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Objective: To investigate the role of programmed death-1 (PD-1), programmed death-ligand 1 (PD-L1), and P16 in patients with head and neck squamous cell carcinoma (HNSCC). Methods: A total of 95 paraffin-embedded samples of tumorous tissue of HNSCC were collected. Expression levels of PD-1, PD-L1, and P16 were determined by immunohistochemistry. Results: A significantly higher proportion of PD-1 among patients infected with the human papillomavirus was found. PD-L1 expression is closely associated with the primary site of the tumor, postoperative recurrence, survival, PD-1 expression and P16 expression. Univariable analysis indicated that T stage, N stage, tumor node metastasis stage, tumor differentiation, and PD-L1 expression were all shown to be prognostic variables for overall survival in patients with HNSCC. In the multivariate analysis, only N stage (P = 0.010) and PD-L1 expression (P = 0.001) were found to be independent prognostic variables for overall survival. In addition, for disease recurrence, multivariate analysis showed that only PD-L1 expression was the associated independent risk factor. For the patients with negative PD-L1 expression, Kaplan-Meier analysis revealed that they had significantly worse outcomes in terms of overall survival (P = 0.001). Similarly, compared with the patients with positive PD-L1 expression, those with negative PD-L1 expression had a higher probability of recurrence (P = 0.026). Conclusions: The expression of PD-L1, PD-1, and P16 in HNSCC is significantly correlated. Human papillomavirus infection (P16 positive) is negatively related to postoperative recurrence. HNSCC patients with positive PD-L1/PD-1 expression tend to have better overall survival outcomes and lower probability of recurrence, providing more evidence for the PD-l-targeted immunotherapy of HNSCC.

Adaptivity is the capacity of software to adjust itself to changes in its environment. A common approach to achieving adaptivity is to introduce dedicated code during software development stage. However, since those code fragments are designed a priori, self-adaptive software cannot handle situations adequately when the contextual changes go beyond those that are originally anticipated. In this case, the original built- in adaptivity should be tuned. For example, new code should be added to provide the capacity to sense the unexpected environment or to replace outdated adaptation decision logic. The technical challenges in this process, especially that of tuning software adaptivity at runtime, cannot be understated. In this paper, we propose an architecture-centric application framework for self-adaptive software named Auxo. Similar to existing work, our framework supports the development and running of self-adaptive software. Furthermore, our framework supports the tuning of software adaptivity without requiring the running self-adaptive software to be terminated. In short, the architecture style that we are introducing can encapsulate not only general functional logic but also the concerns in the self-adaptation loop （such as sensing, decision, and execution） as architecture elements. As a result, a third party, potentially the operator or an augmented software entity equipped with explicit domain knowledge, is able to dynamically and flexibly adjust the self-adaptation concerns through modifying the runtime software architecture. To truly exercise, validate, and evaluate our approach, we describe a self-adaptive application that was deployed on the framework, and conducted several experiments involving self-adaptation and the online tuning of software adaptivity.

Complications arising from tendon injury include tendon sheath infection and peritendinous adhesion, in which tendon adhe- sion often leads to serious motor dysfunction. In this work, the electrospun membranes of poly（L-lactide） （PLA） and poly（ε-caprolactone） （PCL） with different degradation kinetics were used to investigate their efficacy for anti-adhesion toward Achilles tendon repair. Compared with the PCL membrane, the PLA sample showed a faster rate of degradation in 42 d, and all the degradation media （i.e., phosphate-buffered saline） maintained at a constant pH of around 7.4. Meanwhile, the superior biocompatibility of both the PLA and PCL membranes were proved by the in vitro cellular adhesion tests and in vivo histo- pathological assays. Simultaneously, the PLA membrane was more effective than the PCL sample in decreasing adhesion and promoting functional recovery. Furthermore, the experiment result was further confirmed by hematoxylin-eosin and Masson＇s trichrome staining, and type I collagen immunohistochemical analysis. All results revealed that the model treated with the electrospun PLA membrane was obviously better with regard to both anti-adhesion and tendon repair than that in the PCL mem- brane group. Considering the results of degradation and adhesion prevention efficacy, the electrospun polyester membranes, especially the PLA one, would be applied with fascinating potential in clinical prevention of postoperative tendon adhesion.

This study sought to assess the prognostic significance of the degree of extranodal extension （ENE） and several other risk factors in pathological ENE penile carcinoma. We analyzed prospectively collected data on a consecutive series of 31 chemotherapy-naive patients with proven ENE who underwent therapeutic regional lymphadenectomy. Postoperative external radiotherapy was then performed. We studied the extent of ENE utilizing a novel grading system and correlated patient grades with their outcome measures. ENE was graded as 1 - if the capsule of the lymph node （LN） was ruptured less than one-third of its circumference or 2 - if the capsule was disrupted more than one-third of its circumference or the entire LN was disrupted. We estimated overall survival （OS） using the Kaplan-Meier method. Multivariate analysis was performed according to the Cox proportional hazards model using factors that were identified as statistically significant in univariate analysis. The incidence rate of ENE was 51.8% in patients with pathological node-positive carcinoma of the penis. The median OS and 5-year survival were 18 months （95% confidence interval （CI）, 14.4-21.6） and 23%, respectively. Prognostic variables on univariate analysis were ENE grade 2, ≥3 LNs with ENE, maximal LN ≥ 35 mm, 〉5 positive LNs and pelvic LN involvement. On multivariate analysis, only ENE grade 2 remained associated with decreased OS （hazard ratio （HR）： 6.50）. In conclusion, patients with ENE have a poor outcome, and ENE grade 2 is an independent predictive factor of poor OS in patients with pathological ENE penile carcinoma.

Drug use and relapse involve learned associations between drug-associated environmental cues and drug effects. Extinction procedures in the clinic can suppress conditioned responses to drug cues, but the extinguished responses typically reemerge after exposure to the drug itself (reinstatement), the drug-associated environment (renewal), or the passage of time (spontaneous recovery). We describe a memory retrieval-extinction procedure that decreases conditioned drug effects and drug seeking in rat models of relapse, and drug craving in abstinent heroin addicts. In rats, daily retrieval of drug-associated memories 10 minutes or 1 hour but not 6 hours before extinction sessions attenuated drug-induced reinstatement, spontaneous recovery, and renewal of conditioned drug effects and drug seeking. In heroin addicts, retrieval of drug-associated memories 10 minutes before extinction sessions attenuated cue-induced heroin craving 1, 30, and 180 days later. The memory retrieval-extinction procedure is a promising nonpharmacological method for decreasing drug craving and relapse during abstinence.

Abstract Context The activation of orbital fibroblasts, the prime targets in thyroid eye disease (TED), is central to its underlying pathogenesis. Objective We aimed to investigate the mechanism of TED orbital fibroblast activation from the perspective of noncoding RNA regulation. Methods Immunofluorescence (IF) staining was applied to evaluate the fibrotic changes in target cells. Cell proliferation was evaluated by 5-ethoxy 2-deoxyuridine and colony-formation assays. Collagen I concentration was determined by enzyme-linked immunosorbent assay. Human microarray analysis was performed on 3 TED and 3 healthy control orbital tissue samples. Results Bioinformatics analysis showed that cell adhesion signaling factors were differentially expressed in TED tissues, including intercellular adhesion molecule (ICAM)-1, ICAM-4, vascular cell adhesion molecule, and CD44, which were all upregulated in diseased orbital tissues. Long noncoding RNA LPAL2 level was also upregulated in orbital tissues and positively correlated with ICAM-1 and ICAM-4 expression. Stimulation of the TED orbital fibroblasts by transforming growth factor-β1 (TGF-β1) significantly increased the expression of ICAM-1, ICAM-4, and LPAL2. Knockdown of LPAL2 in orbital fibroblasts inhibited TGF-β1–induced increases in cell adhesion factor levels and orbital fibroblast activation. Microarray profiling was performed on TED and normal orbital tissues to identify differentially expressed microRNAs, and miR-1287-5p was remarkably reduced within diseased orbital samples. miR-1287-5p was directly bound to the epidermal growth factor receptor (EGFR) 3′ untranslated region and LPAL2, and LPAL2 modulated EGFR/protein kinase B (AKT) signaling through targeting miR-1287-5p. Conclusion The LPAL2/miR-1287-5p axis modulated TGF-β1–induced increases in cell adhesion factor levels and TED orbital fibroblast activation through EGFR/AKT signaling.

Background： This study was to investigate the relationship among aortic artery calcification （AAC）, cardiac valve calcification （CVC）, and mortality in maintenance hemodialysis （MHD） patients. Methods： All MHD patients in Shanghai Ruijin Hospital in July 2011 were included. To follow up tbr 42 months, clinical data, predialysis blood tests, echocardiography, and lateral lumbar X-ray plain radiography results were collected. Plasma FGF23 level was measured using a C-terminal assay. Results： Totally, 110 MHD patients were involved in this study. Of which, 64 （58.2%） patients were male, the mean age was 55.2 ± 1.4 years old, and the median dialysis duration was 29.85 （3.0-225.5） months. About 25.5% of the 110 MHD patients had CVC from echocardiography while 61.8% of the patients had visible calcification of aorta from lateral lumbar X-ray plain radiography. After 42 months follow-up, 25 （22.7%） patients died. Kaplan-Meier analysis showed that patients with AAC or CVC had a significant greater number of all-cause and cardiovascular deaths than those without. In multivariate analyses, the presence of AAC was a significant factor associated with all-cause±mortality （hazard ratio [HR]： 3.149, P = 0.025） in addition to lower albumin level and lower 25-hydroxy Vitamin D （25（OH）D） level. The presence of CVC was a significant factor associated with cardiovascular mortality （HR： 3.800, P - 0.029） in addition to lower albumin level and lower 25（OH）D level. Conclusion： Lateral lumbar X-ray plain radiography and echocardiography are simple methods to detect AAC and CVC in dialysis patients. The presence of AAC and CVC was independently associated with mortality in MHD patients. Regular follow-up by X-ray and echocardiography could be a useful method to stratify mortality risk in MHD patients.

Depression is one of the most common and debilitating psychiatric illnesses around the world, but the current antidepressants used to treat depression have many limitations. Progressively more studies have shown that neuropeptide systems are potential novel therapeutic targets for depression. However, whether the neuropeptide trefoil factor 3 (TFF3) participates in the development of depression has not been examined. In the current experiments, we assessed the antidepressant effects of TFF3 using the forced swim test (FST), tail suspension test (TST), and chronic mild stress (CMS) paradigm. Furthermore, we determined the mechanism that underlies the antidepressant-like effects of TFF3 in the rat FST. TFF3 dose-dependently reduced immobility time in both FST and TST. CMS elevated plasma TFF3 and decreased basolateral amygdala (BLA) TFF3 levels in rats, and acute TFF3 (0.1 mg/kg, i.p.) treatment reversed the depressive-like behaviors induced by CMS. Furthermore, TFF3 (0.1 mg/kg, i.p.) significantly increased Fos expression in the BLA, medial prefrontal cortex, and hypothalamus in rats subjected to the FST. Intra-BLA infusions of TFF3 (1 ng/side) exerted rapid antidepressant-like effects in the rat FST. Additionally, acute systemic TFF3 administration increased the level of phosphorylated-Akt (p-Akt) in the BLA. Finally, intra-BLA infusions of LY294002 (5 mM/side), a specific phosphatidylinositol 3-kinase (PI3K) inhibitor, significantly blocked the antidepressant-like effect of TFF3. Our results demonstrated that TFF3 exerts antidepressant-like effects that might be mediated by the PI3K/Akt signaling pathway in the BLA. These findings suggest a novel neuropeptide system target in the development of new antidepressants.

Background Abdominal cerebrospinal fluid (CSF) pseudocyst is an uncommon but important complication of ventriculoperitoneal (VP) shunts. While individual articles have reported many cases of abdominal CSF pseudocyst following VP shunts, no case of a hemorrhagic abdominal pseudocyst after VP shunts has been reported so far. Case presentation This article reports a 68-year-old woman with a 4-month history of progressive abdominal pain and distention. She denied any additional symptoms. A VP shunt was performed 15 years earlier to treat idiopathic normal pressure hydrocephalus and no other abdominal surgery was performed. Physical examination revealed an elastic palpable mass in her right lower abdomen, which was dull to percussion. Abdominal computed tomography (CT) scan indicated a large cystic collection of homogenous iso-density fluid in the right lower abdominal region with clear margins. The distal segment of the peritoneal shunt catheter was located within the cystic mass. Abdominal CSF pseudocyst was highly suspected as a diagnosis. Laparoscopic cyst drainage with removal of the whole cystic mass was performed, 15-cm cyst which found with thick walls and organized chronic hematic content. No responsible vessel for the cyst hemorrhage was identified. No further shunt revision was placed. Histological examination showed that the cyst wall consisted of outer fibrous tissue and inner granulation tissue without epithelial lining, and the cystic content was chronic hematoma. The patient had an uneventful postoperative course and remained asymptomatic for 8-mo follow-up. Conclusion To the best of our knowledge, this is the first report of hemorrhagic onset in the abdominal pseudocyst following VP shunt. Such special condition can accelerate the appearance of clinical signs of the abdominal pseudocyst after VP shunts, and its mechanisms may be similar to the evolution of subdural effusion into chronic subdural hematoma (CSDH).