ceRNA regulatory network of FIH inhibitor as a radioprotector for gastrointestinal toxicity by activating the HIF-1 pathway.

Given the relentless renewal ability of intestinal crypt-base stem cells, small intestine in the gastrointestinal (GI) tract is more vulnerable to radiation-induced disruption. Through promoting epithelial integrity and reducing intracellular reactive oxygen species (ROS) levels, hypoxia-inducible factors (HIFs) have been proved to exhibit radioprotective effects in the GI tract. Therefore, enhancing stability or transcriptional activity of HIFs might be a therapeutic strategy for developing radioprotectors. Factor inhibiting HIF (FIH or HIF-1AN) can hamper transcriptional capacity of HIF-1α via interacting with Asn803 in its C-terminal domain. Previously, we discovered promoting HIF-1α transcriptional activity in vitro by FIH inhibitor-N-oxalyl-D-phenylalanine (NOFD) exerts radioprotection on cells. However, the radioprotective effect of FIH inhibitor on the GI tract and its competing endogenous RNA (ceRNA) regulatory network from the FIH/HIF axis has never been addressed. Here we verified radioprotection of NOFD for the GI tract by an animal model and performed whole-transcriptome analysis to fully elucidate the radioprotective mechanism from the FIH/HIF axis against GI syndrome. We identified two novel circular RNAs (circRNAs) (circRNA_2909 and circRNA_0323) and two long non-coding RNAs (lncRNAs) (NONMMUT140549.1 and NONMMUT148249.1) that promote expression of HIF1A and NOS2 in the HIF-1 pathway by sponging microRNAs (miRNAs), especially mmu-miR-92a-1-5p. The de-repression of HIF-1α transcriptional capacity by inhibiting FIH proteomic activity suggests a new therapeutic strategy in alleviating radiation-induced GI syndrome.

Generation of avian-derived anti-B7-H4 antibodies exerts a blockade effect on the immunosuppressive response.

For highly conserved mammalian protein, chicken is a suitable immune host to generate antibodies. Monoclonal antibodies have been successfully targeted with immunity checkpoint proteins as a means of cancer treatment; this treatment enhances tumor-specific immunity responses through immunoregulation. Studies have identified the importance of B7-H4 in immunoregulation and its use as a potential target for cancer treatment. High levels of B7-H4 expression are found in tumor tissues and are associated with adverse clinical and pathological characteristics. Using the phage display technique, this study isolated specific single-chain antibody fragments (scFvs) against B7-H4 from chickens. Our experiment proved that B7-H4 clearly induced the inhibition of T-cell activation. Therefore, use of anti-B7-H4 scFvs can effectively block the exhaustion of immunity cells and also stimulate and activate T-cells in peripheral blood mononuclear cells. Sequence analysis revealed that two isolated scFv S2 and S4 have the same VH complementarity-determining regions (CDRs) sequence. Molecule docking was employed to simulate the complex structures of scFv with B7-H4 to analyze the interaction. Our findings revealed that both scFvs employed CDR-H1 and CDR-H3 as main driving forces and had strong binding effects with the B7-H4. The affinity of scFv S2 was better because the CDR-L2 loop of the scFv S2 had three more hydrogen bond interactions with B7-H4. The results of this experiment suggest the usefulness of B7-H4 as a target for immunity checkpoints; the isolated B7-H4-specific chicken antibodies have the potential for use in future cancer immunotherapy applications.

Overexpression of activin A in oral squamous cell carcinoma: association with poor prognosis and tumor progression.

BACKGROUND: Both activin A, a member of transforming growth factor beta superfamily, and its inhibitor follistatin have been shown to be overexpressed in various cancers. We examined the potential role of activin A and follistatin in tissue and blood samples from patients with oral squamous cell carcinoma. METHODS: For activin A and follistatin, the expression of tissue samples from 92 patients was examined by immunohistochemical study, and the serum levels of blood samples from 111 patients and 91 healthy controls were measured by enzyme-linked immunosorbent assay. RESULTS: We found that overexpression of immunohistochemically detected activin A was correlated with positive N stage, poor histological differentiation, and perineural invasion (P = 0.029, 0.002, and 0.014, respectively). In survival analyses, patients with oral squamous cell carcinoma, whose tumors overexpressed activin A, had a worse prognosis for overall survival and disease-free survival (P = 0.009 and 0.007). However, expression of follistatin in tumor was not correlated with overall survival or disease-free survival. Serum activin A and follistatin levels in 111 untreated patients were neither significantly different from those of 91 control samples nor associated with any clinicopathological manifestations. In vitro suppression of activin A expression in OC3 cells using specific interfering RNA-attenuated cell proliferation, migration, and invasiveness. CONCLUSIONS: These findings suggest that activin A overexpression in oral squamous cell carcinomas is associated with patients' survival and may contribute to tumor progression and metastasis.

Histological differentiation of primary oral squamous cell carcinomas in an area of betel quid chewing prevalence.

OBJECTIVES: This study evaluated associations between the histological differentiation of oral squamous cell carcinoma and additional clinicopathological manifestations, adverse events after treatment, and the outcomes of patients in a region prevalent for betel quid chewing. STUDY DESIGN: Case series with chart review. SETTING: Tertiary referral center. SUBJECTS AND METHODS: A total of 150 patients with primary oral squamous cell carcinomas who underwent surgery with or without adjuvant therapy were enrolled. RESULTS: Well, moderate, and poorly differentiated oral squamous cell carcinomas were reported in 54 (36%), 84 (56%), and 12 (8%) patients, respectively. There were no significant differences among different histological differentiations in age, sex, tumor, node, metastasis stage, bone invasion, depth of invasion, and history of carcinogen exposure. However, we found significant associations between tumor histological differentiation and nodal metastasis (P < 0.0001), extracapsular spread (P = 0.002), and perineural invasion (P < 0.0001). In the analysis of adverse events for survival during patient follow-up, oral squamous cell carcinomas with poor differentiation had a higher probability of developing neck recurrence (P = 0.001) and distant metastasis (P = 0.019), but not local recurrence or a second primary cancer. For survival analysis, univariate analysis showed that patient age, tumor stage, extracapsular spread, presence of perineural invasion, and tumor differentiation were significant factors. Multivariate analysis further demonstrated that poor differentiation (P = 0.007) was still a statistically significant factor. CONCLUSION: The current study demonstrates that poorer tumor histological classifications of oral squamous cell carcinoma are significantly associated with positive nodal status, extracapsular spread, perineural invasion of primary tumors, and the probability of developing neck recurrence and distant metastasis after treatment.

Compliance with antithrombotic prescribing guidelines for patients with atrial fibrillation--a nationwide descriptive study in Taiwan.

OBJECTIVES: This study examined compliance with prescribing guidelines for antithrombotic therapy in patients with atrial fibrillation (AF) in Taiwan, using the 2001 joint guideline from the American College of Cardiology, American Heart Association, and European Society of Cardiology. The study also sought to identify factors associated with the appropriate prescribing of antithrombotic therapy. METHODS: Patients with AF were identified by the presence of > or =2 inpatient or outpatient claims with an International Classification of Diseases, Ninth Revision, Clinical Modification code of 427.31 in the Taiwanese National Health Insurance claims database between July 1, 2003, and June 30, 2004. Patients were stratified according to their stroke risk (highest, high, low, or lowest) and antithrombotic medication (aspirin, warfarin, ticlopidine/clopidogrel, or none). Based on these categories, rates of prescribed treatments that were compliant with the antithrombotic guidelines were calculated. Antithrombotic therapies were considered guideline compliant when warfarin was prescribed for the highest- or high-risk patients, aspirin was prescribed for low-risk patients, and aspirin or no antithrombotic treatment was prescribed for the lowest-risk patients. Because the role of ticlopidine/clopidogrel in AF remains unclear, prescription of these drugs without aspirin or warfarin was considered noncompliant with the guidelines. RESULTS: Of 39,541 identified patients with AF, 70.3% were at high risk for thromboembolic events and 18.3% were at highest risk; however, only 24.7% of the overall population received appropriate antithrombotic therapy. When patients with risk factors for bleeding were excluded, the rate of compliance increased to 26.2%. Factors that were inversely associated with prescription of warfarin included risk factors for bleeding (cancer, predisposition to falls, previous hemorrhage, history of peptic ulcer, cirrhosis, renal dialysis, and psychiatric disease), hypertension, coronary artery disease, thyrotoxicosis, and age > or =60 years. CONCLUSIONS: Most of these patients with AF in Taiwan did not receive appropriate antithrombotic therapy over the period studied. Bleeding risk factors, hypertension, coronary artery disease, thyrotoxicosis, and older age were associated with low rates of warfarin use.

Medical treatment for uterine myomas.

Uterine myomas are the most common benign tumors in the female reproductive tract. Most women with myomas are asymptomatic. Therefore, expectant observation and follow-up are often recommended for these myoma patients. However, myomas may cause menstrual symptoms, pelvic pain, pressure complaints, subfertility or pregnancy-related complications, with resultant requests for a definitive treatment. The management of myomas has become multidisciplinary in the past 20 years. Basically, the choice of treatment depends on the patient's age, the reason for treatment, the issue of fertility preservation, and the patient's preference. The treatment spectrum includes an expectant management, medical therapy, surgical intervention, uterine artery embolization or ablative techniques. Medical therapy is an option for women with symptomatic myomas who prefer non-surgical treatment, consider fertility preservation, or expect a less aggressive operation after shrinkage of the uterine volume. This review will summarize the recent well-documented drugs for the management of uterine myomas.

US-guided catheter drainage of postoperative head and neck fluid collections.

PURPOSE: To analyze results of percutaneous catheter drainage of large fluid collections in the head and neck region noted in the immediate postoperative period. MATERIALS AND METHODS: Thirty-four consecutive patients with 41 large fluid collections in the head and neck detected 7-10 days after oncologic surgery underwent percutaneous catheter drainage. There were 29 men and five women, with a mean age of 52.2 years (95% CI: 47.8-56.7). Each patient had a surgical drain placed in the posterior neck triangle; three patients had low-grade fever and six had diabetes at the time of percutaneous catheter drainage. Conventional management consisting of serial needle aspirations at bedside followed by pressure dressing failed in 15 of 34 patients (44%). Ultrasound-guided drainage was performed and catheters were connected to vacuum balls for continuous suction drainage. RESULTS: The average fluid volume estimated by sonographic measurement was 84 cm(3) (95% CI: 57-112 cm(3)). The fluid content was serosanguinous in 46% (19 of 41), uncoagulated blood in 32% (13 of 41), pus in 15% (six of 41), and saliva in 7% (three of 41). The mean duration of catheter drainage was nine days (95% CI: 7-10 d) and mean fluid drainage was 287 mL (95% CI: 188-387 mL). Ninety-one percent of patients (31 of 34) were successfully treated with initial catheter drainage. Three patients had recurrent fluid collections at the same locations: two were treated with repeated catheter insertions and one required a limited open drainage. No complication related to catheter drainage was noted at 6-month follow-up. CONCLUSION: Percutaneous catheter drainage is effective for large fluid collections in the head and neck region noted in the immediate postoperative period irrespective of contents.