Newly developed preclinical models reveal broad-spectrum CDK inhibitors as potent drugs for CRPC exhibiting primary resistance to enzalutamide.

Androgen-deprivation therapy is a standard treatment for advanced prostate cancer. However, most patients eventually acquire resistance and progress to castration-resistant prostate cancer (CRPC). In this study, we established new CRPC cell lines, AILNCaP14 and AILNCaP15, from LNCaP cells under androgen-deprived conditions. Unlike most pre-existing CRPC cell lines, both cell lines expressed higher levels of androgen receptor (AR) and prostate-specific antigen (PSA) than parental LNCaP cells. Moreover, these cells exhibited primary resistance to enzalutamide. Since AR signaling plays a significant role in the development of CRPC, PSA promoter sequences fused with GFP were introduced into AILNCaP14 cells to conduct GFP fluorescence-based chemical screening. We identified flavopiridol, a broad-spectrum CDK inhibitor, as a candidate drug that could repress AR transactivation of CRPC cells, presumably through the inhibition of phosphorylation of AR on the serine 81 residue (pARSer81 ). Importantly, this broad-spectrum CDK inhibitor inhibited the proliferation of AILNCaP14 cells both in vitro and in vivo. Moreover, a newly developed liver metastatic model using AILNCaP15 cells revealed that the compound attenuated tumor growth of CRPC harboring highly metastatic properties. Finally, we developed a patient-derived xenograft (PDX) model of CRPC and DCaP CR from a patient presenting therapeutic resistance to enzalutamide, abiraterone, and docetaxel. Flavopiridol successfully suppressed the tumor growth of CRPC in this PDX model. Since ARSer81 was found to be phosphorylated in clinical CRPC samples, our data suggested that broad-spectrum CDK inhibitors might be a potent candidate drug for the treatment of CRPC, including those exhibiting primary resistance to enzalutamide.

Adaptive Dynamics Simulation of Interference Phenomenon for Physical and Biological Systems.

Biological systems have been shown to have quantum-like behaviors by applying the adaptive dynamics view on their interaction networks. In particular, in the process of lactose-glucose metabolism, cells generate probabilistic interference patterns similarly to photons in the two-slit experiment. Such quantum-like interference patterns can be found in biological data, on all scales, from proteins to cognitive, ecological, and social systems. The adaptive dynamics approach covers both biological and physical phenomena, including the ones which are typically associated with quantum physics. We guess that the adaptive dynamics can be used for the clarification of quantum foundations, and the present paper is the first step in this direction. We suggest the use of an algorithm for the numerical simulation of the behavior of a billiard ball-like particle passing through two slits by explicitly considering the influence of the two-slit environment (experimental context). Our simulation successfully mimics the interference pattern obtained experimentally in quantum physics. The interference of photons or electrons by two slits is known as a typical quantum mechanical effect. We do not claim that the adaptive dynamics can reproduce the whole body of quantum mechanics, but we hope that this numerical simulation example will stimulate further extensive studies in this direction-the representation of quantum physical phenomena in an adaptive dynamical framework.

Abutment removal torque and implant conical surface morphological changes after standardized artificial aging: An in vitro study.

STATEMENT OF PROBLEM: Zirconia abutments have become popular as they provide favorable esthetic outcomes. However, studies investigating how abutment material affects abutment screw torque performance and implant conical surface morphological changes in internal conical connection systems are scarce. PURPOSE: The purpose of this in vitro study was to investigate the influence of abutment material on abutment removal torque and implant conical surface morphological changes in internal conical connection implant-abutment assemblies of 2 diameters after simulated long-term oral use. MATERIAL AND METHODS: Thirty abutments of 3 materials (1-piece titanium, 1-piece zirconia, zirconia with alloy base) and 2 diameters (regular, narrow) made by the original manufacturer were connected to internal conical connection implants and subjected to a standardized artificial aging process consisting of thermal cycling and mechanical cyclic loading with parameters corresponding to anterior and posterior mastication scenarios simulating long-term oral use. An abutment removal torque test was done before and after aging. Morphological changes in the implant conical contact surface were observed with a scanning electron microscope (SEM). Initial and after-aging torque loss values were calculated and analyzed separately with 1-way ANOVA and Tukey HSD post hoc tests (α=.05). RESULTS: All specimens survived artificial aging. For initial and after-aging torque loss, the 1-piece zirconia groups showed significantly greater values (P<.001) for both diameters. In the SEM observation, the 1-piece zirconia groups showed distinct widespread surface damage while the other groups exhibited only minor damages. CONCLUSIONS: Regardless of diameter, 1-piece zirconia abutments tend to induce more abutment removal torque loss and implant conical surface morphological changes than those with metal connections, both initially and after simulated long-term oral use. Zirconia abutments with an alloy base performed similarly to 1-piece titanium abutments.

Influence of Liquid on the Tooth Surface on the Accuracy of Intraoral Scanners: An In Vitro Study.

PURPOSE: To assess the influence of liquid attached on the tooth surfaces on the accuracy (trueness and precision) of intraoral scanners and the effectiveness of the drying method (using compression air) to exclude the influence of liquid on the scanning results. MATERIALS AND METHODS: A mandibular jaw model was scanned using an industrial computed tomography scanner to obtain a reference model. A scanning platform was designed to simulate three specific tooth surface states (dry, wet, blow-dry). Two kinds of liquids (ultra-pure water and artificial saliva) were used for the test. Two intraoral scanners (Trios 3 and Primescan) were used to scan the mandibular jaw model 10 times under each condition. All scanning data were processed and analyzed using dedicated software (Geomagic Control 2015). Trueness and precision comparison were conducted within the 12 groups of 3D models divided based on different intraoral scanners and liquids used under each condition. The root mean square (RMS) value was used to indicate the difference between the aligned virtual models. The color maps were used to evaluate and observe the deviation distribution patterns. The 3-way ANOVA (condition, intraoral scanner, liquid) followed by the Tukey test were used to assess precision and trueness. The level of significance was set at 0.05. RESULTS: The mean RMS values obtained from wet condition were significantly higher than those of the dry and blow-dry condition (p < 0.001, F = 64.033 for trueness and F = 54.866 for precision), which indicates less accurate trueness and precision for wet condition. For two different types of liquids, the mean RMS value was not significantly different on trueness and precision. The deviations caused by liquid were positive and mainly distributed in the pits and fissures of the occlusal surface of posterior teeth, the interproximal area of the teeth, and the margin of the abutments. CONCLUSIONS: Liquid on the tooth surface could affect intraoral scanning accuracy. Blow-drying with a three-way syringe can reduce scanning errors.

Genetic abnormalities in a large cohort of Coffin-Siris syndrome patients.

Coffin-Siris syndrome (CSS, MIM#135900) is a congenital disorder characterized by coarse facial features, intellectual disability, and hypoplasia of the fifth digit and nails. Pathogenic variants for CSS have been found in genes encoding proteins in the BAF (BRG1-associated factor) chromatin-remodeling complex. To date, more than 150 CSS patients with pathogenic variants in nine BAF-related genes have been reported. We previously reported 71 patients of whom 39 had pathogenic variants. Since then, we have recruited an additional 182 CSS-suspected patients. We performed comprehensive genetic analysis on these 182 patients and on the previously unresolved 32 patients, targeting pathogenic single nucleotide variants, short insertions/deletions and copy number variations (CNVs). We confirmed 78 pathogenic variations in 78 patients. Pathogenic variations in ARID1B, SMARCB1, SMARCA4, ARID1A, SOX11, SMARCE1, and PHF6 were identified in 48, 8, 7, 6, 4, 1, and 1 patients, respectively. In addition, we found three CNVs including SMARCA2. Of particular note, we found a partial deletion of SMARCB1 in one CSS patient and we thoroughly investigated the resulting abnormal transcripts.

Group A streptococcus endocarditis in children: 2 cases and a review of the literature.

BACKGROUND: Infective endocarditis (IE) is defined as endocarditis caused by microorganisms (bacteria or fungi) involving either the heart or great vessels. The clinical course of IE can be complicated by cardiac dysfunction and bacterial embolization to virtually any organ. Staphylococcus aureus and viridans group streptococci are the most common causative organisms, whereas group A Streptococcus (GAS) is less common. Although some GAS serotypes have been associated with severe disease, there are few reports of IE associated with GAS serotypes. Here, we report two cases of GAS endocarditis and review the associated literature. CASE PRESENTATIONS: Patient 1 was a previously healthy 14-year-old girl who developed bacteremia and disseminated intravascular coagulation secondary to left foot cellulitis. She was administered intravenous antibiotics. Two of three blood cultures grew Streptococcus pyogenes (T6 M6, emm6.104). Three days later, a new systolic ejection murmur was heard and echocardiography showed mitral regurgitation with mitral valve vegetation. Because of the resultant severity of the mitral regurgitation, she underwent mitral valve repair after 10 weeks of antibiotic treatment. Patient 2 was a 17-month old boy who presented with a fever. He had a history of spontaneous closure of a ventricular septal defect (VSD). He was started on intravenous antibiotics for possible bacteremia. Two consecutive blood cultures with an interval of more than 12 h grew S. pyogenes (T4 M4, emm4.0). Five days later, echocardiography showed vegetation on a membranous ventricular septal aneurysm. The patient responded well to antibiotics, and recovered fully with no complications. CONCLUSIONS: Although both patients developed GAS endocarditis, patient 1 did not have any predisposing conditions for IE, and patient 2 had a only a low-risk predisposing condition, a VSD that had closed spontaneously at five months of age. We found twelve reports in the literature of GAS endocarditis with information on serotypes. All patients in these reports had GAS endocarditis caused by serotypes generally associated with milder infections, but no specific risk trends were identified. A greater accumulation of cases is necessary to more clearly elucidate the association between GAS IE and specific serotypes.

[A Case of Renal Oncocytosis with Bilateral Multiple Renal Masses].

A 63-year-old man with microscopic hematuria underwent contrast-enhanced CT, which showed multiple bilateral renal masses. Percutaneous biopsy results indicated renal oncocytosis. The tumors remained unchanged for 3 years. Renal oncocytosis is a very rare tumor, but it is an established disease entity characterized by numerous oncocytic tumors and diffuse (sporadic) renal parenchymal epithelial oncocytic changes on an analysis histopathology. Although renal oncocytosis can be sporadic or part of Birt-Hogg-Dube syndrome (BHDS), our case did not associate with BHDS because of absence of lung cyst.

[Evaluation of Lymphoceles by CT Scan Early after Robot-Assisted Radical Prostatectomy].

We report the incidence and characteristics of lymphoceles after robot-assisted radical prostatectomy (RARP). Computed tomography was performed on 79 patients one month after RARP or when symptoms appeared. The lymphocele was defined as a cystic lesion over 10 mm in diameter. Symptomatic and asymptomatic lymphoceles were identified in 25% (20/79) of all cases, and in 40.9% (18/44) of the cases with lymph node dissection (LND). Symptomatic lymphoceles were identified in 2.5% (2/79) of all cases. Lymphoceles were significantly associated with LND, pathological stage over T3, longer period of indwelling drain tube,and higher volume fluid of drain tube (p<0.05). In conclusion, lymphoceles are quiet common after RARP. However, they rarely become symptomatic.

[A Case of Chromophobe Renal Cell Carcinoma Associated with Birt-Hogg-Dubé Syndrome].

A 61-year-old man with a left renal mass, which was detected by ultrasound during a routine health examination, was referred to our department. The patient had a surgical history of two pneumothorax operations, and the patient's brother also had a history of pneumothorax surgery. A case of Birt-Hogg-Dubé (BHD) syndrome was suspected based on patient history. The pathological diagnosis of the resected tumor, which used robot-assisted laparoscopic partial nephrectomy, was determined to be chromophobe renal cell carcinoma (grade 2, pT1a). BHD syndrome was confirmed by genetic testing, where a nonsense mutation of exon 9 in the FOLLICULIN (FLCN) gene was detected. The patient is currently alive 10 months after surgery.

Cross-Sectional Imaging of Boundary Lubrication Layer Formed by Fatty Acid by Means of Frequency-Modulation Atomic Force Microscopy.

To observe in situ the adsorption of fatty acid onto metal surfaces, cross-sectional images of the adsorption layer were acquired by frequency-modulation atomic force microscopy (FM-AFM). Hexadecane and palmitic acid were used as the base oil and typical fatty acid, respectively. A Cu-coated silicon wafer was prepared as the target substrate. The solvation structure formed by hexadecane molecules at the interface between the Cu substrate and the hexadecane was observed, and the layer pitch was found to be about 0.6 nm, which corresponds to the height of hexadecane molecules. This demonstrates that hexadecane molecules physically adsorbed onto the surface due to van der Waals forces with lying orientation because hexadecane is a nonpolar hydrocarbon. When hexadecane with palmitic acid was put on the Cu substrate instead of pure hexadecane, an adsorption layer of palmitic acid was observed at the interface. The layer pitch was about 2.5-2.8 nm, which matches the chain length of palmitic acid molecules well. This indicates that the original adsorption layer was monolayer or single bilayer in the local area. In addition, a cross-sectional image captured 1 h after observation started to reveal that the adsorbed additive layer gradually grew up to be thicker than about 20 nm due to an external stimulus, such as cantilever oscillation. This is the first report of in situ observation of an adsorbed layer by FM-AFM in the tribology field and demonstrates that FM-AFM is useful for clarifying the actual boundary lubrication mechanism.

[Risk Factors for Mortalityin Patients with Urosepsis].

Urosepsis is not uncommon and sometimes causes a critical condition including death. We retrospectivelyanaly zed the risk factors for mortalityin urosepsis. We treated 80 patients as urosepsis from 2010 to 2014 in our hospital. Five patients (6%) died within 30 days of hospitalization. The median age of the patients who died of urosepsis was 92 years (range, 83-95 years). The main causes of urosepsis were complicated pyelonephritis in 4 patients and emphysematous pyelonephritis in one. In the subgroup analysis of elderly patients over 75 years old, bad performance status and lower serum albumin were significantlyrelated to mortality(p ＝0.033, 0.046). The elderlypatients, especiallywith bad performance status and lower serum albumin, are more likelyto die.

[Two Cases of Oncocytic Papillary Renal Cell Carcinoma].

Oncocytic papillary renal cell carcinoma isa variant of papillary renal cell carcinoma (PRCC). We herein report two cases treated with retroperitoneoscopic partial nephrectomy. Histologically, tumor cells of both cases exhibit round and regular nuclei with CK7 positive areas in the cytoplasm typical of TYPE1 PRCC and eosinophilic granular cytoplasm with E-cadherin positive areas in the cytoplasmic membrane, which indicates TYPE2 PRCC. Out of 46 cases reported in the literature, only one died of disease, which reveals its low malignant potential.

Clinical characteristics of patients aged 65 and older with newly developed type 1 diabetes: An analysis of elderly patients at our hospital.

AIM: We herein investigated the clinical features of elderly patients with newly developed type 1 diabetes with respect to onset age, frequency of islet-associated antibodies, and other clinical markers. METHODS: One hundred and ninety-nine patients aged 65 and older with new-onset diabetes, who were admitted to our hospital between July 2000 and June 2013, were classified into 4 types of diabetes. In addition, 85 patients with newly diagnosed type 1A diabetes among all age ranges admitted during the same period were divided into two groups: a younger group (less than 65 years, n=71) and an elderly group (65 years and older, n=14). Clinical features including mode of onset, frequency of islet-associated antibodies, and serum C-peptide (CPR) levels were compared between these groups. The elderly group was further divided into two age groups (less than 75 years, n=7; 75 years and older, n=7), and the frequency of autoantibodies was compared. RESULTS: The patients (n=199) were classified into type 1 (n=16, 8%), type 2 (n=155, 78%), pancreatic (n=22, 11%), and other type (n=6, 3%) diabetes. Between the younger and elderly groups with type 1 diabetes, no significant difference in the CPR levels, frequency of autoantibodies, or other clinical features were observed. Positivity for IA-2 antibody was higher in the younger group (53.5%) than in the elderly group (35.7%), however, it was also considerably high (57.1%) in the oldest age group (75 years and older). CONCLUSIONS: Type 1 diabetes may develop in the elderly, and an IA-2 antibody test may be useful for diagnosing type 1 diabetes in older patients.

Abnormal Temporal Window of Integration in Auditory Sensory Memory in Schizophrenia.

Mismatch negativity (MMN) is automatically elicited by incoming sound deviation compared to the neural representation of preceding homogenous sounds stored in the brain's auditory sensory memory. This study aimed to assess time-functional deviation sensitivity in auditory sensory memory associated with a temporal window of integration (TWI) of 160-170 msec in patients with schizophrenia. To this end, we measured the magnetic counterpart of the MMN (MMNm) in 20 patients with schizophrenia on medication and 20 healthy age-matched adults as a control group responding to an omitted tone segment incorporated into a complex sound of 176 ms duration corresponding to the TWI duration. Overall, the magnitude of the MMNm was smaller in the patients with schizophrenia than in the healthy control group. The peak latency of the MMNm was prolonged in the latter omitted segments for both groups, but to a greater extent in patients with schizophrenia. These results indicate that deviation detection is impaired in the later part of the TWI, corresponding to the duration of auditory sensory memory in patients with schizophrenia. Thus, the specific impairment of MMN in response to duration deviants (duration MMN), as previously reported, might result from a damaged mechanism in the later part of the TWI of sensory memory, suggesting that a decline in sensory memory causes distorted perception or disturbances in cognitive function in patients with schizophrenia.

Plasma angiotensin-converting enzyme 2 (ACE2) is a marker for renal outcome of diabetic kidney disease (DKD) (U-CARE study 3).

INTRODUCTION: ACE cleaves angiotensin I (Ang I) to angiotensin II (Ang II) inducing vasoconstriction via Ang II type 1 (AT1) receptor, while ACE2 cleaves Ang II to Ang (1-7) causing vasodilatation by acting on the Mas receptor. In diabetic kidney disease (DKD), it is still unclear whether plasma or urine ACE2 levels predict renal outcomes or not. RESEARCH DESIGN AND METHODS: Among 777 participants with diabetes enrolled in the Urinary biomarker for Continuous And Rapid progression of diabetic nEphropathy study, the 296 patients followed up for 9 years were investigated. Plasma and urinary ACE2 levels were measured by the ELISA. The primary end point was a composite of a decrease of estimated glomerular filtration rate (eGFR) by at least 30% from baseline or initiation of hemodialysis or peritoneal dialysis. The secondary end points were a 30% increase or a 30% decrease in albumin-to-creatinine ratio from baseline to 1 year. RESULTS: The cumulative incidence of the renal composite outcome was significantly higher in group 1 with lowest tertile of plasma ACE2 (p=0.040). Group 2 with middle and highest tertile was associated with better renal outcomes in the crude Cox regression model adjusted by age and sex (HR 0.56, 95% CI 0.31 to 0.99, p=0.047). Plasma ACE2 levels demonstrated a significant association with 30% decrease in ACR (OR 1.46, 95% CI 1.044 to 2.035, p=0.027) after adjusting for age, sex, systolic blood pressure, hemoglobin A1c, and eGFR. CONCLUSIONS: Higher baseline plasma ACE2 levels in DKD were protective for development and progression of albuminuria and associated with fewer renal end points, suggesting plasma ACE2 may be used as a prognosis marker of DKD. TRIAL REGISTRATION NUMBER: UMIN000011525.

Urinary retention in a female patient caused by a urethral venous thrombus with massive edema.

Female urinary retention is rarely caused by an unknown condition. In such a case, common causes including neurogenic, anatomical, traumatic and iatrogenic voiding dysfunction are excluded. Both the radiological and histological findings specific to the condition remain unclear. We herein report a 75-year-old woman in whom a large venous mass and massive edema at the proximal urethra caused urinary outlet obstruction based on magnetic resonance images and histological findings. Ultrasonography and cystoscopy showed a urethral mass lesion protruding into the bladder neck. Fat-suppressed T2-weighted and gadolinium-enhanced T1-weighted magnetic resonance images suggested thrombosed veins with massive edema under the urethral mucosa. Transurethral resection of the mass lesion was carried out, and histopathological analysis proved the presence of thrombosed large veins. The patient regained normal urination, and the mass lesion did not recur. Thrombosed venous mass with edema at the proximal urethra might be an important cause of atypical urinary retention in women.

[Experience of transobturator sling for iatrogenic male stress urinary incontinence].

We performed transobturator sling (TOS) surgery for iatrogenic stress urinary incontinence (SUI) in 7 men. Assessment with the International Consultation Society Incontinence Questionnaire Short Form revealed that complete continence, significant improvement, and no change of incontinent status were observed in two, three, and two patients, respectively, at one year after surgery. Of the three patients with significant improvement, two patients obtained a pad-free status. Both of the two patients without improvement had a past history of salvage radiation therapy for biochemical recurrence after radical prostatectomy before TOS surgery. The severity of SUI seems not to be associated with the outcome of TOS surgery. TOS surgery can be one of the surgical options for iatrogenic male SUI.

[A case of prostate carcinosarcoma successfully treated with combined modality therapy].

A 58-year-old man was referred to our hospital with dysuria and elevation of prostate specific antigen (38.0 ng/ml). Prostate surface was smooth and elastic hard on digital rectal examination. Transrectal ultrasound (TRUS) indicated irregular boundary and low echoic area of the prostate. Prostate biopsy specimen included the components of adenocarcinoma (Gleason score 9) and sarcoma. The tumor had extended to the rectum and metastasized to bilateral obturator lymph nodes and right ischial bone (cT4N1M1b). We started hormone therapy for the adenocarcinoma component followed by total pelvic exenteration with colostomy and ileal conduit diversion for the sarcoma component. In addition, pelvic cavity and the bone metastasis were irradiated. The patient was free of recurrence at four and a half years after surgery.

Repeated ultrasound tests could be used to identify an isolated gastric duplication cyst before surgery.

A toddler girl was diagnosed with intra-abdominal simple cyst in the splenic flexure at the gestational period. Due to a severe fever that persisted for 6 days, she was admitted to the emergency room. The diagnosis of intraperitoneal cyst infection was made after contrast-enhanced CT revealed an enlarged cyst and a heterogeneous contrast effect on the cyst wall. A double-wall sign was observed on the cyst wall during continuous ultrasound follow-up, which led to the preoperative diagnosis of the cyst as a duplication cyst. The double-wall sign and cyst peristalsis were identified via successive ultrasound examinations to support the cyst diagnosis. Identifying a duplication cyst based solely on symptoms alone is difficult because the condition may present in different ways.