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Pituitary neuroendocrine tumor (PitNET) is one of the most common intracranial tumors. Due to its extensive tumor heterogeneity and the lack of high-quality tissues for biomarker discovery, the causative molecular mechanisms are far from being fully defined. Therefore, more studies are needed to improve the current clinicopathological classification system, and advanced treatment strategies such as targeted therapy and immunotherapy are yet to be explored. Here, we performed the largest integrative genomics, transcriptomics, proteomics, and phosphoproteomics analysis reported to date for a cohort of 200 PitNET patients. Genomics data indicate that GNAS copy number gain can serve as a reliable diagnostic marker for hyperproliferation of the PIT1 lineage. Proteomics-based classification of PitNETs identified 7 clusters, among which, tumors overexpressing epithelial-mesenchymal transition (EMT) markers clustered into a more invasive subgroup. Further analysis identified potential therapeutic targets, including CDK6, TWIST1, EGFR, and VEGFR2, for different clusters. Immune subtyping to explore the potential for application of immunotherapy in PitNET identified an association between alterations in the JAK1-STAT1-PDL1 axis and immune exhaustion, and between changes in the JAK3-STAT6-FOS/JUN axis and immune infiltration. These identified molecular markers and alternations in various clusters/subtypes were further confirmed in an independent cohort of 750 PitNET patients. This proteogenomic analysis across traditional histological boundaries improves our current understanding of PitNET pathophysiology and suggests novel therapeutic targets and strategies.

Objective: Gonadal and sexual disturbances are commonly encountered in patients with Cushing’s disease. Nevertheless, the prevalence of hypogonadism in male Cushing’s disease, the risk factors as well as the recovery time have been scarcely reported. Therefore, we aimed to explore the prevalence of hypogonadism at baseline and its determinants. In addition, the recovery time of hypogonadism and risk factors for unrecovered gonadal axis in male Cushing’s disease with biochemical remission were investigated.Methods: We reviewed medical records of males with Cushing’s disease managed between 2010 and 2020. Fifty-two male patients were enrolled according to the criteria. Each case attained biochemical remission after transsphenoidal surgery. Demographic details, clinical features, 24-hour UFC, hormonal profile [serum PRL, FSH, LH, TT, ACTH, cortisol, TT4/FT4, TT3/ FT3, TSH and IGF-1] were measured at baseline and during follow-up. The maximal tumor diameter on MRI was recorded at diagnosis.Results: Hypogonadotropic hypogonadism was observed in thirty-nine patients (75%) at diagnosis. Total testosterone was negatively correlated with ACTH and 24-hour UFC. Midnight serum ACTH level at diagnosis was significantly associated with hypogonadism after adjusting for confounding factors. Thirty-two (80%) patients achieved eugonadism within 12 months after the surgery, of which twenty-eight (87.5%) achieved eugonadism within 3 months. Seven patients were persistently hypogonadal during the follow-up (>1 year), mainly due to the hypopituitarism as a complication of the therapies such as surgery.Conclusion: Hypogonadotropic hypogonadism is frequent in male Cushing’s disease, but it is reversible in most cases within one-year follow-up after remission.

The processing efficiency of dentures is generally quite low due to the complex profile form and high brittleness of the dentures. However, there is little research for efficient path optimization and look-ahead speed control algorithm in denture machining field, which hinders the improvement of the machining efficiency and denture quality. In this work, an optimization method for both straight transition and curve paths was proposed, and look-ahead speed control algorithms for different machining paths were designed. The anomalous points were deleted according to the preprocessing algorithm before the path optimization. The straight transition path and curve path were fitted by the quasi-parabola model and cubic B-spline curve, respectively. The error between the optimized path and original path was analyzed, and the results demonstrated that the path optimization methods were reliable. A look-ahead speed control model based on S-type speed control was proposed, and the boundary conditions for different paths were calculated. The simulated and experimental results indicated that optimized algorithm significantly improved the machining efficiency and reduced the vibration of the machine tool. The accuracy and surface roughness of the denture processed using the optimized algorithm met the medical standard. This work can provide a theoretical guidance for high-efficiency and precision machining of dentures of glass ceramics.

Forming process of internal thread is an advanced manufacturing process. A new planetary rolling process for forming the internal thread is proposed. The structures of rolling system and working process are described in detail. The finite element model of forming internal thread is established, and the forming experiments are conducted by a homemade experimental rig. The material displacement, microstructure, strain, and microhardness are investigated by finite element model and experiment. The results show that the formed internal thread meets requirements and the results of simulation and experiment are consistent. Through the planetary rolling process, the microstructure is stretched and forms the fibrous tissue at the bottom of tooth space of the internal thread. The maximum deformation is located at the bottom of tooth space, and the deformation characteristics are corresponding to the microstructure distribution. At the bottom of tooth space, the microhardness and the equivalent strain are also largest. The maximum microhardness of formed internal thread is improved 37.6%. The new planetary rolling process can improve the production performances and simplify the processing equipment.

The transient elevation of cytoplasmic calcium is essential for pathogen-associated molecular pattern (PAMP)-triggered immunity (PTI). However, the calcium channels responsible for this process have remained unknown. Here, we show that rice CDS1 (CELL DEATH and SUSCEPTIBLE to BLAST 1) encoding OsCNGC9, a cyclic nucleotide-gated channel protein, positively regulates the resistance to rice blast disease. We show that OsCNGC9 mediates PAMP-induced Ca(2+) influx and that this event is critical for PAMPs-triggered ROS burst and induction of PTI-related defense gene expression. We further show that a PTI-related receptor-like cytoplasmic kinase OsRLCK185 physically interacts with and phosphorylates OsCNGC9 to activate its channel activity. Our results suggest a signaling cascade linking pattern recognition to calcium channel activation, which is required for initiation of PTI and disease resistance in rice.

Cardiac resynchronization therapy with defibrillator (CRT-D) implantation involves left ventricular (LV) lead placement for biventricular pacing and is more complex than implantable cardioverter-defibrillator (ICD)-only implantation. Differences in the prescription of CRT-D versus ICD may result from clinician biases based on patient body habitus, and body habitus may be associated with LV lead implantation failure. We sought to evaluate whether patient body mass index (BMI) was associated with planned use and implantation failure of CRT-D therapy. We studied all patients enrolled in the National Cardiovascular Data Registry ICD Registry who met standard CRT-D criteria and received either an ICD or CRT-D between 2010 and 2012. BMI was categorized based on World Health Organization classification. Using hierarchical logistic regression, two multivariate models adjusted for patient demographic and clinical characteristics were fit based on the following outcome variables: (1) planned implantation with CRT-D versus ICD and (2) failed versus successful LV lead placement. Of 337,547 patients, 41,872 met inclusion criteria for the first analysis and 35,186 met criteria for the second analysis. After multivariable adjustment, patients with extreme (BMI > 40 kg/m2) obesity were less likely to receive guideline-concordant CRT-D compared with patients with normal weight (adjusted odds ratio (AOR), 0.86; 95% confidence interval (CI), 0.75–0.99; p = 0.04). Extreme (BMI > 40 kg/m2) obesity was associated with higher odds of failed LV lead placement (AOR, 1.35; 95% CI, 1.07–1.72, p = 0.01). Compared with normal weight patients, extremely obese (BMI > 40 kg/m2) CRT-D eligible patients were less likely to be prescribed CRT-D and were at higher odds for failed LV lead placement.

The objective of this study was to develop an authentic ionic-driven osmotic pump system and investigate the release mechanism, simultaneously exploring the in vitro and in vivo correlation of the ionic-driven osmotic pump tablet. A comparison of the ionic-driven and conventional theophylline osmotic pump, the influence of pH and the amount of sodium chloride on drug release, the relationship between the ionic osmotic pressure and the drug release, and the pharmacokinetics experiment in beagle dogs were investigated. Consequently, the similarity factor (f 2 ) between the novel and conventional theophylline osmotic pump tablet was 60.18, which indicated a similar drug-release behavior. Also, the release profile fitted a zero-order kinetic model. The relative bioavailability of the ionic-driven osmotic pump to the conventional osmotic pump calculated from the AUC (0-∞) was 93.6% and the coefficient (R = 0.9945) confirmed that the ionic-driven osmotic pump exhibited excellent IVIVC. The driving power of the ionic-driven osmotic pump was produced only by ions, which was strongly dependent on the ion strength, and a novel formula for the ionic-driven osmotic pump was derived which indicated that the drug-release rate was proportional to the ionic osmotic pressure and the sodium chloride concentration. Significantly, the formula can predict the drug-release rate and release characteristics of theophylline ionic-driven osmotic pumps, guiding future modification of the ionic osmotic pump.

Radial forging (RF) was proposed as a novel deformation method to prepare semisolid 6063 aluminum alloy in the recrystallization and partial melting (RAP) process. The effects of area reduction rate, isothermal holding temperature and time on the microstructural evolution of RF-deformed 6063 aluminum alloy were investigated. Results showed that RF can be successfully introduced in RAP process to prepare large semisolid 6063 aluminum alloy bar. With the increase of the area reduction rate, the average grain size firstly decreased and then no significant change occurred. Meanwhile, the spheroidization degree of solid grains firstly increased rapidly, and then increased slowly. The effects of isothermal holding temperature and time are similar, with the increase of the isothermal holding temperature or time, the average grain size initially decreased but then increased; and the spheroidization degree of solid grains gradually increased. High-quality semisolid 6063 aluminum alloy can be prepared with 70% area reduction rate and subsequent semisolid isothermal treatment (SSIT) at 630 °C for 10 min. The coarsening rate constant was 5185.2 µm3/s at 630 °C. Additionally, a strong deformation texture was created in the RF-deformed alloy with 70% area reduction rate, which was transformed to a weakened texture following the SSIT process.

In this study, the Recrystallization and partial melting (RAP) process was performed to prepare 6061 aluminum alloy semi-solid billets. The microstructural evolution and coarsening of the materials were investigated. During the RAP process, the 6061 aluminum alloy plate supplied in cold rolled state was heated to the semi-solid range. The results showed that both the average grain size and shape factor of solid grains increased along with the isothermal holding time and temperature. The coarsening of solid grains could be attributed to the coalescence and Ostwald ripening mechanisms, with the latter playing an increasingly important role as the isothermal holding time and temperature increased. At isothermal holding temperatures of 620, 625, 630 and 635 °C, the coarsening rate constants reached 333.1, 833.8, 1034.7 and 1271.9 μm/s3, respectively. Moreover, the coarsening rate constant gradually increased along with isothermal holding temperature.

Background Health insurance contributes to reducing the economic burden of disease and improving access to healthcare. In 2016, the Chinese government announced the integration of the New Cooperative Medical Scheme (NCMS) and Urban Resident Basic Medical Insurance (URBMI) to reduce system segmentation. Nevertheless, it was unclear whether there would be any geographic variation in health insurance benefits if the two types of insurance were integrated. The aim of this study was to identify the potential geographic variation in health insurance benefits and the related contributing factors. Methods This cross-sectional study was carried out in Qianjiang District, where the NCMS and URBMI were integrated into Urban and Rural Resident Basic Medical Insurance Scheme (URRBMI) in 2010. All beneficiaries under the URRBMI were hospitalized at least once in 2013, totaling 445,254 persons and 65,877 person-times, were included in this study. Town-level data on health insurance benefits, healthcare utilization, and socioeconomic and geographical characteristics were collected through health insurance system, self-report questionnaires, and the 2014 Statistical Yearbook of Qianjiang District. A simplified Theil index at town level was calculated to measure geographic variation in health insurance benefits. Colored maps were created to visualize the variation in geographic distribution of benefits. The effects of healthcare utilization and socioeconomic and geographical characteristics on geographic variation in health insurance benefits were estimated with a multiple linear regression analysis. Results Different Theil index values were calculated for different towns, and the Theil index values for compensation by person-times and amount were 2.5028 and 1.8394 in primary healthcare institutions and 1.1466 and 0.9204 in secondary healthcare institutions. Healthcare-seeking behavior and economic factors were positively associated with health insurance benefits in compensation by person-times significantly, meanwhile, geographical accessibility and economic factors had positive effects (p

There have been no studies investigating the correlation between structural [thickness of the retinal nerve fiber layer (RNFL) as determined by optical coherence tomography (OCT)] and functional [Humphrey visual field (HVF) or visual evoked potential (VEP) amplitude] measures of optic nerve integrity in patients with pituitary adenomas (PA). Patients with PAs were recruited between September 2010 and September 2013. OCT, standard automated perimetry (SAP), and multifical VEP (mfVEP) were performed. Agreement between OCT, SAP, and mfVEP values in classifying eyes/quadrants was determined using AC1 statistics. Pearson’s correlation was used to examine relationships between structural and functional data. In total, 88.7 % of the eyes tested showed abnormal SAP findings and 93.7 % showed abnormal mfVEP findings. Only 14.8 % of the eyes showed abnormal OCT findings. The agreement between SAP and mfVEP findings was 88.9 % (AC1 = 0.87). The agreement between OCT and mfVEP findings was 24.2 % (AC1 = −0.52), and that between OCT and SAP findings was 21.5 % (AC1 = −0.56). The correlation values between RNFL thickness and the functional measurements were −0.601 for the mfVEP score (P = 0.000) and −0.441 for the SAP score (P = 0.000). The correlation between the mfVEP and SAP scores was −0.617 (P = 0.000). mfVEP, SAP, and OCT provided complementary information for detecting visual pathway abnormalities in patients with PAs. Good agreement was demonstrated between SAP and mfVEP and quantitative analysis of structure–function measurements revealed a moderate correlation.

The aim of this study is to determine if contrast enhanced (CE) sampling perfection with application-optimized contrasts using different flip-angle evolutions (SPACE) images can provide clearer pituitary adenoma margin than conventional CE T1-weighted spin echo (T1-SE) sequence for cavernous sinus (CS) invasion evaluation. 21 healthy volunteers were preformed with SPACE scans before and after administration of gadopentetate dimeglumine at different time points (1, 7 and 13 min). Signal intensity (SI) of regions of interest was plotted in SI/time curves for bilateral CS, pituitary and temporal lobe. 35 patients with pituitary adenoma (≥1 cm) were performed CE T1-SE and CE SPACE scans. Two observers made the visual assessment of the tumor margin delineation and CS invasion evaluation on both SPACE and T1-SE images. Surgical findings were compared with the invasion assessment results. At 1, 7 and 13 min after enhancement, SI of left CS increased 6.7, 9.5 and 11.2 % respectively compared with unenhanced images (all p

Background We aim to study surgical technique and analyze the related factors affecting tumor total removal and postoperative endocrinological remission for endoscopic endonasal pituitary adenomas surgery. Methods We retrospectively analyzed 178 endoscopic endonasal pituitary adenomas surgery from March 2011 to May 2014. Endonasal approach included the routine transnasal-sphenoidal approach, transnasal- maxillary sinus approach in four cases and transnasal-clivus approach in one case. Results According to postoperative imaging data and endocrine examination results, total removal was achieved in 129 patients (72.5%), and endocrinological remission was achieved in 38 patients with functional adenomas (44.1%). Statistical analysis of the clinical data showed that total removal rate was much closely related to tumor volume ( P = 0.006), and tumor invasiveness ( P Conclusions In this study, we found tumor sizes and invasion of cavernous sinus were related to total removal rate and endocrinological remission rate; the direction and degree of tumor invasion, and the surgeon’s experience were the key influence factors of the endocrinological remission rate for invasive functional pituitary adenomas.

Colorectal cancer is the third most frequent malignancy worldwide, and represents the fourth most common cause of cancer-related deaths, leading to an estimated 608 000 deaths by 2008 (Ferlay et al, 2010). Despite recent advances in the management of colorectal cancer and new developments of cancer surveillance, the majority of colorectal cancer patients are still diagnosed at an advanced stage when the therapeutic options are limited, and the 5-year survival rate of colorectal cancer patients remains much lower than expected (Ferlay et al, 2010; Jemal et al, 2010). Many efforts have been made to identify the molecular prognostic biomarkers including epigenetic markers for patients with colorectal cancer, in order to make a better selection of therapeutic approaches after surgery and improve patients' survival (Draht et al, 2012). CDKN2A gene functions as an important tumour suppressor in various human malignancies including colorectal cancer, and its activation prevents carcinogenesis via induction of cell growth arrest and senescence (Collado et al, 2007; Rayess et al, 2012). CDKN2A promoter methylation is a frequent epigenetic event and an important mechanism leading to silencing and dysfunction of CDKN2A gene, which further results in uncontrolled cell proliferation and tumour development and progression (Samowitz et al, 2005). Ever since Liang et al (1999) reported that the presence of CDKN2A promoter hypermethylation predicted shorter survival in colorectal cancer patients, the prognostic value of CDKN2A hypermethylation in colorectal cancer have been widely investigated, owing to the fact that these results exhibited an increasing relevance with clinical practice. Although multiple studies were conducted on colorectal cancer patients, whether CDKN2A hypermethylation is a predictive factor for poor prognosis remains controversial, and several studies in this field possessed a small sample size. Therefore, we conducted the present meta-analysis to appraise the prognostic value of CDKN2A hypermethylation in colorectal cancer.

Human cerebral cavernous malformation (CM) is a common vascular malformation of the central nervous system. We have investigated the biological characteristics of CM endothelial cells and the cellular and molecular mechanisms of CM angiogenesis to offer new insights into exploring effective measures for treatment of this disease. The endothelial cells were isolated from CM tissue masses dissected during operation and expanded in vitro. Expression of VEGFR-1 and VEGFR-2 was examined with immunocytochemical staining. Proliferation, migration and tube formation of CM endothelial cells were determined using MTT, wounding and transmigration assays, and three-dimensional collagen type I gel respectively. The endothelial cells were successfully isolated from the tissue specimens of 25 CMs dissected without dipolar electrocoagulation. The cells show the general characteristics of the vascular endothelial cells. Expression of VEGFR-1 and VEGFR-2 on the cells is higher than that on the normal cerebral microvascular endothelial cells. After treatment with VEGF, numbers of the proliferated and migrated cells, the maximal distance of cell migration and the length and area of capillary-like structures formed in the three-dimensional collagen gel increase significantly. These results demonstrate that expression of VEGFR-1 and VEGFR-2 on CM endothelial cells is up-regulated. By binding to receptors, VEGF may activate the downstream signaling pathways and promote proliferation, migration and tube formation of CM endothelial cells. VEGF/VEGFR signaling pathways play important regulating roles in CM angiogenesis.