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Abstract Emerging evidence indicates that androgen receptor (AR) signaling plays a critical role in the pathogenesis of male-dominant urothelial cancer and its outgrowth. Meanwhile, latrophilins (LPHNs), a group of the G-protein-coupled receptors to which a spider venom latrotoxin (LTX) is known to bind, remain largely uncharacterized in neoplastic diseases. The present study aimed to determine the functional role of LPHN3 (encoded by the ADGRL3 gene), in association with AR signaling, in the progression of bladder cancer. In AR-positive bladder cancer lines, dihydrotestosterone considerably increased the expression levels of ADGRL3 and LPHN3, while chromatin immunoprecipitation assay revealed the binding of AR to the promoter region of ADGRL3. Treatment with LPHN3 ligands (e.g. α-LTX, FLRT3) resulted in the induction of ADGRL3 expression, as well as cell viability, in bladder cancer lines. By contrast, LPHN3 knockdown via shRNA virus infection significantly reduced the viability and migration of these cells. Immunohistochemistry in transurethral resection specimens further showed a strong correlation between LPHN3 and AR expression. Moreover, LPHN3 positivity in muscle-invasive bladder tumors, as an independent prognosticator, was associated with a significantly higher risk of disease progression and disease-specific mortality following radical cystectomy. These findings suggest that LPHN3 functions as a downstream effector of AR and promotes the growth of bladder cancer.

ABSTRACT Background Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer. Recent studies indicated that cancer‐associated adipocytes (CAAs) play crucial roles in tumor progression; however, the precise mechanism remains unknown. Here, we analyzed specific exosomal microRNAs (miRNA) signatures derived from pancreatic CAAs to investigate their role in cancer progression. Methods CAAs were generated by co‐culturing human adipocytes with human pancreatic cancer cells, and exosomes were isolated from the CAA‐conditioned medium (CAA‐CM). Small RNA‐seq analysis was used to identify differentially expressed miRNAs in these exosomes. The effects of miRNAs on cell proliferation, migration/invasion, and drug sensitivity were examined. Luciferase reporter assays, real‐time polymerase chain reaction, and western blotting were performed to investigate the molecular mechanisms of the miRNAs. The clinical relevance of the miRNAs was investigated using publicly available data and our cohort of patients with PDAC. Results miR‐199a‐3p expression was significantly increased in CAA‐CM‐derived exosomes. CAA‐derived exosomes transferred miR‐199a‐3p to pancreatic cancer cells. Transfection with miR‐199a‐3p increased the proliferation, invasion, migration, and drug resistance of pancreatic cancer cells by downregulating SOCS7, increasing STAT3 phosphorylation, and upregulating SAA1 expression. High tissue miR‐199a‐3p expression is correlated with poor prognosis in patients with PDAC. Liquid biopsies revealed that exosomal miR‐199a‐3p could accurately differentiate patients with PDAC from healthy controls. Multivariate survival analysis indicated that miR‐199a is an independent prognostic factor for PDAC. Conclusion miR‐199a‐3p in CAA‐derived exosomes contributes to the malignant transformation of pancreatic cancer via the SOCS7/STAT3/SAA1 pathway, suggesting its potential as a biomarker and therapeutic target for PDAC.

Abstract Background and Aims We aimed to evaluate the efficacy and safety of durvalumab plus tremelimumab (Dur + Tre) combination therapy in patients with unresectable hepatocellular carcinoma (uHCC) in clinical practice. Methods We retrospectively evaluated 37 patients with uHCC from our institutions between April 2023 and January 2024. Patients were divided into first‐ and later‐line groups for analysis of antitumor efficacy, adverse events (AEs), and transition rate to second‐line treatment according to the Response Evaluation Criteria in Solid Tumors (RECIST). Results The disease control rate (DCR) for the first‐line group was 80.9%, which was significantly higher than that for the later‐line group (50%). The incidence of immune‐related AEs (irAEs) was 24.3%, with grade 3 or higher irAEs including increased transaminase (8.1%), diarrhea (8.1%), and adrenal insufficiency (2.7%). The rates of drug withdrawal and discontinuation owing to AEs were 23.8% and 19%, respectively, in the first‐line treatment and 31.2% and 12.5%, respectively, in the later‐line treatment, with no significant difference. Analysis of changes in liver reserve using the albumin–bilirubin (ALBI) score showed no obvious loss of liver reserve for up to 12 weeks. The transition rate from first‐ to second‐line therapy after progressive disease (PD) was as high as 94.7%. Conclusion The efficacy and safety of Dur + Tre in clinical practice were comparable to those reported in a recent phase III trial. The first‐line Dur + Tre therapy had a higher DCR than that of the later lines, and the transition rate to second‐line therapy was considerably high, suggesting that Dur + Tre therapy would be more beneficial in first‐line treatment.

Abstract No clinically relevant biomarker has been identified for predicting the response of esophageal squamous cell carcinoma (ESCC) to chemoradiotherapy (CRT). Herein, we established a CT-based radiomics model with artificial intelligence (AI) to predict the response and prognosis of CRT in ESCC. A total of 44 ESCC patients (stage I-IV) were enrolled in this study; training (n = 27) and validation (n = 17) cohorts. First, we extracted a total of 476 radiomics features from three-dimensional CT images of cancer lesions in training cohort, selected 110 features associated with the CRT response by ROC analysis (AUC ≥ 0.7) and identified 12 independent features, excluding correlated features by Pearson’s correlation analysis (r ≥ 0.7). Based on the 12 features, we constructed 5 prediction models of different machine learning algorithms (Random Forest (RF), Ridge Regression, Naive Bayes, Support Vector Machine, and Artificial Neural Network models). Among those, the RF model showed the highest AUC in the training cohort (0.99 [95%CI 0.86–1.00]) as well as in the validation cohort (0.92 [95%CI 0.71–0.99]) to predict the CRT response. Additionally, Kaplan-Meyer analysis of the validation cohort and all the patient data showed significantly longer progression-free and overall survival in the high-prediction score group compared with the low-prediction score group in the RF model. Univariate and multivariate analyses revealed that the radiomics prediction score and lymph node metastasis were independent prognostic biomarkers for CRT of ESCC. In conclusion, we have developed a CT-based radiomics model using AI, which may have the potential to predict the CRT response as well as the prognosis for ESCC patients with non-invasiveness and cost-effectiveness.

Abstract Background Histological assessment of smooth muscle is a critical step particularly in staging malignant tumors in various internal organs including the urinary bladder. Nonetheless, manual segmentation and classification of muscular tissues by pathologists is often challenging. Therefore, a fully automated and reliable smooth muscle image segmentation system is in high demand. Methods To characterize muscle fibers in the urinary bladder, including muscularis mucosa (MM) and muscularis propria (MP), we assessed 277 histological images from surgical specimens, using two well-known deep learning (DL) model groups, one including VGG16, ResNet18, SqueezeNet, and MobileNetV2, considered as a patch-based approach, and the other including U-Net, MA-Net, DeepLabv3 + , and FPN, considered as a pixel-based approach. All the trained models in both the groups were evaluated at pixel-level for their performance. Results For segmenting MP and non-MP (including MM) regions, MobileNetV2, in the patch-based approach and U-Net, in the pixel-based approach outperformed their peers in the groups with mean Jaccard Index equal to 0.74 and 0.79, and mean Dice co-efficient equal to 0.82 and 0.88, respectively. We also demonstrated the strengths and weaknesses of the models in terms of speed and prediction accuracy. Conclusions This work not only creates a benchmark for future development of tools for the histological segmentation of smooth muscle but also provides an effective DL-based diagnostic system for accurate pathological staging of bladder cancer.

Background: Coronavirus disease 2019 (COVID-19), first reported in December 2019, spread worldwide in a short period, resulting in numerous cases and associated deaths; however, the toll was relatively low in East Asia. A genetic polymorphism unique to East Asians, Aldehyde dehydrogenase 2 rs671, has been reported to confer protection against infections. Method: We retrospectively investigated the association between the surrogate marker of the rs671 variant, the skin flushing phenomenon after alcohol consumption, and the timing of COVID-19 incidence using a web-based survey tool to test any protective effects of rs671 against COVID-19. Results: A total of 807 valid responses were received from 362 non-flushers and 445 flushers. During the 42 months, from 12/1/2019 to 5/31/2023, 40.6% of non-flushers and 35.7% of flushers experienced COVID-19. Flushers tended to have a later onset (Spearman’s partial rank correlation test, p = 0.057, adjusted for sex and age). Similarly, 2.5% of non-flushers and 0.5% of flushers were hospitalized because of COVID-19. Survival analysis estimated lower risks of COVID-19 and associated hospitalization among flushers (p = 0.03 and

Abstract Although several angiogenesis-related factors are reportedly involved in the pathogenesis of ulcerative colitis (UC), the mechanisms by which they contribute to disease are unclear. We first examined the expression of angiogenesis-related factors in inflamed colorectal tissue of UC patients using antibody array, and identified the 5 factors with highest expression, which included matrix metalloproteinase-8, urokinase-type plasminogen activator (uPA), angiostatin/plasminogen, hepatocyte growth factor and endoglin. Subsequent real-time PCR experiments using additional colorectal tissues revealed that uPA mRNA levels were significantly higher in inflamed tissues than in non-inflamed tissues, and significantly correlated with the severity of UC. Mirror section immunohistochemistry revealed that uPA was expressed in the neutrophils of inflamed colorectal tissues. We administered dextran sulfate sodium (DSS) in drinking water to uPA knockout (uPA−/−) mice, and found that the disease activity index in uPA-/- mice was marginally lower and the histological score in uPA−/− mice was significantly lower than those in wild-type mice, suggesting the importance of uPA in colitis. When an uPA-selective inhibitor, UK122, was administered to DSS-treated C57BL6J mice, the disease activity index and histological score in those mice were significantly lower compared with control mice. Multiple cytokine/chemokine assay using colorectal tissues from uPA−/− and UK122-treated mice revealed significantly lowered level of RANTES. In conclusion, uPA was highly expressed in neutrophils of the inflamed mucosa of UC patients, and the expression level correlated with the severity of UC. Genetic uPA deletion or pharmacological uPA blockade significantly ameliorated colitis in mice, concomitant with downregulation of RANTES.

Abstract Aim We analyzed the association between the modified albumin–bilirubin (mALBI) grade and therapeutic efficacy of atezolizumab plus bevacizumab (Atezo+Bev) for the treatment of unresectable hepatocellular carcinoma (u‐HCC). Methods In this retrospective observational study, we included 71 u‐HCC patients treated with Atezo+Bev between September 2020 and September 2021. Patients were grouped corresponding to the mALBI grade at the start of treatment (mALBI 1+2a or mALBI 2b+3) and analyzed for therapeutic effect and the transition rate to secondary treatment. Results According to the Response Evaluation Criteria in Solid Tumors, the overall response rate was significantly higher for the mALBI 1+2a group, than for the mALBI 2b+3 group, with 26.2% and 3.4%, respectively. The progression‐free survival (PFS) was significantly longer in the mALBI 1+2a group (10.5 months) than in the mALBI 2b+3 group (3.0 months). In the multivariate analysis, an mALBI of 1+2a was found to be an independent factor of PFS. The rate of second‐line treatment with multi‐targeted agents was also significantly higher in the mALBI 1+2a group. Conclusions In real‐world practice, Atezo+Bev treatment might have higher therapeutic efficacy in u‐HCC patients with mALBI 1+2a.

Abstract Background K-line is widely recognized as a useful index for evaluating cervical alignment and the size of the cervical ossification at the posterior longitudinal ligament (OPLL). The purpose of this study was to investigate whether the K-line could be a useful clinical tool for predicting the prognosis of laminoplasty (LP) for cervical spondylotic myelopathy (CSM). Methods Adult CSM patients scheduled for cervical LP were recruited for this study. C2-7 angle, local kyphosis angle, and K-line was evaluated by T2-weighted sagittal magnetic resonance imaging (MRI). Clinical findings were evaluated by the JOA score and the recovery rate. Clinical and radiological findings were evaluated preoperation and final follow-up. Patients were grouped into K-line ( +) and K-line (-). Patients with Kline (-) were further divided into two sub-groups: disc type (anterior cord compression due to disc protrusion with kyphosis) and osseous type (due to osseous structure such as osteophyte). Results Sixty-eight patients were included in the analysis. The recovery rate of K-line (-) group (n = 11,19.4%) was significantly worse than that of K-line ( +) group (n = 57, 50.6%, p

Abstract The clinical difference between nonalcoholic fatty liver disease (NAFLD) and metabolic-associated fatty liver disease (MAFLD) between the two sexes is unclear. This study aimed to determine the influences of alcohol consumption and qualitative abdominal fat between male and female patients with NAFLD and MAFLD. This cross-sectional study examined 11,766 participants who underwent health check-ups comparing lifestyle habits, biochemical features, and noninvasive liver fibrosis scores, between non-MAFLD and MAFLD groups. Furthermore, differences in alcohol consumption and qualitative abdominal fat were examined between male and female patients with NAFLD and MAFLD. The prevalence of metabolic dysregulation, ratio of visceral fat area to subcutaneous fat area, and noninvasive liver fibrosis scores were significantly higher in male patients with MAFLD than in those with NAFLD (p 70 g/week, several noninvasive liver fibrosis scores were significantly higher in the MAFLD group than in the NAFLD group (all p

BackgroundImmune checkpoint inhibitors (ICIs) are the standard treatment for metastatic colorectal cancer (mCRC) with high microsatellite instability (MSI-H). Among immune-related adverse events (irAEs), drug-induced sarcoidosis-like reactions (DISR) are often difficult to differentiate from cancer progression.Main BodyThis is a case of a woman in her mid-60s, with mCRC (RAS wild/BRAF mutant/MSI-H) and abdominal lymph node metastasis, treated with four courses of ipilimumab + nivolumab every 3 weeks, followed by nivolumab every 2 weeks as third-line treatment. After treatment, the original lymph node metastases shrank, but hilar/mediastinal lymph nodes appeared. Endoscopic ultrasound-guided fine-needle aspiration of these lymph nodes revealed multiple epithelioid granulomas without necrosis, indicating a sarcoidosis-like reaction. Fluorodeoxyglucose-positron emission tomography scan showed abnormal subcutaneous accumulation in bilateral forearms and bilateral knee joints. Biopsy of the cutaneous lesions was also performed, which revealed epithelioid granulomas. As the patient had no symptoms in other organs, no specific therapeutic intervention was administered. After the discontinuation of immunotherapy, the sarcoidosis-like reaction regressed without cancer relapse.ConclusionsClinicians should be aware of the possibility of DISR as an irAE during the ICI treatment of mCRC. In suspected cases of DISR following ICI therapy, it is important to differentiate between cancer progression and DISR through histological diagnosis for the subsequent strategy, as radiological and serological findings are not definitive.

BackgroundTreatment with anti-EGFR antibody has been shown to prolong survival in patients with RAS wild-type metastatic colorectal cancer (mCRC). However, even patients who initially respond to anti-EGFR antibody therapy, almost without exception, develop resistance to the therapy and then fail to respond. Secondary mutations in the mitogen-activated protein (MAPK) signaling pathway (mainly in NRAS and BRAF) have been implicated in anti-EGFR resistance. However, the process by which resistant clones develop during therapy has not been elucidated, and considerable intrapatient and interpatient heterogeneity exists. Circulating tumor DNA (ctDNA) testing has recently allowed the noninvasive detection of heterogeneous molecular alterations that underlie the evolution of resistance to anti-EGFR. In this report, we describe our observation of genomic alterations in KRAS and NRAS in a patient with acquired resistance to anti-EGFR antibody drugs by tracking clonal evolution using serial ctDNA anaylsis.Case presentationA 54-year-old woman was initially diagnosed with sigmoid colon cancer with multiple liver metastases. After receiving first-line mFOLFOX + cetuximab, second-line FOLFIRI + ramucirumab, third-line trifluridine/tipiracil + bevacizumab, fourth-line regorafenib, and fifth-line CAPOX + bevacizumab, she was rechallenged with CPT-11 + cetuximab. The best response to anti-EGFR rechallenge therapy was a partial response. RAS in the ctDNA was assessed during treatment. The RAS status changed from wild type to mutant type, back to wild type, and again to mutant type (NRAS/KRAS codon 61) during the course of treatment.ConclusionIn this report, tracking of ctDNA allowed us to describe clonal evolution in a case in which we observed genomic alterations in KRAS and NRAS in a patient who acquired resistance to anti-EGFR antibody drugs during treatment. It is reasonable to consider repeat molecular interrogation during progression in patients with mCRC by using ctDNA analysis, which could help to identify patients who may benefit from a rechallenge strategy.

Abstract Background The use of spinal instrumentation is an established risk factor for postoperative infection. To address this problem, we prepared silver‐containing hydroxyapatite coating, consisting of highly osteoconductive hydroxyapatite interfused with silver. The technology has been adopted for total hip arthroplasty. Silver‐containing hydroxyapatite coating has been reported to have good biocompatibility and low toxicity. However, no studies about applying this coating in spinal surgery have addressed the osteoconductivity and direct neurotoxicity to the spinal cord of silver‐containing hydroxyapatite cages in spinal interbody fusion. Aim In this study, we evaluated the osteoconductivity and neurotoxicity of silver‐containing hydroxyapatite‐coated implants in rats. Materials & Methods Titanium (non‐coated, hydroxyapatite‐coated, and silver‐containing hydroxyapatite‐coated) interbody cages were inserted into the spine for anterior lumbar fusion. At 8 weeks postoperatively, micro‐computed tomography and histology were performed to evaluate the osteoconductivity of the cage. Inclined plane test and toe pinch test were performed postoperatively to assess neurotoxicity. Results Micro‐computed tomography data indicated no significant difference in bone volume/total volume among the three groups. Histologically, the hydroxyapatite‐coated and silver‐containing hydroxyapatite‐coated groups showed significantly higher bone contact rate than that of the titanium group. In contrast, there was no significant difference in bone formation rate among the three groups. Data of inclined plane and toe pinch test showed no significant loss of motor and sensory function in the three groups. Furthermore, there was no degeneration, necrosis, or accumulation of silver in the spinal cord on histology. Conclusions This study suggests that silver‐hydroxyapatite‐coated interbody cages produce good osteoconductivity and are not associated with direct neurotoxicity.

Objective To clarify the complications of posterior fusion for atlantoaxial instability (AAI) in children with Down syndrome and to discuss the significance of surgical intervention. Methods Twenty pediatric patients with Down syndrome underwent posterior fusion for AAI between February 2000 and September 2018 (age, 6.1±1.9 years). C1–2 or C1–3 fusion and occipitocervical fusion were performed in 14 and 6 patients, respectively. The past medical history, operation time, estimated blood loss (EBL), duration of Halo vest immobilization, postoperative follow-up period, and intra- and perioperative complications were examined. Results The operation time was 257.9±55.6 minutes, and the EBL was 101.6±77.9 mL. Complications related to the operation occurred in 6 patients (30.0%). They included 1 major complication (5.0%): hydrocephalus at 3 months postoperatively, possibly related to an intraoperative dural tear. Other surgery-related complications included 3 cases of superficial infections, 1 case of bone graft donor site deep infection, 1 case of C2 pedicle fracture, 1 case of Halo ring dislocation, 1 case of pseudoarthrosis that required revision surgery, and 1 case of temporary neurological deficit after Halo removal at 2 months postoperatively. Complications unrelated to the operation included 2 cases of respiratory infections and 1 case of implant loosening due to a fall at 9 months postoperatively. Conclusion The complication rate of upper cervical fusion in patients with Down syndrome remained high; however, major complications decreased substantially. Improved intra- and perioperative management facilitates successful surgical intervention for upper cervical instability in pediatric patients with Down syndrome.

Abstract Aim To investigate the therapeutic effect of lenvatinib (LEN) in liver disease etiology, especially nonviral hepatocellular carcinoma (HCC). Methods and Results Sixty‐seven patients with unresectable advanced HCC (u‐HCC) treated with LEN and consisting of 26 hepatitis C virus (HCV), 19 hepatitis B virus (HBV), 11 alcohol, and 11 nonalcoholic steatohepatitis (NASH) cases were retrospectively recruited. Univariate and multivariate Cox proportional hazard models were used to determine predictive factors for survival. The objective response rate in the nonviral (alcohol and NASH) group was higher than that in the viral group (59.1% [13/22] vs. 46.7% [21/45]). Progression‐free survival was significantly longer in the nonviral group than in the viral group (13.7 vs. 6.6 months; hazard ratio [HR] 0.324; 95% confidence interval [CI] 0.174–0.602; P

Abstract Background Autoimmune gastritis is known to be associated with neoplastic lesions but the relationship between autoimmunity and tumorigenesis have not been sufficiently clarified. The aim of this study is to assess the clinicopathological characteristics of gastric cancer cases associated with autoimmune gastritis. Methods A total of 24 patients diagnosed as early gastric cancer with autoimmune gastritis were registered. Chart reviews with the data including age, gender, state of Helicobacter pylori infection, comorbidity, and concomitant gastric diseases were conducted. As for the characteristics of gastric cancer, location, size, morphological type, histopathology, invasion depth, and the presence of metachronous or simultaneous lesion were assessed. These data from autoimmune gastritis group were compared with those from 301 patients of early gastric cancer as a control group. Results The gastric cancer associated with autoimmune gastritis was located in the upper, middle, and lower parts in 28.1%, 53.1%, and 18.8%, respectively. The morphological types are as follows: 0‐I, 9.4%; 0‐IIa, 28.1%; 0‐IIb, 15.6%; 0‐IIc, 46.9%; and 0‐III, 0.0%. The mean tumor size was 21.8 mm. While 90.6% were confined to the mucosa, 9.4% showed submucosal invasion. The histological classifications are as follows: tub1, 50.0%; tub2, 15.6%; pap, 21.9%; sig, 9.4%; and por, 3.1%. More numbers of female, protruded types, larger tumor size, papillary tumor, and that in the upper location were observed in autoimmune gastritis group compared to control group. Conclusion Early gastric cancer associated with autoimmune gastritis demonstrated different characteristics from those without autoimmune gastritis including variety of tumor morphologies and histological types with female dominancy.

A primary splenic angiosarcoma is a rare type of soft tissue sarcoma and is associated with an extremely poor prognosis. In this study, we describe the case of a patient who was diagnosed with metastatic primary splenic angiosarcoma and survived for about 2 years. A 62-year-old female was referred to us for the treatment of splenic angiosarcoma with disseminated intravascular coagulation (DIC) and multiple liver and bone metastases. Paclitaxel therapy resulted in recovery from DIC and enabled her to continue sequential treatment through to sixth-line chemotherapy. We reviewed all splenic angiosarcoma case reports which were described as stage IV to date and compared with our case. From these data, we found that the median overall survival was 105 days, and the prognosis of splenic angiosarcoma of stage IV was worse than conventional case series. Splenectomy was performed in more patients than chemotherapy as a treatment. Moreover, various chemotherapeutic regimens were used. These data suggest that administering chemotherapy including paclitaxel to patients with splenic angiosarcoma might improve their prognosis.

Abstract Objective We developed a silver-containing hydroxyapatite (Ag-HA) coating to prevent periprosthetic joint infection (PJI). Methicillin-resistant Staphylococcus aureus (MRSA) is the main PJI-causing bacteria. Previously, we had reported the combined effect of Ag-HA coating and vancomycin (VCM) on MRSA biofilm formation 24 h after MRSA inoculation. In this study, we investigated the time-dependent efficacy of Ag-HA coating and VCM on MRSA biofilm formation on Ti discs in vitro by three-dimensional confocal laser scanning microscopic analysis. Results For the Ti VCM and HA VCM groups, the total biofilm volumes per area at 96 h after MRSA inoculation were significantly larger than those at 48 h after MRSA inoculation, respectively (p

Data analysis of clinical samples suggests that higher estrogen receptor α (ERα) expression could be associated with worse overall survival in some patients with non‐small‐cell lung cancer (NSCLC). Immunofluorescence results further showed that higher ERα expression was linked to larger numbers of infiltrated macrophages in NSCLC tissues. However, the detailed mechanisms underlying this phenomenon remain unclear. Results from in vitro studies with multiple cell lines revealed that, in NSCLC cells, ERα can activate the CCL2/CCR2 axis to promote macrophage infiltration, M2 polarization, and MMP9 production, which can then increase NSCLC cell invasion. Mechanistic studies using chromatin immunoprecipitation and promoter luciferase assays demonstrated that ERα could bind to estrogen response elements (EREs) on the CCL2 promoter to increase CCL2 expression. Furthermore, ERα‐increased macrophage infiltration can induce a positive feedback mechanism to increase lung cancer cell ERα expression via the up‐regulation of the CXCL12/CXCR4 pathway. Targeting these newly identified pathways, NSCLC ERα‐increased macrophage infiltration or the macrophage‐to‐NSCLC CXCL12/CXCR4/ERα signal, with anti‐estrogens or CCR2/CXCR4 antagonists, may help in the development of new alternative therapies to better treat NSCLC.

Abstract Background One of the most challenging tasks for bladder cancer diagnosis is to histologically differentiate two early stages, non-invasive Ta and superficially invasive T1, the latter of which is associated with a significantly higher risk of disease progression. Indeed, in a considerable number of cases, Ta and T1 tumors look very similar under microscope, making the distinction very difficult even for experienced pathologists. Thus, there is an urgent need for a favoring system based on machine learning (ML) to distinguish between the two stages of bladder cancer. Methods A total of 1177 images of bladder tumor tissues stained by hematoxylin and eosin were collected by pathologists at University of Rochester Medical Center, which included 460 non-invasive (stage Ta) and 717 invasive (stage T1) tumors. Automatic pipelines were developed to extract features for three invasive patterns characteristic to the T1 stage bladder cancer (i.e., desmoplastic reaction, retraction artifact, and abundant pinker cytoplasm), using imaging processing software ImageJ and CellProfiler. Features extracted from the images were analyzed by a suite of machine learning approaches. Results We extracted nearly 700 features from the Ta and T1 tumor images. Unsupervised clustering analysis failed to distinguish hematoxylin and eosin images of Ta vs. T1 tumors. With a reduced set of features, we successfully distinguished 1177 Ta or T1 images with an accuracy of 91–96% by six supervised learning methods. By contrast, convolutional neural network (CNN) models that automatically extract features from images produced an accuracy of 84%, indicating that feature extraction driven by domain knowledge outperforms CNN-based automatic feature extraction. Further analysis revealed that desmoplastic reaction was more important than the other two patterns, and the number and size of nuclei of tumor cells were the most predictive features. Conclusions We provide a ML-empowered, feature-centered, and interpretable diagnostic system to facilitate the accurate staging of Ta and T1 diseases, which has a potential to apply to other types of cancer.

Abstract Background Esophagogastroduodenoscopy (EGD) provides an indispensable and unambiguous inspection allowing the discovery upper gastrointestinal lesions. However, many patients are anxious about undergoing EGD. Few studies have investigated the influence on patients’ vital signs and tolerance during EGD using subjective and objective assessments. This study was a prospective randomized controlled study that investigated the influence of audio and visual distraction on EGD. Methods We randomly divided 289 subjects who underwent EGD into 4 groups (control group, audio group, visual group, combination group) and examined their vital signs, heart rate variability (HRV), psychological items, and acceptance of distraction. Results Pulse rate (PR) at post-distraction and post-EGD in the 3 distraction groups were significantly lower than those of control group (p

The year 2021 marked the 10th anniversary of the publication of Cells [...]

Abstract Background Perivesical lymph nodes (PVLNs) are occasionally isolated during grossing of cystectomy specimens. However, the prognostic implications of the involvement of PVLNs in bladder cancer patients, especially those with comparisons to pN0 disease, remain poorly understood. Methods A retrospective review identified 115 radical cystectomy cases where PVLNs had been histologically assessed. These cases were then divided into 4 groups – Group 1 (n = 76): PVLN-negative/other pelvic lymph node (non-PVLN)-negative; Group 2 (n = 5): PVLN-positive/non-PVLN-negative; Group 3 (n = 17): PVLN-negative/non-PVLN-positive; and Group 4 (n = 17): PVLN-positive/non-PVLN-positive. Results pT stage at cystectomy was significantly higher in Group 3 (P = 0.013), Group 4 (P

In 2020, a total of 106 original research articles, 84 reviews, and 1 other paper were published within the “Cell Nuclei: Function, Transport and Receptors” section [...]

Neoadjuvant chemotherapy (NAC) for locally advanced gastric cancer (LAGC) has been recognized as an effective therapeutic option because it is expected to improve the curative resection rate by reducing the tumor size and preventing recurrence of micrometastases. However, for patients resistant to NAC, not only will operation timing be delayed, but they will also suffer from side effects. Thus, it is crucial to develop a comprehensive strategy and select patients sensitive to NAC. However, the therapeutic effect of NAC is unpredictable due to tumor heterogeneity and a lack of predictive biomarkers for guiding the choice of optimal preoperative treatment in clinical practice. This article summarizes the related research progress on predictive biomarkers of NAC for gastric cancer. Among the many investigated biomarkers, metabolic enzymes for cytotoxic agents, nucleotide excision repair, and microsatellite instability, have shown promising results and should be assessed in prospective clinical trials. Noninvasive liquid biopsy detection, including miRNA and exosome detection, is also a promising strategy.

Epidemiological data have indicated that there are some sex-related differences in bladder cancer. Indeed, the incidence of bladder cancer in men has been substantially higher than that in women throughout the world, while women tend to have higher stage disease and poorer prognosis. These gender disparities have prompted to investigate sex hormones and their cognitive receptors in bladder cancer. Specifically, estrogen receptors, including estrogen receptor-α and estrogen receptor-β, have been shown to contribute to urothelial carcinogenesis and cancer progression, as well as to modulating chemosensitivity in bladder cancer, although conflicting findings exist. Meanwhile, immunohistochemical studies in surgical specimens have assessed the expression of estrogen receptors and related proteins as well as its associations with clinicopathologic features of bladder cancer and patient outcomes. This review article summarizes and discusses available data indicating that estrogen receptor signaling plays an important role in urothelial cancer.

Background: Glucocorticoid receptor (GR) signaling pathway has been shown to involve epithelial -to- mesenchymal transition which was implicated in the regulation of bladder cancer stem cells (CSCs) in our previous study. Herein, we aim to figure out how GR affects the stem-like properties of bladder cancer cells.Methods: We used dexamethasone (DEX) treatment or gene-knockdown/-knockout techniques to activate or silence the GR pathway, respectively. Then we applied immunohistochemical staining and flow cytometry to assess the associations between the expression levels of GR and a stem cell surface marker CD44. Stem-like properties were assessed by reactive oxygen species (ROS), sphere-formation and side population assays. The expression levels of cancer stem cell-associated molecules were assessed by quantitative PCR and Western blotting. Tumor growth was compared using mouse xenograft models.Results: In GR-positive bladder cancer cells, DEX significantly reduced the expression of CD44 as well as pluripotency transcription factors including β-catenin and its downstream target (C-MYC, Snail, and OCT-4), the rate of sphere formation, and the proportion of side populations, and induced the intracellular levels of ROS. By contrast, GR silencing in bladder cancer cells showed the opposite effects. In xenograft-bearing mice, GR silencing resulted in the enhancement of tumor growth.Conclusions: These data suggested that GR activity was inversely associated with the stem-like properties of bladder cancer cells, potentially via inactivating the β-catenin pathway.

We investigated the functional role of ATF2, a transcription factor normally activated via its phosphorylation in response to phospho-ERK/MAPK signals, in the outgrowth of urothelial cancer. In both neoplastic and non-neoplastic urothelial cells, the expression levels of androgen receptor (AR) correlated with those of phospho-ATF2. Dihydrotestosterone treatment in AR-positive bladder cancer cells also induced the expression of phospho-ATF2 and phospho-ERK as well as nuclear translocation and transcriptional activity of ATF2. Meanwhile, ATF2 knockdown via shRNA resulted in significant decreases in cell viability, migration and invasion of AR-positive bladder cancer lines, but not AR-negative lines, as well as significant increases and decreases in apoptosis or G0/G1 cell cycle phase and S or G2/M phase, respectively. Additionally, the growth of AR-positive tumors expressing ATF2-shRNA in xenograft-bearing mice was retarded, compared with that of control tumors. ATF2 knockdown also resulted in significant inhibition of neoplastic transformation induced by a chemical carcinogen 3-methylcholanthrene, as well as the expression of Bcl-2/cyclin-A2/cyclin-D1/JUN/MMP-2, in immortalized human normal urothelial SVHUC cells stably expressing AR, but not AR-negative SVHUC cells. Finally, immunohistochemistry in surgical specimens demonstrated significant elevation of ATF2/phospho-ATF2/phospho-ERK expression in bladder tumors, compared with non-neoplastic urothelial tissues. Multivariate analysis further showed that moderate/strong ATF2 expression and phospho-ATF2 positivity were independent predictors for recurrence of low-grade tumors (hazard ratio (HR) = 2.956, P = 0.045) and cancer-specific mortality of muscle-invasive tumors (HR = 5.317, P = 0.012), respectively. Thus, ATF2 appears to be activated in urothelial cells through the AR pathway and promotes the development and progression of urothelial cancer.

The rectal tonsil is a rare polypoid lesion exclusively found in the rectum and is considered a reactive proliferation of the lymphoid tissue. Although this lesion is benign, we recommend that it should be differentiated from carcinoid or polypoid type of mucosa-associated lymphoid tissue lymphomas, based on gross findings. In this case report, we describe a case of rectal lesions with a unique appearance in a 41-year-old man. Colonoscopy revealed two 5-mm-sized nodules located opposite from each other on the left and right sides of the lower rectum. Endoscopic mucosal resection was conducted. Histopathologically, both lesions were mainly located in the submucosa and consisted of prominent lymphoid follicles with germinal centers of various sizes. No immunoreactivity of Bcl-2 was seen in the germinal centers. Immunohistochemical staining for kappa and lambda light chains revealed a polyclonal pattern. Therefore, these lesions were diagnosed as rectal tonsils.

Abstract Aberrant crypt foci (ACF), the earliest precursor lesion of colorectal cancers (CRCs), are a good surrogate marker for CRC risk stratification and chemoprevention. However, the conventional ACF detection method with dye-spraying by magnifying colonoscopy is labor- and skill-intensive. We sought to identify rat and human ACF using a fluorescent imaging technique that targets a molecule specific for ACF. We found that glutathione S-transferase (GST) P1-1 was overexpressed in ACF tissues in a screening experiment. We then synthesized the fluorogenic probe, DNAT-Me, which is fluorescently quenched but is activated by GSTP1-1. A CRC cell line incubated with DNAT-Me showed strong fluorescence in the cytosol. Fluorescence intensities correlated significantly with GST activities in cancer cell lines. When we sprayed DNAT-Me onto colorectal mucosa excised from azoxymethane-treated rats and surgically resected from CRC patients, ACF with strong fluorescent signals were clearly observed. The ACF number determined by postoperative DNAT-Me imaging was almost identical to that determined by preoperative methylene blue staining. The signal-to-noise ratio for ACF in DNAT-Me images was significantly higher than that in methylene blue staining. Thus, we sensitively visualized ACF on rat and human colorectal mucosa by using a GST-activated fluorogenic probe without dye-spraying and magnifying colonoscopy.

We recently found that NFATc1, a member of the NFAT family and a key regulator of the immune response, could induce bladder carcinogenesis and cancer progression. In this study, we immunohistochemically stained for NFATc1 in upper urinary tract urothelial carcinoma (UUTUC) specimens and paired nonneoplastic urothelial tissues. NFATc1 was positive in 51 [52%; 40 (40%) weak (1+), 9 (9%) moderate (2+), and 2 (2%) strong (3+)] of 99 UUTUCs, which was significantly higher than in benign urothelium [30 (36%) of 83; 28 (34%) weak and 2 (2%) moderate] (0 vs 1+/2+/3+, P = .038; 0/1+ vs 2+/3+, P = .023). There were no significant associations between NFATc1 expression pattern and tumor grade or pT stage. However, the positive rates of NFATc1 expression tended to be higher in renal pelvic tumors (60%) than in ureteral tumors (42%; P = .080) as well as in pN+ tumors (75%) than in pN0 tumors (49%; P = .089). Kaplan-Meier and log-rank tests revealed that moderate (2+) to strong (3+) NFATc1 expression correlated with lower progression-free survival (P = .032) and cancer-specific survival (P = .005) rates in the 99 cases. Patients with high (2+/3+) NFATc1 muscle-invasive tumor (n = 9) also had a significantly higher risk of cancer-specific mortality (P = .021) compared to those with low (0/1+) NFATc1 muscle-invasive tumor (n = 53). Thus, compared with nonneoplastic urothelium, a significant increase in the expression of NFATc1 in UUTUC was seen, implying the involvement of NFATc1 signals in the development of UUTUC. The current results further suggest that NFATc1 overexpression serves as a predictor of poor prognosis in patients with UUTUC.

There have been critical problems in the non-surgical treatment for bladder cancer, especially residence to intravesical pharmacotherapy, including BCG immunotherapy, cisplatin-based chemotherapy, and radiotherapy. Recent preclinical and clinical evidence has suggested a vital role of sex steroid hormone-mediated signaling in the progression of urothelial cancer. Moreover, activation of the androgen receptor and estrogen receptor pathways has been implicated in modulating sensitivity to conventional non-surgical therapy for bladder cancer. This may indicate the possibility of anti-androgenic and anti-estrogenic drugs, apart from their direct anti-tumor activity, to function as sensitizers of such conventional treatment. This article summarizes available data suggesting the involvement of sex hormone receptors, such as androgen receptor, estrogen receptor-α, and estrogen receptor-β, in the progression of urothelial cancer, focusing on their modulation for the efficacy of conventional therapy, and discusses their potential of overcoming therapeutic resistance.

Background and study aims Conventional detection of aberrant crypt foci (ACF) with dye-spraying and magnifying observation is labor- and skill-intensive. We performed a prospective non-inferiority study to investigate the utility of image-enhanced endoscopy (IEE) for detection of ACF. Patients and methods Patients with a history of colorectal neoplasm were eligible. The number of ACF in the lower rectum was counted first using IEE magnification with narrow-band imaging (NBI) or blue-laser imaging (BLI), and subsequently using the methylene blue method. The primary endpoint was the ACF detection rate with IEE, i. e., the number of ACF detected with IEE relative to the number of ACF detected with methylene blue. The secondary endpoints were bowel preparation time, ACF detection time, and the detection rate with NBI or BLI. Results A total of 40 patients were enrolled (NBI 20 and BLI 20). The overall detection rate for ACF with IEE was 81.7 % (503/616; 95 %CI 78.8 – 84.6 %), meeting the primary endpoint. The detection rate for ACF with BLI (84.9 %, 258/304) was significantly higher than with NBI (78.5 %, 245/312; P

Background and study aims Although new image-enhanced endoscopy (IEE) technologies such as blue laser imaging (BLI), BLI-bright, and linked color imaging (LCI) have been developed, their utility for the detection of sessile serrated adenoma/polyps (SSA/Ps) is still unclear. This study aimed to evaluate the utility of BLI, BLI-bright, and LCI for SSA/P detection in still image examinations and in a prospective randomized controlled trial (RCT). Patients and methods A group of 6 expert and non-expert endoscopists read 200 endoscopic still images containing SSA/P lesions using white light image (WLI), BLI, BLI-bright, and LCI. Color differences were calculated using the color space method. A prospective RCT of tandem colonoscopy with WLI and LCI was performed. Patients with SSA/P and those with a history of SSA/P that had been endoscopically removed were enrolled and randomly allocated to WLI-LCI or LCI-WLI groups. Additional endoscopic detection rates for SSA/P were compared between the 2 groups. Results LCI showed the highest SSA/P detection rate among the 4 modes for both expert and non-expert endoscopists. The detection rate with LCI for the 6 expert endoscopists (mean 98.3 ± standard deviation 2.0 %) was significantly higher than that with WLI (86.7 ± 6.0 %, P

Signal transducer and activator of transcription 3 (STAT3) plays a prominent role in the growth and invasion of several types of solid tumors. In this study, to assess the expression status and prognostic significance of the STAT3 pathway in upper urinary tract urothelial carcinoma (UTUC), we immunohistochemically stained for STAT3 and STAT3 pathway proteins, sphingosine-1-phosphate receptor 1 (S1PR1) and interleukin-6 (IL-6), in a tissue microarray containing 99 UTUC specimens. There were no significant associations between STAT3, S1PR1, or IL-6 expression pattern and tumor grade or pT stage. However, the patients with high STAT3 tumor had a significantly higher risk of both disease progression (p = 0.009) and cancer-specific mortality (p = 0.009), but not with tumors expressing S1PR1 or IL-6. High STAT3 expression in the nucleus was also associated with a significantly higher risk of both disease progression (p = 0.003) and cancer-specific mortality (p = 0.034). Multivariate analysis revealed that high STAT3 expression in the nucleus was significantly associated with cancer-specific survival after adjustment for pathological stage, lymph node involvement, lymphovascular invasion, and tumor grade (HR = 2.136, 95% CI = 1.009-4.767, p = 0.047). Our findings indicated that STAT3 could be a cancer-promoting factor and potentially a significant prognostic factor in UTUC.

The insulin sensitizers, thiazolidinediones (TZDs), have been used as anti-diabetic drugs since the discovery of their ability to alter insulin resistance through transactivation of peroxisome proliferator-activated receptors (PPARs). However, their side effects in hepatitis, cardiovascular diseases, and bladder cancer resulted in some selling restrictions in the USA and Europe. Here, we found that the potential impact of TZDs on the prostate cancer (PCa) progression might be linked to the TR4 nuclear receptor expression. Clinical surveys found that 9% of PCa patients had one allele TR4 deletion in their tumors. TZD increased cell growth and invasion in PCa cells when TR4 was knocked down. In contrast, TZD decreased PCa progression in PCa cells with wild type TR4. Mechanism dissection found that the Harvey Rat Sarcoma (HRAS) oncogene increased on TZD treatment of the TR4 knocked-down CWR22Rv1 and C4-2 cells, and interruption with HRAS inhibitor resulted in reversal of TZD-induced PCa progression. Together, these results suggest that TZD treatment may promote PCa progression depending on the TR4 expression status that may be clinically relevant since extra caution may be needed for those diabetic PCa patients receiving TZD treatment who have one allele TR4 deletion.

OBJECTIVE:Emerging preclinical evidence suggests the involvement of sex hormones and their receptor signals in the development and progression of bladder cancer. Meanwhile, previous studies have demonstrated conflicting results on the relationship between the status of sex hormone receptors in urothelial tumors and histopathological characteristics of the tumors or patient outcomes. We therefore conducted this meta-analysis to assess the clinicopathological impact of the expression of androgen receptor (AR) and estrogen receptors (ERs) in bladder cancer. METHODS:A comprehensive literature search in databases (i.e. PubMed, Web of Science, Cochrane) was performed for all immunohistochemical studies stained for AR, ERα, and/or ERβ in surgically resected bladder cancer specimens and analyzed for patient outcomes. We selected eligible studies in accordance with the PRISMA guidelines and analyzed data using R software. RESULTS:A total of 2,049 patients from 13 retrospective studies were included in this meta-analysis. The difference in ERα expression between non-tumors and tumors was significant [odds ratio (OR) = 0.412; P

BACKGROUND:Nonalcoholic fatty liver disease (NAFLD) is known to be strongly associated with obesity, visceral fat, metabolic syndrome (MS), lifestyle, and lifestyle-related diseases in both males and females. However, the prevalence of NAFLD, MS, and clinical backgrounds is different between males and females. OBJECTIVE:We conducted a cross-sectional study to examine the differing influence of lifestyle-related factors and visceral fat on fatty liver (FL) with elevation of liver enzymes between males and females with MS. METHODS:We enrolled 42,134 persons who underwent a regular health check-up, and after excluding subjects who fulfilled excluding criteria, the remaining subjects were 2,110 persons with MS. We examined the differing influence of lifestyle-related factors and visceral fat on FL with elevation of alanine aminotransferase (ALT) (ALT elevation was defined as ALT level of ≥31 IU/l in the present study). RESULTS:The odds rations for FL with ALT elevation were as follows: WC, 1.83 (95% confidence interval (CI) 1.36-2.46); dyslipidemia, 1.89 (95% CI 1.34-2.68); hemoglobin A1c, 1.36 (95% CI 1.00-1.85); visceral fat type MS (V-type MS), 5.78 (95% CI 4.29-7.80); and light drinker, 0.56 (95% CI 0.41-0.78) in males with MS and BMI, 2.18 (95% CI 1.43-3.33); WC, 1.85 (95% CI 1.27-2.70); diastolic blood pressure, 1.69 (95% CI 1.16-2.45); triglyceride, 2.22 (95% CI 1.56-3.17); impaired glucose tolerance, 1.66 (95% CI 1.11-2.47); and V-type MS, 3.83 (95% CI 2.57-5.70) in females with MS. The prevalence of FL with ALT elevation and ALT was significantly higher in V-type MS than in the subcutaneous fat type MS in both males and females with MS (P < 0.001). CONCLUSION:Although V-type MS and WC is a common significant predictor of an increased prevalence of FL with ALT elevation in both males and females with MS, gender, lifestyle-related factors, and MS type in individuals with MS should be considered for the development of FL with ALT elevation.

Emerging evidence has suggested that androgen receptor signaling plays an important role in ovarian cancer outgrowth. Specifically, androgen receptor activation appears to be associated with increased risks of developing ovarian cancer and inducing tumor progression. However, conflicting findings have also been reported. This review summarizes and discusses the available data indicating the involvement of androgens as well as androgen receptor and related signals in ovarian carcinogenesis and cancer growth. Although the underlying molecular mechanisms for androgen receptor functions in ovarian cancer remain far from being fully understood, current observations may offer effective chemopreventive and therapeutic approaches, via modulation of androgen receptor activity, against ovarian cancer. Indeed, several clinical trials have been conducted to determine the efficacy of androgen deprivation therapy in patients with ovarian cancer.

Early studies suggested androgen receptor (AR) splice variants might contribute to the progression of prostate cancer (PCa) into castration resistance. However, the therapeutic strategy to target these AR splice variants still remains unresolved. Through tissue survey of tumors from the same patients before and after castration resistance, we found that the expression of AR3, a major AR splice variant that lacks the AR ligand-binding domain, was substantially increased after castration resistance development. The currently used antiandrogen, Casodex, showed little growth suppression in CWR22Rv1 cells. Importantly, we found that AR degradation enhancer ASC-J9 could degrade both full-length (fAR) and AR3 in CWR22Rv1 cells as well as in C4-2 and C81 cells with addition of AR3. The consequences of such degradation of both fAR and AR3 might then result in the inhibition of AR transcriptional activity and cell growth in vitro. More importantly, suppression of AR3 specifically by short-hairpin AR3 or degradation of AR3 by ASC-J9 resulted in suppression of AR transcriptional activity and cell growth in CWR22Rv1-fARKD (fAR knockdown) cells in which DHT failed to induce, suggesting the importance of targeting AR3. Finally, we demonstrated the in vivo therapeutic effects of ASC-J9 by showing the inhibition of PCa growth using the xenografted model of CWR22Rv1 cells orthotopically implanted into castrated nude mice with undetectable serum testosterone. These results suggested that targeting both fAR- and AR3-mediated PCa growth by ASC-J9 may represent the novel therapeutic approach to suppress castration-resistant PCa. Successful clinical trials targeting both fAR and AR3 may help us to battle castration-resistant PCa in the future.

Discolored ureteral stents are sometimes encountered in daily clinical practice; however, the mechanism(s) underlying the development of discolored ureteral stents remain unknown. In this study, we retrospectively analyzed the characteristics of discolored ureteral stents based on the results of a urinalysis and urine culture.We identified a total of 26 patients with discolored ureteral stents and compared the findings in the urinalyses and urine culture in 21 discolored versus 45 non-colored ureteral stents.The median and mean (± SD) duration of stenting time was 78.0 and 81.3 (± 21.3) days for the discolored ureteral stents and 69.0 and 74.9 (± 19.8) days for the non-colored ureteral stents, respectively (P = 0.25). The discolored ureteral stents were associated with a higher mean urine pH than the non-colored ureteral stents (mean: 6.4 vs 6.0, P< 0.05). There were no significant differences between the two groups in the RBC (P = 0.51) and WBC (P = 0.35) counts in the urinalyses. In addition, the rate of a positive culture in the patients with discolored stents [20 of 21 (95.2%)] was significantly (P

For the past several years, large scale earthquakes happened. A lot of industrial facilities were damaged. For example, a lot of power plants were stopped in The 2011 off the Pacific coast of Tohoku Earthquake or The Southern Hyogo prefecture earthquake in 1995. These earthquakes have larger acceleration level than the seismic design level. Therefore, the earthquake proof measures are required. In this study, earthquake proof effect of the beam and the long column having initial twist is focused. The design guidelines for application to the pre-twisted beam structure and the long column structure is proposed. The pre-twisted beam and long column are modelled by FEM and calculated. The natural frequency of the pre-twisted beam and long column are related to the Young's modulus, density, length and cross-sectional area. The tendency of the natural frequency respected to the total twisted angle and the aspect ratio of the cross-section is obtained considering the vibration mode and the natural frequency. Furthermore, when attention is focused on the vibration mode, the influence of the total twisted angle is different for the modal shapes, and the case where the modal shapes are interchanged is shown. The acceleration response to the vibration input is determined by the natural frequency of the primary cross-section, the aspect ratio and boundary conditions. In order to evaluate the response reduction effect, the acceleration amplification respected to the total twisted angle and the 1st natural frequency of the system is analyzed. And the response reduction map is proposed. Using this map, it is possible to estimate the advantage of the pre-twisted effect for the vibration characteristics in a simple manner.

OBJECTIVE: To clarify the incidence and predictive risk factors of cervical spine instabilities which may induce compression myelopathy in patients with rheumatoid arthritis (RA). METHODS: Three types of cervical spine instability were radiographically categorized into "moderate" and "severe" based on atlantoaxial subluxation (AAS: atlantodental interval >3 mm versus ≥10 mm), vertical subluxation (VS: Ranawat value 5 years. The endpoint incidence of "severe" instabilities and predictors for "severe" instability were determined. RESULTS: Patients with baseline "moderate" instability, including all sub-groups (AAS(+) [VS(-) SAS(-)], VS(+) [SAS(-) AAS(±)], and SAS(+) [AAS(±) VS(±)]), developed "severe" instabilities more frequently (33.3% with AAS(+), 75.0% with VS(+), and 42.9% with SAS(+)) than those initially without instability (12.9%; p

Osteoclasts are unique multinucleated cells formed by fusion of preosteoclasts derived from cells of the monocyte/macrophage lineage, which are induced by RANKL. However, characteristics and subpopulations of osteoclast precursor cells are poorly understood. We show here that a combination of TNF-α, TGF-β, and M-CSF efficiently generates mononuclear preosteoclasts but not multinucleated osteoclasts (MNCs) in rat bone marrow cultures depleted of stromal cells. Using a rat osteoclast-specific mAb, Kat1, we found that TNF-α and TGF-β specifically increased Kat1(+)c-fms(+) and Kat1(+)c-fms(-) cells but not Kat1(-)c-fms(+) cells. Kat1(-)c-fms(+) cells appeared in early stages of culture, but Kat1(+)c-fms(+) and Kat1(+)c-fms(-) cells increased later. Preosteoclasts induced by TNF-α, TGF-β, and M-CSF rapidly differentiated into osteoclasts in the presence of RANKL and hydroxyurea, an inhibitor of DNA synthesis, suggesting that preosteoclasts are terminally differentiated cells. We further analyzed the expression levels of genes encoding surface proteins in bone marrow macrophages (BMM), preosteoclasts, and MNCs. Preosteoclasts expressed itgam (CD11b) and chemokine receptors CCR1 and CCR2; however, in preosteoclasts the expression of chemokine receptors CCR1 and CCR2 was not up-regulated compared to their expression in BMM. However, addition of RANKL to preosteoclasts markedly increased the expression of CCR1. In contrast, expression of macrophage antigen emr-1 (F4/80) and chemokine receptor CCR5 was down-regulated in preosteoclasts. The combination of TNF-α, TGF-β, and M-CSF induced Kat1(+)CD11b(+) cells, but these cells were also induced by TNF-α alone. In addition, MIP-1α and MCP-1, which are ligands for CCR1 and CCR2, were chemotactic for preosteoclasts, and promoted multinucleation of preosteoclasts. Finally, we found that Kat1(+)c-fms(+) cells were present in bone tissues of rats with adjuvant arthritis. These data demonstrate that TNF-α in combination with TGF-β efficiently generates preosteoclasts in vitro. We delineated characteristics that are useful for identifying and isolating rat preosteoclasts, and found that CCR1 expression was regulated in the fusion step in osteoclastogenesis.

Infection of macrophages with bacteria induces the production of pro-inflammatory cytokines including TNF-α. TNF-α directly stimulates osteoclast differentiation from bone marrow macrophages in vitro as well as indirectly via osteoblasts. Recently, it was reported that bacterial components such as LPS inhibited RANKL-induced osteoclastogenesis in early stages, but promoted osteoclast differentiation in late stages. However, the contribution to osteoclast differentiation of TNF-α produced by infected macrophages remains unclear. We show here that Porphyromonas gingivalis, one of the major pathogens in periodontitis, directly promotes osteoclastogenesis from RANKL-primed RAW-D (subclone of RAW264) mouse macrophages, and we show that TNF-α is not involved in the stimulatory effect on osteoclastogenesis. P. gingivalis infection of RANKL-primed RAW-D macrophages markedly stimulated osteoclastogenesis in a RANKL-independent manner. In the presence of the TLR4 inhibitor, polymyxin B, infection of RANKL-primed RAW-D cells with P. gingivalis also induced osteoclastogenesis, indicating that TLR4 is not involved. Infection of RAW-D cells with P. gingivalis stimulated the production of TNF-α, whereas the production of TNF-α by similarly infected RANKL-primed RAW-D cells was markedly down-regulated. In addition, infection of RANKL-primed macrophages with P. gingivalis induced osteoclastogenesis in the presence of neutralizing antibody against TNF-α. Inhibitors of NFATc1 and p38MAPK, but not of NF-κB signaling, significantly suppressed P. gingivalis-induced osteoclastogenesis from RANKL-primed macrophages. Moreover, re-treatment of RANKL-primed macrophages with RANKL stimulated osteoclastogenesis in the presence or absence of P. gingivalis infection, whereas re-treatment of RANKL-primed macrophages with TNF-α did not enhance osteoclastogenesis in the presence of live P. gingivalis. Thus, P. gingivalis infection of RANKL-primed macrophages promoted osteoclastogenesis in a TNF-α independent manner, and RANKL but not TNF-α was effective in inducing osteoclastogenesis from RANKL-primed RAW-D cells in the presence of P. gingivalis.

Background/Aim: Precise molecular mechanisms underlying resistance to cisplatin-based chemotherapy remain unclear, while the activity of estrogen receptor-β (ERβ) has been suggested to be associated with chemosensitivity in urothelial cancer. We aimed to determine if GULP1, an adapter protein known to facilitate phagocytosis, could represent a downstream effector of ERβ and thereby modulate cisplatin sensitivity in bladder cancer. Materials and Methods: GULP1 expression and cisplatin cytotoxicity were compared in bladder cancer lines. Immunohistochemistry was used to determine the expression of GULP1 and ERβ in two sets of tissue microarray (TMA) consisting of transurethral resection specimens. Results: The levels of GULP1 expression were considerably higher in ERβknockdown sublines than in the respective control ERβ-positive sublines. Estradiol treatment reduced GULP1 expression in ERα-negative/ERβ-positive lines, which was restored by the antiestrogen tamoxifen. Chromatin immunoprecipitation assay revealed the binding of ERβ to the GULP1 promoter in bladder cancer cells. Moreover, GULP1 knockdown sublines were significantly more resistant to cisplatin treatment, but not to other chemotherapeutic agents, including gemcitabine, methotrexate, vinblastine, and doxorubicin. In the first set of TMA (n=129), the expression of ERβ and GULP1 was inversely correlated (p=0.023), and ERβ(–)/GULP1(+) in 51 muscleinvasive tumors was associated with significantly lower risk of disease progression and cancer-specific mortality. Similarly, in the second set (n=43), patients with ERβ(–)/GULP1(+) muscleinvasive disease were significantly (p=0.021) more likely to be responders to cisplatin-based neoadjuvant chemotherapy before radical cystectomy. Conclusion: ERβ activation was found to reduce the expression of GULP1 as a direct downstream target in bladder cancer cells, resulting in the induction of cisplatin resistance. [ABSTRACT FROM AUTHOR]

Background/Aim: In patients with metastatic castration-sensitive prostate cancer (mCSPC), upfront treatment intensification with the addition of new hormonal agents and/or docetaxel to androgen deprivation therapy (ADT) is recommended. However, this modality is potentially excessive in a subset of these patients. This study aimed to identify patients who may be eligible to omit upfront treatment intensification. Patients and Methods: Patients with mCSPC who underwent ADT were enrolled. The association between undetectable prostate-specific antigen (PSA) (<0.2 ng/ml) after ADT initiation and overall or castration-resistance-free survival was evaluated. Results: Ninety-seven out of the 242 enrolled patients had low-risk and/or low-volume cancer and were further analyzed. Of these, 45 (46.4%) patients achieved undetectable PSA. The median follow-up period after ADT initiation was 70 months. The median overall survival among patients with undetectable PSA was quite long, reaching 226 months and significantly longer than that among patients with detectable PSA [71 months, hazard ratio (HR)=0.27, 95% confidence interval (CI)=0.15-0.49, p<0.001]. Time to development of castration-resistance was also long and significantly longer in the undetectable PSA group than that in the detectable PSA group (median: 124 vs. 17 months, HR=0.20, 95% CI=0.12-0.34, p<0.001). Conclusion: Patients with low-risk and/or low-volume mCSPC showed long-term survival when undetectable PSA was achieved during conventional ADT. In these patients, skipping upfront treatment intensification does not seem to negatively impact survival. [ABSTRACT FROM AUTHOR]

Background/Aim: The efficacy of melatonin and its biological significance in human bladder cancer remain poorly understood. This study aimed to investigate the functional role of melatonin in urothelial carcinogenesis. Materials and Methods: In human normal urothelial SVHUC cells with exposure to the chemical carcinogen 3-methylcholanthrene, we assessed the effects of melatonin on the neoplastic/malignant transformation. Results: In the in vitro system with carcinogen challenge, melatonin significantly prevented the neoplastic transformation of SV-HUC-1 cells. In addition, melatonin treatment resulted in increased expression of SIRT1, Rb1, and E-cadherin, and decreased expression of N-cadherin and FGFR3 in SV-HUC-1 cells. Furthermore, publicly available datasets from GSE3167 revealed that the expression of melatonin receptor 1 and melatonin receptor 2 was significantly down-regulated in bladder urothelial carcinoma tissues, compared with adjacent normal urothelial tissues. Conclusion: These findings indicate that melatonin serves as a suppressor for urothelial tumorigenesis. To the best of our knowledge, this is the first preclinical study demonstrating the impact of melatonin on the development of urothelial cancer. [ABSTRACT FROM AUTHOR]