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Background and Aim: Pancreatic cancer is one of the most fatal cancers. Cytotoxic chemotherapy remains the mainstream treatment for unresectable pancreatic cancer. This systematic review evaluated and compared the overall survival (OS) and progression-free survival (PFS) outcomes obtained from recent phase 2 and 3 clinical trials of pancreatic cancer chemotherapy. Materials and methods: Thirty-two studies were included and compared based on chemotherapy agents or combinations used. Additionally, outcomes of first-line versus second-line chemotherapy in pancreatic cancer were compared. Results: In studies that investigated the treatments in adjuvant settings, the highest OS reported was for S-1 in patients, who received prior surgical resection (46.5 months). In neoadjuvant settings, the combination of gemcitabine, docetaxel, and capecitabine prior to the surgical resection had promising outcomes (OS of 32.5 months). In non-adjuvant settings, the highest OS reported was for the combination of temsirolimus plus bevacizumab (34.0 months). Amongst studies that investigated second-line treatment, the highest OS reported was for the combination of gemcitabine plus cisplatin (35.5 months), then temsirolimus plus bevacizumab (34.0 months). Conclusions: There is a need to develop further strategies besides chemotherapy to improve the outcomes in pancreatic cancer treatment. Future studies should consider surgical interventions, combination chemotherapy, and individualized second-line treatment based on the prior chemotherapy.

Identification of robust biomarkers of malignancy and methods to establish disease progression is a major goal in paediatric neuro-oncology. We investigated whether methylation of the TERT promoter can be a biomarker for malignancy and patient outcome in paediatric brain tumours. For the discovery cohort, we used samples obtained from patients with paediatric brain tumours and individuals with normal brain tissues stored at the German Cancer Research Center (Heidelberg, Germany). We used methylation arrays for genome-wide assessment of DNA. For the validation cohort, we used samples obtained from several tissues for which full clinical and follow-up data were available from two hospitals in Toronto (ON, Canada). We did methylation analysis using quantitative Sequenom and pyrosequencing of an identified region of the TERT promoter. We assessed TERT expression by real-time PCR. To establish whether the biomarker could be used to assess and predict progression, we analysed methylation in paired samples of tumours that transformed from low to high grade and from localised to metastatic, and in choroid plexus tumours of different grades. Finally, we investigated overall survival in patients with posterior fossa ependymomas in which the identified region was hypermethylated or not. All individuals responsible for assays were masked to the outcome of the patients. Analysis of 280 samples in the discovery cohort identified one CpG site (cg11625005) in which 78 (99%) of 79 samples from normal brain tissues and low-grade tumours were not hypermethylated, but 145 (72%) of 201 samples from malignant tumours were hypermethylated (>15% methylated; p<0·0001). Analysis of 68 samples in the validation cohort identified a subset of five CpG sites (henceforth, upstream of the transcription start site [UTSS]) that was hypermethylated in all malignant paediatric brain tumours that expressed TERT but not in normal tissues that did not express TERT (p<0·0001). UTSS had a positive predictive value of 1·00 (95% CI 0·95–1·00) and a negative predictive value of 0·95 (0·87–0·99). In two paired samples of paediatric gliomas, UTSS methylation increased during transformation from low to high grade; it also increased in two paired samples that progressed from localised to metastatic disease. Two of eight atypical papillomas that had high UTSS methylation progressed to carcinomas, while the other six assessed did not progress or require additional treatment. 5-year overall survival was 51% (95% CI 31–71) for 25 patients with hypermethylated UTSS posterior fossa ependymomas and 95% (86–100) for 20 with non-hypermethylated tumours (p=0·0008). 5-year progression-free survival was 86% (68–100) for the 25 patients with non-hypermethylated UTSS tumours and 30% (10–50) for those with hypermethylated tumours (p=0·0008). Hypermethylation of the UTSS region in the TERT promoter is associated with TERT expression in cancers. In paediatric brain tumours, UTSS hypermethylation is associated with tumour progression and poor prognosis. This region is easy to amplify, and the assay to establish hypermethylation can be done on most tissues in most clinical laboratories. Therefore the UTSS region is a potentially accessible biomarker for various cancers. The Canadian Institute of Health Research and the Terry Fox Foundation.

Human Rhinovirus (HRV) is a pathogen of significant medical importance, being a major cause of upper respiratory tract infections (common colds) as well as causing the majority of virus-induced asthma exacerbations. We investigated whether HRV could modulate apoptosis, an innate antiviral response. Apoptotic signals are generated either extrinsically or intrinsically and are propagated via caspase cascades that lead to cell death, reducing viral replication, which relies on cellular machinery. Using HRV16 infected cells, in combination with chemical inducers and inhibitors of extrinsic apoptosis we show that HRV16 3C protease cleaves a key intermediate in extrinsic apoptosis. Receptor-interacting protein kinase-1 (RIPK1), an extrinsic apoptosis adaptor protein, was cleaved by caspase 8, as expected, during chemical induction of apoptosis. RIPK1 was cleaved in HRV infection albeit at a different site. Caspase 8 activation, which is associated with extrinsic apoptosis, was concurrent with HRV 3C protease mediated cleavage of RIPK1, and potentially increased the accessibility of the HRV 3C cleavage site within RIPK1 in-vitro . The caspase 8 mediated RIPK1 cleavage product has a pro-apoptotic function, and further cleavage of this pro-apoptotic cleavage product by HRV 3C may provide a mechanism by which HRV limits apoptosis.

Infected cells can undergo apoptosis as a protective response to viral infection, thereby limiting viral infection. As viruses require a viable cell for replication, the death of the cell limits cellular functions that are required for virus replication and propagation. Picornaviruses are single-stranded RNA viruses that modify the host cell apoptotic response, probably in order to promote viral replication, largely as a function of the viral proteases 2A, 3C, and 3CD. These proteases are essential for viral polyprotein processing and also cleave cellular proteins. Picornavirus proteases cleave proapoptotic adaptor proteins, resulting in downregulation of apoptosis. Picornavirus proteases also cleave nucleoporins, disrupting the orchestrated manner in which signaling pathways use active nucleocytoplasmic trafficking, including those involved in apoptosis. In addition to viral proteases, the transmembrane 2B protein alters intracellular ion signaling, which may also modulate apoptosis. Overall, picornaviruses, via the action of virally encoded proteins, exercise intricate control over and subvert cell death pathways, specifically apoptosis, thereby allowing viral replication to continue.

Human Rhinovirus (HRV) infection results in shut down of essential cellular processes, in part through disruption of nucleocytoplasmic transport by cleavage of the nucleoporin proteins (Nups) that make up the host cell nuclear pore. Although the HRV genome encodes two proteases (2A and 3C) able to cleave host proteins such as Nup62, little is known regarding the specific contribution of each. Here we use transfected as well as HRV-infected cells to establish for the first time that 3C protease is most likely the mediator of cleavage of Nup153 during HRV infection, while Nup62 and Nup98 are likely to be targets of HRV2A protease. HRV16 3C protease was also able to elicit changes in the appearance and distribution of the nuclear speckle protein SC35 in transfected cells, implicating it as a key mediator of the mislocalisation of SC35 in HRV16-infected cells. In addition, 3C protease activity led to the redistribution of the nucleolin protein out of the nucleolus, but did not affect nuclear localisation of hnRNP proteins, implying that complete disruption of nucleocytoplasmic transport leading to relocalisation of hnRNP proteins from the nucleus to the cytoplasm in HRV-infected cells almost certainly requires 2A in addition to 3C protease. Thus, a specific role for HRV 3C protease in cleavage and mislocalisation of host cell nuclear proteins, in concert with 2A, is implicated for the first time in HRV pathogenesis.

Objectives To describe and reflect on the methods and influence of involvement of young people with lived experience within a complex evidence synthesis. Study design and setting Linked syntheses of quantitative and qualitative systematic reviews of evidence about interventions to improve the mental health of children and young people (CYP) with long‐term physical conditions (LTCs). Methods Involvement was led by an experienced patient and public involvement in research lead. Young people with long‐term physical conditions and mental health issues were invited to join a study‐specific Children and Young People's Advisory Group (CYPAG). The CYPAG met face to face on four occasions during the project with individuals continuing to contribute to dissemination following report submission. Results Eight young people joined the CYPAG. Their views and experiences informed (a) a systematic review evaluating the effectiveness of interventions intended to improve the mental health of CYP with LTCs, (b) a systematic review exploring the experiences of interventions intended to improve the mental well‐being of CYP with LTCs and (c) an overarching synthesis. The CYPAG greatly contributed to the team's understanding and appreciation of the wider context of the research. The young people found the experience of involvement empowering and felt they would use the knowledge they had gained about the research process in the future. Conclusion Creating an environment that enabled meaningful engagement between the research team and the CYPAG had a beneficial influence on the young people themselves, as well as on the review process and the interpretation, presentation and dissemination of findings.

Background Malaria is a deadly parasitic disease that affects more than 3 billion people worldwide, in predominantly resource-poor countries. Despite malaria being preventable and treatable, a large number of adults and children, mostly in Africa, die from this disease each year. One contributor to needless morbidity and mortality is the production and distribution of poor-quality antimalarial medicines; indeed, it is estimated that over 122,000 deaths of children under 5 years of age in sub-Saharan countries were caused by poor-quality antimalarial medicines, in 2013 alone. Discussion Poor-quality medicines include those that are deliberately falsified for monetary gain and may contain incorrect amounts or even no active ingredients at all, as well as products that are inadequate due to poor compliance to conventional quality standards and medicines that have degraded over time. Across a number of studies it has been reported that 4-92% of antimalarials tested are poor quality. This represents a massive risk to the population subjected to the use of these medicines, in the form of more severe and prolonged illness, additional costs to individuals who already have very little money, and lack of confidence in treatments. The continuing circulation of poor-quality medicines results from a number of factors, including insufficient regulatory capacity in susceptible countries, inadequate funding to perform regulatory functions, poor coordination between regulatory authorities, and inefficient import/export control systems. To combat the distribution of poor-quality medicines a number of organisations have developed guidelines for the procurement of antimalarials, and programs to educate consumers about the risks of poor-quality medicines and incentivise retailers to identify and report falsified medicines. The development of new technologies to quickly identify poor-quality medicines in the field is also essential, and some significant advances have been made. Conclusion There has been considerable improvement in the delivery of high-quality antimalarials to those who need them; however, there is still an urgent need for a collective response by the international community, political leaders, regulatory bodies, and pharmaceutical companies. This should include political commitment for enhanced research and development funding, such as for new innovative track-and-trace field devices, and international efforts to strengthen and harmonise drug regulation practices.

The inclusion of community voices in research is important. Over the years, research training programs have continued to emphasize that engagement with communities at the focus of research can promote thoughtful, sensitive designs (Rivera et al., 2004). In this paper, we discuss a method for youth participation in the research process. In an attempt to move beyond “staged and superficial” participation in gathering youth perspectives, we advocate for including co-researchers in the development and modification of fundamental aspects of the research process, from data analysis to the development of additional research questions and collection methods (Guishard & Tuck, 2013). In the course of a study designed to enroll middle school students in participatory co-design sessions (Cahill, 2007) to aid in the development of educational technologies, it became apparent that our youth participants, as co-researchers, could also aid in the development, analysis, and coding of anonymized interview transcripts; development of themes; and creation of models for behaviors found in the transcripts (Docan-Morgan, 2010; Luchtenberg et al., 2020). Thus, this paper presents a practical example of a co-research process that includes youth participants, with an emphasis on training in qualitative coding and the fundamentals of research design.

A genomewide association analysis of patients with primary biliary cirrhosis suggests that variation in interleukin-12 signaling may confer a risk of disease. This study also firmly implicates variants at the HLA locus as a risk factor. A genomewide association analysis of patients with primary biliary cirrhosis suggests that variation in interleukin-12 signaling may confer a risk of disease. This study also firmly implicates variants at the HLA locus as a risk factor. Primary biliary cirrhosis is the most common autoimmune liver disease, affecting up to 1 in 1000 women over 40 years of age. 1 Treatment for this chronic cholestatic condition remains empirical. 2 The granulomatous destruction of interlobular bile ducts that characterizes primary biliary cirrhosis is almost always associated with antimitochondrial antibodies specific for the E2 subunit of the pyruvate dehydrogenase complex. 3 The hepatic accumulation of autoreactive T lymphocytes in patients with primary biliary cirrhosis, as well as data from animal models of autoimmune cholangitis, implicate T lymphocytes — CD4+ T helper lymphocytes in particular — in the pathogenesis of primary biliary cirrhosis. . . .