• breast cancer
• cancer genomics
• genomic data integration
• homologous recombination deficiency
• semi‐supervised learning
• tumour biomarkers

• Breast Cancer as part of Programme Funding to the Breast Cancer Now Toby Robins Research Centre
• BRC-1215-20014 NIHR Cambridge Biomedical Research Centre
• MC_UU_00002/16 Medical Research Council

• Embryonic development
• Inflammation
• Netrin-1
• Tumorigenesis

• Netrin-1/genetics
• Netrin-1/metabolism
• Humans
• Animals
• Neurogenesis/genetics
• Neurodegenerative Diseases/genetics
• Neurodegenerative Diseases/metabolism
• Neurodegenerative Diseases/pathology
• Cell Movement

• Dyrk1a
• Netrin
• cancer biology
• dormancy
• high grade serous ovarian cancer
• mouse
• quiescence
• spheroids

• Humans
• Female
• Animals
• Signal Transduction
• Cell Line, Tumor
• Carcinoma, Ovarian Epithelial/genetics
• Carcinoma, Ovarian Epithelial/metabolism
• Carcinoma, Ovarian Epithelial/pathology
• Cell Survival
• Ovarian Neoplasms/genetics
• Ovarian Neoplasms/pathology
• Ovarian Neoplasms/metabolism
• Netrins/metabolism
• Netrins/genetics
• Mice
• Netrin-1/metabolism
• Netrin-1/genetics
• Cell Proliferation
• Netrin Receptors/metabolism
• Netrin Receptors/genetics

• 23150 Cancer Research Society
• 25021 Cancer Research Society
• P.CTIP.966 Ontario Institute for Cancer Research
• PJT173391 CIHR
• Canadian Institutes of Health Research

• Axon guidance
• Laminin-111
• Larynx
• Netrin-1
• Recurrent laryngeal nerve
• Vocal fold paralysis

• Netrin-1/metabolism
• Animals
• Humans
• Nerve Regeneration/physiology
• Larynx/physiology
• Nerve Growth Factors/metabolism
• Nerve Growth Factors/physiology
• Tumor Suppressor Proteins/metabolism
• Axon Guidance/physiology

• ADAMTS proteases
• extracellular matrix
• fibrillin microfibrils
• matricellular proteins
• musculoskeletal system

• Female
• Animals
• Drosophila melanogaster
• Genome-Wide Association Study
• Extracellular Matrix/genetics
• ADAMTS Proteins/genetics
• Caenorhabditis elegans
• Connective Tissue
• Mammals

• Caenorhabditis elegans
• Cell rearrangement
• Convergent extension
• Morphogenesis
• TIAM-1
• UNC-5

• Animals
• Actins/metabolism
• Caenorhabditis elegans/metabolism
• Caenorhabditis elegans Proteins/metabolism
• Epithelial Cells/metabolism
• Guanine Nucleotide Exchange Factors/metabolism
• Receptors, Cell Surface
• T-Lymphoma Invasion and Metastasis-inducing Protein 1/metabolism

• P40 OD010440 NIH HHS
• R01 GM127687 NIGMS NIH HHS
• R35 GM145312 NIGMS NIH HHS
• R01GM127687 NIH HHS
• National Institutes of Health

• ACC
• DCC
• dystonic postures
• mirror movements

• BRCA2
• Cholangiocarcinoma
• Genetic Testing
• Hepatocellular Carcinoma
• Personalized Medicine

• Male
• Humans
• Genome-Wide Association Study
• Genetic Predisposition to Disease
• Genetic Testing/methods
• Pancreatic Neoplasms/genetics
• Germ Cells

• R01 CA249929 NCI NIH HHS
• R37 CA259201 NCI NIH HHS
• R37 CA259201 NCI NIH HHS

• Axin
• Wnt
• adenomatous polyposis coli (APC)
• beta-catenin
• cancer
• glycogen synthase kinase 3 (GSK-3)
• mTOR

• Animals
• Wnt Signaling Pathway
• Glycogen Synthase Kinase 3
• Axin Protein
• beta Catenin
• Adenomatous Polyposis Coli

• R01 GM147210 NIGMS NIH HHS
• R01 CA277795 NCI NIH HHS
• R01 HL141759 NHLBI NIH HHS
• R21 AI161678 NIAID NIH HHS
• P30 CA013696 NCI NIH HHS
• R56 DK133258 NIDDK NIH HHS

• R01 NS123290 NINDS NIH HHS
• R25 GM109439 NIGMS NIH HHS

• ApcMin /+ mouse
• immunoguided laser microdissection
• interstitial deletion
• intestinal tumor
• radiation signature

• JP15K00550 Japan Society for the Promotion of Science

For optimizing fecal immunochemical test (FIT)-based screening programs, reducing the rate of missed colorectal cancers (CRCs) by FIT (FIT-interval CRCs) is an important aspect. Knowledge of the molecular make-up of these missed lesions could facilitate more accurate detection of all (precursor) lesions.

To compare the molecular make-up of FIT-interval CRCs to lesions that are detected by FIT [screen-detected CRCs (SD-CRCs)].

FIT-interval CRCs observed in a Dutch pilot-program of FIT-based screening were compared to a control group of SD-CRCs in a 1:2 ratio, resulting in 27 FIT-interval CRC and 54 SD-CRCs. Molecular analyses included microsatellite instability (MSI), CpG island methylator phenotype (CIMP), DNA sequence mutations and copy number alterations (CNAs).

Although no significant differences were reached, FIT-interval CRCs were more often CIMP positive and MSI positive (33% CIMP in FIT-interval CRCs vs 21% in SD-CRCs (P = 0.274); 19% MSI in FIT-interval CRCs vs 12% in SD-CRCs (P = 0.469)), and showed more often serrated pathway associated features such as BRAF (30% vs 12%, P = 0.090) and PTEN (15% vs 2.4%, P = 0.063) mutations. APC mutations, a classic feature of the adenoma-carcinoma-sequence, were more abundant in SD-CRCs (68% vs 40% in FIT-interval CRCs P = 0.035). Regarding CNAs differences between the two groups; FIT-interval CRCs less often showed gains at the regions 8p11.22-q24.3 (P = 0.009), and more often gains at 20p13-p12.1 (P = 0.039).

Serrated pathway associated molecular features seem to be more common in FIT-interval CRCs, while classic adenoma carcinoma pathway associated molecular features seem to be more common in SD-CRCs. This indicates that proximal serrated lesions may be overrepresented among FIT-interval CRCs.

• Fecal immunochemical test-interval colorectal cancer
• Mutation analysis
• Colorectal cancer screening
• Serrated pathway
• Adenoma-carcinoma pathway

The CSF1 receptor (CSF1R) encoding mRNA represents a direct target of miR-34a. However, the in vivo relevance of the suppression of CSF1R by miR-34a for intestinal tumor suppression mediated by the p53/miR-34a pathway has remained unknown. Here, Apc^Min/+ mice with intestinal-epithelial cell (IEC)-specific deletions of Mir34a showed increased formation of adenomas and decreased survival, whereas deletion of Csf1r decreased adenoma formation and increased survival. In adenomas deletion of Mir34a enhanced proliferation, STAT3 signaling, infiltration with fibroblasts, immune cells and microbes, and tumor stem cell abundance and decreased apoptosis. Deletion of Csf1r had the opposite effects. In addition, homeostasis of intestinal secretory and stem cells, and tumoroid formation were affected in opposite directions by deletion of Mir34a and CSF1R. Concomitant deletion of Csf1r and Mir34a neutralized the effects of the single deletions. mRNAs containing Mir34a seed-matching sites, which encode proteins related to EMT (epithelial-mesenchymal transition), stemness and Wnt signaling, were enriched after Mir34a inactivation in adenomas and derived tumoroids. Netrin-1/Ntn1 and Transgelin/Tagln were characterized as direct targets of Mir34a and Csf1r signaling. Mir34a-inactivation related expression signatures were associated with CMS4/CRISB+D, stage 4 CRCs and poor patient survival. In tumoroids the loss of Mir34a conferred resistance to 5-FU which was mediated by Csf1r. This study provides genetic evidence for a requirement of Mir34a-mediated Csf1r suppression for intestinal stem/secretory cell homeostasis and tumor suppression, and suggests that therapeutic targeting of CSF1R may be effective for the treatment of CRCs with defects in the p53/miR-34a pathway.

• Csf1r
• Tagln
• miR-34a
• APC
• CSF1R
• MiR34a
• Ntn1
• colorectal cancer
• intestinal adenomas
• p53

• A20
• Colon
• Inflammation
• Nitric oxide
• Tnfaip3
• Tumor
• Ulcerative colitis

• R03 DK118178 NIDDK NIH HHS

• Axon guidance
• Colorectal cancer
• DNA methylation
• Netrin-1
• VEGF-A

Although ileal neuroendocrine tumors are the most common tumors of the small intestine, they are not well-defined at the genetic level. Unlike most cancers, they have an unusually low number of mutations, and also lack recurrently mutated genes. Moreover ileal NETs have been difficult to study in the laboratory because there were no animal models and because cell lines were generally unavailable. But recent advances, including the first ileal NET mouse model as well as methods for culturing patient tumor samples, have been described and have already helped to identify IGF2 and CDK4 as two of the genetic drivers for this tumor type. These advances may help in the development of new treatments for patients.

The genetic causes of ileal neuroendocrine tumors (ileal NETs, or I-NETs) have been a mystery. For most types of tumors, key genes were revealed by large scale genomic sequencing that demonstrated recurrent mutations of specific oncogenes or tumor suppressors. In contrast, genomic sequencing of ileal NETs demonstrated a distinct lack of recurrently mutated genes, suggesting that the mechanisms that drive the formation of I-NETs may be quite different than the cell-intrinsic mutations that drive the formation of other tumor types. However, recent mouse studies have identified the IGF2 and RB1 pathways in the formation of ileal NETs, which is supported by the subsequent analysis of patient samples. Thus, ileal NETs no longer appear to be a cancer without genetic causes.

• ileal
• neuroendocrine

• DCC
• Netrin-1
• UNC5
• dependence receptors
• multiple myeloma

• Colorectal cancer
• Jammu and Kashmir
• MassARRAY™
• Single nucleotide polymorphism (SNPs)

• Case-Control Studies
• DCC Receptor/genetics
• Gallbladder Neoplasms/genetics
• Gallbladder Neoplasms/pathology
• Genes, DCC
• Genetic Predisposition to Disease
• Genotype
• Humans
• Polymorphism, Single Nucleotide
• Risk Factors

Dopamine (DA) is a behaviorally and clinically diverse neuromodulator that controls CNS function. DA plays major roles in many behaviors including locomotion, learning, habit formation, perception, and memory processing. Reflecting this, DA dysregulation produces a wide variety of cognitive symptoms seen in neuropsychiatric diseases such as Parkinson’s, Schizophrenia, addiction, and Alzheimer’s disease. Here, we review recent advances in the DA systems neuroscience field and explore the advancing hypothesis that DA’s behavioral function is linked to disease deficits in a neural circuit-dependent manner. We survey different brain areas including the basal ganglia’s dorsomedial/dorsolateral striatum, the ventral striatum, the auditory striatum, and the hippocampus in rodent models. Each of these regions have different reported functions and, correspondingly, DA’s reflecting role in each of these regions also has support for being different. We then focus on DA dysregulation states in Parkinson’s disease, addiction, and Alzheimer’s Disease, emphasizing how these afflictions are linked to different DA pathways. We draw upon ideas such as selective vulnerability and region-dependent physiology. These bodies of work suggest that different channels of DA may be dysregulated in different sets of disease. While these are great advances, the fine and definitive segregation of such pathways in behavior and disease remains to be seen. Future studies will be required to define DA’s necessity and contribution to the functional plasticity of different striatal regions.

• Alzheimer’s disease
• D1 Receptor
• D2 Receptor
• Parkinson’s disease
• addiction
• auditory striatum
• dopamine
• dopamine transporter
• dorsal striatum
• dorsolateral striatum
• dorsomedial striatum
• hippocampus
• neural circuits
• nucleus accumbens
• schizophrenia
• substantia nigra pars compacta
• ventral striatum
• ventral tegmental area

• T32 GM008444 NIGMS NIH HHS
• R21 DC016746 NIDCD NIH HHS
• F30 DC018214 NIDCD NIH HHS
• R01 DC017470 NIDCD NIH HHS

• BRCA1 y 2
• CAIX
• CDKN2A: cyclin-dependent kinase Inhibitor 2A
• Clear cell renal carcinoma
• MLPA
• p53

Colorectal cancer (CRC), the third most common type of cancer, is the second leading cause of cancer-related mortality rates worldwide. Although modern research was able to shed light on the pathogenesis of CRC and provide enhanced screening strategies, the prevalence of CRC is still on the rise. Studies showed several cellular signaling pathways dysregulated in CRC, leading to the onset of malignant phenotypes. Therefore, analyzing signaling pathways involved in CRC metastasis is necessary to elucidate the underlying mechanism of CRC progression and pharmacotherapy. This review focused on target genes as well as various cellular signaling pathways including Wnt/β-catenin, p53, TGF-β/SMAD, NF-κB, Notch, VEGF, and JAKs/STAT3, which are associated with CRC progression and metastasis. Additionally, alternations in methylation patterns in relation with signaling pathways involved in regulating various cellular mechanisms such as cell cycle, transcription, apoptosis, and angiogenesis as well as invasion and metastasis were also reviewed. To date, understanding the genomic and epigenomic instability has identified candidate biomarkers that are validated for routine clinical use in CRC management. Nevertheless, better understanding of the onset and progression of CRC can aid in the development of early detection molecular markers and risk stratification methods to improve the clinical care of CRC patients.

• Colorectal cancer
• chromosomal instability
• microsatellite instability
• molecular pathways
• therapeutics

The netrins form a family of laminin-related proteins which were first described as modulators of cell migration and axonal guidance during fetal development. Netrin-1 is the most extensively studied member of this family and, since its discovery, non-neural roles have been associated with it. Together with its receptors, DCC/neogenin and UNC5, netrin-1 has been shown to be involved in the regulation of angiogenesis, organogenesis, cancer and inflammation. An NF-κB-dependent truncated isoform of netrin-1 has also been shown to be produced in endothelial and some types of cancer cells, which both accumulates in and affects the function of the nucleus. In atherosclerosis, conflicting roles for netrin-1 have been reported on plaque progression via its receptor UNC5b. Whereas endothelial-derived netrin-1 inhibits chemotaxis of leukocytes and reduces the migration of monocytes to the atherosclerotic plaque, netrin-1 expressed by macrophages within the plaque plays a pro-atherogenic role, promoting cell survival, recruiting smooth muscle cells and inhibiting foam cell egress to the lymphatic system. In contrast, there is evidence that netrin-1 promotes macrophage differentiation to an alternative activated phenotype and induces expression of IL-4 and IL-13, while downregulate expression of IL-6 and COX-2. Further work is needed to elucidate the precise roles of the two isoforms of netrin-1 in different cell types in the context of atherosclerosis, and its potential as a putative novel therapeutic target in this disease.

• Pathophysiology
• atherosclerosis
• cardiology
• cell biology/structural biology
• cell signalling/signal transduction
• mechanism of atherosclerosis/growth factors
• vascular biology

• DCC gene mutation
• HGPPS2
• exome sequencing
• genotyping
• horizontal gaze palsy
• progressive scoliosis

• IL-17
• colorectal cancer
• gut
• intestine
• intraepithelial lymphocyte
• γδ T cells

• Humans
• Immunotherapy
• Neoplasms
• Receptors, Antigen, T-Cell, gamma-delta
• T-Lymphocyte Subsets

• A25142 Cancer Research UK
• MR/R502327/1 Medical Research Council
• 208990/Z/17/Z Wellcome Trust

• DCC
• Netrin1
• axon guidance
• chemoattractant molecules
• interpeduncular nucleus (IPN)
• neuronal tangential migration
• rhombomeres
• transcription factors

• Ataxia Telangiectasia Mutated Proteins/metabolism
• Cell Line, Tumor
• Chromosomes, Human/genetics
• Chromosomes, Human/metabolism
• Chromothripsis
• DNA Breaks, Double-Stranded
• DNA Cleavage
• DNA Repeat Expansion/genetics
• DNA Replication
• DNA-Binding Proteins/metabolism
• Dinucleotide Repeats/genetics
• Endodeoxyribonucleases/metabolism
• Endonucleases/metabolism
• Genomic Instability
• Humans
• Neoplasms/genetics
• Recombinases/metabolism
• Werner Syndrome Helicase/metabolism

• European Research Council
• 11582 Cancer Research UK
• MR/R009368/1 Medical Research Council
• ZIA BC010959 Intramural NIH HHS
• MR/R009368/1 Wellcome Trust
• R01 GM122880 NIGMS NIH HHS
• Wellcome Trust

• DCC
• apoptosis
• lnc-LAMC2-1:1
• miR-128
• ovarian cancer
• rs2147578

During neuronal development, the formation of neural circuits requires developing axons to traverse a diverse cellular and molecular environment to establish synaptic contacts with the appropriate postsynaptic partners. Essential to this process is the ability of developing axons to navigate guidance molecules presented by specialized populations of cells. These cells partition the distance traveled by growing axons into shorter intervals by serving as intermediate targets, orchestrating the arrival and departure of axons by providing attractive and repulsive guidance cues. The floor plate in the central nervous system (CNS) is a critical intermediate target during neuronal development, required for the extension of commissural axons across the ventral midline. In this review, we begin by giving a historical overview of the ventral commissure and the evolutionary purpose of decussation. We then review the axon guidance studies that have revealed a diverse assortment of midline guidance cues, as well as genetic and molecular regulatory mechanisms required for coordinating the commissural axon response to these cues. Finally, we examine the contribution of dysfunctional axon guidance to neurological diseases.

• Commissural axons
• Decussation
• Floor plate
• Midline guidance cues
• Neurological diseases
• Ventral commissure

Purpose: We determined whether electroacupuncture (EA) reduces Netrin-1-induced myelinated primary afferent nerve fiber sprouting in the spinal cord and pain hypersensitivity associated with postherpetic neuralgia (PHN) through activation of μ-opioid receptors.

Methods: PHN was induced by systemic injection of resiniferatoxin (RTX) in rats. Thirty-six days after RTX injection, a μ-opioid receptor antagonist, beta-funaltrexamine (β-FNA) or a κ-opioid receptor antagonist, nor Binaltorphimine (nor-BNI), was injected intrathecally 30 mins before EA, once every other day for 4 times. Mechanical allodynia was tested with von Frey filaments. The protein expression level of Netrin-1 and its receptors (DCC and UNC5H2) were quantified by using western blotting. The myelinated primary afferent nerve fiber sprouting was mapped with the transganglionic tracer cholera toxin B-subunit (CTB).

Results: Treatment with 2 Hz EA at “Huantiao” (GB30) and “Yanglingquan” (GB34) decreased the mechanical allodynia at 22 days and the myelinated primary afferent nerve fiber preternatural sprouting into the lamina II of the spinal dorsal horn at 42 days after RTX injection. Also, treatment with 2 Hz EA reduced the protein levels of DCC and Netrin-1 and promoted the expression of UNC5H2 in the spinal dorsal horn 42 days after RTX injection. Furthermore, the μ-opioid receptor antagonist β-FNA, but not the κ-opioid receptor antagonist nor-BNI, reversed the effect of EA on neuropathic pain caused by RTX. In addition, morphine inhibited the Netrin-1 protein level induced by RTX in SH-SY5Y cells.

Conclusions: Through activation of μ-opioid receptors, treatment with EA reduces the expression level of DCC and Netrin-1 and changes a growth-permissive environment in spinal dorsal horn into an inhibitory environment by increasing UNC5H2, thus decreasing RTX-caused primary afferent nerve sprouting in the spinal dorsal horn and neuropathic pain.

• analgesia
• mechanical hyperalgesia
• postherpetic neuralgia
• rat
• μ-opioid receptors