Identification of circulating biomarkers for differentiating patients with papillary thyroid cancers from benign thyroid tumors.

BACKGROUND: This study aimed to identify the potential circulating biomarkers of protein, mRNAs, and long non-coding RNAs (lncRNAs) to differentiate the papillary thyroid cancers from benign thyroid tumors. METHODS: The study population of 100 patients was classified into identification (10 patients with papillary thyroid cancers and 10 patients with benign thyroid tumors) and validation groups (45 patients with papillary thyroid cancers and 35 patients with benign thyroid tumors). The Sengenics Immunome Protein Array-combined data mining approach using the Open Targets Platform was used to identify the putative protein biomarkers, and their expression validated using the enzyme-linked immunosorbent assay. Next-generation sequencing by Illumina HiSeq was used for the detection of dysregulated mRNAs and lncRNAs. The website Timer v2.0 helped identify the putative mRNA biomarkers, which were significantly over-expressed in papillary thyroid cancers than in adjacent normal thyroid tissue. The mRNA and lncRNA biomarker expression was validated by a real-time polymerase chain reaction. RESULTS: Although putative protein and mRNA biomarkers have been identified, their serum expression could not be confirmed in the validation cohorts. In addition, seven lncRNAs (TCONS_00516490, TCONS_00336559, TCONS_00311568, TCONS_00321917, TCONS_00336522, TCONS_00282483, and TCONS_00494326) were identified and validated as significantly downregulated in patients with papillary thyroid cancers compared to those with benign thyroid tumors. These seven lncRNAs showed moderate accuracy based on the area under the curve (AUC = 0.736) of receiver operating characteristic in predicting the occurrence of papillary thyroid cancers. CONCLUSIONS: We identified seven downregulated circulating lncRNAs with the potential for predicting the occurrence of papillary thyroid cancers.

A real-time prediction model for post-irradiation malignant cervical lymph nodes.

OBJECTIVE: To establish a real-time predictive scoring model based on sonographic characteristics for identifying malignant cervical lymph nodes (LNs) in cancer patients after neck irradiation. METHODS: One-hundred forty-four irradiation-treated patients underwent ultrasonography and ultrasound-guided fine-needle aspirations (USgFNAs), and the resultant data were used to construct a real-time and computerised predictive scoring model. This scoring system was further compared with our previously proposed prediction model. RESULTS: A predictive scoring model, 1.35 × (L axis) + 2.03 × (S axis) + 2.27 × (margin) + 1.48 × (echogenic hilum) + 3.7, was generated by stepwise multivariate logistic regression analysis. Neck LNs were considered to be malignant when the score was ≥ 7, corresponding to a sensitivity of 85.5%, specificity of 79.4%, positive predictive value (PPV) of 82.3%, negative predictive value (NPV) of 83.1%, and overall accuracy of 82.6%. When this new model and the original model were compared, the areas under the receiver operating characteristic curve (c-statistic) were 0.89 and 0.81, respectively (P < .05). CONCLUSIONS: A real-time sonographic predictive scoring model was constructed to provide prompt and reliable guidance for USgFNA biopsies to manage cervical LNs after neck irradiation.

Prognostic impact of pre-treatment neutrophil-to-lymphocyte ratio (NLR) in nasopharyngeal carcinoma: A retrospective study of 180 Taiwanese patients.

OBJECTIVES: Nasopharyngeal cancer (NPC) is an endemic disease in Taiwan. Prognostic factors the anatomical TNM stage are important for its prognostic stratification. An elevated neutrophil-to-lymphocyte ratio (NLR) has been reported to be associated with poor prognosis in various solid tumours. In this study, we analysed the prognostic impact of the NLR in NPC in Taiwan. DESIGN: Single-institution retrospective study. SETTING: Medical centre. PARTICIPANTS: One hundred and eighty patients with NPC treated at the Far Eastern Memorial Hospital, Taiwan, from January 2007 to December 2013. MAIN OUTCOME MEASURES: The association between the clinical or haematological presentations and the prognosis. RESULTS: The majority of the 180 patients included in this study were men (80%) and were <65 years old (91.7%). A neck mass (55.6%) was the most common clinical presentation, followed by nasal (39.4%) and aural (30.6%) symptoms. In addition, the majority (75.4%) of patients had advanced stage (III and IV) disease. Patients with a high NLR (≧3.6) had significantly lower progression-free survival, overall survival and disease-specific survival rates. The association between high NLR and poor prognosis was more pronounced in patients with advanced disease than in those with early-stage NPC. The results of a multivariate analysis revealed that advanced age, clinical symptoms including headache, diplopia and facial numbness, advanced disease stage, and high NLR were independent prognostic factors. CONCLUSION: A high NLR is an independent poor prognostic factor of NPC in Taiwan.

Predictive value of nodal maximum standardized uptake value of pretreatment [18F]fluorodeoxyglucose positron emission tomography imaging in patients with esophageal cancer.

We retrospectively reviewed 102 patients with esophageal cancer (97.1% squamous cell carcinoma, 96.1% stage III) received FDG-PET staging and were treated by chemoradiotherapy with or without resection to assess whether the pretreatment [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) maximum standardized uptake value (SUVmax) of the primary tumor and metastatic lymph nodes can predict the prognosis of patients with esophageal cancer. Receiver operating characteristic analysis was performed to find the cutoff values for primary tumor SUVmax and nodal SUVmax. The influence of clinical factors including primary tumor SUVmax and nodal SUVmax on local progression-free survival, nodal progression-free survival (NPFS), distant metastases-free survival (DMFS), and overall survival (OS) were evaluated using univariate and multivariate analyses. A total of 40 patients received esophagectomy after neoadjuvant chemoradiotherapy (trimodality), while 62 patients received definitive chemoradiotherapy (dCRT). The median follow-up was 26.4 months. The SUVmax of primary tumor had no significant predictive value on all outcomes, while the SUVmax of metastatic lymph nodes had predictive value on several outcomes. High nodal SUVmax (≥7) predicted for worse outcomes than low nodal SUVmax (<7) in the patients who received dCRT (two-year DMFS, 17% vs. 92%, P < 0.001; NPFS, 14% vs. 81%, P = 0.001; OS, 21% vs. 50%, P = 0.003), but not in those received trimodality. On multivariate analysis of patients receiving dCRT, nodal SUVmax was the strongest independent predictor on DMFS (hazard ratio [HR] 13.93, P < 0.001), NPFS (HR 3.99, P = 0.026), PFS (HR 2.90, P = 0.003), and OS (HR 3.80, P = 0.001). High pretreatment nodal SUVmax predicts worse treatment outcomes for the patients treated with dCRT.

A targetable HB-EGF-CITED4 axis controls oncogenesis in lung cancer.

Aberrant epidermal growth factor (EGF) receptor (EGFR) signaling contributes to neoplastic initiation and progression in lung. Mutated EGFR has become as an important therapeutic target in lung cancer, whereas targeted treatment is not available for wild-type EGFR or its ligands. In this study, we found that heparin-binding (HB)-EGF, a member of the EGF family, was highly expressed in a subset of lung cancer, proliferation of which was dependent on HB-EGF signaling. Silencing of HB-EGF with RNA interference inhibited cell cycle progression in lung cancer cells. We observed that, upon HB-EGF induction, CITED4 was induced through a signal transducer and activator of transcription 3 (STAT3)-dependent pathway, regulating cell proliferation. CITED4 interacted with MYC and potentiated MYC-mediated transactivation of the CCND1 promoter, leading to cell cycle progression. Correlation analysis revealed that HB-EGF and CITED4 were significantly positively associated in primary lung tumors, and expression of HB-EGF predicted a poor survival outcome in patients. In vitro and in vivo experiments revealed that pharmacological inhibition of HB-EGF with CRM197 significantly attenuated tumor cell growth. Thus, CITED4 functions as a molecular switch in HB-EGF-induced growth control, and HB-EGF provides a novel therapeutic target for lung cancer intervention.

Herb formula enhances treatment of impotent patients after penile venous stripping: a randomised clinical trials.

Herbs have been regarded as aphrodisiacs in treating impotence for many centuries despite little true scientific evidence. Our latest refined penile venous stripping (PVS) technique is effective in treating impotence, although this procedure remains controversial. A synergic effect of PVS and oral herbs was confirmed in our practice but lacked rigorous scientific proof. The objective of this report was to review our experience with this combination. From August 2010 to May 2014, 263 males underwent PVS. Among these, 67 unsatisfied men chose additional salvage therapy and were randomly assigned to oral herbs (n = 35) or placebo treatment (n = 32) which replaced herb eventually. All were evaluated with the international index of erectile function (IIEF-5) scoring and our dual pharmaco-cavernosography. The pre-op IIEF-5 score for the herb group was 9.7 ± 3.7, post-operative 13.9 ± 3.3 and post-herb 19.6 ± 3.4, while the control group scores were as follows: pre-op 9.3 ± 4.1, post-op 14.5 ± 3.6, post-placebo 15.1 ± 3.5 and post-herb 19.9 ± 3.2. Although there was no significant difference between the two groups pre-operatively, post-operatively and post-herb, a statistically significant difference was found post-salvage therapy (19.6 ± 3.4 versus 15.1 ± 3.6, P < 0.001). It appears that the combination of oral herbs and PVS treatment provides an enhanced outcome to impotent patients refractory to medicine and unsatisfied with PVS monotherapy alone.

Improvement of glycemic control in streptozotocin-induced diabetic rats by Atlantic salmon skin gelatin hydrolysate as the dipeptidyl-peptidase IV inhibitor.

In our previous study, Atlantic salmon skin gelatin hydrolysed with flavourzyme possessed 42.5% dipeptidyl-peptidase (DPP)-IV inhibitory activity at a concentration of 5 mg mL(-1). The oral administration of the hydrolysate (FSGH) at a single dose of 300 mg per day in streptozotocin (STZ)-induced diabetic rats for 5 weeks was evaluated for its antidiabetic effect. During the 5-week experiment, body weight increased, and the food and water intake was reduced by FSGH in diabetic rats. The daily administration of FSGH for 5 weeks was effective for lowering the blood glucose levels of diabetic rats during an oral glucose tolerance test (OGTT). After the 5-week treatment, plasma DPP-IV activity was inhibited; the plasma activity of glucagon-like peptide-1 (GLP-1), insulin, and the insulin-to-glucagon ratio were increased by FSGH in diabetic rats. The results indicate that FSGH has the function of inhibiting GLP-1 degradation by DPP-IV, resulting in the enhancement of insulin secretion and improvement of glycemic control in STZ-induced diabetic rats.

Urinary tuberculosis is associated with the development of urothelial carcinoma but not renal cell carcinoma: a nationwide cohort study in Taiwan.

BACKGROUND: Obstructive uropathy and chronic urinary tract infection increase the risk of urinary tract cancer. Urinary tuberculosis (UTB) can cause chronic urinary tract inflammation, lead to obstructive uropathy, and potentially contribute to the development of urinary tract cancer. However, the association between UTB and urinary tract cancer has not been studied. METHODS: This study enrolled 135 142 tuberculosis (TB) cases (male, 69%) from a nationwide health insurance research database in Taiwan and investigated the risk factors for urinary tract cancer, with emphasis on a history of UTB. The incidence of urinary tract cancer in the general population without TB was also calculated for comparison. RESULTS: The TB patients had a mean age of 57.5 ± 19.5 years. Of the 1287 UTB and 133 855 non-UTB patients, 15 (1.2%) and 396 (0.3%) developed urothelial carcinoma, respectively (P<0.001); and 2 (0.2%) and 96 (0.1%) developed renal cell carcinoma, respectively (P=0.240). Cox regression analysis revealed that age, male sex, end-stage renal disease, obstructive uropathy, arsenic intoxication, organ transplantation, and UTB (hazard ratio: 3.38 (2.01-5.69)) were independent risk factors for urothelial carcinoma. The hazard ratio of UTB was higher among female patients (5.26 (2.12-13.06)) than that among male patients (2.96 (1.57-5.60)). CONCLUSION: Urinary tuberculosis had a strong association with urothelial carcinoma, but not with renal cell carcinoma. In TB endemic areas, the urinary tract of TB patients should be scrutinised. It is also imperative that these patients be followed-up carefully in the post-treatment period, and urinalysis, ultrasonography or endoscopy should be an integral part of the follow-up.

Clinical feasibility of a novel biphasic osteochondral composite for matrix-associated autologous chondrocyte implantation.

OBJECTIVE: Matrix-associated autologous chondrocyte implantation has been used to treat cartilage defects. We developed a biphasic cylindrical osteochondral composite construct for such use, and conducted this study to determine its feasibility for treating osteochondral lesions in human knees. METHOD: Ten patients with symptomatic osteochondral lesions at femoral condyles were treated by replacing pathological tissue with the construct of dl-poly-lactide-co-glycolide, whose lower body was impregnated with ß-tricalcium phosphate and served as osseous phase. The construct had a chamber to load double-minced autologous cartilage, serving as source of chondrocytes. Osteochondral lesion was drill-fashioned a pit of identical dimension as the construct. Chondrocyte-laden construct was press-fit to fill the pit. Postoperative outcome was evaluated using Knee Injury and Osteoarthritis Outcome Score (KOOS) scale up to 24 months. Magnetic resonance image was taken, and sample tissue was collected with second-look arthroscopic needle biopsy at 12 months. Outcome parameters were primarily safety of surgery, and secondarily postoperative change in KOOS and regeneration of hyaline cartilage and cancellous bone. RESULTS: No patient experienced serious adverse events. Postoperative mean KOOS in "symptoms" subscale had not changed significantly from pre-operation until 24 months; whereas those in the other four subscales were significantly higher than pre-operation at 12 and 24 months. Second-look arthroscopy showed completely filled grafted sites, with regenerate cartilaginous surfaces flushed with surrounding native joint surface. Microscopically, regenerated cartilage appeared hyaline. CONCLUSION: This novel construct for chondrocyte implantation is safe for surgical application in knee. It repairs osteochondral lesions of femoral condyles by successful regeneration of hyaline cartilage.

CITED2 functions as a molecular switch of cytokine-induced proliferation and quiescence.

Transforming growth factor-α (TGF-α)-induced proliferation and transforming growth factor-ß (TGF-ß)-mediated quiescence are intricately balanced in normal lung-tissue homeostasis but are deregulated during neoplastic progression of lung cancer. Here, we show that Cbp/p300-interacting transactivator with Glu/Asp-rich carboxy-terminal domain 2 (CITED2), a novel MYC-interacting transcriptional modulator, responds to TGF-α induction and TGF-ß suppression to orchestrate cellular proliferation and quiescence, respectively. Upon TGF-α induction, CITED2 was induced by MYC and further modulated MYC-mediated transcription in a feed-forward manner. CITED2 recruited p300 to promote MYC-p300-mediated transactivation of E2F3, leading to increased G1/S cell cycle progression. Moreover, CITED2 inhibited cellular quiescence by enhancing MYC-mediated suppression of p21(CIP1). CITED2 interacted with histone deacetylase 1 (HDAC1) and potentiated MYC-HDAC1 complex formation. TGF-ß stimulation provoked downregulation of CITED2, which abrogated MYC-HDAC1-mediated p21(CIP1) suppression, causing cellular quiescence. Ectopic CITED2 expression enhanced tumor growth in nude mice; furthermore, CITED2 knockdown caused tumor shrinkage and increased overall host mouse survival rates. Expression of CITED2/MYC/E2F3/p21(CIP1) signaling molecules was associated with poor prognosis of lung cancer patients. Thus, CITED2 functions as a molecular switch of TGF-α and TGF-ß-induced growth control, and MYC-CITED2 signaling axis provides a new index for predicting clinical outcome.

Lodox/Statscan facilitates the early detection of commonly overlooked extracranial injuries in patients with traumatic brain injury.

INTRODUCTION: Traumatic brain injury (TBI) is a common diagnosis in the emergency department. Brain computed tomography (CT) has become a standard diagnostic tool with which to examine TBI patients. Conventional X-rays are ineffective for the evaluation of torso or extremity injuries. In the current study, we attempted to establish a diagnostic modality to evaluate systemically initially unconscious patients in the emergency department with a rapid screening technique characterized by sufficient information, low cost and low radiation exposure. MATERIALS AND METHODS: From January 2008 to December 2009, patients with diminished level of consciousness received the Lodox/Statscan for evaluation of extracranial injuries were enrolled in this study. The accuracy of this diagnostic modality in detecting torso or extremity injuries in initially unconscious patients was analyzed by comparing the initial diagnosis (by the Lodox/Statscan) with the final diagnosis (confirmed by torso CT scan or after two weeks of follow-up). RESULTS: There were 1,210 patients with TBI whose extracranial injuries were evaluated by the Lodox/Statscan. After excluding intra-abdominal injuries, the overall sensitivity rates of the Lodox/Statscan in diagnosing torso injuries and extremity injuries were 89.7% and 90.2%, respectively. No long bone fracture was missed by the Lodox/Statscan. The sensitivity and specificity of the Lodox/Statscan in diagnosing long bone fractures were both 100%. Most patients with torso injuries that were missed by the Lodox/Statscan could be managed conservatively without further treatment or complications. All of the missed extremity injuries were distal bone fractures. CONCLUSION: The Lodox/Statscan can provide benefits for surveying extracranial injuries in patients with diminished level of consciousness. The Lodox/Statscan also emits a notably low dose of radiation and appears to be a relatively inexpensive adjunct to screen torso or extremity injuries in TBI patients.

Portable potentiostatic sensor integrated with neopterin-imprinted poly(ethylene-co-vinyl alcohol)-based electrode.

Neopterin is a catabolic product of guanosine triphosphate, a purine nucleotide. Measuring neopterin concentrations in biological fluids such as urine provides information about cellular immune activation in humans under control of T helper cells. A high neopterin concentration in bodily fluids, including serum and urine, indicates cellular immunity activation, which is associated with oxidative stress. In this work, neopterin is the target molecule and imprinted onto poly(ethylene-co-vinyl alcohol) via solvent evaporation. The template molecules on the thin film are then removed, and the membrane is used as a sensing element for electrochemical urinalysis. Poly(ethylene-co-vinyl alcohol) containing 27 mol% ethylene had high imprinting effectiveness and may be integrated with the proposed portable biosensor. In random urine analysis, the cyclic voltammetry measurements of neopterin with an additional recovery method achieved >95% recovery for the neopterin concentration of 15 ng/mL.

PTEN, tau-AP-3, thymidylate synthase immunohistochemistry scoring expression in patients with uterine leiomyomas, uterine smooth muscle tumors of uncertain malignancy potential and uterine leiomyosarcomas.

Uterine smooth muscle tumors are frequently classified as benign and malignant. However, an assortment of mitotic counts and nuclear atypia can be indecisive between uncertain malignant potential, and malignant uterine smooth muscle tumors. We applied three immunohistochemical parameters to distinguish between cases of benign, malignant, and those with uncertain malignant histology.

Deleterious effects of MRI on chondrocytes.

OBJECTIVE: To assess how magnetic fields (MFs), with or without concurrent radio frequency (RF), influence chondrocytes and knee joint repair, we applied an MF strength via magnetic resonance imaging (MRI) slightly greater than the frequently used dosage in the clinics and examined the effects of these treatments in vitro on human chondrocytes and in vivo in pigs. METHODS: Human chondrocytes were directly exposed to a 3-tesla (T) magnetic field (MF group) or a 3-T static magnetic field plus 125.3 MHz radio frequency (MF+RF group), and cell proliferation, apoptosis, cytosolic Ca2+ ([Ca2+]i) fluxes and expression of the apoptosis-related proteins of the treated cells were examined to assess the effects of the treatments. In the pig study, we examined the effects of the treatments on the recovery of surgically damaged pig knees. RESULTS: A 3-T static MF and RF suppressed cell growth and induced apoptosis through p53, p21, p27 and Bax protein expression. In the pig model, we found that MRI surveillance had a deleterious effect on the recovery of the damaged knee cartilage. CONCLUSION: Magnetic strength, with or without concurrent RF, suppressed chondrocyte growth in vitro and affected recovery of damaged knee cartilage in vivo in the pig model. These results may be specific to the parameters used in this study and may not apply to other situations, field strengths, forms of cartilage injury, or animal species.

The application of mini-implants for orthodontic anchorage.

The aim of this study was to explore the use of mini-implants for skeletal anchorage, and to assess their stability and the causes of failure. Forty-five mini-implants were used in orthodontic treatment. The diameter of the implants was 2mm, and their lengths were 8, 10, 12 and 14mm. The drill procedure was directly through the cortical bone without any incision or flap operation. Two weeks later, a force of 100-200g was applied by an elastometric chain or NiTi coil spring. Risk factors for the failure of mini-implants were examined statistically using the Chi-square or Fisher exact test as applicable. The average placement time of a mini-implant was about 10-15min. Four mini-implants loosened after orthodontic force loading. The overall success rate was 91.1%. The location of the implant was the significant factor related to failure. In conclusion, the mini-implants are easy to insert for skeletal anchorage and could be successful in the control of tooth movement.

Formulas for determining the dimensions of venous graft required for penile curvature correction.

To evaluate the quantity of penile veins for use as patch material for the treatment of penile curvature, we devised two formulas: from the calculus of applied civil engineering and a diagram from the goniometry of the cadavers' penises, respectively, and the techniques for their application. From March 1995 to July 2003, a total of 65 consecutive patients with penile curvature - 41 men with Peyronie's deformity and 24 with congenital penile deviations - underwent grafting with autologous deep dorsal veins with or without cavernosal veins as patch material. The patched veins required were calculated from the formula (pi)r(2)theta/45 degrees , which is derived from calculus. The tunical incision sector was meticulously performed in accordance with our diagram which is interpolated from seven male cadavers via goniometry and consequently the length of patched veins required was 2 (pi)r(theta)(')/theta. The corporotomy defect was fashioned with the detubularized veins after they were adequately prepared and spliced. In these patients, the average available area of the veins was 4.9 x 2.2 cm(2) (range, 4.5 x 1.8 to 5.6 x 2.4), which seemed adequate in all cases for patching, although 11 of them required two patches. Overall, 21 patients required a modified Nesbit's procedure on the contralateral/ipsilateral tunica to attain a satisfactory penile shape. Because of its anatomical vicinity and its availability as material, the deep dorsal vein associated with the cavernosal vein may play an indispensable role in grafting even with local anaesthesia on an outpatient basis.

A simple model for quantification of the radiobiological effectiveness of the 10B(n,alpha)7Li capture reaction in BNCT.

A simple model has been developed for predicting radiobiological effectiveness of the neutron capture reaction in boron neutron capture therapy. This model was derived from the relationship between the cell survival from the boron capture reaction, the intracellular boron concentration, and the thermal neutron fluence. We found that the cell-killing effect of the boron capture reaction was well described using a power function of the intracellular boron concentration. Hence the relationship between cell survival from the boron capture reaction, intracellular boron concentration, and the thermal neutron fluence could be determined using a simple mathematical equation. We consider that our current approach is more appropriate and realistic than the conventional theoretical mathematical model used to estimate the radiobiological effectiveness of the neutron capture reaction in boron neutron capture therapy.