Impact of deep learning on radiologists and radiology residents in detecting breast cancer on CT: a cross-vendor test study.

AIM: To investigate the effect of deep learning on the diagnostic performance of radiologists and radiology residents in detecting breast cancers on computed tomography (CT). MATERIALS AND METHODS: In this retrospective study, patients undergoing contrast-enhanced chest CT between January 2010 and December 2020 using equipment from two vendors were included. Patients with confirmed breast cancer were categorised as the training (n=201) and validation (n=26) group and the testing group (n=30) using processed CT images from either vendor. The trained deep-learning model was applied to test group patients with (30 females; mean age = 59.2 ± 15.8 years) and without (19 males, 21 females; mean age = 64 ± 15.9 years) breast cancer. Image-based diagnostic performance of the deep-learning model was evaluated with the area under the receiver operating characteristic curve (AUC). Two radiologists and three radiology residents were asked to detect malignant lesions by recording a four-point diagnostic confidence score before and after referring to the result from the deep-learning model, and their diagnostic performance was evaluated using jackknife alternative free-response receiver operating characteristic analysis by calculating the figure of merit (FOM). RESULTS: The AUCs of the trained deep-learning model on the validation and test data were 0.976 and 0.967, respectively. After referencing with the result of the deep learning model, the FOMs of readers significantly improved (reader 1/2/3/4/5: from 0.933/0.962/0.883/0.944/0.867 to 0.958/0.968/0.917/0.947/0.900; p=0.038). CONCLUSION: Deep learning can help radiologists and radiology residents detect breast cancer on CT.

Clinical characteristics and outcomes of pheochromocytoma crisis: a literature review of 200 cases.

PURPOSE: Pheochromocytoma crisis is a life-threatening endocrine emergency that requires prompt diagnosis and treatment. Because of its rarity, sudden onset, and lack of internationally uniform and validated diagnostic criteria, pheochromocytoma crisis remains to be fully clarified. Therefore, we aimed to describe the clinical characteristics and outcomes of pheochromocytoma crisis through a literature review. METHODS: We performed a systematic literature search of PubMed/MEDLINE database, Igaku-Chuo-Zasshi (Japanese database), and Google Scholar to identify case reports of pheochromocytoma crisis published until February 5, 2021. Information was extracted and analyzed from the literature that reported adequate individual patient data of pheochromocytoma crisis in English or Japanese. Cases were also termed as pheochromocytoma multisystem crisis (PMC) if patients had signs of hyperthermia, multiple organ failure, encephalopathy, and labile blood pressure. RESULTS: In the 200 cases of pheochromocytoma crisis identified from 187 articles, the mean patient age was 43.8 ± 15.5 years. The most common symptom was headache (39.5%). The heart was the most commonly damaged organ resulting from a complication of a pheochromocytoma crisis (99.0%), followed by the lungs (44.0%) and the kidney (21.5%). PMC accounted for 19.0% of all pheochromocytoma crisis cases. After excluding 12 cases with unknown survival statuses, the mortality rate was 13.8% (26/188 cases). Multivariable logistic regression analysis revealed that nausea and vomiting were significantly associated with a higher mortality rate. CONCLUSION: Pheochromocytoma can present with different symptomatology, affecting different organ systems. Clinicians should be aware that patients with nausea or vomiting are at a higher risk of death because of pheochromocytoma crisis.

Regulation of nursing professionals in Cambodia: strategies to overcome underpinning challenges.

AIMS: To elucidate (i) the challenges and constraints in the development and implementation of the regulatory framework for nursing professionals in Cambodia and (ii) the specific strategies adopted to address the challenges experienced in Cambodia. INTRODUCTION: The health workforce will be critical to achieving the health-related and wider Sustainable Development Goals in the years up to 2030. BACKGROUND: In 2006, the countries of the Association of Southeast Asian Nations signed a Mutual Recognition Arrangement in relation to nursing services in the region with the main aim of facilitating the mobility of nursing professionals between countries. To ensure the competency of the health workforce and the quality and safety of health services, member states are required to establish an appropriate regulatory framework. METHODS: This is a qualitative descriptive study. Eighteen key informant interviews were conducted in Cambodia in 2018. Walt and Gilson's policy analysis model was applied to organize and synthesize the data. FINDINGS: Major challenges were identified such as conceptual and cultural issues, limited capacity of Cambodian stakeholders and an unstandardized system with limited coordination. DISCUSSION: In Cambodia, the nursing regulatory environment has expanded greatly over the last decade. Strategies adopted were 'political leadership', optimal utilization of 'outsider's capacity', strengthening 'insider's capacity', and 'dedicated consultation and collaboration and consensus building' involving all players. IMPLICATIONS FOR NURSING AND HEALTH POLICIES: Policymakers in similar resource-limited countries could apply and adapt similar strategic efforts when formulating and implementing health policies, legislation and regulations. 'Outsiders', in this case, represented by development partners can play a vital role in the process, but should not be leading the charge. They should be aligned with national priority to support recipient countries. It is imperative for these countries and development partners to invest in increasing the quantity and quality of nursing leaders who can develop and advance regulatory functions.

Image quality and radiation dose of renal perfusion CT with low-dose contrast agent: a comparison with conventional CT using a 320-row system.

AIM: To compare perfusion computed tomography (CT) with reconstructed image from source data using low-dose contrast agent and conventional 320-row CT for the evaluation of renal tumours. MATERIALS AND METHODS: Twenty-eight patients underwent conventional CT (C-CT) and 26 patients underwent perfusion CT with low-dose (40 ml) contrast agent. Image noise, arterial visualisation, the sharpness of the corticomedullary junction (CMJ), and overall image quality were each assessed using a four-point scale. The tumour detection rate for lesions <4 cm (n=66) was also evaluated. Quantitative image parameters including image noise and the contrast-to-noise ratios (CNRs) of the renal artery and CMJ were measured. The volume CT dose index (CTDI), dose-length product (DLP), and size-specific dose estimate (SSDE) were also recorded. RESULTS: Although the image noise of perfusion CT was higher than that of C-CT and the overall image quality of perfusion CT was lower than that of C-CT, the arterial visualisation score of perfusion CT was significantly higher than that of C-CT. The CMJ sharpness scores of the two techniques were equivalent. Sensitivity and positive predictive values were also equivalent with respect to tumour detection. The CNRs of both the left and right renal arteries were significantly higher on perfusion CT than on C-CT. The CTDI, DLP, and SSDE of perfusion CT were significantly lower than those of C-CT. CONCLUSION: Perfusion CT using low-dose contrast agent preserved arterial visualisation and the tumour detection rate and achieved a low radiation dose despite image quality degradation and image noise.

Predictors of therapeutic effect of transarterial chemoembolisation using drug-eluting beads for hepatocellular carcinoma.

AIMS: To identify predictors of a therapeutic effect after transarterial chemoembolisation using drug-eluting beads (DEB-TACE) for hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Between January 2015 and July 2015, tumour variables and angiographic data were collected for 25 patients (49 target lesions) after they had undergone the DEB-TACE procedure for HCC. The therapeutic effect was evaluated according to the Response Evaluation Criteria in Cancer of the Liver at follow-up dynamic computed tomography (CT) performed within 1-4 months after the procedure. A p<0.05 was considered significant. RESULTS: On a target lesion basis, the objective response (TE3/4) rate was 63.3% (31 of 49). On univariate analysis, larger size (≥2 cm) was a predictor of an objective response (p=0.029). The tumour location of the medial (segment 4) or caudate (segment 1) lobe also indicated a poor therapeutic effect (TE1/2), but not at the level of significance (p=0.051). Multivariate analysis identified tumour size (odds ratio, 8.60; 95% confidence interval, 1.87-62.8) and tumour location (odds ratio, 12.2; 95% confidence interval, 2.12-129.8) as significant factors associated with a therapeutic effect. On a patient basis, 10 of 25 (40%) patients showed complete response/partial response. There were no significant differences between complete response/partial response and stable disease/progressive disease regarding age, gender, tumour markers, history of previous treatment, Child-Pugh class, T-stage, or Barcelona Clinic Liver Cancer Staging. CONCLUSION: A short-term therapeutic effect was associated with tumour size and location on a target lesion basis.

Heterogeneity of non-cancerous liver parenchyma on gadoxetic acid-enhanced MRI: an imaging biomarker for hepatocellular carcinoma development in chronic liver disease.

AIM: To clarify whether the heterogeneity of non-cancerous liver parenchyma (NLP) in the hepatobiliary phase on gadoxetic acid enhanced magnetic resonance imaging (MRI) is correlated with hepatocellular carcinoma (HCC) development. MATERIALS AND METHODS: Institutional review board approval was obtained, and the requirements for informed consent were waived for this retrospective study. The imaging characteristics of 84 patients with chronic liver disease who underwent gadoxetic acid-enhanced 3T MRI between January 2013 and October 2014 were examined retrospectively. For the evaluation of the heterogeneity of the intensity in the hepatobiliary phase, the largest possible region of interest was placed on the NLP, and the skewness and kurtosis were calculated using ImageJ software. Skewness is the degree of asymmetry of a histogram, and kurtosis is a measure of the peak. Based on the median values of kurtosis and skewness, the patients were classified into four categories and the categories were compared between the 49 patients with HCC (HCC group) and the 35 patients without HCC (non-HCC group). RESULTS: Kurtosis was significantly higher in the HCC group compared to the non-HCC group (1.19±1.15 versus 0.43±0.83; p=0.0006). Skewness was significantly lower in the HCC group than in the non-HCC group (1.19±1.15 versus 0.43±0.83; p=0.0152). In a multivariate logistic analysis, the category showing lower-than-the-median (-0.1185) skewness and higher-than-the-median (0.547) kurtosis was significantly and independently associated with HCC development (p=0.0031). CONCLUSION: The heterogeneity of NLP in the hepatobiliary phase on gadoxetic acid enhanced MRI may reflect the development of HCC.

Fatty change in moderately and poorly differentiated hepatocellular carcinoma on MRI: a possible mechanism related to decreased arterial flow.

AIM: To clarify the frequency of fatty change in moderately and poorly differentiated hepatocellular carcinomas (mHCCs and pHCCs) and its relationship to arterial blood flow. MATERIALS AND METHODS: One hundred and thirty-six surgically resected HCC lesions were studied. All patients had undergone dynamic magnetic resonance imaging (MRI) with chemical-shift-encoded water-fat imaging (CSI). The presence of fat was identified by a signal drop-off on CSI and confirmed at pathology. Lesions were classified into four groups in the arterial phase; G1, hypointense; G2, isointense; G3, slightly and heterogeneously hyperintense; G4, markedly and homogeneously hyperintense. The number of cumulative arteries (CAs) in the tumours in the pathology examination were counted. RESULTS: A fat component was observed significantly more frequently in the pHCCs (13/21; 61.9%) compared to the mHCCs (32/101; 31.7%; p=0.013). The numbers of lesions in each group were as follows: (G1, G2, G3, G4) = (18, 9, 23, 4) in the HCCs with fat; (1, 6, 24, 51) in the HCCs without fat (p<0.001); (5, 5, 18, 4) in the mHCCs with fat; (0, 3, 19, 47) in the mHCCs without fat (p<0.001); (11, 0, 2, 0) in the pHCCs with fat; (0, 2, 3, 3) in the pHCCs without fat (p=0.001). The number of CAs in the fat-containing HCCs (5.5±2.9) was significantly lower than that in the HCCs without fat (10.8±5.3; p<0.001). CONCLUSION: A fat component was more commonly observed in the pHCCs than in the mHCCs. The present results showed a possible mechanism of fatty change in mHCCs and pHCCs in relation to decreased arterial blood supply.

Detectability of hepatocellular carcinoma on gadoxetic acid-enhanced MRI at 3 T in patients with severe liver dysfunction: clinical impact of dual-source parallel radiofrequency excitation.

AIM: To clarify the detectability of hepatocellular carcinoma (HCC) on gadoxetic acid-enhanced MRI at 3 T with dual-source parallel radiofrequency (RF) excitation. MATERIALS AND METHODS: Twelve patients with 26 HCCs who each underwent multidetector row CT (MDCT), gadoxetic acid-enhanced MRI with dual-source parallel RF excitation, and angiography-assisted CT prior to living related-liver transplantation. Three blinded readers independently reviewed the images obtained by each imaging technique for the presence of HCC on a segment-by-segment basis using a five-point confidence scale. The area under the receiver operating characteristic curve (Az), sensitivity, and specificity were compared among the three techniques. RESULTS: The Az values of gadoxetic acid-enhanced MRI were highest for all readers, although no significant difference in Az value among the three methods was obtained. No significant differences in sensitivity or specificity were observed among the three techniques for each reader. CONCLUSION: Gadoxetic acid-enhanced MRI at 3 T with dual-source parallel RF excitation has relatively high-level diagnostic potential for the detection of HCC in patients with severe liver dysfunction, which was equivalent to that of MDCT and angiography-assisted CT. Dual-source parallel RF excitation would have a clinical impact on 3 T MRI of the liver.

Effect of heat stress soon after muscle injury on the expression of MyoD and myogenin during regeneration process.

Heat stress could promote skeletal muscle regeneration. But, in the regeneration process, effects of heat stress on myogenic cells and the regulating factors is unknown. Therefore, Influences of heat stress soon after injury on distribution of the myogenic cells and chronological changes in expression of MyoD and myogenin were examined. The first peak of MyoD expression was temporally correlated with the time when proliferating satellite cells began to appear, and the rapid decline of the MyoD expression from the first peak, with the appearance time of myoblasts, respectively in both the non-Heat and Heat groups. The first peak of myogenin expression was temporally correlated with the time when multinuclear cells began to form in the both groups. Due to the heat stress, proliferation and differentiation of myogenic cells and chronological changes in these factors were accelerated one day earlier than in the non-Heat group. As MyoD and myogenin are regulating factor of proliferation and differentiation, heat stress soon after the muscle injury could accelerate the proliferation and differentiation of myogenic cells and the expression of their regulating factors MyoD and myogenin.

A prospective, randomized, double-blind, controlled trial on the efficacy of carbon dioxide insufflation in gastric endoscopic submucosal dissection.

BACKGROUND AND STUDY AIMS: Carbon dioxide (CO2) insufflation is expected to be safe and effective in endoscopic submucosal dissection (ESD) as well as in other endoscopic procedures. The present study aimed to clarify the usefulness and safety of CO2 insufflation in gastric ESD. PATIENTS AND METHODS: A total of 102 consecutive patients were randomly assigned to CO2 insufflation (CO2 group, n = 54) or air insufflation (Air group, n = 48). Abdominal pain and distension were chronologically recorded on a 100-mm visual analog scale (VAS). The volume of residual gas in the digestive tract was measured by computed tomography performed immediately after ESD. RESULTS: Abdominal pain on a 100-mm VAS in the CO2 vs. Air group was 4 vs. 3 immediately after ESD, 4 vs. 4 one hour after the procedure, 3 vs. 3 three hours after the procedure, and 1 vs. 4 the next morning, showing no difference between the groups. In addition, there was no difference in abdominal distension on the 100-mm VAS over the time course of the study. The volume of residual gas in the digestive tract in the CO2 group was significantly smaller than that in the Air group (643 mL vs. 1037 mL, P < 0.001). The dose of sedative drugs did not differ between the groups. Neither the incidences of complications nor clinical courses differed between the groups. CONCLUSIONS: Compared with air insufflation, CO2 insufflation during gastric ESD significantly reduced the volume of residual gas in the digestive tract but not the VAS score of abdominal pain and distension.

De-escalation of antimicrobial therapy for bacteraemia due to difficult-to-treat Gram-negative bacilli.

PURPOSE: To examine the status and clinical outcome of de-escalating antimicrobial therapy for bacteraemia due to hospital-acquired, Gram-negative bacilli that are difficult to treat. METHODS: Among 1,610 patients presenting with positive blood cultures collected at our medical centre over a 6-year period, 133 were infected with Serratia, Pseudomonas, Acinetobacter, Citrobacter or Enterobacter sp. (SPACES). We examined the appropriateness of an empiric initial administration of antimicrobials based on in vitro sensitivity, and the success and outcomes of a pathogen-directed de-escalation of therapy. The treatment was considered to be successfully de-escalated when the antimicrobial spectrum was narrowed according to a spectrum ranking or when ≥ 2 antimicrobials prescribed initially were lowered to one agent. Outcome measures included persistent, recurrent and metastatic infections, infection-related deaths and cost of antimicrobials. RESULTS: The treatment was initially appropriate in 79 of 133 patients (59 %), of whom 49 (62 %) were candidates for and 28 (57 %) underwent treatment de-escalation. No treatment failure was observed among these 28 patients, while 2 of 11 patients (18 %) whose treatment was not de-escalated died (p = 0.13). The median cost of antimicrobials was 250/patient lower in the de-escalated than in the non-de-escalated group (p < 0.001). CONCLUSIONS: Antimicrobial therapy for bacteraemia due to hard-to-treat SPACES was de-escalated in 57 % of candidates, based on the in vitro sensitivity, with no deaths and significantly lower costs of antimicrobial therapy.

A pilot study to assess mediastinal emphysema after esophageal endoscopic submucosal dissection with carbon dioxide insufflation.

BACKGROUND AND AIMS: Mediastinal emphysema sometimes develops following esophageal endoscopic submucosal dissection (ESD) without perforation because the esophagus has no serosa. Carbon dioxide (CO2) insufflation during esophageal ESD may reduce the incidence of mediastinal emphysema. The aim of the present study was to compare the incidence and severity of post-ESD mediastinal emphysema in patients receiving CO2 insufflation vs. standard air insufflation during esophageal ESD. PATIENTS AND METHODS: A total of 27 patients who had undergone esophageal ESD with insufflation of CO2 between July 2009 and March 2010 were enrolled in this study (CO2 group). Another 105 patients who had undergone esophageal ESD with air insufflation between March 2004 and May 2009 were included as historical controls (air group). Multi-detector row computed tomography (MDCT) was carried out immediately after ESD. A conventional chest radiograph was taken the next day. Mediastinal emphysema findings on MDCT and radiography were compared between the groups. RESULTS: Mediastinal emphysema detected by chest radiography was 0 % in the CO2 group vs. 6.6 % in the air group (n.s.). Mediastinal emphysema on MDCT was significantly less frequent in the CO2 group compared with the air group (30 % vs. 63 %; P = 0.002). The severity of mediastinal emphysema also tended to be lower in the CO2 group. CONCLUSIONS: Whereas mediastinal emphysema detected by radiography is not so common, MDCT immediately after ESD revealed a certain prevalence of post-ESD mediastinal emphysema. Insufflation of CO2 rather than air during esophageal ESD significantly reduced postprocedural mediastinal emphysema. CO2 can be considered as insufflating gas for esophageal ESD.

Effects of renal function on the pharmacokinetics and pharmacodynamics of prophylactic cefazolin in cardiothoracic surgery.

The purpose of this investigation was to study the effects of renal function on the pharmacokinetics and pharmacodynamics (PK-PD) of free cefazolin administered prophylactically in cardiothoracic surgery. Patients received an initial 2-g dose of cefazolin, followed by 1-g doses 6, 12, 18 and 24 h after the first dose. In patients who underwent cardiopulmonary bypass, 1 g was added to the priming solution. In 35 patients with a normal estimated creatinine clearance (CLcr) ≥50 ml/min, a free cefazolin concentration <4 µg/ml was observed in 11.4, 5.7 and 54.3% of patients before the second dose, at the end and 24 h after operation, respectively. In contrast, only 7.4% of 27 patients with CLcr <49 ml/min had a free cefazolin concentration <4 µg/ml 24 h after the operation. There was a high negative correlation between CLcr and time above the target minimal inhibitory concentration (MIC) when the CLcr was <50 ml/min (r(2) = 0.807), and no correlation when the CLcr was ≥50 ml/min. Renal function has a significant impact on the PK-PD of prophylactic cefazolin in cardiothoracic surgery. The postoperative drug dosing intervals should be <6 h in order to achieve a 100% time above the MIC in patients with CLcr ≥ 50 ml/min.

Regional spread and control of vancomycin-resistant Enterococcus faecium and Enterococcus faecalis in Kyoto, Japan.

The purpose of this investigation was to control the post-outbreak prevalence of vancomycin-resistant enterococci (VRE) in the affected Kyoto region. The study period was from 2005 to 2010. Faecal samples were subjected to VRE screening, and vancomycin resistance genes were detected by polymerase chain reaction (PCR). The genotype was determined by pulsed-field gel electrophoresis (PFGE) of genomic DNA digested with SmaI and by multilocus sequence typing (MLST). A VRE control programme was established in 2006, consisting of a laboratory-based faecal VRE screening system, annual surveillance of hospital inpatients and the promotion of adequate infection control measures. vanA-Enterococcus faecium, vanB-E. faecium and vanB-E. faecalis were detected at 35, 12 and 5 hospitals, respectively. Genotype analysis revealed that all of the vancomycin-resistant E. faecium isolates obtained since 2005 belonged to ST78, and that clonally related vanB-E. faecalis of ST64 had spread to three hospitals. The rate of faecal VRE carriage among the patients enrolled in the annual surveillance increased until 2007, when it reached 24 (1.2%) of the 2,035 enrolled patients. The rate began to decrease in 2008 and, by 2010, reached a low of 4 (0.17%) of the 2,408 enrolled patients. While VRE did spread within the Kyoto region, the VRE control programme succeeded in controlling the overall VRE spread.

Experimental observation of the bifurcation dynamics of an intrinsic localized mode in a driven 1D nonlinear lattice.

Linear response spectra of a driven intrinsic localized mode in a micromechanical array are measured as it approaches two fundamentally different kinds of bifurcation points. A linear phase mode associated with this autoresonant state softens in frequency and its amplitude grows as the upper frequency bifurcation point is approached, similar to the soft-mode kinetic transition for a single driven Duffing resonator. A lower frequency bifurcation point occurs when the four-wave-mixing partner of this same phase mode intercepts the top of the extended wave branch, initiating a second kinetic transition process.

De-escalation of antimicrobials in the treatment of bacteraemia due to antibiotic-sensitive pathogens in immunocompetent patients.

BACKGROUND: The aim of this study was to examine the safety and efficacy of de-escalating antimicrobial therapy in immunocompetent patients presenting with bacteraemia due to antibiotic-sensitive pathogens. METHODS: We screened 1,350 positive blood cultures identified in a single, 1,065-bed university hospital over 5 years, and retained 310 cases of bacteraemia due to antibiotic-sensitive pathogens, including (1) methicillin-sensitive staphylococci, (2) penicillin-sensitive streptococci, (3) ß-lactam-sensitive (a) Escherichia coli, and (b) Klebsiella species. The efficacy of appropriate initial empirical antimicrobial therapy, the performance of de-escalated pathogen-directed therapy, and the safety and efficacy of de-escalated therapy were evaluated. RESULTS: Among 270 appropriately treated patients, 16 (6%) died, versus 6 (15%) among 40 who were inappropriately treated (p = 0.04). While 201 of 270 patients (74%) who received appropriate initial empirical therapy were candidates for de-escalation, the treatment was de-escalated in only 79 (39%). De-escalation was associated with (1) a trend toward a lower (a) death rate (1 vs. 5%) and (b) treatment failure (4 vs. 10%), and (2) (a) a 4-day longer median duration and (b) a $50 higher median cost of antimicrobial therapy (p < 0.001). CONCLUSIONS: When the pathogen was sensitive to antimicrobial therapy and the initial empirical treatment was effective, de-escalation of antimicrobial therapy in immunocompetent patients with bacteraemia was safe and associated with acceptable outcomes. The rate of de-escalation of antimicrobial therapy was low.

Regional spread of vanA- or vanB-positive Enterococcus gallinarum in hospitals and long-term care facilities in Kyoto prefecture, Japan.

Following an outbreak of vanA-positive Enterococcus faecium in 2005 in Kyoto prefecture, regional surveillance of vancomycin-resistant enterococci (VRE) was initiated. This revealed vanA- or vanB-positive Enterococcus gallinarum in multiple facilities. Eighty-eight vanA-positive E. gallinarum faecal carriers from 12 facilities and ten vanB-positive E. gallinarum faecal carriers from eight facilities were found. Pulsed-field gel electrophoresis profiles of the first isolate from each facility showed that 11 of the 12 vanA isolates and three of the eight vanB-positive E. gallinarum isolates belonged to a single clone. This study confirms the clonal spread of vanA- or vanB-positive E. gallinarum in a region and underlines the importance of surveillance of VRE for the presence of vancomycin resistance determinants.

The involvement of calpain-dependent proteolysis of the tumor suppressor NF2 (merlin) in schwannomas and meningiomas.

Neurofibromatosis type 2 (NF2) protein, also known as merlin or schwannomin, is a tumor suppressor, and NF2 is mutated in most schwannomas and meningiomas. Although these tumors are dependent on NF2, some lack detectable NF2 mutations, which indicates that alternative mechanisms exist for inactivating merlin. Here, we demonstrate cleavage of merlin by the ubiquitous protease calpain and considerable activation of the calpain system resulting in the loss of merlin expression in these tumors. Increased proteolysis of merlin by calpain in some schwannomas and meningiomas exemplifies tumorigenesis linked to the calpain-mediated proteolytic pathway.

GRIP1 enhances estrogen receptor alpha-dependent extracellular matrix gene expression in chondrogenic cells.

OBJECTIVE: The role of postmenopause on the pathogenesis of cartilage degeneration has been an open question. We assessed cartilage degeneration in estrogen receptor (ER)alpha null mice and examined the role of glucocorticoid receptor-interacting protein 1 (GRIP1) in the ERalpha-dependent transcription of a type II collagen gene (col2a1) with special reference to a crosstalk with the transforming growth factor (TGF)-beta signaling pathway. METHODS: The vertebral cartilaginous endplate from female ERalpha null mice was subjected to histological analyses. Col2a1 expression of primary chondrocytes (PCs) obtained from ERalpha null mice after 17beta-estradiol (E(2)) and TGF-beta1 stimulation was examined by reverse transcription polymerase chain reaction (RT-PCR). Estrogen response element (ERE) or col2a1 promoter-enhancer luciferase reporter system was used to investigate the crosstalk among ERalpha, GRIP1, and MKK6. Col2a1 expression and glycosaminoglycan (GAG) content were measured in ATDC5 cells treated with GRIP1 small interfering RNA (siRNA). RESULTS: ERalpha deficiency clearly accelerated impairment of the vertebral cartilaginous endplate. E(2) and TGF-beta1 stimulation increased col2a1 expression in PC from wild-type mice, but not that from ERalpha null mice. The same stimulation increased the col2a1 promoter-enhancer reporter activity, and the elevated activity was decreased by dominant-negative ERalpha and p38 mitogen-activated protein kinase (MAPK) inhibitor. GRIP1 increased the E(2)-dependent ERE activation in the presence of ERalpha and constitutive-active MKK6. GRIP1 siRNA repressed col2a1 expression and GAG production in ATDC5 cells. CONCLUSIONS: Crosstalks between ERalpha/GRIP1 and TGF-beta/MKK6/p38 MAPK pathway have protective roles on cartilage metabolism via regulating the extracellular matrices expression. The finding may lead to the development of a novel therapeutic approach for cartilage degeneration.