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The majority of corticotroph adenomas are benign but some are locally invasive, demonstrate high rates of recurrence, and exhibit a relatively poor response to often repeated surgical, medical, and radiation treatment. Herein, we summarize the currently known somatic and genetic mutations and other molecular factors that influence the pathogenesis of these tumors and discuss currently available therapies. Although recent molecular studies have advanced our understanding of the pathogenesis and behavior of these refractory corticotroph adenomas, these insights do not reliably guide treatment choices at present. Development of additional diagnostic tools and novel tumor-directed therapies that offer efficacious treatment choices for patients with refractory corticotroph adenomas are needed.

BackgroundFK506 binding protein 51 (FKBP5) is a co-chaperone regulator of the glucocorticoid receptor (GR). Recent studies have reported increased FKBP5 mRNA in the circulation from patients with Cushing disease (CD) which returned to comparable levels seen in healthy controls following successful trans-nasal trans-sphenoidal (TNTS) surgical corticotroph tumor removal. However, the expression of circulating FKBP5 mRNA levels in other pituitary tumor subtypes and its specificity to corticotroph tumors is unknown.MethodsPre-operative blood was collected from consecutive patients undergoing TNTS for pituitary tumors (n = 57) at our center between 2015 and 2019. Total RNA was isolated from whole blood using RiboPure blood RNA isolation kit and real-time qPCR was used to quantitate circulating FKBP5 mRNA expression.ResultsConsistent with the prior report, higher circulating FKBP5 mRNA levels were observed in 20 patients with CD prior to surgical tumor removal, compared to 21 healthy controls (p

GH3536 and GH4169 nickel-based superalloys are widely used in aerospace engines and other hot-end components. In this paper，GH3536 and GH4169 alloy samples were fabricated by optimizing the process parameters using selective laser melting（SLM），the defect characteristics and microstructure of two alloys，as well as the effects of different homogenization temperatures and holding times on microstructure evolution，average grain size，and properties of two alloys were studied. The defect characteristics and microstructure were investigated by OM，SEM，and EDS, et al. The Vickers hardness meter was used to test the alloy’s microhardness. The results indicate that the as-built GH3536 alloy exhibits more defects，including pores，cracks，and lack of fusion， while only pores are present in as-built GH4169 alloy. The melt pool of alloy is eliminated by homogenization treatment，and the grains grow into equiaxed grains. M23C6 are found to distribute within grain boundaries and grain interiors of GH3536 alloy，while NbC are found to distribute within grain boundaries and grain interiors of GH4169 alloy，and the amount of precipitates is significantly reduced with the increase of homogenization temperature. The average grain size of GH3536 alloy is increased by 106.8% from 48.5 μm at 1130 ℃/1 h to 100.9 μm at 1250 ℃/4 h . The grain size of GH4169 alloy is increased by 53.3% from 57 μm at 1080 ℃/1 h to 87.4 μm at 1200 ℃/4 h.The homogenization treatment of GH3536 alloy and GH4169 alloy results in a significant decrease in microhardness of the former，from 262HV to 180-190HV，while the latter shows a significant increase，from 313HV to 430-450HV.

ObjectiveProvide insights into the defective POMC processing and invasive behavior in silent pituitary corticotroph tumors.Design and methodsSingle-cell RNAseq was used to compare the cellular makeup and transcriptome of silent and active corticotroph tumors.ResultsA series of transcripts related to hormone processing peptidases and genes involved in the structural organization of secretory vesicles were reduced in silent compared to active corticotroph tumors. Most relevant to their invasive behavior, silent corticotroph tumors exhibited several features of epithelial-to-mesenchymal transition, with increased expression of mesenchymal genes along with the loss of transcripts that regulate hormonal biogenesis and secretion. Silent corticotroph tumor vascular smooth muscle cell and pericyte stromal cell populations also exhibited plasticity in their mesenchymal features.ConclusionsOur findings provide novel insights into the mechanisms of impaired POMC processing and invasion in silent corticotroph tumors and suggest that a common transcriptional reprogramming mechanism simultaneously impairs POMC processing and activates tumor invasion.

Circulating tumor cell (CTC) clusters are present in cancer patients with severe metastasis, resulting in poor clinical outcomes. However, CTC clusters have not been studied as extensively as single CTCs, and the clinical utility of CTC clusters remains largely unknown. In this study, we aim sought to explore the feasibility of NanoVelcro Chips to simultaneously detect both single CTCs and CTC clusters with negligible perturbation to their intrinsic properties in neuroendocrine tumors (NETs). We discovered frequent CTC clusters in patients with advanced NETs and examined their potential roles, together with single NET CTCs, as novel biomarkers of patient response following peptide receptor radionuclide therapy (PRRT). We observed dynamic changes in both total NET CTCs and NET CTC cluster counts in NET patients undergoing PRRT which correlated with clinical outcome. These preliminary findings suggest that CTC clusters, along with single CTCs, offer a potential non-invasive option to monitor the treatment response in NET patients undergoing PRRT.

Neurocytomas are rare low-grade brain tumors predominantly affecting young adults, but their cellular origin and molecular pathogenesis is largely unknown. We previously reported a sellar neurocytoma that secreted excess arginine vasopressin causing syndrome of inappropriate anti-diuretic hormone (SIADH). Whole exome sequencing in 21 neurocytoma tumor tissues identified somatic mutations in the plant homeodomain finger protein 14 (PHF14) in 3/21 (14%) tumors. Of these mutations, two were missense mutations and 4 caused splicing site losses, resulting in PHF14 dysfunction. Employing shRNA-mediated knockdown and CRISPR/Cas9-based knockout approaches, we demonstrated that loss of PHF14 increased proliferation and colony formation in five different human, mouse and rat mesenchymal and differentiated cell lines. Additionally, we demonstrated that PHF14 depletion resulted in upregulation of platelet derived growth factor receptor-alpha (PDGFRα) mRNA and protein in neuroblastoma SHSY-5Y cells and led to increased sensitivity to treatment with the PDGFR inhibitor Sunitinib. Furthermore, in a neurocytoma primary culture harboring splicing loss PHF14 mutations, overexpression of wild-type PHF14 and sunitinib treatment inhibited cell proliferation. Nude mice, inoculated with PHF14 knockout SHSY-5Y cells developed earlier and larger tumors than control cell-inoculated mice and Sunitinib administration caused greater tumor suppression in mice harboring PHF-14 knockout than control SHSY-5Y cells. Altogether our studies identified mutations of PHF14 in 14% of neurocytomas, demonstrate it can serve as an alternative pathway for certain cancerous behavior, and suggest a potential role for Sunitinib treatment in some patients with residual/recurrent neurocytoma.

Purpose: The purpose of this study is to provide an alternative approach to teacher learning on top of the usual practices of listening to experts' lectures and conducting school-based activities among peers in China. A boundary-crossing lesson study (BCLS) through school-university partnership served as an example to illustrate how a class teacher's mindset changed towards her students in equal interactions with university scholars. Design/methodology/approach: With the lenses of action science theory and boundary-crossing learning theory, the study used qualitative research approach to collect and analyze data. One Chinese primary school class teacher from a workshop on narrative action research was selected as the case for this study. Interviewing, observation and document analysis were used to collect data. Data analysis methods included categorization and contextualization of the teacher's mindset change towards her student. Findings: The case teacher, Mrs. Li, collaborated closely in paired teaching with her university partner AP Yu in all the four phases of their BCLS. Each phase was marked with an interactive event such as dialogic illumination, reflexive theorization, embodied conversation, and fusion of teacher and trainer roles. With inspirational trust as a major interactive mechanism, Mrs. Li jumped out of her single-loop learning (changing strategies according to results) to double-loop learning (changing both strategies and values/values). As a result, her mindset changed from attribution to appreciation towards her low-achieving student. Originality/value: This study made contributions in two ways. First, it examined a class teacher's mindset change towards her student, rather than that of subject matter teachers towards their teaching materials and methods. Second, it revealed how reflective interactions in a special kind of BCLS by school teachers and university scholars may promote the teacher's mindset change. The findings further confirm that having differences as boundaries is not enough for teacher learning. For deep learning like Mrs. Li's mindset change, it requires a respectful and inspirational relationship between school teachers and university scholars in the BCLS.

Background: Previous studies have failed to investigate the specific effects of advanced age on survival outcomes by considering the Charlson Comorbidity Index (CCI) and age permutation in patients with T1a renal cell carcinoma (T1a RCC) treated by microwave ablation (MWA). Notably, RCC guidelines recommended radiofrequency ablation (RFA) and active surveillance (AS) are both treatment options for elderly T1a RCC, but whether MWA is superior to AS in light of higher heating efficiency and larger ablation zone compared with RFA is not clear. This study aimed to investigate the specific effects of advanced age on survival outcomes of T1a RCC patients stratified by CCI score and indicate better intervention for elderly T1a RCC between MWA and AS. Methods: This was a retrospective study. We retrospectively reviewed 237 patients with T1a RCC who had undergone MWA over the last 16 years. Data were analyzed by Cox regression and Landmark analysis. Interaction tests and propensity score matching were used to account for potential biases. We compared the overall survival (OS) and cancer-specific survival (CSS) rates of patients ≥75 years in our study with corresponding figures from 4251 counterparts undergoing AS in published articles. Results: Using patients ＜75 years with a CCI ≤2 as a reference, the hazard ratio (HR) and 95% confidence interval (CI) of OS for patients＜75 years with a CCI ≥3, patients ≥75 years with a CCI ≤2, and patients ≥75 years with CCI ≥3, were 2.954 (1.139-7.663), 3.48 (1.487-8.146), and 3.357 (1.162-9.698), respectively. The adverse effect of an age ≥75 years on OS was attenuated in patients with a CCI ≥3. The attenuation lasted for 62.5 months of follow-up (P =.017). Notably, advanced age exerted a protective effect on progression-free survival (PFS) in patients with a CCI ≥3, increasing the 8-year PFS from 67.8% to 100% (P =.049). Relative to 1-, 3-, 5-, and 8-year survival data for patients aged ≥75 undergoing AS, the OS rates for 5-year follow-up were always better in MWA. However, beyond 5 years, the OS rates dropped to levels that were similar to AS. Conclusions: Advanced age exerts adverse effects and significantly protective effects on OS and PFS, respectively, in T1a RCC patients with a CCI ≥ 3. According to our study, elderly patients with T1a RCC underwent radical MWA may yield a better medium-term OS relative to AS. [ABSTRACT FROM AUTHOR]