CCL24 regulates biliary inflammation and fibrosis in primary sclerosing cholangitis

ˆCCL24 is a pro-fibrotic, pro-inflammatory chemokine expressed in several chronic fibrotic diseases. In the liver, CCL24 plays a role in fibrosis and inflammation, and blocking CCL24 led to reduced liver injury in experimental models. We studied the role of CCL24 in primary sclerosing cholangitis (PSC) and evaluated the potential therapeutic effect of blocking CCL24 in this disease. Multidrug resistance gene 2-knockout (Mdr2-/-) mice demonstrated CCL24 expression in liver macrophages and were used as a relevant experimental PSC model. CCL24-neutralizing monoclonal antibody, CM-101, significantly improved inflammation, fibrosis, and cholestasis-related markers in the biliary area. Moreover, using spatial transcriptomics, we observed reduced proliferation and senescence of cholangiocytes following CCL24 neutralization. Next, we demonstrated that CCL24 expression was elevated under pro-fibrotic conditions in primary human cholangiocytes and macrophages, and it induced proliferation of primary human hepatic stellate cells and cholangiocytes, which was attenuated following CCL24 inhibition. Correspondingly, CCL24 was found to be highly expressed in liver biopsies of patients with PSC. CCL24 serum levels correlated with Enhanced Liver Fibrosis score, most notably in patients with high alkaline phosphatase levels. These results suggest that blocking CCL24 may have a therapeutic effect in patients with PSC by reducing liver inflammation, fibrosis, and cholestasis

Mutational heterogeneity in cancer and the search for new cancer genes

Major international projects are now underway aimed at creating a comprehensive catalog of all genes responsible for the initiation and progression of cancer. These studies involve sequencing of matched tumor–normal samples followed by mathematical analysis to identify those genes in which mutations occur more frequently than expected by random chance. Here, we describe a fundamental problem with cancer genome studies: as the sample size increases, the list of putatively significant genes produced by current analytical methods burgeons into the hundreds. The list includes many implausible genes (such as those encoding olfactory receptors and the muscle protein titin), suggesting extensive false positive findings that overshadow true driver events. Here, we show that this problem stems largely from mutational heterogeneity and provide a novel analytical methodology, MutSigCV, for resolving the problem. We apply MutSigCV to exome sequences from 3,083 tumor-normal pairs and discover extraordinary variation in (i) mutation frequency and spectrum within cancer types, which shed light on mutational processes and disease etiology, and (ii) mutation frequency across the genome, which is strongly correlated with DNA replication timing and also with transcriptional activity. By incorporating mutational heterogeneity into the analyses, MutSigCV is able to eliminate most of the apparent artefactual findings and allow true cancer genes to rise to attention

Invasive Prenatal Diagnostic Testing Recommendations are Influenced by Maternal Age, Statistical Misconception and Perceived Liability

Funding policy and medico-legal climate are part of physicians’ reality and might permeate clinical decisions. This study evaluates the influence of maternal age and government funding on obstetrician/gynecologist recommendation for invasive prenatal testing (i.e. amniocentesis) for Down syndrome (DS), and its association with the physician’s assessment of the risk of liability for medical malpractice unless they recommend amniocentesis. Israeli physicians (N = 171) completed a questionnaire and provided amniocentesis recommendations for women at 18 weeks gestation with normal preliminary screening results, identical except aged 28 and 37. Amniocentesis recommendations were reversed for the younger (‘yes’ regardless of testing results: 6.4%; ‘no’ regardless of testing results: 31.6%) versus older woman (‘yes’ regardless of testing results: 40.9%; ‘no’ regardless of testing results: 7.0%; χ2 = 71.55, p < .01). About half of the physicians endorsed different recommendations per scenario; of these, 65.6% recommended amniocentesis regardless of testing results for the 37-year-old woman. Physicians routinely performing amniocentesis and those advocating for amniocentesis for all women ≥ age 35 were approximately twice as likely to vary their recommendations per scenario. Physicians who perceived risk of liability for malpractice as large were nearly one-and-a-half times more likely to vary recommendations. The results indicate physicians’ recommendations are influenced by maternal age, though age is already incorporated in prenatal DS risk evaluations. The physician’s assessment of the risk that they will be sued unless they recommend amniocentesis may contribute to this spurious influence

Fixational stability as a measure for the recovery of visual function in amblyopia

People with amblyopia have been shown to have decreased fixational stability, particularly those with strabismic amblyopia. Fixational stability and visual acuity have been shown to be tightly correlated across multiple studies, suggesting a relationship between acuity and oculomotor stability. Reduced visual acuity is the sine qua non of amblyopia, and recovery is measured by the improvement in visual acuity. Here we ask whether fixational stability can be used as an objective marker for the recovery of visual function in amblyopia. We tracked children's fixational stability during patching treatment over time and found fixational stability changes alongside improvements in visual acuity. This suggests fixational stability can be used as an objective measure for monitoring treatment in amblyopia and other disorders