Clinical evidence that a dysregulated master neural network modulator may aid in diagnosing schizophrenia.

There are no validated biomarkers for schizophrenia (SCZ), a disorder linked to neural network dysfunction. We demonstrate that collapsin response mediator protein-2 (CRMP2), a master regulator of cytoskeleton and, hence, neural circuitry, may form the basis for a biomarker because its activity is uniquely imbalanced in SCZ patients. CRMP2's activity depends upon its phosphorylation state. While an equilibrium between inactive (phosphorylated) and active (nonphosphorylated) CRMP2 is present in unaffected individuals, we show that SCZ patients are characterized by excess active CRMP2. We examined CRMP2 levels first in postmortem brains (correlated with neuronal morphometrics) and then, because CRMP2 is expressed in lymphocytes as well, in the peripheral blood of SCZ patients versus age-matched unaffected controls. In the brains and, more starkly, in the lymphocytes of SCZ patients <40 y old, we observed that nonphosphorylated CRMP2 was higher than in controls, while phosphorylated CRMP2 remained unchanged from control. In the brain, these changes were associated with dendritic structural abnormalities. The abundance of active CRMP2 with insufficient opposing inactive p-CRMP2 yielded a unique lowering of the p-CRMP2:CRMP2 ratio in SCZ patients, implying a disruption in the normal equilibrium between active and inactive CRMP2. These clinical data suggest that measuring CRMP2 and p-CRMP2 in peripheral blood might reflect intracerebral processes and suggest a rapid, minimally invasive, sensitive, and specific adjunctive diagnostic aid for early SCZ: increased CRMP2 or a decreased p-CRMP2:CRMP2 ratio may help cinch the diagnosis in a newly presenting young patient suspected of SCZ (versus such mimics as mania in bipolar disorder, where the ratio is high).

DNA methylation is required for the control of stem cell differentiation in the small intestine.

The mammalian intestinal epithelium has a unique organization in which crypts harboring stem cells produce progenitors and finally clonal populations of differentiated cells. Remarkably, the epithelium is replaced every 3-5 d throughout adult life. Disrupted maintenance of the intricate balance of proliferation and differentiation leads to loss of epithelial integrity or barrier function or to cancer. There is a tight correlation between the epigenetic status of genes and expression changes during differentiation; however, the mechanism of how changes in DNA methylation direct gene expression and the progression from stem cells to their differentiated descendants is unclear. Using conditional gene ablation of the maintenance methyltransferase Dnmt1, we demonstrate that reducing DNA methylation causes intestinal crypt expansion in vivo. Determination of the base-resolution DNA methylome in intestinal stem cells and their differentiated descendants shows that DNA methylation is dynamic at enhancers, which are often associated with genes important for both stem cell maintenance and differentiation. We establish that the loss of DNA methylation at intestinal stem cell gene enhancers causes inappropriate gene expression and delayed differentiation.

Computer-Aided Detection of Quantitative Signatures for Breast Fibroepithelial Tumors Using Label-Free Multi-Photon Imaging.

Fibroadenomas (FAs) and phyllodes tumors (PTs) are major benign breast tumors, pathologically classified as fibroepithelial tumors. Although the clinical management of PTs differs from FAs, distinction by core needle biopsy diagnoses is still challenging. Here, a combined technique of label-free imaging with multi-photon microscopy and artificial intelligence was applied to detect quantitative signatures that differentiate fibroepithelial lesions. Multi-photon excited autofluorescence and second harmonic generation (SHG) signals were detected in tissue sections. A pixel-wise semantic segmentation method using a deep learning framework was used to separate epithelial and stromal regions automatically. The epithelial to stromal area ratio and the collagen SHG signal strength were investigated for their ability to distinguish fibroepithelial lesions. An image segmentation analysis with a pixel-wise semantic segmentation framework using a deep convolutional neural network showed the accurate separation of epithelial and stromal regions. A further investigation, to determine if scoring the epithelial to stromal area ratio and the SHG signal strength within the stromal area could be a marker for differentiating fibroepithelial tumors, showed accurate classification. Therefore, molecular and morphological changes, detected through the assistance of computational and label-free multi-photon imaging techniques, enable us to propose quantitative signatures for epithelial and stromal alterations in breast tissues.

[A Case of Breast Cancer during Pregnancy Treated with Neoadjuvant Chemotherapy during Pregnancy].

Although breast cancer during pregnancy is relatively rare, the number of such cases has risen in recent years owing to an increase in mean childbirth age and the increasing prevalence of breast cancer. Here we report the case of a 37-year-old breast cancer patient who received neoadjuvant chemotherapy during pregnancy. The woman previously consulted an outside physician after noting a mass in her right breast at 25 weeks' gestation. Breast ultrasonography revealed a right breast tumor and axillary lymphadenopathy. A histopathological examination indicated right breast cancer and axillary lymph node metastasis. She was referred to our department for pregnancy management. Chest X-rays and abdominal ultrasonography were utilized in the search for metastases. She received 2 courses of doxorubicin and cyclophosphamide(AC)therapy during pregnancy and gave birth via cesarean section at 35 weeks' gestation. After delivery, the AC was resumed. The patient completed a total of 4 courses of AC followed by 4 courses of docetaxel (dosed every 3 weeks). She underwent total right mastectomy and axillary dissection; because the tumor was BRCA2 mutation-positive, a risk-reducing salpingo- oophorectomy was also performed. Adjuvant therapy included radiotherapy and tamoxifen but no luteinizing hormone- releasing hormone agonists. At the time of this writing more than 1 year post-surgery, she has not experienced recurrence; although the infant has a congenital clubfoot, she suffers from no other cognitive or developmental delays.

Metaplastic carcinoma of the breast and BRCA1 germline mutation: a case report and review.

BACKGROUND: Metaplastic carcinoma of the breast consists of both invasive ductal carcinoma and metaplastic carcinoma. This rare subtype of cancer has a poor prognosis. The development of metaplastic breast cancer and relationship with BRCA1 are not well known. Here, we report a rare case of germline BRCA1 mutation-positive breast cancer with chondroid metaplasia. CASE PRESENTATION: A 39-year-old Japanese woman with a family history of breast cancer in her mother and ovarian cancer in her maternal grandmother consulted at our hospital with a left breast mass. Needle biopsy for the mass was performed, leading to a diagnosis of invasive breast cancer with chondroid metaplasia. We performed left mastectomy + sentinel lymph node biopsy + tissue expander insertion and replaced with a silicone implant later. Pathological examination revealed that the patient had triple-negative breast cancer. Four courses of doxorubicin+ cyclophosphamide therapy were performed as adjuvant therapy after surgery. We performed genetic counseling and genetic testing, and the results suggested the germline BRCA1 mutation 307 T> A (L63*). She has currently lived without a relapse for 2 years post-surgery. CONCLUSIONS: There have been only 6 cases of metaplastic breast carcinoma with germline BRCA1 mutations including our case. Patients with BRCA1 mutations may develop basal-like subtypes or M type of triple-negative breast cancer besides metaplastic breast cancers.

Foxl1-Cre-marked adult hepatic progenitors have clonogenic and bilineage differentiation potential.

Isolation of hepatic progenitor cells is a promising approach for cell replacement therapy of chronic liver disease. The winged helix transcription factor Foxl1 is a marker for progenitor cells and their descendants in the mouse liver in vivo. Here, we purify progenitor cells from Foxl1-Cre; RosaYFP mice and evaluate their proliferative and differentiation potential in vitro. Treatment of Foxl1-Cre; RosaYFP mice with a 3,5-diethoxycarbonyl-1,4-dihydrocollidine diet led to an increase of the percentage of YFP-labeled Foxl1(+) cells. Clonogenic assays demonstrated that up to 3.6% of Foxl1(+) cells had proliferative potential. Foxl1(+) cells differentiated into cholangiocytes and hepatocytes in vitro, depending on the culture condition employed. Microarray analyses indicated that Foxl1(+) cells express stem cell markers such as Prom1 as well as differentiation markers such as Ck19 and Hnf4a. Thus, the Foxl1-Cre; RosaYFP model allows for easy isolation of adult hepatic progenitor cells that can be expanded and differentiated in culture.

[A Treatment Strategy against Double Presentation of Breast Cancer and Malignant Lymphoma].

Case 1 involved a 75-year-old woman with breast cancer and diffuse large B-cell lymphoma(DLBCL).Although we initially administered the R-CHOP regimen, the breast tumor increased in size and surgery had to be performed.After surgery, the R-CHOP regimen was re-initiated and DLBCL achieved clinical complete response.Case 2 involved a 74-year-old woman with breast cancer and gastric MALT lymphoma.After administration of rituximab and H. pylori eradication, a therapeutic effect was achieved in the lymphoma.A docetaxel and FEC regimen was continuously administered and surgery was performed. Case 3 involved a 62-year-old woman with breast cancer and follicular lymphoma.She presented with a history of DLBCL treatment.We performed mastectomy and sentinel lymph node biopsy, which revealed metastasis of breast cancer, and axillary lymph node dissection was subsequently performed.Considering the pathological stage, adjuvant chemotherapy was needed.We selected the TCH regimen based on her past treatment.In conclusion, it is necessary to treat patients with double presentation of breast cancer and malignant lymphoma through cooperation with different departments.

[A Case of Microangiopathic Hemolytic Anemia with Bone Marrow Carcinomatosis from Breast Cancer].

We report a case of microangiopathic hemolytic anemia(MHA)caused by metastatic breast cancer treated with weekly paclitaxel. A 58-year-old woman was diagnosed with metastatic breast cancer 2 years earlier. She was treated with various chemotherapy regimens and hormonal therapy, before being switched to fulvestrant 3 months earlier. She presented with severe anemia, and was diagnosed with MHA with bone marrow carcinomatosis following bone marrow biopsy. She was treated with weekly paclitaxel and recovered successfully. A subsequent biopsy showed that the bone marrow carcinomatosis had decreased. MHA due to breast cancer is rare and is associated with poor prognosis; however, rapid initiation of chemotherapy may be effective.

A seven-transmembrane receptor that mediates avoidance response to dihydrocaffeic acid, a water-soluble repellent in Caenorhabditis elegans.

The ability to detect harmful chemicals rapidly is essential for the survival of all animals. In Caenorhabditis elegans (C. elegans), repellents trigger an avoidance response, causing animals to move away from repellents. Dihydrocaffeic acid (DHCA) is a water-soluble repellent and nonflavonoid catecholic compound that can be found in plant products. Using a Xenopus laevis (X. laevis) oocyte expression system, we identified a candidate dihydrocaffeic acid receptor (DCAR), DCAR-1. DCAR-1 is a novel seven-transmembrane protein that is expressed in the ASH avoidance sensory neurons of C. elegans. dcar-1 mutant animals are defective in avoidance response to DHCA, and cell-specific expression of dcar-1 in the ASH neurons of dcar-1 mutant animals rescued the defect in avoidance response to DHCA. Our findings identify DCAR-1 as the first seven-transmembrane receptor required for avoidance of a water-soluble repellent, DHCA, in C. elegans.

Non-traumatic bilateral rectus sheath hematoma during septic disseminated intravascular coagulation.

A non-traumatic abdominal wall hematoma is rare, and occurs occasionally due to coughing, physical activity, or antithrombotic/anticoagulant therapy. The condition is usually unilateral; however, rare bilateral cases have been reported. Here, we report a rare case of a non-traumatic bilateral rectus sheath hematoma. The patient was a 60-year-old woman who was urgently admitted to our hospital due to the occurrence of pneumonia during postoperative chemotherapy for breast cancer. Because she exhibited disseminated intravascular coagulation, a therapy with antibacterial agents, thrombomodulin alpha, and catecholamines was initiated. During hospitalization, hemorrhagic shock due to hematomas in both rectus abdominis muscles was observed without any discernible cause. Subsequent emergency angioembolization was successful, and abdominal computed tomography performed 3 months after the onset of the rectus sheath hematoma confirmed a reduction in the hematoma size.

A Case of a Rapidly Growing Granulocyte Colony-Stimulating Factor-Producing Squamous Cell Carcinoma of the Breast.

A 34-year-old woman with a rapidly growing right breast mass visited our hospital. The mass was diagnosed as a right breast cancer (cT3N1M0 stage ⦀A). Her serum leucocyte count and C-reactive protein levels were high, and she had persistent fever. However, serum procalcitonin and ß-D-glucan levels were normal, and no apparent infection focus was detected, although her serum granulocyte colony-stimulating factor (G-CSF) level was markedly elevated to 42.7 pg/mL. Therefore, a G-CSF-producing breast cancer was suspected. A pathological analysis of the surgical specimen revealed a squamous cell carcinoma of the breast (pT2N0 [i+] M0 stage ∥A). Right mastectomy (with the resection of the pectoralis major muscle), axillary lymph node dissection, and split layer grafting were performed. The leucocyte count and serum G-CSF level decreased on postoperative day (POD) 1 and normalized on POD 6. As adjuvant chemotherapy, 4 cycles of a combination chemotherapy with adriamycin and cyclophosphamide and 12 cycles of weekly paclitaxel were administered. After chemotherapy, the patient also underwent postmastectomy radiotherapy. Currently, 30 months after surgery, the patient is alive and well with neither progression nor distant metastasis. G-CSF-producing breast cancers tend to rapidly grow such as in the current case; thus, surgery should be performed immediately, followed by appropriate adjuvant treatment.

Patient-related Risk Factors for Nausea and Vomiting with Standard Antiemetics in Patients with Breast Cancer Receiving Anthracycline-based Chemotherapy: A Retrospective Observational Study.

PURPOSE: The aim of this study was to identify a high-risk or low-risk population for chemotherapy-induced nausea and vomiting among patients with breast cancer treated with a current standard 3-drug antiemetic regimen and receiving anthracycline. METHODS: We analyzed data from chemotherapy-naive Japanese patients with breast cancer, who had received the first cycle of anthracycline-based regimen and were treated with a 3-drug combination of aprepitant, palonosetron, and dexamethasone. This study was carried out at Ehime University Hospital (Toon, Japan) using electronic medical records from May 2011 to June 2017. The primary end point was complete response (CR), which was defined as no emesis and no use of rescue medication. FINDINGS: A total of 103 patients were included in this study. The percentages of patients who had a CR in the overall, acute, and delayed phases were 35.0%, 40.8%, and 50.5%, respectively. Multivariate logistic regression analysis revealed that age <55 years and body mass index <27.5 kg/m2 were significantly associated with an increased risk for CR failure in the overall and acute phases. In contrast, a history of alcohol habit was significantly associated with a decreased risk for CR failure in overall phase. IMPLICATIONS: The present findings suggest that, among patients with breast cancer receiving anthracycline and treated with aprepitant, palonosetron, and dexamethasone, patients younger than 55 years and having a body mass index <27.5 kg/m2 are high-risk populations for chemotherapy-induced nausea and vomiting, whereas those with a history of habitual alcohol consumption is a low-risk one.

Voltage-gated calcium and sodium channels mediate Sema3A retrograde signaling that regulates dendritic development.

Growing axons rely on local signaling at the growth cone for guidance cues. Semaphorin3A (Sema3A), a secreted repulsive axon guidance molecule, regulates synapse maturation and dendritic branching. We previously showed that local Sema3A signaling in the growth cones elicits retrograde retrograde signaling via PlexinA4 (PlexA4), one component of the Sema3A receptor, thereby regulating dendritic localization of AMPA receptor GluA2 and proper dendritic development. In present study, we found that nimodipine (voltage-gated L-type Ca(2+) channel blocker) and tetrodotoxin (TTX; voltage-gated Na(+) channel blocker) suppress Sema3A-induced dendritic localization of GluA2 and dendritic branch formation in cultured hippocampal neurons. The local application of nimodipine or TTX to distal axons suppresses retrograde transport of Venus-Sema3A that has been exogenously applied to the distal axons. Sema3A facilitates axonal transport of PlexA4, which is also suppressed in neurons treated with either TTX or nimodipine. These data suggest that voltage-gated calcium and sodium channels mediate Sema3A retrograde signaling that regulates dendritic GluA2 localization and branch formation.

Foxl1-expressing mesenchymal cells constitute the intestinal stem cell niche.

BACKGROUND & AIMS: Intestinal epithelial stem cells that express Lgr5 and/or Bmi1 continuously replicate and generate differentiated cells throughout life1. Previously, Paneth cells were suggested to constitute an epithelium-intrinsic niche that regulates the behavior of these stem cells2. However, ablating Paneth cells has no effect on maintenance of functional stem cells3-5. Here, we demonstrate definitively that a small subset of mesenchymal, subepithelial cells expressing the winged-helix transcription factor Foxl1 are a critical component of the intestinal stem cell niche. METHODS: We genetically ablated Foxl1+ mesenchymal cells in adult mice using two separate models by expressing either the human or simian diphtheria toxin receptor (DTR) under Foxl1 promoter control. CONCLUSIONS: Killing Foxl1+ cells by diphtheria toxin administration led to an abrupt cessation of proliferation of both epithelial stem- and transit-amplifying progenitor-cell populations that was associated with a loss of active Wnt signaling to the intestinal epithelium. Therefore, Foxl1-expressing mesenchymal cells constitute the fundamental niche for intestinal stem cells.

Localized role of CRMP1 and CRMP2 in neurite outgrowth and growth cone steering.

Collapsin response mediator protein 1 (CRMP1) and CRMP2 have been known as mediators of extracellular guidance cues such as semaphorin 3A and contribute to cytoskeletal reorganization in the axonal pathfinding process. To date, how CRMP1 and CRMP2 focally regulate axonal pathfinding in the growth cone has not been elucidated. To delineate the local functions of these CRMPs, we carried out microscale-chromophore-assisted light inactivation (micro-CALI), which enables investigation of localized molecular functions with highly spatial and temporal resolutions. Inactivation of either CRMP1 or CRMP2 in the neurite shaft led to arrested neurite outgrowth. Micro-CALI of CRMP2 in the central domain of the growth cones consistently arrested neurite outgrowth, whereas micro-CALI of CRMP1 in the same region caused significant lamellipodial retraction, followed by retardation of neurite outgrowth. Focal inactivation of CRMP1 in its half region of the growth cone resulted in the growth cone turning away from the irradiated site. Conversely, focal inactivation of CRMP2 resulted in the growth cone turning toward the irradiated site. These findings suggest different functions for CRMP1 and CRMP2 in growth cone behavior and neurite outgrowth.

α-synuclein promotes neuroprotection through NF-κB-mediated transcriptional regulation of protein kinase Cδ.

Parkinson's disease (PD) is a neurodegenerative disorder that results in a progressively debilitating loss of motor function and hypokinesia and is characterized by the selective loss of dopaminergic neurons in the substantia nigra pars compacta. Recent evidence suggests that caspase-3-dependent proteolytic cleavage and nuclear translocation of the δ isoform of protein kinase C (PKCδ) may be required for oxidative stress-induced dopaminergic cell death. Whereas several proteins have been postulated to contribute to dopaminergic neuron loss, the signaling cascades that mediate this selective neuron loss in PD are not well understood. The presynaptic protein α-synuclein (α-syn), mutations in which cause familial PD, has been implicated in pathways that influence both neuronal protection and apoptosis. However, the activities of α-syn in PD have not been elucidated at the molecular level, and whether α-syn is neuroprotective or neurotoxic remains controversial. This Journal Club discusses recent research indicating that α-syn may protect against dopaminergic cell death by down-regulating PKCδ, a key molecule that mediates apoptosis in these cells. These findings are the first steps toward the understanding of critical signaling pathways that might be important in PD pathogenesis and represent potential targets for developing new therapies.

Expression, transcription, and possible antagonistic interaction of the human Nedd4L gene variant: implications for essential hypertension.

Net sodium balances in humans are maintained through various ion transporters expressed along the entire nephron. Among these ion transporters, epithelial sodium channels (ENaC) located along the aldosterone-sensitive distal nephron (ASDN) play a pivotal role in the homeostasis of sodium balance. This is supported by analyses of inherited hypertensive disorders, showing that genes encoding ENaC and other modulatory proteins cause hereditary hypertension, such as Liddle syndrome. Among various modulating proteins, E3 ubiquitin ligase, Nedd4L, binds the PY motif of ENaC COOH terminals and catalyzes ubiquitination of the NH(2) terminus of the protein for subsequent degradation. Both evolutionarily conserved and evolutionarily new C2 domains of human Nedd4L, a cryptic splice variant resulting in a disrupted isoform product formed by a frame-shift mutation, were reported previously. We focused on one of the isoforms, isoform I, generated by SNP (rs4149601), and studied its expression and interactions with other isoforms by molecular biological, immunohistochemical, and electrophysiological methods. We found that isoform I may interact with other human isoforms in a dominant-negative fashion. Such interactions might abnormally increase sodium reabsorption. Taken together, our analyses suggest that the human Nedd4L gene, especially the evolutionarily new isoform I, is a candidate gene for hypertension.