasons for exclusions. Only approximately 1 in 3 screened IC patients was suitable for and willing to undertake SEP. Levels of adherence to SEPs and definitions of satisfactory adherence were also lacking in most the current literature. Current clinical guidelines based on this evidence base may not be applicable to most IC patients and changes to SEPs may be needed to encourage and/or retain participants.

Background Extracorporeal shockwave therapy (ESWT) is emerging as a potential new treatment option for a variety of clinical scenarios including promotion of wound healing and symptom control in end-stage ischemic heart disease. A number of small trials have investigated ESWT in the management of peripheral arterial disease (PAD). A systematic review of the literature was performed investigating the efficacy and potential mechanism of action of ESWT for PAD. Methods A systematic review was conducted using MEDLINE and PubMed databases in keeping with the standard reporting guidelines set by the Preferred Reporting Items for Systematic Reviews and Meta-Analysis group to identify any publications relating to the use of ESWT in PAD. Results Systematic literature review identified 5 studies in 4 articles investigating ESWT in the treatment of symptomatic PAD. Although participant numbers within the identified studies were small, significant improvements in pain-free walking distance and maximum walking distance were demonstrated. The mechanism of action is thought to be due to mechanotransduction and subsequent angiogenesis. Conclusions ESWT shows promise as a potentially efficacious novel treatment for symptomatic PAD. However, studies to date are small and record heterogeneous outcomes. Appropriately powered, randomized, sham-controlled data including objective clinical outcomes to comprehensively assess the efficacy of this novel treatment modality is still required before determining if ESWT should be brought into routine clinical practice.

Intermittent claudication is the most common symptom of peripheral arterial disease. Previous research has suggested that extracorporeal shockwave therapy (ESWT) may induce angiogenesis in treated tissue. The objective of this feasibility pilot trial was to assess the safety, tolerability, and efficacy of ESWT as a novel treatment.Patients with unilateral claudication were randomized to receive ESWT or sham treatment to the calf muscle three times per week for 3 weeks. Primary outcomes were pain-free walking distance (PFWD) and maximum walking distance (MWD). Secondary outcomes included safety and tolerability of ESWT treatment, ankle-brachial index before and after exercise, and quality of life assessed using generic (36-Item Short Form Health Survey, EuroQol-5 Dimension 3-Level) and disease-specific (Vascular Quality of Life) instruments. Participants were assessed at baseline and 4, 8, and 12 weeks after treatment. Feasibility outcomes included recruitment and attendance rates for treatment and follow-up.Thirty patients were recruited in total. Statistically significant (P .05) improvements at all time points were observed in the active treatment group for both MWD and PFWD compared with the sham treatment group. PFWD improved by 276% in the active group and MWD improved by 167% in the active group at 12 weeks after treatment. There were no immediate or delayed treatment safety concerns or documented adverse effects of treatment with ESWT in this trial.ESWT is safe and well tolerated when it is applied to the calf and demonstrated significant improvements in walking distances. Current conservative management of intermittent claudication includes supervised exercise. The early results with ESWT as an alternative, noninvasive treatment option show great potential. The mechanism of action, durability of the clinical effect, and cost-effectiveness of ESWT for claudication require further investigation.

Background Intermittent claudication (IC) is a common condition which is associated with significant quality of life limitation. National Institute for Health and Care Excellence guidelines recommend a group-based supervised exercise program as the primary treatment option for claudication, based on clinical and cost effectiveness. This review aims to assess the mechanisms by which exercise improves outcomes in patients with IC. Methods MEDLINE, EMBASE, and PubMed were searched using the search strategy “claudication” [AND] “exercise” [AND] “mechanisms.” Searches were limited from 1947 to October 2014. Only full-text articles published in the English language in adults (over 18 years of age) were eligible for the review. Any trial involving a nonsupervised exercise program was excluded. Abstracts identified by the database search were interrogated for relevance and citations from the shortlisted papers were hand searched for relevant references. Results The search yielded a total of 112 studies, of which 42 were duplicates. Forty-seven of the remaining 70 were deemed appropriate for inclusion in the review. Exercise is the first-line treatment for IC. Supervised exercise programs improve walking distances, endothelial and mitochondrial function, muscle strength, and endurance. Furthermore, it leads to a generalized improvement in cardiovascular fitness and overall quality of life. Conclusions The mechanism by which exercise improves outcome in claudicants is complicated and multifactorial. Further research is required in this area to fully elucidate the precise and predominant mechanisms and to assess whether targeted exercise program modification maximizes mechanism efficacy and patient outcome.

Background Peripheral arterial disease (PAD) has a population prevalence of 4.6% with intermittent claudication (IC) presenting as one of the earliest and most common symptoms. PAD has detrimental effects on patients’ walking ability in terms of maximum walking distance (MWD) and pain-free walking distance (PFWD). Research has suggested extracorporeal shockwave therapy (ESWT) may induce angiogenesis in treated tissue; therefore, our objective is to assess the tolerability and efficacy of ESWT as a novel treatment of intermittent claudication. Methods/design Patients with unilateral claudication will be randomised to receive either ESWT (PiezoWave 2 shockwave system) or sham treatment to the calf muscle bulk three times per week for 3 weeks. All patients are blinded to treatment group, and all assessments will be performed by a masked assessor. Treatment tolerability using a visual analogue scale, ankle-brachial pressure index, MWD, PFWD and safety will all be formally assessed as outcome measures at baseline and at 4, 8 and 12 weeks follow-up. Discussion This trial will be the first of its kind in terms of methodology in relation to ESWT for intermittent claudication. A double-masked randomised controlled trial will provide useful information about the potential for the use of ESWT as a non-invasive treatment option and the need for further robust research. Trial registration ClinicalTrials.gov, NCT02652078. Registered on 17 October 2014. Electronic supplementary material The online version of this article (doi:10.1186/s13063-017-1844-4) contains supplementary material, which is available to authorized users.