Irreversible Electroporation (IRE) in Locally Advanced Pancreatic Cancer: A Review of Current Clinical Outcomes, Mechanism of Action and Opportunities for Synergistic Therapy

Locally advanced pancreatic cancer (LAPC) accounts for 30% of patients with pancreatic cancer. Irreversible electroporation (IRE) is a novel cancer treatment that may improve survival and quality of life in LAPC. This narrative review will provide a perspective on the clinical experience of pancreas IRE therapy, explore the evidence for the mode of action, assess treatment complications, and propose strategies for augmenting IRE response. A systematic search was performed using PubMed regarding the clinical use and safety profile of IRE on pancreatic cancer, post-IRE sequential histological changes, associated immune response, and synergistic therapies. Animal data demonstrate that IRE induces both apoptosis and necrosis followed by fibrosis. Major complications may result from IRE; procedure related mortality is up to 2%, with an average morbidity as high as 36%. Nevertheless, prospective and retrospective studies suggest that IRE treatment may increase median overall survival of LAPC to as much as 30 months and provide preliminary data justifying the well-designed trials currently underway, comparing IRE to the standard of care treatment. The mechanism of action of IRE remains unknown, and there is a lack of data on treatment variables and efficiency in humans. There is emerging data suggesting that IRE can be augmented with synergistic therapies such as immunotherapy

Familial adenomatous patients with desmoid tumours show increased expression of miR-34a in serum and high levels in tumours

Familial adenomatous polyposis (FAP) is rare affecting 1 in 10,000 people and a subset (10%) are at risk of myofibroblastic desmoid tumours (DTs) after colectomy to prevent cancer. DTs are a major cause of morbidity and mortality. The absence of markers to monitor progression and a lack of treatment options are significant limitations to clinical management. We investigated microRNAs (miRNA) levels in DTs and serum using expression array analysis on two independent cohorts of FAP patients (total, n=24). Each comprised equal numbers of patients who had formed DTs (cases) and those who had not (controls). All controls had absence of DTs confirmed by clinical and radiological assessment over at least three years post- colectomy. Technical qPCR validation was performed using an expanded cohort (29 FAP patients; 16 cases and 13 controls). The most significant elevated serum miRNA marker of DTs was miR-34a-5p and in-situ hybridisation (ISH) showed most DTs analysed (5/6) expressed miRNA-34a-5p. Exome sequencing of tumour and matched germline DNA did not detect mutations within the miR-34a-5p transcript sites or 3'-UTR of target genes that would alter functional miRNA activity. In conclusion, miR-34a-5p is a potential circulatory marker and therapy target. A large prospective world-wide multi-centre study is now warranted

Analysis of colorectal cancers in British Bangladeshi identifies early onset, frequent mucinous histotype and a high prevalence of RBFOX1 deletion

PMCID: PMC3544714This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited

Remodelling of microRNAs in colorectal cancer by hypoxia alters metabolism profiles and 5-fluorouracil resistance

AN, HT and AP are Constance Travis post-graduate fellows. NS is a Barts and The London post-doctoral fellow. SMD is a Bowel & Cancer Research post-doctoral fellow. TS is supported by a Grant-in-Aid for scientific research on Innovative Areas, Japan (No. 22134007 to T.S.), and the Yamagata Prefectural Government and City of Tsuruoka

Hydroclimate in the Pamirs Was Driven by Changes in Precipitation‐Evaporation Seasonality Since theLast Glacial Period

The Central Asian Pamir Mountains (Pamirs) are a high‐altitude region sensitive to climatic change, with only few paleoclimatic records available. To examine the glacial‐interglacial hydrological changes in the region, we analyzed the geochemical parameters of a 31‐kyr record from Lake Karakul and performed a set of experiments with climate models to interpret the results. δD values of terrestrial biomarkers showed insolation‐driven trends reflecting major shifts of water vapor sources. For aquatic biomarkers, positive δD shifts driven by changes in precipitation seasonality were observed at ca. 31–30, 28–26, and 17–14 kyr BP. Multiproxy paleoecological data and modelling results suggest that increased water availability, induced by decreased summer evaporation, triggered higher lake levels during those episodes, possibly synchronous to northern hemispheric rapid climate events. We conclude that seasonal changes in precipitation‐evaporation balance significantly influenced the hydrological state of a large waterbody such as Lake Karakul, while annual precipitation amount and inflows remained fairly constant

Trends in kidney function testing in UK primary care since the introduction of the Quality and Outcomes Framework:a retrospective cohort study using CPRD

Objectives: To characterise serum creatinine and urinary protein testing in UK general practices from 2005 to 2013 and to examine how the frequency of testing varies across demographic factors, with the presence of chronic conditions and with the prescribing of drugs for which kidney function monitoring is recommended. Design: Retrospective open cohort study. Setting: Routinely collected data from 630 UK general practices contributing to the Clinical Practice Research Datalink. Participants: 4 573 275 patients aged over 18 years registered at up-to-standard practices between 1 April 2005 and 31 March 2013. At study entry, no patients were kidney transplant donors or recipients, pregnant or on dialysis. Primary outcome measures: The rate of serum creatinine and urinary protein testing per year and the percentage of patients with isolated and repeated testing per year. Results: The rate of serum creatinine testing increased linearly across all age groups. The rate of proteinuria testing increased sharply in the 2009–2010 financial year but only for patients aged 60 years or over. For patients with established chronic kidney disease (CKD), creatinine testing increased rapidly in 2006–2007 and 2007–2008, and proteinuria testing in 2009–2010, reflecting the introduction of Quality and Outcomes Framework indicators. In adjusted analyses, CKD Read codes were associated with up to a twofold increase in the rate of serum creatinine testing, while other chronic conditions and potentially nephrotoxic drugs were associated with up to a sixfold increase. Regional variation in serum creatinine testing reflected country boundaries. Conclusions: Over a nine-year period, there have been increases in the numbers of patients having kidney function tests annually and in the frequency of testing. Changes in the recommended management of CKD in primary care were the primary determinant, and increases persist even after controlling for demographic and patient-level factors. Future studies should address whether increased testing has led to better outcomes.</p

High temperatures in the terrestrial mid-latitudes during the early Palaeogene

The early Paleogene (56–48 Myr) provides valuable information about the Earth’s climate system in an equilibrium high pCO2 world. High ocean temperatures have been reconstructed for this greenhouse period, but land temperature estimates have been cooler than expected. This mismatch between marine and terrestrial temperatures has been difficult to reconcile. Here we present terrestrial temperature estimates from a newly calibrated branched glycerol dialkyl glycerol tetraether-based palaeothermometer in ancient lignites (fossilized peat). Our results suggest early Palaeogene mid-latitude mean annual air temperatures of 23–29 °C (with an uncertainty of ± 4.7 °C), 5–10 °C higher than most previous estimates. The identification of archaeal biomarkers in these same lignites, previously observed only in thermophiles and hyperthermophilic settings, support these high temperature estimates. These mid-latitude terrestrial temperature estimates are consistent with reconstructed ocean temperatures and indicate that the terrestrial realm was much warmer during the early Palaeogene than previously thought

Separation of Dual Oxidase 2 and Lactoperoxidase Expression in Intestinal Crypts and Species Differences May Limit Hydrogen Peroxide Scavenging During Mucosal Healing in Mice and Humans.

Background: DUOX2 and DUOXA2 form the predominant H2O2-producing system in human colorectal mucosa. Inflammation, hypoxia, and 5-aminosalicylic acid increase H2O2 production, supporting innate defense and mucosal healing. Thiocyanate reacts with H2O2 in the presence of lactoperoxidase (LPO) to form hypothiocyanate (OSCN-), which acts as a biocide and H2O2 scavenging system to reduce damage during inflammation. We aimed to discover the organization of Duox2, Duoxa2, and Lpo expression in colonic crypts of Lieberkühn (intestinal glands) of mice and how distributions respond to dextran sodium sulfate (DSS)-induced colitis and subsequent mucosal regeneration. Methods: We studied tissue from DSS-exposed mice and human biopsies using in situ hybridization, reverse transcription quantitative polymerase chain reaction, and cDNA microarray analysis. Results: Duox2 mRNA expression was mostly in the upper crypt quintile while Duoxa2 was more apically focused. Most Lpo mRNA was in the basal quintile, where stem cells reside. Duox2 and Duoxa2 mRNA were increased during the induction and resolution of DSS colitis, while Lpo expression did not increase during the acute phase. Patterns of Lpo expression differed from Duox2 in normal, inflamed, and regenerative mouse crypts (P < 0.001). We found no evidence of LPO expression in the human gut. Conclusions: The spatial and temporal separation of H2O2-consuming and -producing enzymes enables a thiocyanate- H2O2 "scavenging" system in murine intestinal crypts to protect the stem/proliferative zones from DNA damage, while still supporting higher H2O2 concentrations apically to aid mucosal healing. The absence of LPO expression in the human gut suggests an alternative mechanism or less protection from DNA damage during H2O2-driven mucosal healing.R.P. was funded by the Monument Trust. M.P.C. was funded by the CARIPLO Foundation (project 2010-0790) and the Italian Ministry of Health. A.R. was supported by an annual fellowship from Fondazione Umberto Veronesi

Epigenetic and metabolic reprogramming of fibroblasts in Crohn's disease strictures reveals histone deacetylases as therapeutic targets.

BACKGROUND & AIMS: No effective therapeutic intervention exists for intestinal fibrosis in Crohn's disease [CD]. We characterised fibroblast subtypes, epigenetic and metabolic changes, and signalling pathways in CD fibrosis to inform future therapeutic strategies. METHODS: We undertook immunohistochemistry, metabolic, signalling pathway and Epigenetic [Transposase-Accessible Chromatin using sequencing] analyses associated with collagen production in CCD-18Co intestinal fibroblasts and primary fibroblasts isolated from stricturing [SCD] and non-stricturing [NSCD] CD small intestine. SCD/ NSCD fibroblasts were cultured with TGFβ and valproic acid [VPA]. RESULTS: Stricturing CD was characterised by distinct histone deacetylase [HDAC] expression profiles, particularly HDAC1, HDAC2, and HDAC7. As a proxy for HDAC activity, reduced numbers of H3K27ac+ cells were found in SCD compared to NSCD sections. Primary fibroblasts had increased extracellular lactate [increased glycolytic activity] and intracellular hydroxyproline [increased collagen production] in SCD compared to NSCD cultures. The metabolic effect of TGFβ-stimulation was reversed by the HDAC inhibitor VPA. SCD fibroblasts appear "metabolically primed" and responded more strongly to both TGFβ and VPA. Treatment with VPA revealed TGFβ-dependent and independent Collagen-I production in CCD-18Co cells and primary fibroblasts. VPA altered the epigenetic landscape with reduced chromatin accessibility at the COL1A1 and COL1A2 promoters. CONCLUSIONS: Increased HDAC expression profiles, H3K27ac hypoacetylation, a significant glycolytic phenotype, and metabolic priming, characterise SCD-derived as compared to NSCD fibroblasts. Our results reveal a novel epigenetic component to Collagen-I regulation and TGFβ-mediated CD fibrosis. HDAC inhibitor therapy may 'reset' the epigenetic changes associated with fibrosis