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Pancreatic cancer is not caused by a specific series of genetic alterations that occur sequentially but by one, or few, catastrophic events that result in simultaneous oncogenic genetic rearrangements, giving rise to highly aggressive tumours. Pancreatic cancer genome evolution Pancreatic cancer is a highly aggressive tumour type. With a view to examining the evolution of rapid tumour progression in this cancer, this paper presents an analysis of more than a hundred tumour-enriched whole-genome sequences from primary and metastatic pancreas cancers obtained from collaborating hospitals in Canada and the United States of America. Challenging a traditional model of progressive evolution based on ordered mutations in several genes, the authors find support for a role of complex rearrangements and chromothripsis in pancreatic cancer progression, which suggests that the genomic instability that marks this cancer may be explained by a punctuated equilibrium model. Pancreatic cancer, a highly aggressive tumour type with uniformly poor prognosis, exemplifies the classically held view of stepwise cancer development 1 . The current model of tumorigenesis, based on analyses of precursor lesions, termed pancreatic intraepithelial neoplasm (PanINs) lesions, makes two predictions: first, that pancreatic cancer develops through a particular sequence of genetic alterations 2 , 3 , 4 , 5 ( KRAS , followed by CDKN2A , then TP53 and SMAD4 ); and second, that the evolutionary trajectory of pancreatic cancer progression is gradual because each alteration is acquired independently. A shortcoming of this model is that clonally expanded precursor lesions do not always belong to the tumour lineage 2 , 5 , 6 , 7 , 8 , 9 , indicating that the evolutionary trajectory of the tumour lineage and precursor lesions can be divergent. This prevailing model of tumorigenesis has contributed to the clinical notion that pancreatic cancer evolves slowly and presents at a late stage 10 . However, the propensity for this disease to rapidly metastasize and the inability to improve patient outcomes, despite efforts aimed at early detection 11 , suggest that pancreatic cancer progression is not gradual. Here, using newly developed informatics tools, we tracked changes in DNA copy number and their associated rearrangements in tumour-enriched genomes and found that pancreatic cancer tumorigenesis is neither gradual nor follows the accepted mutation order. Two-thirds of tumours harbour complex rearrangement patterns associated with mitotic errors, consistent with punctuated equilibrium as the principal evolutionary trajectory 12 . In a subset of cases, the consequence of such errors is the simultaneous, rather than sequential, knockout of canonical preneoplastic genetic drivers that are likely to set-off invasive cancer growth. These findings challenge the current progression model of pancreatic cancer and provide insights into the mutational processes that give rise to these aggressive tumours.

Chemotherapy treatment of cancer remains a challenge due to the molecular and functional heterogeneity displayed by tumours originating from the same cell type. The pronounced heterogeneity makes it difficult for oncologists to devise an effective therapeutic strategy for the patient. One approach for increasing treatment efficacy is to test the chemosensitivity of cancer cells obtained from the patient's tumour. 3D culture represents a promising method for modelling patient tumours in vitro. The aim of this study was therefore to evaluate how closely short-term spheroid cultures of primary colorectal cancer cells resemble the original tumour. Colorectal cancer cells were isolated from human tumour tissue and cultured as spheroids. Spheroid cultures were established with a high success rate and remained viable for at least 10 days. The spheroids exhibited significant growth over a period of 7 days and no difference in growth rate was observed for spheroids of different sizes. Comparison of spheroids with the original tumour revealed that spheroid culture generally preserved adenocarcinoma histology and expression patterns of cytokeratin 20 and carcinoembryonic antigen. Interestingly, spheroids had a tendency to resemble tumour protein expression more closely after 10 days of culture compared to 3 days. Chemosensitivity screening using spheroids from five patients demonstrated individual response profiles. This indicates that the spheroids maintained patient-to-patient differences in sensitivity towards the drugs and combinations most commonly used for treatment of colorectal cancer. In summary, short-term spheroid culture of primary colorectal adenocarcinoma cells represents a promising in vitro model for use in personalized medicine.

Balanced chromosomal rearrangements are associated with infertility and recurrent miscarriage but are difficult to detect. In this study, long-read DNA sequencing identified BCRs in 11 of 27 euploid embryos from 11 couples; transfer of euploid embryos has resulted in 6 euploid live births.

To determine levels of objectively measured physical activity (PA) and the proportion of adults with multimorbidity that adheres to PA guidelines. All studies, where PA was measured at baseline using an activity monitor in an adult ([greater than or equal to]18 years) multimorbid ([greater than or equal to]80% of the population had [greater than or equal to]2 chronic conditions) population. A systematic literature search was performed in Medline, EMBASE, CINAHL, CENTRAL, ClinicalTrials.gov, opengrey.eu and google.com from inception up until 18.sup.th of January 2022. Risk of bias was assessed with a modified version of the Quality Assessment Tool for Quantitative Studies. A random-effects meta-analyses was performed to estimate daily minutes of sedentary behavior (SB), light PA (LPA), moderate PA (MPA), moderate to vigorous PA (MVPA) and steps. Proportions adhering to PA guidelines was narratively synthesized. Certainty of evidence was determined using The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Fifteen studies (2,172 participants) were included. The most frequent combination of conditions were type 2 diabetes and hypertension (six studies). Participants spent a daily average of 500.5 (95% CI: 407.1 to 593.9) minutes in SB, 325.6 (95% CI: 246.4 to 404.7 minutes in LPA and 32.7 (95% CI: 20.2 to 45.3) minutes in MVPA. The mean daily number of steps was 5,145 (95% CI: 4264 to 6026) for people in free-living conditions. The proportion adhering to PA guidelines ranged widely (7.4% to 43%). All studies were rated as at high risk of bias and the certainty of evidence was very low. PA levels and adherence varied from low to above guideline recommended levels for adults with chronic conditions, depending on PA intensity. The very low certainty of evidence calls for high quality studies focusing on detailed descriptions of PA behavior in people with multimorbidity.

Ingenol is a diterpenoid with unique architecture and has derivatives possessing important anticancer activity, including the recently Food and Drug Administration—approved Picato, a first-in-class drug for the treatment of the precancerous skin condition actinic keratosis. Currently, that compound is sourced inefficiently from Euphorbia peplus. Here, we detail an efficient, highly stereocontrolled synthesis of (+)-ingenol proceeding in only 14 steps from inexpensive (+)-3-carene and using a two-phase design. This synthesis will allow for the creation of fully synthetic analogs of bioactive ingenanes to address pharmacological limitations and provides a strategic blueprint for chemical production. These results validate two-phase terpene total synthesis as not only an academic curiosity but also a viable alternative to isolation or bioengineering for the efficient preparation of polyoxygenated terpenoids at the limits of chemical complexity.

Background Open component separation (OCS) for tension-free approximation of fascial borders is increasingly used for repair of large midline ventral hernias. Recent studies suggested lower complication rates following a modified version of this technique with an endoscopic approach (ECS). The aim of this meta-analysis was to compare the outcomes after ECS and OCS. Methods A literature search was performed in PubMed and Embase in order to identify studies comparing ECS and OCS as a supplementary procedure for surgical repair of ventral hernia. The included studies were independently assessed using the Newcastle Ottawa Scale. Outcomes analyzed were wound complications, hernia recurrence and length of stay. A meta-analysis on the pooled data was performed. Results The literature search identified 222 articles, of which five retrospective comparative cohort studies were included in the review and meta-analysis reporting on a total of 163 patients. Patient demography and the rates of mesh repair were comparable between the ECS and OCS patient groups. The incidence of wound complications comprising surgical site infection, skin necrosis, subcutaneous abscess, seroma, skin dehiscence, cellulitis, and fistula was significantly less after ECS (odds ratio [OR] 0.27, 95 % confidence interval [CI] 0.12–0.58, p  < 0.001). The incidence of recurrent hernia was 13 % after ECS and 16 % after OCS (OR 0.76, 95 % CI 0.29–1.98, p  = 0.57). Four studies reported length of stay that was comparable between the groups (mean difference −0.14 days, 95 % CI −1.49 to 1.21, p  = 0.84). Conclusions ECS causes fewer wound complications compared with OCS.

Background The Cochrane risk of bias tool for randomized clinical trials was introduced in 2008 and has frequently been commented on and used in systematic reviews. We wanted to evaluate the tool by reviewing published comments on its strengths and challenges and by describing and analysing how the tool is applied to both Cochrane and non-Cochrane systematic reviews. Methods A review of published comments (searches in PubMed, The Cochrane Methodology Register and Google Scholar) and an observational study (100 Cochrane and 100 non-Cochrane reviews from 2014). Results Our review included 68 comments, 15 of which were categorised as major. The main strengths of the tool were considered to be its aim (to assess trial conduct and not reporting), its developmental basis (wide consultation, empirical and theoretical evidence) and its transparent procedures. The challenges of the tool were mainly considered to be its choice of core bias domains (e.g. not involving funding/conflicts of interest) and issues to do with implementation (i.e. modest inter-rater agreement) and terminology. Our observational study found that the tool was used in all Cochrane reviews (100/100) and was the preferred tool in non-Cochrane reviews (31/100). Both types of reviews frequently implemented the tool in non-recommended ways. Most Cochrane reviews planned to use risk of bias assessments as basis for sensitivity analyses (70 %), but only a minority conducted such analyses (19 %) because, in many cases, few trials were assessed as having “low” risk of bias for all standard domains (6 %). The judgement of at least one risk of bias domain as “unclear” was found in 89 % of included randomized clinical trials (1103/1242). Conclusions The Cochrane tool has become the standard approach to assess risk of bias in randomized clinical trials but is frequently implemented in a non-recommended way. Based on published comments and how it is applied in practice in systematic reviews, the tool may be further improved by a revised structure and more focused guidance.

Background No standardized written or volumetric definition exists for ‘loss of domain’ (LOD). This limits the utility of LOD as a morphological descriptor and as a predictor of peri- and postoperative outcomes. Consequently, our aim was to establish definitions for LOD via consensus of expert abdominal wall surgeons. Methods A Delphi study involving 20 internationally recognized abdominal wall reconstruction (AWR) surgeons was performed. Four written and two volumetric definitions of LOD were identified via systematic review. Panelists completed a questionnaire that suggested these definitions as standardized definitions of LOD. Consensus on a preferred term was pre-defined as achieved when selected by ≥80% of panelists. Terms scoring <20% were removed. Results Voting commenced August 2018 and was completed in January 2019. Written definition: During Round 1, two definitions were removed and seven new definitions were suggested, leaving nine definitions for consideration. For Round 2, panelists were asked to select all appealing definitions. Thereafter, common concepts were identified during analysis, from which the facilitators advanced a new written definition. This received 100% agreement in Round 3. Volumetric definition: Initially, panelists were evenly split, but consensus for the Sabbagh method was achieved. Panelists could not reach consensus regarding a threshold LOD value that would preclude surgery. Conclusions Consensus for written and volumetric definitions of LOD was achieved from 20 internationally recognized AWR surgeons. Adoption of these definitions will help standardize the use of LOD for both clinical and academic activities.

Background Mesh reinforcement is recommended for repair of primary ventral hernias; however, this recommendation does not consider a potential subsequent pregnancy. The aim of this prospective cohort study was to compare mesh and suture repair of a primary ventral hernia in women with a subsequent pregnancy. Methods All women of childbearing age who underwent repair of a primary ventral hernia between 2007 and 2014 were identified in the Danish Ventral Hernia Database. Data were merged with the Danish Medical Birth Registry. Women with a subsequent pregnancy and a propensity-score matched control group of women without a subsequent pregnancy were included. A structured questionnaire was sent out, and the primary outcome was hernia recurrence, while the secondary outcome was chronic postoperative pain. Results In total, 632 women were included, of whom 441 (69.8%) responded to the questionnaire (195 and 246 with and without subsequent pregnancy, respectively). The 8-year cumulative incidence of recurrence was 24.8%. In women with a subsequent pregnancy, mesh repair was associated with a decreased risk of recurrence (hazard ratio 0.44, 95% CI 0.20–0.95, p  = 0.038, number needed to treat = 5.1) and an increased risk of chronic pain (OR 5.07, 95% CI 1.20–23.38, p  = 0.029, number needed to harm = 4.7) compared with suture repair, in multivariable analyses. Conclusions Mesh repair was associated with a decreased risk of recurrence, but an increased risk of chronic pain, compared with suture repair in women with a subsequent pregnancy.

Fibroblast-driven deposition of extracellular matrix, particularly type III collagen, is linked to poor outcomes in patients with liver fibrosis, fibrotic solid tumors such as hepatocellular carcinoma and pancreatic cancer as well as in patients with other fibrotic diseases. The pro-peptide of type III collagen (PRO-C3) serves as a serum biomarker of active collagen formation. PRO-C3 is elevated and prognostic in patients with liver fibrosis and pancreatic cancer, suggesting that targeting mechanisms behind PRO-C3 elevation could benefit these individuals. In this study, we sought to identify genetic variants associated with circulating PRO-C3 levels as potential therapeutic targets for fibrotic diseases and cancer. A genome-wide association study (GWAS) of the PERF cohort ( n  = 4968) identified variants in the gene TGFBI (BIGH3/βigH3), a known risk factor for tumor fibrosis, as associated with elevated PRO-C3. Further analyses of serum samples from patients with pancreatic ductal adenocarcinoma and liver fibrosis confirmed significant correlations between PRO-C3 and BIGH3 levels. Functional studies in a fibroblast model demonstrated that BIGH3 induces PRO-C3 in a dose-dependent manner, which was blocked by an anti-BIGH3 antibody, indicating a causal role. BIGH3 expression was observed in macrophages and fibroblasts, especially under TGFβ stimulation, positioning BIGH3 as a downstream mediator of TGFβ-induced fibrosis. Finally, blocking BIGH3 in a TGFβ-induced fibrosis model led to reduced PRO-C3 levels, demonstrating that BIGH3 is local mediator of pathological TGFβ signaling. This highlights that BIGH3 may be implicated in TGFβ-induced fibrosis and underscore the potential for treatment of pathological fibrotic processes by inhibiting BIGH3 in patients with elevated PRO-C3 levels.