NDRG4 When you get on the gut’s nerves

Despite improved early detection and treatment options, colorectal cancer (CRC) is one of the deadliest forms of cancer. I discovered that NDRG4, an established biomarker for the early detection of CRC (Cologuard®) is specifically expressed in the gut’s intrinsic nervous system: enteric nervous system (ENS). While defects in the ENS have been implicated in life-threatening conditions, its contribution to CRC is hardly studied. This is remarkable as cells in the “tumor microenvironment” can contribute to (colorectal) carcinogenesis. I uncovered that NDRG4 affects ENS development and GI-functioning. Moreover, loss of NDRG4 enhanced colorectal tumorigenesis by the increased release of soluble factors. These findings implicate that the ENS is an new member of the (tumor) microenvironment which opens new perspectives for the development of clinical applications (biomarkers and/or treatment) for GI-disorders

Contraversive neglect? A modulation of visuospatial neglect in association with contraversive pushing

Objective: Contraversive pushing (CP) is a neurologic disorder characterized by a lateral postural imbalance. Pusher patients actively push toward their contralesional side due to a misperception of the body's orientation in relation to gravity. Although not every patient with CP suffers from spatial neglect (SN), both phenomena are highly correlated in right-hemispheric patients. The present study investigates whether peripersonal visuospatial functioning differs in neglect patients with versus without CP (NP+ vs. NP+ patients). Method: Eighteen right-hemispheric stroke patients with SN were included, of which 17 in a double-blind case-control study and 1 single case with posterior pushing to supplement the discourse. A computer-based visuospatial navigation task, in which lateralized deviation can freely emerge, was used to quantify visuospatial behavior. In addition, visuospatial orienting was monitored using line bisection. Results: Significant intergroup differences were found. The NP+ patients demonstrated a smaller ipsilesional navigational deviation and more cross-over (contralesional instead of ipsilesional deviation) in long line bisection. As such, they demonstrated a contraversive (contralesionally directed) shift in comparison with the NP+ patients. Conclusions: These findings highlight the similarity between 2 systems of space representation. They are consistent with a coherence between the neural processing system that mainly provides for postural control, and the one responsible for nonpredominantly postural, visuospatial behavior

Diagnostic DNA Methylation Biomarkers for Renal Cell Carcinoma:A Systematic Review

CONTEXT: The 5-yr survival of early-stage renal cell carcinoma (RCC) is approximately 93%, but once metastasised, the 5-yr survival plummets to 12%, indicating that early RCC detection is crucial to improvement in survival. DNA methylation biomarkers have been suggested to be of potential diagnostic value; however, their current state of clinical translation is unclear and a comprehensive overview is lacking. OBJECTIVE: To systematically review and summarise all literature regarding diagnostic DNA methylation biomarkers for RCC. EVIDENCE ACQUISITION: We performed a systematic literature review of PubMed, EMBASE, Medline, and Google Scholar up to January 2019, according to the Preferred Reporting Items for Systematic Review and Meta-Analysis of Diagnostic Test Accuracy Studies (PRISMA-DTA) guidelines. Included studies were scored according to the Standards for Reporting of Diagnostic Accuracy Studies (STARD) criteria. Forest plots were generated to summarise diagnostic performance of all biomarkers. Level of evidence (LoE) and potential risk of bias were determined for all included studies. EVIDENCE SYNTHESIS: After selection, 19 articles reporting on 44 diagnostic DNA methylation biomarkers and 11 multimarker panels were included; however, only 15 biomarkers were independently validated. STARD scores varied from 4 to 13 out of 23 points, with a median of 10 points. Large variation in subgroups, methods, and primer locations was observed. None of the reported biomarkers exceeded LoE III, and the majority of studies reported inadequately. CONCLUSIONS: None of the reported biomarkers exceeded LoE III, indicating their limited clinical utility. Moreover, study reproducibility and further development of these RCC biomarkers are greatly hampered by inadequate reporting. PATIENT SUMMARY: In this report, we reviewed whether specific biomarkers could be used to diagnose the most common form of kidney cancer. We conclude that due to limited evidence and reporting inconsistencies, none of these biomarkers can be used in clinical practice, and further development towards clinical use is hindered

The emerging role of nerves and glia in colorectal cancer

The role of the nervous system as a contributor in the tumor microenvironment has been recognized in different cancer types, including colorectal cancer (CRC). The gastrointestinal tract is a highly innervated organ system, which is not only innervated by the autonomic nervous system, but also contains an extensive nervous system of its own; the enteric nervous system (ENS). The ENS is important for gut function and homeostasis by regulating processes such as fluid absorption, blood flow, and gut motility. Dysfunction of the ENS has been linked with multiple gastrointestinal

Vitamin B-12 deficiency stimulates osteoclastogenesis via increased homocysteine and methylmalonic acid

The risk of nutrient deficiencies increases with age in our modern Western society, and vitamin B(12) deficiency is especially prevalent in the elderly and causes increased homocysteine (Hcy) and methylmalonic acid (MMA) levels. These three factors have been recognized as risk factors for reduced bone mineral density and increased fracture risk, though mechanistic evidence is still lacking. In the present study, we investigated the influence of B(12), Hcy, and MMA on differentiation and activity of bone cells. B(12) deficiency did not affect the onset of osteoblast differentiation, maturation, matrix mineralization, or adipocyte differentiation from human mesenchymal stem cells (hMSCs). B(12) deficiency caused an increase in the secretion of Hcy and MMA into the culture medium by osteoblasts, but Hcy and MMA appeared to have no effect on hMSC osteoblast differentiation. We further studied the effect of B(12), Hcy, and MMA on the formation of multinucleated tartrate-resistant acid phosphatase-positive osteoclasts from mouse bone marrow. We observed that B(12) did not show an effect on osteoclastogenesis. However, Hcy as well as MMA were found to induce osteoclastogenesis in a dose-dependent manner. On the basis of these results, we conclude that B(12) deficiency may lead to decreased bone mass by increased osteoclast formation due to increased MMA and Hcy levels

Rationale and design of the B-PROOF study, a randomized controlled trial on the effect of supplemental intake of vitamin B12 and folic acid on fracture incidence

Background: Osteoporosis is a major health problem, and the economic burden is expected to rise due to an increase in life expectancy throughout the world. Current observational evidence suggests that an elevated homocysteine concentration and poor vitamin B12and folate status are associated with an increased fracture risk. As vitamin B12and folate intake and status play a large role in homocysteine metabolism, it is hypothesized that supplementation with these B-vitamins will reduce fracture incidence in elderly people with an elevated homocysteine concentration. Methods/Design. The B-PROOF (B-Vitamins for the PRevention Of Osteoporotic Fractures) study is a randomized double-blind placebo-controlled trial. The intervention comprises a period of two years, and includes 2919 subjects, aged 65 years and older, independently living or institutionalized, with an elevated homocysteine concentration ( 12 mol/L). One group receives daily a tablet with 500 g vitamin B12and 400 g folic acid and the other group receives a placebo tablet. In both tablets 15 g (600 IU) vitamin D is included. The primary outcome of the study is osteoporotic fractures. Measurements are performed at baseline and after two years and cover bone health

Contraversive neglect? A potential modulation of spatial neglect in association with contraversive pushing

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