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Background: The incidence, predictors, and clinical impact of lead break during transvenous lead extraction (TLE) were previously unknown., Methods: We included consecutive patients who underwent TLE between September 2013 and July 2019 at our institute. Lead break during removal was defined as lead stretching and becoming misshapen, as assessed by fluoroscopy., Results: A total of 246 patients underwent TLE for 501 leads. At a patient level, complete success was achieved in 226 patients (91.9%). At a lead level, 481 leads (96.0%) were completely removed and 101 leads (20.1%) were broken during the procedure. Of 392 identified pacemaker leads, 71 (18.3%) were broken during the TLE procedure. A multivariable analysis confirmed high lead age (odds ratio [OR] 1.12, 95% confidence interval (CI) 1.07-1.17; P  < .001), passive leads (OR 2.29 95% CI 1.09-4.80; P  = .028), coradial leads (OR 3.45 95% CI 1.72-6.92; P  < .001), and insulators made of nonpolyurethane (OR 2.38 95% CI 1.03-5.26; P  = .04) as predictors of lead break. Broken leads needed longer procedure times and were associated with a higher rate of cardiac tamponade., Conclusions: Lead age, coradial bipolar leads, passive leads, and leads without polyurethane insulation were predictors of lead break and could increase the difficulty of lead extraction., Competing Interests: Authors declare no Conflict of Interests for this article., (© 2021 The Authors. Journal of Arrhythmia published by John Wiley & Sons Australia, Ltd on behalf of the Japanese Heart Rhythm Society.)

Achieving multiple physical properties from a single material through three-dimensional (3D) printing is important for manufacturing applications. In addition, industrial-level durability and reliability is necessary for realizing individualized manufacturing of devices using 3D printers. We investigated the properties of architected materials composed of ultraviolet (UV)-cured urethane elastomers for use as insoles. The durability and reliability of microlattice and metafoam architected materials were compared with those composed of various foamed materials currently used in medical insoles. The hardness of the architected materials was able to be continuously adjusted by controlling the design parameters, and the combination of the two materials was effective in controlling rebound resilience. In particular, the features of the architected materials were helpful for customizing the insole properties, such as hardness, propulsive force, and shock absorption, according to the user's needs. Further, using elastomer as a component led to better results in fatigue testing and UV resistance compared with the plastic foam currently used for medical purposes. Specifically, polyethylene and ethylene vinyl acetate were deformed in the fatigue test, and polyurethane was mechanically deteriorated by UV rays. Therefore, these architected materials are expected to be reliable for long-term use in insoles.

Seven years after the Great East Japan Earthquake, we investigated telomeres as a potential biomarker of maternal chronic stress in children according to the timing of exposure to the disaster. The subjects were children aged 5-9 years living in Rikuzentakata, Japan. Relative telomere length (rTL) was measured with PCR in saliva samples. The partial regression coefficient of the rTL was significantly shorter in the group of children conceived after the disaster than in the children who were in utero on the day of the disaster. Telomere length should be investigated as a biomarker for assessing disaster-related trauma in future studies., (Copyright © 2020. Published by Elsevier B.V.)

An anesthetic mixture of medetomidine, midazolam and butorphanol (MMB) has been recently used in laboratory animals. We observed corneal opacity in nephrectomized rats that had undergone two operations under MMB anesthesia at 4 and 5 weeks of age. To evaluate the features of this corneal opacity, ophthalmic examinations were conducted in 83 nephrectomized rats, and 8 representative animals with corneal opacity were evaluated histopathologically 4 weeks after operation. The ophthalmic examinations revealed that 66/83 animals had corneal opacity, which was characterized histopathologically by mineralization with or without inflammation in the corneal stroma. In addition, to examine the possible causes of this corneal opacity, we investigated whether similar corneal changes were induced by the MMB anesthetic treatment in normal rats. The MMB anesthetic was administered twice to 4- and 5-week-old normal SD rats (5 animals/age) in the same manner as for the nephrectomized rats. Ophthalmic examinations were conducted in all the animals once a week, and the animals were necropsied 4 weeks after the first administration. In normal rats, similar corneal opacity was observed after the first administration, and increases in the severity and size of the corneal opacity were noted after the second administration. In conclusion, this study revealed the features of corneal opacity in rats undergoing nephrectomy under MMB anesthesia and the occurrence of similar corneal opacity in normal rats treated with MMB anesthetic. To the best of our knowledge, this is the first report of corneal opacity related to MMB anesthetic treatment in rats.

The critical phenomena of double percolation on polybutadiene (PB)/polyethylene glycol (PEG) blends loaded with poly-3-hexylthiophene (P3HT) nanofibers is investigated. P3HT nanofibers are selectively localized in the PB phase of the PB/PEG blend, as observed by scanning force microscopy (SFM). Moreover, double percolation is observed, i.e., the percolation of the PB phase in PB/PEG blends and that of the P3HT nanofibers in the PB phase. The percolation threshold ( φ c I ) and critical exponent ( t I ) of the percolation of the PB phase in PB/PEG blends are estimated to be 0.57 and 1.3, respectively, indicating that the percolation exhibits two-dimensional properties. For the percolation of P3HT nanofibers in the PB phase, the percolation threshold ( φ c II ) and critical exponent ( t II ) are estimated to be 0.02 and 1.7, respectively. In this case, the percolation exhibits properties in between two and three dimensions. In addition, we investigated the dimensionality with respect to the carrier transport in the P3HT nanofiber network. From the temperature dependence of the field-effect mobility estimated by field-effect transistor (FET) measurements, the carrier transport was explained by a three-dimensional variable range hopping (VRH) model.

Objective: This study aimed to assess the relationship of the prostate cancer and Gleason scores (GSs) or ISUP Grade system with prostate volume (PV) as assessed by magnetic resonance imaging (MRI) cognitive biopsy and standard biopsy., Material and Methods: Data were collected from 659 patients who underwent MRI cognitive biopsy and standard biopsy from January 2014 to January 2018. The biopsies were performed because of increased prostate-specific antigen (PSA) levels (>4 ng/mL) and/or abnormal digital rectal examination findings. Transrectal ultrasound was used to measure PV., Results: Prostate cancer detection rates in patients with increased PVs of ≤40 cc and >40 cc were 68.8% and 51.6% (p<0.001), respectively. ISUP Grade group ≥2 (Gleason score ≥3+4) detection rates for increased PVs of ≤40 cc and >40 cc were 68% and 73%, and 22.3% and 37.8%, respectively, for those with ISUP Grade group ≥4 (Gleason score ≥8) (p=0.003). Among the patients with PV>40 cc, univariate logistic regression showed a significant relationship between ISUP Grade group ≥2 and PSA, free/total PSA, PSA density, and MRI (p<0.05). On multivariable logistic regression, MRI (p=0.014) and PSA (p=0.039) predicted ISUP Grade group ≥2 in patients with PV>40 cc., Conclusion: Although the detection rates of prostate cancer decreased as PV increased, the detection of prostate cancer aggressiveness increased as PV increased. This increase in high ISUP Grade lesions with the rise in PV is due to the use of MRI during prostate biopsy with standard biopsy.

This paper presents a cognitive model that simulates an adaptation process to automation in a time-critical task. The paper uses a simple tracking task (which represents vehicle operation) to reveal how the reliance on automation changes as the success probabilities of the automatic and manual mode vary. The model was developed by using a cognitive architecture, ACT-R (Adaptive Control of Thought-Rational). We also introduce two methods of reinforcement learning: the summation of rewards over time and a gating mechanism. The model performs this task through productions that manage perception and motor control. The utility values of these productions are updated based on rewards in every perception-action cycle. A run of this model simulated the overall trends of the behavioral data such as the performance (tracking accuracy), the auto use ratio, and the number of switches between the two modes, suggesting some validity of the assumptions made in our model. This work shows how combining different paradigms of cognitive modeling can lead to practical representations and solutions to automation and trust in automation., (Copyright © 2020 Morita, Miwa, Maehigashi, Terai, Kojima and Ritter.)

We investigated the electrical properties of a composite film loaded with semi-conductive poly(3-hexylthiophene) (P3HT) nanofibers dispersed in poly(styrene- b -butadiene- b -styrene) (SBS). This structure can be regarded as the hybrid of SBS matrix with elastic mechanical properties and P3HT nanofibers with semiconducting properties. The P3HT nanofibers were embedded in the fingerprint pattern of microphase-separated SBS, as observed by scanning force microscopy. Furthermore, the electrical conductivity and field-effect mobility of the composite films were evaluated. The field-effect mobility was estimated to be 6.96 × 10 -3 cm 2 V -1 s -1 , which is consistent with the results of previous studies on P3HT nanofibers dispersed in an amorphous polymer matrix including poly(methyl methacrylate) and polystyrene, and we found that the P3HT nanofiber network was connected in the SBS bulk matrix. The film was stretchable; however, at elongation by two times, the nanofiber network could not follow the elongation of the SBS matrix, and the conductivity decreased drastically. The field-effect transistor of this film was operated by bending deformation with a radius of curvature of 1.75 cm, though we could not obtain an off-state and the device operated in a normally-on state.

Background: Excessive loading from the occlusion is known as a major pathological factor in implant failure. The force applied to the implant varies depending on the positional relationship to an opposing tooth in clinical cases. However, no studies have clarified the relationship between the discrepancy and mechanical complications., Materials and Methods: The study enrolled patients whose mandibular first molar was missing and was opposed by a natural maxillary first molar. The horizontal and vertical distance between the residual ridge and the occlusal surface of the maxillary first molar were measured from computerized tomograms. Subsequently, four finite element models were constructed in combinations of horizontal and vertical discrepancies. Additionally, the effect of inclined implantation and angled abutments were examined in a large clearance model. Maximum von Mises stress values generated in abutments under 90° or 60° loading vectors were compared with a three-dimensional finite element method., Results: Data from 123 subjects (39 males and 84 females, average age 55.2 ± 11.4 (SD) years) were collected for the analyses. Under all conditions, the stress on the load side (the buccal side) was concentrated on the platform, and the stress on the opposite side (the lingual side) was concentrated on the top of the abutment tube inserted into the implant. In comparison to 90° loading vectors, the maximum von Mises stresses of each model were 1.20 to 2.67 times under 60° loading vectors. For inclined implantation, the maximum stress was 8.4% less at a 90° load and 9.7% less at a 60° load compared with vertical implantation. With angled abutments, the maximum stress was 15.7% less at a 90° load and 30.0% less at a 60° load compared with vertical implantation., Conclusion: In cases of progressive alveolar resorption with a large clearance between the implant and the opposing teeth, a higher stress concentration was observed at the joint between the implant and the abutment. Our findings also showed that stress concentration around this area can be reduced by the use of inclined implantation and angled abutments under the condition of a horizontal offset between the implant and opposing teeth.

We collected historical control data derived from pretreatment ophthalmologic examinations of young (4 to 7 wk of age) Sprague-Dawley (Crl:CD[SD]) male, (2033, 42 lots) and female (1322, 32 lots) rats used in toxicity studies at our facility from 2004 through 2015. Ophthalmologic examination of male and female rats by using a binocular indirect ophthalmoscope and slit lamp revealed high incidences of corneal opacity (61% and 60%, respectively), lenticular opacity (43% and 47%), persistent hyaloid artery (21% and 17%), and retinal folds (27% and 27%). All other ocular abnormalities of the globe, conjunctiva, cornea, anterior chamber, lens, iris, vitreous, and choroid or retina occurred at incidences of less than 5%. Corneal opacities were localized mainly in the corneal nasal (38% and 37%) and paracentral (32% and 33%) areas, and lenticular opacities predominantly occurred in the nuclear area (31% and 34%). We then compared the incidences of spontaneous ocular abnormalities between the first (2004 through 2009) and second (2010 through 2015) 6-y periods. Corneal opacity and persistent hyaloid artery in male and female rats occurred more frequently during the second 6-y than during the first (corneal opacity, second period: male, 68%; female, 66%; corneal opacity, first period: 49% and 51%; persistent artery, second period, 26% and 23%; persistent artery, first period; 12% and 10%). These results support the importance of updating historical control data regularly and providing useful information for toxicologists and ophthalmologists to differentiate treatment-related changes from spontaneous lesions.

Background: The AR-V7 splice variant is a cause of castration-resistant prostate cancer (CRPC). However, testing for the presence of AR-V7 by real-time polymerase chain reaction (RT-PCR) shows AR-V7 positivity in healthy individuals. We hypothesized that the positivity reflects contamination by hematopoietic cells. We tried a novel circulating tumor cell (CTC) enrichment instrument, using Celsee, to clear hematopoietic cells., Methods: We tested whole blood or Celsee-enriched samples for AR-V7 by RT-PCR, and included samples from 41 CRPC patients undergoing sequential therapy. We evaluated the associations between AR-V7 status and clinical factors. We evaluated factors affecting AR-V7 positivity., Results: AR-V7 positivity was lower in Celsee-enriched than in whole blood specimens. AR-V7 and clinical factors did not predict the therapy effectiveness. We found no significant differences in the effectiveness of enzalutamide/abiraterone (Enz/Abi) upon AR-V7 evaluation. All AR-V7 positive patients had resistance to Enz/Abi. Docetaxel (DTX), cabazitaxel (CBZ), and Radium223 treatment showed no significant difference in the treatment effectiveness, regardless of AR-V7 presence. AR-V7 was more frequently positive than Extent of disease (EOD) 2 in cases with bone metastases., Conclusion: Celsee CTC enrichment suppresses AR-V7 false positivity. All AR-V7 positive patients presented resistance to Enz/Abi. DTX, CBZ, and Radium223 were effective and remain treatment options. AR-V7 positivity should progressively appear in patients with advanced bone metastases.

TP0446131, developed as an antidepressant agent, was found to cause lenticular opacity in a 13-week repeated-dose study in dogs. Histopathologically, the lenticular opacity was observed as a degeneration of the lens fibers, characterized by irregularity in the ordered arrangement of the fibers which is necessary to maintain the transparency of the lens, and was considered to manifest clinically as cataract. To evaluate the development mechanism of the lenticular opacity, the chemical constituents of the lens, which is known to be associated with the development of cataract, were examined. The results of liquid chromatography-tandem mass spectrometry analysis revealed an increase in the amplitudes of 3 unknown peaks in a dose- and time-dependent manner in the lens, with no remarkable changes in the other chemical components tested. In addition, the content of cholesterol, alterations of which have been reported to be associated with cataract, remained unchanged. The mass spectral data and chromatographic behavior of the 3 peaks indicated that these peaks corresponded to sterol-related substances, and that one of them was 7-dehydrocholesterol, a precursor of cholesterol biosynthesis. This finding suggested that TP0446131 exerts some effects on the cholesterol biosynthesis pathway, which could be involved in the development of the cataracts. Furthermore, increases in the levels of these sterol-related substances were also detected in the serum, and were, in fact, noted prior to the onset of the cataract, suggesting the possibility that these substances in the serum could be used as potential safety biomarkers for predicting the onset of cataract induced by TP0446131.

The patient was a 73-year-old man. A liver tumor was found in the posterior segment(S6)during the follow-up period post the interferon treatment for hepatitis C in September 1999. An S6 sub-segmentectomy was performed. The tumor was diagnosed as a moderately differentiated carcinoma, hepatocellular carcinoma(HCC)with pT2N0M0, pStage Ⅱ(UICC TNM 7th edition). The tumor recurred twice post-surgery. The recurrent tumors were treated with local therapies such as transcatheter arterial chemoembolization(TACE), percutaneous ethanol injection(PEI)and radiofrequency ablation(RFA). The third recurrence was found in the posterior segment(S7)in April 2009. RFA was unsuccessful because an appropriate puncture route could not be found. Then, a transdiaphragmatic RFA under thoracotomy was performed as an alternative treatment, which led to an optimal outcome. We report a case of HCC that could not be treated with percutaneous RFA but with a transdiaphragmatic RFA under thoracotomy.

Personality disorders exist on a spectrum in the general population and therefore may coexist in patients who have cancer. Patients with these disorders exhibit character rigidity resulting from enduring patterns of inner experience and behavior and may experience some level of interpersonal conflict among medical staff caring for them. These conditions become exacerbated under stressful cancer-related situations and may lead to adverse consequences and outcomes. This review highlights the conceptual and diagnostic issues of personality disorders for practicing oncologists and provides recommendations for recognizing and managing cancer patients with difficult personality traits or personality disorders.

We report a case of altered consciousness related to hyperammonemia due to FOLFIRI plus bevacizumab therapy in a patient with recurrent colorectal cancer and renal dysfunction.A 76-year-old man received third-line chemotherapy for left mediastinal lymph node metastasis.He complained of diarrhea on the evening of the same day, and mental confusion on day 3 of the first FOLFIRI therapy.He had a JCS of Ⅲ(200).The laboratory results revealed a marked hyperammonemia.5 - fluorouracil(5-FU)-induced hyperammonemia was diagnosed and the patient was ventilated and managed with branchedchain amino acid solutions, lactulose, and hemodialysis in the ICU.After hemodialysis, the blood ammonia level reduced to the normal limits, and the symptoms of encephalopathy resolved on the following day.He was discharged home on the 19th day of hospitalization.5 -FU-containing therapy should be carefully administered in patients with renal dysfunction.Herein, we report a case of 5-FU-induced hyperammonemia with literature considerations.

Purpose: Liquid biopsy is becoming increasingly important as a guide for selecting new drugs and determining their efficacy. In urological cancer, serum markers for renal cell and urothelial cancers has made the development of liquid biopsy for these cancers strongly desirable. Liquid biopsy is less invasive than conventional tissue biopsy is, enabling frequent biopsies and, therefore, is considered effective for monitoring the treatment course. Circulating tumor cells (CTCs) are a representative liquid biopsy specimen. In the present study, we focused on developing our novel technology for capturing renal cell cancer (RCC)-CTCs using an anti-G250 antibody combined with new devices. Basic experiments of our technology showed that it was possible to detect RCC-CTC with a fairly high accuracy of about 95%. Also, RCC-CTC was identified in the peripheral blood of actual RCC patients. Additionally, during the treatment course of the RCC patient, change in the number of RCC-CTC was confirmed in one case. We believe that the technology we developed will be useful for determining the treatment efficacy and drug selection for the treatment of renal cell cancer (RCC). In order to solve issues such as thresholds setting of this technology, large-scale clinical trials are expected., Competing Interests: The authors declare that they have no conflicts of interest.

Thoughts of suicide while dealing with cancer are exceedingly common, though relatively few patients make a suicide attempt or complete suicide. Suicide rates among cancer patients are generally thought to be twice as high as that of the general population. However, patients with certain cancer types are at much higher risk for suicide; patients may also be more at risk at certain times during their cancer trajectory. While it is not possible to predict a suicidal act, key features identify those who should be screened more closely. Depression, psychiatric history, previous suicide attempts, hopelessness, demoralization, pain, lack of social support, feeling like a burden to others, and existential concerns (regret, loss of meaning, purpose, and dignity), along with specific demographic characteristics and cancer types confer increased suicidality. Oncologists play a crucial role in identifying these high-risk patients. The Columbia-Suicide Severity Rating Scale is a well-established screening instrument that staff members can use to assess suicidal thinking in patients.

In a 65-year-old woman, anemia was observed during outpatient follow-up after right lung cancer surgery, and upper gastrointestinal endoscopy was performed for examination.Gastrointestinal endoscopy revealed a Type 2 tumor on the small curvature in the middle part of the stomach, and she was diagnosed with gastric cancer.Distal gastrectomy with D2 lymph node dissection and BillrothⅠ reconstruction was performed for the gastric cancer.There were no postoperative complications, and she was discharged on the ninth day after surgery.The pathological diagnosis was gastric cancer, ML, Less, Type 2, 67×55×15 mm, muc>sig>por, pT4a(SE)N2M0, fStage ⅢB.S -1 adjuvant chemotherapy was administered, but then discontinued in the second course due to the development of adverse events.Reflux symptoms appeared after the surgery, and her dietary intake was poor.Her body weight and serum albumin level at 3 and 5 months after surgery were 51 kg and 52.5 kg, respectively, and 3.2 g/dL and 2.7 g/dL, respectively.Because there was no improvement in the reflux symptom, oral administration of acotiamide hydrochloride was initiated 7 months after the surgery.After initiating oral intake of acotiamide hydrochloride, her dietary intake improved, and her body weight and serum albumin level at 11 and 15 months after surgery were 54 kg and 57 kg, respectively, and 3.0 g/dL and 2.7 g/dL, respectively.Peritoneal recurrence was observed 23 months after surgery, and her oral intake decreased, but the recurrence of reflux symptoms was not observed.Acotiamide hydrochloride could be an option for the treatment of reflux symptoms after gastrectomy.

Background: Dissection and division of tissues are widely performed in microscopic neurosurgery, especially in brain tumor resection. Dissection maneuvers can be divided into two types: sharp dissection with microscissors and blunt dissection using a dissector. It is essential to use the appropriate method according to the intraoperative situation and conditions. Therefore, specific tools for each type of dissection maneuver are required. We developed an ultrasonic microdissector, a newly designed tool that functions as both microscissors and dissector to further advance brain tumor surgery. This preliminary experimental study was performed to evaluate the usefulness of this new device., Methods: Solfy F (J. Morita Mfg. Corp., Kyoto, Japan), a dental ultrasonic instrument, was used to provide power in this study. Two experiments were performed. The first one involved touching the brain parenchyma of a pig cadaver with the tip of the ultrasonic microdissector under various conditions to investigate its side effects. In the second experiment, the rat femoral artery, vein, and nerve were dissected from surrounding structures using a prototype of the ultrasonic microdissector. The effects of this device were then investigated histologically., Results: The amount of tissue damage was greater with the higher ultrasonic power. No irrigation and a long manipulation time also affected tissue degeneration. Dissection using the ultrasonic microdissector was superior to conventional dissection methods in terms of time ( p  < 0.05) and safety without any additional histologic damages., Conclusions: The newly developed ultrasonic microdissector can dissect soft tissue without damage to the surrounding tissue. Further studies are required to determine the optimal intensity for its clinical use., Competing Interests: None., (Georg Thieme Verlag KG Stuttgart · New York.)

A 66-year-old woman diagnosed with advanced Stage Ⅳ gastric cancer(T4aN3M1[LYM])received RAM plus wPTX as third-line chemotherapy(ramucirumab 8mg/kg on the 1st and 15th day, paclitaxel 80mg/m2 on the 1st, 8th, and 15th day).After receiving 3 courses of this treatment, para-aortic lymphadenopathy had diminished but anemia had progressed because of tumor hemorrhage.Six weeks after the last administration of RAM, an open distal gastrectomy with D1 plus lymph node dissection and Billroth Ⅰ reconstruction was performed.The patient was discharged on the 9th day after surgery without complications such as postoperative bleeding and delayed wound healing.RAM plus wPTX therapy was restarted 6 weeks after the operation.Postoperative late complication there is no adverse event including adenocarcinoma and continues the same therapy at present.The perioperative treatment under the use of angiogenesis inhibitor has risk of postoperative bleeding and wound healing delay and includes surgery timing of treatment may be difficult.In our case, surgery was performed 6 weeks after the final administration of RAM.

This is a case of a 70-year-old man. Two courses of docetaxel/cisplatin/S-1 combination therapy were administered after clinical trial registration with diagnosis of Stage Ⅳ gastric cancer(ypT3N3aM1). In June 2014, gastrectomy and splenectomy were performed. Postoperative S-1 adjuvant chemotherapy was administered; however, in September 2014, aorticl ymph node metastasis was diagnosed as recurrent. After recurrence, irinotecan/cisplatin therapy was administered. In February 2015, recurrent lymph node metastasis increased, and chemotherapy was changed to paclitaxel. In May 2015, numbness (Grade 2)of the fingers was observed, and treatment was changed to oxaliplatin/S-1. In February 2016, storage of ascites became remarkable; therefore, chemotherapy was discontinued as per policy. After that, we continued outpatient visit and observed increased recurrent lymph node metastasis on image evaluation; however, as the patient's general condition was good, chemotherapy was restarted. Ramucirumab/paclitaxel therapy started in February 2017. During the course of treatment, neutropenia(Grade 2)was observed as an adverse event, but therapy continuation was possible without loss of ramucirumab only with loss of paclitaxel. Thereafter, the recurrence of lymph node metastasis was reduced, and the ascites accumulation decreased. Until now, 1 year after the start of ramucirumab/paclitaxel therapy, the patient still visits the outpa- tient clinic.

Background: Apert syndrome is characterized by craniosynostosis and bony syndactyly of the hands and feet. The cause of Apert syndrome is a single nucleotide substitution mutation (S252W or P253R) in fibroblast growth factor receptor 2 (FGFR2). Clinical experience suggests increased production of saliva by Apert syndrome patients, but this has not been formally investigated. FGFR2 signaling is known to regulate branching morphogenesis of the submandibular glands (SMGs). With the Apert syndrome mouse model (Ap mouse), we investigated the role of FGFR2 in SMGs and analyzed the SMG pathology of Apert syndrome., Results: Ap mice demonstrated significantly greater SMG and sublingual gland (SMG/SLG complex) mass/body weight and percentage of parenchyma per unit area of the SMG compared with control mice. Furthermore, gene expression of Fgf1, Fgf2, Fgf3, Pdgfra, Pdgfrb, Mmp2, Bmp4, Lama5, Etv5, and Dusp6 was significantly higher in the SMG/SLG complex of Ap mice. FGF3 and BMP4 exhibited altered detection patterns. The numbers of macrophages were significantly greater in SMGs of Ap mice than in controls. Regarding functional evaluations of the salivary glands, no significant differences were observed., Conclusions: These results suggest that the gain-of-function mutation in FGFR2 in the SMGs of Ap mice enhances branching morphogenesis. Developmental Dynamics 247:1175-1185, 2018. © 2018 Wiley Periodicals, Inc., (© 2018 Wiley Periodicals, Inc.)

Beetle horns are attractive models for studying the evolution of novel traits, as they display diverse shapes, sizes, and numbers among closely related species within the family Scarabaeidae. Horns radiated prolifically and independently in two distant subfamilies of scarabs, the dung beetles (Scarabaeinae), and the rhinoceros beetles (Dynastinae). However, current knowledge of the mechanisms underlying horn diversification remains limited to a single genus of dung beetles, Onthophagus. Here we unveil 11 horn formation genes in a rhinoceros beetle, Trypoxylus dichotomus. These 11 genes are mostly categorized as larval head- and appendage-patterning genes that also are involved in Onthophagus horn formation, suggesting the same suite of genes was recruited in each lineage during horn evolution. Although our RNAi analyses reveal interesting differences in the functions of a few of these genes, the overwhelming conclusion is that both head and thoracic horns develop similarly in Trypoxylus and Onthophagus, originating in the same developmental regions and deploying similar portions of appendage patterning networks during their growth. Our findings highlight deep parallels in the development of rhinoceros and dung beetle horns, suggesting either that both horn types arose in the common ancestor of all scarabs, a surprising reconstruction of horn evolution that would mean the majority of scarab species (~35,000) actively repress horn growth, or that parallel origins of these extravagant structures resulted from repeated co-option of the same underlying developmental processes., Competing Interests: The authors have declared that no competing interests exist.

A 74-year-old woman was found to have a hepatic mass based on CT findings. She was diagnosed as having cecum cancer, and it was difficult to distinguish whether the hepatic mass was liver metastasis or biliary cystadenocarcinoma. We proceeded with the surgery for cecum cancer, and laparoscopic ileocecal resection with D3 lymph node dissection was performed. The histopathological diagnosis was mucinous adenocarcinoma, and the pathological stage was T3N2H1P0M1a, Stage IV. After the surgery, her CEA level was elevated, and we diagnosed the hepatic mass as a liver metastasis. A CapeOX plus bevacizumab regimen was administered but was discontinued for 2 courses due to the development of adverse effects and her decision. Gd-EOB-DTPA-enhanced MRI revealed a multilocular and lobulated mass, which was a low-intensity area in T1WI and high-intensity area in T2WI, and the mass had no significant contrast effects. These images were unspecific for liver metastasis of colorectal cancer, and we performed segmental 6 hepatectomy for diagnosis and curative surgery. A histopathological diagnosis of liver metastasis of cecum cancer was made. Here, we report a case of liver metastasis of colorectal cancer that was undifferentiated from biliary cystadenocarcinoma.

A 59-year-old woman was diagnosed with advanced gastric cancer with para-aortic and Virchow's lymph node metastases (L, Less, type 2, tub1, cT3N2H0P0M1[LYM: #16, Virchow's]). Four courses of S-1(80mg/m / 2, days 1-21)and CDDP(60mg/ m2, day 8)were administered. After the chemotherapy, CT showed that the primary tumor and para-aortic and Virchow's lymph nodes had reduced in size. The clinical stage was ycT3N1H0P0M0, stage III A. The patient underwent distalgastrectomy, D2 dissection, and sampling of the para-aortic lymph nodes(#16b1lat, #16a2int). The pathological diagnosis was L, less, type 1, por1/2, pT2N2H0P0M0CY0, pStage III B. The patient was treated with S-1(80mg/m2, days 1-28)as adjuvant chemotherapy. After 3 courses had been administered(6 months after the resection), swelling of a para-aortic lymph node (#16b1int)was detected using CT. Based on the diagnosis of recurrence in the lymph node, weekly paclitaxel(80mg/m2, days 1, 8, and 15)was administered. After receiving 9 courses of weekly paclitaxel, the swelling of the lymph node disappeared, and the response evaluation was complete response. She discontinued the chemotherapy 5 years and 9 months after the surgery. To date, she has survived more than 6 years after surgery without recurrence. We report a long-surviving patient with advanced gastric cancer with para-aortic lymph node metastasis who received combined modality therapy.

We report of a long-surviving patient with retroperitoneal liposarcoma that required 6 surgeries in 16 years. A 62-year-old man was diagnosed with liposarcoma, which was first excised in 2001. Thereafter, we excised recurrences in the retroperitoneum with the left kidney in February 2004. We excised recurrences with the left half of the colon in November 2007 and February 2010 and recurrences with a part of the intestine in November 2014. This time, we excised recurrences under the right abdominal rectus muscle and near the left half of the colon. The pathological diagnosis was well-differentiated liposarcoma. There is currently no evidence of recurrence 16 years after the first recurrence excision. In this case, active excision of recurrences and identification of high-grade dedifferentiated-type liposarcomas were factors of long survival.

A 32-year-old woman with a history of undergoing upper gastrointestinal surgery was administered prednisolone for abortive Behçet's disease since 2015. In March 2017, upper gastrointestinal endoscopy revealed a 0-IIc type early stage gastric carcinoma at the posterior wall of the gastric antrum. The pathological diagnosis was signet-ring cell carcinoma. This gastric carcinoma was classified as cT1aN0M0; therefore, endoscopic submucosal dissection(ESD)was performed for the expanded indication lesion in April 2017. The pathological diagnosis after ESD indicated the need for non-curative resection; thus, laparoscopy-assisted distal gastrectomy and Billroth I anastomosis were performed in July 2017. A transient anastomotic structure was admitted after this surgery, but she was discharged from the hospital lighthearted. A preoperative important aspect was the careful examination of all intestinal tracts for ulcer lesions, and an intraoperative important aspect was hand-sewn anastomosis because using a metallic stapler conferred a high risk of ulcer lesions and suture failure. We encountered a case wherein laparoscopy-assisted distal gastrectomy was performed in a patient with abortive Behçet's disease, early stage gastric carcinoma, and a history of undergoing upper gastrointestinal surgery.

Although chemotherapy is the standard treatment for unresectable advanced gastric cancer, its prognosis is poor and the median survival time is only around 10 months. With some literature consideration, we report that ovarian metastasis triggered the diagnosis of unresectable advanced gastric cancer with long-term survival through multidisciplinary treatment. This is the case of a 69-year-old woman, who was diagnosed with ovarian tumor and underwent right extracorporectomy and omentum resection in 2011. Pathological diagnosis suspected adenocarcinoma. In February 2012, EGD found a type 4 tumor in the upper portion of the pyloric area of the stomach. She was diagnosed with gastric cancer with Stage IV(T4aN0M1 [ovary])ovarian metastasis. Because the primary tumor was HER2 positive, XP plus HER therapy(capecitabine 1,000mg/m2 twice a day for 14 days, CDDP 80mg/m2 every 3 weeks on the first day, and trastuzumab 8 mg/kg every 3 weeks on the first day)was administered since March 2012. No metastasis was found in the imaging examination after 8 courses of chemotherapy, and we also confirmed the reduction of the primary tumor in the EGD. Based on the images, primary resection was already possible. In December 2012, after a diagnostic laparoscopy, total gastrectomy with D2 lymph node dissection was performed. Postoperative pathology was diagnosed as Stage IV(pT4aN0M1). To control postoperative micrometastasis, capecitabine therapy(1,000mg/m2 twice a day for 14 days)was administered for 12 months starting from February 2013. Then, recurrence and metastasis were not observed during follow-up. However, in January 2017, a circumstellar stenotic tumor was found in the rectum and was diagnosed as recurrence of peritoneal dissemination through images. In February 2017, artificial ostomy(in the sigmoid colon, double-mouth type)was made. Then, the patient underwent an outpatient chemotherapy, with hospital visits, and she survives.

We report the case of a 74-year-old man with a previously implanted pacemaker lead. He had undergone Medtronic™ Micra Transcatheter Pacing System (TPS, Medtronic plc, MN, USA) implantation because of lead fracture. We implanted a new TPS and retrieved the dislodged one. We used a multiple-loop snare (EN snare ® ) and an 8.5F steerable sheath (Agilis NXT; St. Jude Medical, St Paul, MN, USA). The TPS was obstructed by the chordae tendineae of the tricuspid valve and the pacemaker lead. We pushed the TPS to the apex site; this enabled us to move the TPS away from the chordae tendineae and pacemaker lead. The TPS body was caught in the inferior vena cava and was successfully retrieved. To our knowledge, this is the first case reporting TPS retrieval in a heart with preexisting lead., (Copyright © 2018 Indian Heart Rhythm Society. Production and hosting by Elsevier B.V. All rights reserved.)

Driver fatigue is a cause of serious accidents for heavy machinery operators. Monitoring operator position, as indicated by their Center of Gravity (CoG), may be a means to non-invasively detect driver fatigue. We prototyped a research tool that tracks CoG from four sensors located within the legs of a seat, and validated its accuracy and precision. Our primary contributions are the development of a low-cost integrated CoG detector for seated drivers and the design of a flexure structure to protect load cells from shocks, tensile and shear forces. This system will enable research into CoG as an indicator of fatigue.

Background/aim: Previous studies have shown that laparoscopic colorectal cancer surgery is highly safe and effective compared to laparotomy. However, whether laparoscopic colorectal cancer surgery can be safely performed in patients with severe comorbidities remains unclear. The aim of this study was to evaluate the safety of laparoscopic colorectal cancer surgery in patients with severe comorbidities., Patients and Methods: A total of 82 consecutive patients with colorectal cancer who underwent laparoscopic surgery were retrospectively divided into two groups according to whether they had severe comorbidity (50 patients) or non-severe comorbidity (32 patients). An age-adjusted Charlson comorbidity index of ≥6 was defined as severe comorbidity., Results: Operative time, blood loss, and rate of conversion to laparotomy did not differ between the groups. Postoperative complications and the length of the postoperative hospital stay also did not differ significantly between the groups., Conclusion: Laparoscopic colorectal cancer surgery is feasible and safe, even in patients with severe comorbidities., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

In 2013, National Immunization Survey-Teen data indicated that >40% of female adolescents had not initiated the human papillomavirus (HPV) vaccine series and >60% had not completed the series, documenting vaccination rates much lower than those for other vaccines recommended for adolescents. The Chicago Department of Public Health (CDPH) was 1 of 22 jurisdictions nationwide to receive a Prevention and Public Health Fund award through the Centers for Disease Control and Prevention to improve HPV vaccination rates among adolescents. The CDPH implemented 5 interventions targeting the public, clinicians and their staff, and diverse immunization and cancer prevention stakeholders. Compared with 2013 jurisdiction-specific HPV vaccination rates among all adolescents, Chicago's HPV vaccination rates were increased significantly in 2014 and 2015. This article details the methods and results of Chicago's successful interventions, the particular strengths as well as barriers encountered, and future steps necessary for sustaining improvement., (Copyright © 2017 Academic Pediatric Association. All rights reserved.)

Background/aim: To evaluate the safety of laparoscopic colorectal cancer surgery for patients with severe comorbidities., Patients and Methods: A total of 203 consecutive patients with severe comorbidities who underwent resection for colorectal cancer were retrospectively divided into laparoscopic and open primary resection groups. An age-adjusted Charlson comorbidity index ≥6 was considered as severe comorbidity., Results: Blood loss (31 g vs. 207 g, p<0.01) and total postoperative complications (10.0% vs. 27.5%, p<0.01) in the laparoscopic group were significantly decreased compared to the open group. Incidence of postoperative ileus (0.0% vs. 7.2%, p=0.06) and length of postoperative hospital stay (11 days vs. 14 days, p=0.08) in the laparoscopic group were improved, though not significantly, compared to the open group., Conclusion: Laparoscopic resection for patients with severe comorbidities is safe, and is associated with a lower rate of overall operative complications compared to open surgery., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Upper urinary tract neuroendocrine carcinoma (UUT-NEC) is extremely rare and has a poor prognosis. Although a few cases of successful treatment have been reported, no treatment has shown established efficacy., Patients and Methods: We analyzed 70 UUT-NEC patients, including 68 with small cell neuroendocrine carcinoma (SCNEC) and large cell neuroendocrine carcinoma (LCNEC) reported between 1985 and 2017 and 2 treated at our hospital., Results: Median patient age was 66 years, 58.6% were men, and 60% were of Asian descent. Most UUT-NECs were SCNEC (68; 95.7%), whereas LCNEC was very rare (2; 2.9%). More than half of the patients had accompanying other histological components, the most common being urothelial carcinoma (51.5%), whereas 41.4% had NEC alone. Of the 70 patients, 27 underwent additional therapy (e.g., chemotherapy and radiotherapy) along with surgery. Median survival was 15 months. In univariate analysis, stages T1-2 disease showed better prognosis than stages T3-4 (P < 0.001). Additional treatment (e.g., chemotherapy and radiotherapy) significantly improved prognosis (P = 0.014). Moreover, platinum-based chemotherapy also was associated with improved prognosis (P = 0.017). For platinum-based chemotherapy, multicollinearity with additional treatments was strong, and, thus, these data were not included in the analysis. Multivariate analysis revealed pathological stage (T1-2 vs. T3-4; P = 0.003) and additional treatment (P = 0.028) to be independent predictors of improved prognosis., Conclusion: Although UUT-NEC has a poor prognosis, additional treatment along with surgery and therapeutic intervention and stage T1-2 disease are independent factors to improve prognosis., (Copyright © 2018. Published by Elsevier Ltd.)

Background: Major Depressive Disorder (MDD) and Social Anxiety Disorder (SAD) are highly comorbid, yet the combined condition has not been subject to any placebo-controlled treatment trials. This study reports a trial of vortioxetine, an antidepressant that has also shown benefit in Generalized Anxiety Disorder (GAD), in patients meeting DSM-5 criteria for both MDD and SAD., Methods: The study was a 12-week double-blind, placebo-controlled comparison of vortioxetine 10-20 mg/day or placebo administered on a 1:1 ratio. The study was designed to include 40 male or female outpatients aged 18-70 years. The primary endpoint was the "composite" Clinical Global Impression of Improvement (CGI-I) responder rate, factoring in improvement in both MDD and SAD features. Major secondary outcome measures were changes on the Montgomery Asberg Depression Rating Scale (MADRS) and Liebowitz Social Anxiety Scale (LSAS)., Results: On the composite CGI-I, 10 of 20 (50%) vortioxetine and six of 20 (30%) placebo-treated patients were rated as responders, a non-significant difference. However, vortioxetine-treated patients did show significantly greater improvement than those on placebo on both the MADRS (effect size 0.672) and LSAS (effect size 0.714). Efficacy in depression was seen before improvement in SAD. Adverse effects were similar to those previously reported., Conclusions: In this preliminary trial vortioxetine appears safe and effective for patients with MDD comorbid with SAD, with robust effect sizes on dimensional measures of both depression and social anxiety, but failure to separate from placebo on the primary outcome measure of composite responder rate. More studies of patients with comorbid conditions are needed, as this mirrors what is often seen in clinical practice., (© 2017 Wiley Periodicals, Inc.)

Peroxiredoxin from Pyrococcus horikoshii (PhPrx) is a decameric protein formed by ring-type assembly of five dimers. To engineer the quaternary structure of PhPrx, we created a mutant PhPrx (PhPrx6m) by introducing six point mutations designed to dissociate PhPrx into dimers. Although PhPrx6m was a dimer in solution, the six dimers assembled into a dodecamer following crystallization. In the crystal structure, PhPrx6m was overoxidized, and the peroxidatic cysteine was in sulfonic acid form and two cysteines in the C-terminal region were linked by an intramolecular disulfide bond. Thus, we characterized the wild-type PhPrx overoxidized by hydrogen peroxide (PhPrxPer). Analytical ultracentrifugation showed that PhPrxPer had a higher molecular mass in solution than PhPrx. This was confirmed by analysis of the crystal structure of PhPrxPer, which was found to form a ring-type dodecamer composed of six dimers. The monomeric structures of PhPrx6m and PhPrxPer differed from that of PhPrx in the relative orientation of two domains, reflecting the number of dimers in the ring-type assembly. Unlike PhPrx, homologous peroxiredoxin from Aeropyrum pernix (ApPrx) did not undergo hexameric association. This property can be explained by the stronger connection between the two domains in ApPrx due to its C-terminal extension relative to PhPrx., (© The Authors 2017. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved.)

A 65-year-old female received distal gastrectomy for gastric cancer.The pathological diagnosis was well differentiated adenocarcinoma(tub1), type 2, pT3, ly: 1, v: 1, N0, H0, P0, M0, CY0, pStage II A.She had been observed without adjuvant chemotherapy.Five years after the resection, umbilical tumor and intraperitoneal nodules were detected by computed tomography. Needle biopsy cytology of umbilical tumor revealed metastasis from gastric cancer.Based on the diagnosis of umbilical metastasis and peritoneal dissemination, S-1(80mg/m / 2, day 1-21)and CDDP(60mg/m2, day 8)were administered for 7 courses.Because of diarrhea(Grade 3), chemotherapy was changed to paclitaxel(80mg/m2, day 1, 8, 15).To date, the patient has undergone 33 courses of paclitaxel.The response evaluation is complete response and no other metastases are detected.She has survived more than 3 years from recurrence of gastric cancer.We report a long-surviving case of umbilical metastasis from post operative gastric cancer with chemotherapy.

Patchy thickening and reddish discoloration of active hair growth areas of skin in rabbits are occasionally found, and this gross feature could affect precise evaluation when conducting a dermal irritation test. Since little is known about the mechanism of this phenomenon, we examined the dorsal skin of New Zealand White rabbits morphologically and immunohistochemically in order to identify the possible mechanism responsible for developing these skin changes in relation to the hair cycle. Skin samples from 4 rabbits were divided into three groups (5 samples/group) based on their macroscopic characteristics: a thickened skin, erythematous skin, and smooth skin group. Histomorphological examination revealed that the percentage of hair follicles in the anagen phase, hair follicle length, hair follicle area, and proliferating cell nuclear antigen-positive cells in the hair follicles were greater in the thickened skin and erythematous skin groups than in the smooth skin group. Unlike mice and rats, the dermis was nearly adjacent to the muscular layer with a thin hypodermis, and the whole lengths of hair follicles in the anagen phase were located in the dermis in the rabbit skin. These results suggest that large hair follicles in the anagen phase compressed the surrounding dermis; therefore, the skin was grossly raised and showed thickening. A higher number of CD31-positive blood vessels, suggesting the occurrence of angiogenesis, was observed around the hair follicles in the erythematous skin group, and they seemed to affect the reddish discoloration of skin noted grossly.

Background and Objectives: Relaxin (RLN) is an insulin-like hormone associated with extracellular matrix degradation, osteoclastogenesis, and osteoblast differentiation. This study aimed to assess the effect of RLN during and after lateral expansion of murine calvarial sagittal sutures., Materials and Methods: RLN was injected topically using a nano-sized liposome carrier into the sagittal sutures of 8- to 10-week-old wild type mice just before lateral expansion. Suture morphology, bone mineral density (BMD), and bone volume were analysed by micro-computed tomography. Collagen deposition and osteoclast differentiation were observed by Verhoeff-Van Gieson (VVG) and tartrate-resistant acid phosphatase (TRAP) staining, respectively., Results: Less collagen staining and higher tissue-specific relaxin/insulin-like family peptide receptor (Rxfp)-1 and -2 expression were observed in the RLN-treated samples after 48 hours. Increased BMD and volume, and thick well-organised osteoid tissue, with multinucleated TRAP-positive cells, were observed in RLN-treated samples after 1 week. Increased Rxfp-1 expression was observed in the sagittal sutures in the mid-suture fibrous tissue following RLN treatment. Rxfp-2 was only expressed in the calvarial bone under tensile stimulation and RLN treatment further increased its expression., Limitations: RLN-liposomes were not detected at any instance under the current experimental conditions. This is a preliminary study and the sample number limits the power of its results. VVG staining cannot quantify collagen contents but can provide preliminary information on the presence of collagen fibres., Conclusions: RLN treatment may modify bone remodelling and collagen metabolism during and after suture expansion., (© The Author 2016. Published by Oxford University Press on behalf of the European Orthodontic Society. All rights reserved. For permissions, please email: journals.permissions@oup.com)

This study sought to clarify the effects of reduced feeding on physiological parameters in dogs to enable appropriate evaluations of the safety and toxicity of test compounds. We measured alkaline phosphatase isozymes and the circulating blood volume, as well as clinical signs, body weight, hematology, blood chemistry, electrocardiography, organ weight, and histopathology, in male beagle dogs fed a diet consisting of 300 g/day or 150 g/day for 4 weeks. There were no abnormal clinical signs in any of the dogs. In the 150-g/day feeding group, a decreased alkaline phosphatase 3 suggesting effects on the bone and a decreased circulating blood volume associated with body weight loss were observed. Additionally, the following changes were also observed in the 150-g/day group: a decrease in body weight; hematologic changes including decreases in white blood cells, neutrophils, red blood cells, hemoglobin, hematocrit and reticulocytes; blood chemical changes including decreases in aspartate aminotransferase, lactate dehydrogenase and calcium and an increase in the creatinine at week 1 or thereafter; electrocardiographic changes including a decrease in the heart rate, a prolonged QRS duration and the occurrence of a second-degree atrioventricular block at week 3 or thereafter; and pathological changes including decreases in the weights of the liver and thymus, a decrease in hepatocyte rarefaction, and thymic atrophy. These results provide useful information for assessing the safety of compounds in toxicological studies, enabling direct treatment effects and secondary changes caused by decreased food intake to be distinguished.

Enzymes of carbohydrate esterase (CE) family 14 catalyze hydrolysis of N-acetyl groups at the non-reducing end of the N-acetylglucosamine (GlcNAc) residue of chitooligosaccharides or related compounds. N,N'-diacetylchitobiose deacetylase (Dac) belongs to the CE-14 family and plays a role in the chitinolytic pathway in archaea by deacetylating N,N'-diacetylchitobiose (GlcNAc2), which is the end product of chitinase. In this study, we revealed the structural basis of reaction specificity in CE-14 deacetylases by solving a crystal structure of Dac from Pyrococcus horikoshii (Ph-Dac) in complex with a novel reaction intermediate analog. We developed 2-deoxy-2-methylphosphoramido-d-glucose (MPG) as the analog of the tetrahedral oxyanion intermediate of the monosaccharide substrate GlcNAc. The crystal structure of Ph-Dac in complex with MPG demonstrated that Arg92, Asp115, and His152 side chains interact with hydroxyl groups of the glucose moiety of the non-reducing-end GlcNAc residue. The amino acid residues responsible for recognition of the MPG glucose moiety are spatially conserved in other CE-14 deacetylases. Molecular dynamics simulation of the structure of the Ph-Dac-GlcNAc2 complex indicated that the reducing GlcNAc residue is placed in a large intermolecular cleft and is not involved with specific interactions with the enzyme. This observation was consistent with results indicating that Ph-Dac displayed similar kinetic parameters for both GlcNAc and GlcNAc2. This study provides the structural basis of reaction-site specificity of Dac and related CE-14 enzymes., (Copyright © 2016 Elsevier Inc. All rights reserved.)

In plants, leucine-rich repeat receptor-like kinases (LRR-RKs) perceive ligands, including peptides and small molecules, to regulate various physiological processes. TDIF, a member of the CLE peptide family, specifically interacts with the LRR-RK TDR to inhibit meristem differentiation into tracheary elements, and promotes cell proliferation. Here we report the crystal structure of the extracellular domain of TDR in complex with the TDIF peptide. The extracellular domain of TDR adopts a superhelical structure comprising 22 LRRs, and specifically recognizes TDIF by its inner concave surface. Together with our biochemical and sequence analyses, our structure reveals a conserved TDIF-recognition mechanism of TDR among plant species. Furthermore, a structural comparison of TDR with other plant LRR-RKs suggested the activation mechanism of TDR by TDIF. The structure of this CLE peptide receptor provides insights into the recognition mechanism of the CLE family peptides.