TNF-α can promote membrane invasion by activating the MAPK/MMP9 signaling pathway through autocrine in bone-invasive pituitary adenoma.

AIMS: A bone-invasive pituitary adenoma exhibits aggressive behavior, leading to a worse prognosis. We have found that TNF-α promotes bone invasion by facilitating the differentiation of osteoclasts, however, before bone-invasive pituitary adenoma invades bone tissue, it needs to penetrate the dura mater, and this mechanism is not yet clear. METHODS: We performed transcriptome microarrays on specimens of bone-invasive pituitary adenomas (BIPAs) and noninvasive pituitary adenomas (NIPAs) and conducted differential expressed gene analysis and enrichment analysis. We altered the expression of TNF-α through plasmids, then validated the effects of TNF-α on GH3 cells and verified the efficacy of the TNF-α inhibitor SPD304. Finally, the effects of TNF-α were validated in in vivo experiments. RESULTS: Pathway act work showed that the MAPK pathway was significantly implicated in the pathway network. The expression of TNF-α, MMP9, and p-p38 is higher in BIPAs than in NIPAs. Overexpression of TNF-α elevated the expression of MAPK pathway proteins and MMP9 in GH3 cells, as well as promoted proliferation, migration, and invasion of GH3 cells. Flow cytometry indicated that TNF-α overexpression increased the G2 phase ratio in GH3 cells and inhibited apoptosis. The expression of MMP9 was reduced after blocking the P38 MAPK pathway; overexpression of MMP9 promoted invasion of GH3 cells. In vivo experiments confirm that the TNF-α overexpression group has larger tumor volumes. SPD304 was able to suppress the effects caused by TNF-α overexpression. CONCLUSION: Bone-invasive pituitary adenoma secretes higher levels of TNF-α, which then acts on itself in an autocrine manner, activating the MAPK pathway and promoting the expression of MMP9, thereby accelerating the membrane invasion process. SPD304 significantly inhibits the effect of TNF-α and may be applied in the clinical treatment of bone-invasive pituitary adenoma.

Three-dimensional chromatin landscapes in somatotroph tumour.

BACKGROUND: The three-dimensional (3D) genome architecture plays a critical role inregulating gene expression. However, the specific alterations in thisarchitecture within somatotroph tumors and their implications for gene expression remain largely unexplored. METHODS: We employed Hi-C and RNA-seq analyses to compare the 3D genomic structures of somatotroph tumors with normal pituitary tissue. This comprehensive approachenabled the characterization of A/B compartments, topologically associateddomains (TADs), and chromatin loops, integrating these with gene expression patterns. RESULTS: We observed a decrease in both the frequency of chromosomal interactions andthe size of TADs in tumor tissue compared to normal tissue. Conversely, the number of TADs and chromatin loops was found to be increased in tumors. Integrated analysis of Hi-C and RNA-seq data demonstrated that changes inhigher-order chromat in structure were associated with alterations in gene expression. Specifically, genes in A compartments showed higher density and increased expression relative to those in B compartments. Moreover, the weakand enhanced insulation boundaries were identified, and the associated genes were enriched in the Wnt/ß-Catenin signaling pathway. We identified the gainedand lost loops in tumor and integrated these differences with transcriptional changes to examine the functional relevance of the identified loops. Notably, we observed an enhanced insulation boundary and a greater number of loops in the TCF7L2 gene region within tumors, which was accompanied by an upregulation of TCF7L2 expression. Subsequently, TCF7L2 expression was confirmed through qRT-PCR, and upregulated TCF7L2 prompted cell proliferation and growth hormone (GH) secretion in vitro. CONCLUSION: Our results provide comprehensive 3D chromatin architecture maps of somatotroph tumors and offer a valuable resource for furthering the understanding of the underlying biology and mechanisms of gene expression regulation.

Butylated hydroxyanisole induces vascular endothelial injury via TFEB-mediated degradation of GPX4 and FTH1.

Butylated hydroxyanisole (BHA) is one of the most commonly used antioxidants and is widely used in food, but whether it causes vascular damage has not been clearly studied. The present study demonstrated for the first time that BHA reduced the viability of human umbilical vein endothelial cells (HUVECs) and mouse brain microvascular endothelial cells (BEND3) in a dose- and time-dependent manner. Moreover, BHA inhibited the migration and proliferation of vascular endothelial cells (ECs). Further analysis revealed that in ECs, the ferroptosis inhibitor ferrostatin-1 (Fer-1) reversed the BHA-induced increase in Fe2+ and malonaldehyde (MDA) levels. Acridine orange staining demonstrated that BHA increased lysosomal permeability. At the protein level, BHA increased the expression of transcription factor EB (TFEB) and decreased the expression of glutathione peroxidase (GPX4), solute carrier family 7 member 11 (SLC7A11, xCT), and ferritin heavy chain 1 (FTH1). Moreover, these effects of BHA could be reversed by knocking down TFEB. In vivo experiments confirmed that BHA caused elevated pulse wave velocity (PWV) and reduced acetylcholine-dependent vascular endothelial diastole. In conclusion, BHA degrades GPX4, xCT, and FTH1 through activation of the TFEB-mediated lysosomal pathway and promotes ferroptosis, ultimately leading to vascular endothelial cell injury.

HSPB1 promotes tumor invasion by inducing angiogenesis in PitNETs.

The clinical diagnosis and treatment of pituitary neuroendocrine tumors (PitNETs) that invade the cavernous sinus are fraught with difficulties and challenges. Exploring the biological characteristics involved in the occurrence and development of PitNETs that invade the cavernous sinus will help to elucidate the mechanism of cavernous sinus invasion. There are differences between intrasellar tumors (IST) and cavernous sinus-invasion tumors (CST) in ultramicrostructure, tumor microenvironment (TME), gene expression, and signaling pathways. The microvascular endothelial cell is increased in CST. The VEGFR signaling pathway, VEGF signaling pathway, and chemokine signaling pathway are activated in CST. HSPB1 is upregulated in CST and promotes cell proliferation, cell viability, and migration. HSPB1 promotes the release of VEGF from GT1-1 cells and activates the VEGF signaling pathway in bEnd.3 cells. HSPB1 promotes the migration of bEnd.3 cells to GT1-1 cells and promotes the formation of blood vessels of bEnd.3 cells. bEnd.3 cells can release CCL3 and CCL4 and promote the vitality, proliferation, and migration of GT1-1 cells. HSPB1 promotes the formation of blood vessels of bEnd.3 cells and ultimately leads to tumor growth in vivo. HSPB1 acts as a key gene for invasion of the cavernous sinus in PitNETs, remodeling TME by promoting the formation of blood vessels of brain microvascular endothelial cells. The synergistic effect of tumor cells and microvascular endothelial cells promotes tumor progression. The mechanism by which HSPB1 promotes tumor invasion by inducing angiogenesis in PitNETs may be a new target for the treatment of PitNETs invading the cavernous sinus.

Phosphorylation of PBK at Thr9 by CDK5 correlates with invasion of prolactinomas.

CONTEXT: Prolactinomas are the most prevalent functional pituitary neuroendocrine tumors (PitNETs), and they are invasive to surrounding anatomic structures. The detailed mechanisms of invasion are not yet clear. OBJECTIVE: We explored the role of PBK phosphorylation in the proliferation and invasion of prolactinomas and its possible mechanism. RESULTS: We report that PBK directly binds to and is phosphorylated at Thr9 by cyclin-dependent kinase 5 (CDK5), which promotes GH3 cell EMT progression and proliferation. Phosphorylation of PBK at Thr9 (pPBK-T9) by CDK5 enhances the stability of PBK. p38 is one of the downstream targets of PBK, and its phosphorylation is reduced as pPBK-T9 increases in vivo and in vitro. Furthermore, we found that pPBK-T9 is highly expressed in invasive PitNETs and was significantly correlated with invasion by univariate and multivariate analyses. CONCLUSIONS: Phosphorylation of PBK at Thr9 by CDK5 promotes cell proliferation and EMT progression in prolactinomas.

Drug resistance mechanisms in dopamine agonist-resistant prolactin pituitary neuroendocrine tumors and exploration for new drugs.

BACKGROUND: The treatment of dopamine agonists (DA) resistant prolactinomas remains a formidable challenge, as the mechanism of resistance is still unclear, and there are currently no viable alternative drug therapies available. This study seeks to investigate the mechanism of DA resistance in prolactinomas and identify new potentially effective drugs. METHODS: To explore the mechanism of DA resistance in prolactinomas, this study conducted transcriptome sequencing analysis on 27 cases of DA-resistant prolactinomas and 10 cases of sensitive prolactinomas. In addition, single-cell sequencing analysis was performed on 3 cases of DA-resistant prolactinomas and 3 cases of sensitive prolactinomas. Furthermore, to screen for potential therapeutic drugs, the study successfully established an organoids model for DA-resistant prolactinomas and screened 180 small molecule compounds using 8 organoids. The efficacy of the identified drugs was verified through various assays, including CCK-8, colony formation, CTG, and flow cytometry, and their mechanisms of action were confirmed through WB and IHC. The effectiveness of the identified drugs was evaluated both in vitro and in vivo. RESULTS: The results of transcriptome sequencing and single-cell sequencing analyses showed that DA resistance in prolactinomas is associated with the upregulation of the Focal Adhesion (FA) signaling pathway. Additionally, immunohistochemical validation revealed that FAK and Paxillin were significantly upregulated in DA-resistant prolactinomas. Screening of 180 small molecule compounds using 8 organoids identified Genistein as a potentially effective drug for DA-resistant prolactinomas. Experimental validation demonstrated that Genistein inhibited the proliferation of pituitary tumor cell lines and organoids and promoted apoptosis in pituitary tumor cells. Moreover, both the cell sequencing results and WB validation results of the drug-treated cells indicated that Genistein exerts its anti-tumor effect by inhibiting the FA pathway. In vivo, experiments also showed that Genistein can inhibit subcutaneous tumor formation. CONCLUSION: DA resistance in prolactinomas is associated with upregulation of the Focal Adhesion (FA) signaling pathway, and Genistein can exert its anti-tumor effect by inhibiting the expression of the FA pathway.

Single-cell transcriptomic analysis reveals tumor cell heterogeneity and immune microenvironment features of pituitary neuroendocrine tumors.

BACKGROUND: Pituitary neuroendocrine tumors (PitNETs) are one of the most common types of intracranial tumors. Currently, the cellular characteristics of normal pituitary and various other types of PitNETs are still not completely understood. METHODS: We performed single-cell RNA sequencing (scRNA-seq) on 4 normal samples and 24 PitNET samples for comprehensive bioinformatics analysis. Findings regarding the function of PBK in the aggressive tumor cells were validated by siRNA knockdown, overexpression, and transwell experiments. RESULTS: We first constructed a reference cell atlas of the human pituitary. Subsequent scRNA-seq analysis of PitNET samples, representing major tumor subtypes, shed light on the intrinsic cellular heterogeneities of the tumor cells and tumor microenvironment (TME). We found that the expression of hormone-encoding genes defined the major variations of the PIT1-lineage tumor cell transcriptomic heterogeneities. A sub-population of TPIT-lineage tumor cells highly expressing GZMK suggested a novel subtype of corticotroph tumors. In immune cells, we found two clusters of tumor-associated macrophages, which were both highly enriched in PitNETs but with distinct functional characteristics. In PitNETs, the stress response pathway was significantly activated in T cells. While a majority of these tumors are benign, our study unveils a common existence of aggressive tumor cells in the studied samples, which highly express a set of malignant signature genes. The following functional experiments confirmed the oncogenic role of selected up-regulated genes. The over-expression of PBK could promote both tumor cell proliferation and migration, and it was also significantly associated with poor prognosis in PitNET patients. CONCLUSIONS: Our data and analysis manifested the basic cell types in the normal pituitary and inherent heterogeneity of PitNETs, identified several features of the tumor immune microenvironments, and found a novel epithelial cell sub-population with aggressive signatures across all the studied cases.

Risk factors for cerebrospinal fluid leak after extended endoscopic endonasal surgery for adult patients with craniopharyngiomas: a multivariate analysis of 364 cases.

OBJECTIVE: Over the last decade, the extended endoscopic endonasal approach (EEEA) has evolved as a credible surgical alternative for removing craniopharyngiomas. However, postoperative cerebrospinal fluid (CSF) leak remains one of the most pressing concerns. Craniopharyngiomas often invade the third ventricle, resulting in a higher rate of third ventricle opening after surgery and potentially increasing the risk of postoperative CSF leak. Identifying the risk factors associated with CSF leak after EEEA for craniopharyngiomas may have more clinical value. Nevertheless, there is a lack of systematic studies on the topic. Previous studies yielded inconsistent results, probably due to heterogeneous pathologies or small sample sizes. Hence, the authors present the largest known single-institution case series of the use of purely EEEA for craniopharyngiomas to systematically study the risk factors for postoperative CSF leak. METHODS: The authors retrospectively reviewed 364 cases of adult patients with craniopharyngiomas who were treated at their institution from January 2019 to August 2022, and they analyzed the risk factors for postoperative CSF leak. RESULTS: The overall rate of postoperative CSF leak was 4.7%. In the univariate analysis, larger dural defect size (OR 8.293, 95% CI 3.711-18.534, p < 0.001) and lower preoperative serum albumin level (OR 0.812, 95% CI 0.710-0.928, p = 0.002) were associated with higher rates of postoperative CSF leak. Predominantly cystic tumors (OR 0.325, 95% CI 0.122-0.869, p = 0.025) were linked to decreased risk of postoperative CSF leak. However, postoperative lumbar drainage (OR 2.587, 95% CI 0.580-11.537, p = 0.213) and third ventricle opening (OR 1.718, 95% CI 0.548-5.384, p = 0.353) were not related to postoperative CSF leak. In the multivariate analysis, larger dural defect size (OR 8.545, 95% CI 3.684-19.821, p < 0.001) and lower preoperative serum albumin level (OR 0.787, 95% CI 0.673-0.919, p = 0.002) were identified as independent risk factors for postoperative CSF leak. CONCLUSIONS: The authors' repair technique yielded a reliable reconstructive outcome for high-flow CSF leak in EEEA for craniopharyngioma. Lower preoperative serum albumin level and larger dural defect size were identified as independent risk factors for postoperative CSF leak, potentially providing new insights into minimizing the risk of postoperative CSF leak. Third ventricle opening was not associated with postoperative CSF leak. Lumbar drainage may not be necessary for high-flow intraoperative leak, but this finding may require validation with a prospective randomized controlled trial in the future.

MiR-320a Acts as a Tumor Suppressor in Somatotroph Pituitary Neuroendocrine Tumors by Targeting BCAT1.

INTRODUCTION: Aberrant miR-320a has been reported to be involved in the tumorigenesis of several cancers. In our previous study, we identified the low expression of circulating miR-320a in patients with somatotroph pituitary neuroendocrine tumor (PitNET); however, the role of miR-320a in somatotroph PitNET proliferation is still unclear. METHODS: Cell viability and colony formation assays were used to detect the effect of miR-320a and BCAT1 on GH3 cells. TargetScan was used to identify the target genes of miR-320a. Dual-luciferase reporter gene assay was used to explore the relation between miR-320a and BCAT1. Transcriptome and proteome analyses were performed between somatotroph PitNETs and healthy controls. The expression level of miR-320a in somatotroph PitNETs were detected by RT-qPCR and Western blot. RESULTS: miR-320a mimics inhibit cell proliferation, while miR-320a inhibitors promote cell proliferation in GH3 cells. An overlap analysis using a Venn diagram revealed that BCAT1 is the only target gene of miR-320a overexpressed in somatotroph PitNETs compared to healthy controls, as revealed by both microarray and proteomics results. A dual-luciferase reporter gene assay showed that miR-320a may bind to the BCAT1-3'UTR. The transfection of miR-320a mimics downregulated the expression and miR-320a inhibitors and upregulated the expression of BCAT1 in GH3 cells. The interference of BCAT1 expression in GH3 cells downregulated cell proliferation and growth. Pan-cancer analyses demonstrated that high BCAT1 expression often indicates a poor prognosis. CONCLUSION: Our findings illustrate that miR-320a may function as a tumor suppressor and BCAT1 may promote tumor progression. miR-320a may inhibit the growth of somatotroph PitNETs by targeting BCAT1.

Metformin inhibits cell proliferation and ACTH secretion in AtT20 cells via regulating the MAPK pathway.

We investigated the impact of metformin on ACTH secretion and tumorigenesis in pituitary corticotroph tumors. The mouse pituitary tumor AtT20 cell line was treated with varying concentrations of metformin. Cell viability was assessed using the CCK-8 assay, ACTH secretion was measured using an ELISA kit, changes in the cell cycle were analyzed using flow cytometry, and the expression of related proteins was evaluated using western blotting. RNA sequencing was performed on metformin-treated cells. Additionally, an in vivo BALB/c nude xenograft tumor model was established in nude mice, and immunohistochemical staining was conducted for further verification. Following metformin treatment, cell proliferation was inhibited, ACTH secretion decreased, and G1/S phase arrest occurred. Analysis of differentially expressed genes revealed cancer-related pathways, including the MAPK pathway. Western blotting confirmed a decrease in phosphorylated ERK1/2 and phosphorylated JNK. Combining metformin with the ERK1/2 inhibitor Ulixertinib resulted in a stronger inhibitory effect on cell proliferation and POMC (Precursors of ACTH) expression. In vivo studies confirmed that metformin inhibited tumor growth and reduced ACTH secretion. In conclusion, metformin inhibits tumor progression and ACTH secretion, potentially through suppression of the MAPK pathway in AtT20 cell lines. These findings suggest metformin as a potential drug for the treatment of Cushing's disease.

PitNETs and the gut microbiota: potential connections, future directions.

The role of the gut microbiome has been widely discussed in numerous works of literature. The biggest concern is the association of the gut microbiome with the central nervous system through the microbiome-brain-gut axis in the past ten years. As more and more research has been done on the relationship between the disease of the central nervous system and gut microbes. This fact is being revealed that gut microbes seem to play an important role from the onset and progression of the disease to clinical symptoms, and new treatments. As a special tumor of the central nervous system, pituitary neuroendocrine tumors (PitNETs)are closely related to metabolism, endocrinology, and immunity. These factors are the vectors through which intestinal microbes interact with the central nervous system. However, little is known about the effects of gut microbes on the PitNET. In this review, the relationship of gut microbiota in PitNETs is introduced, the potential effects of the gut-brain axis in this relationship are analyzed, and future research directions are presented.

Correlations between the expression of molecules in the TGF-ß signaling pathway and clinical factors in adamantinomatous craniopharyngiomas.

Objective: To investigate the clinical and pathological factors associated with preoperative hypothalamus invasion and postoperative outcomes of adamantinomatous craniopharyngiomas (ACPs) after the expanded endonasal approach (EEA) resection. Methods: Ninety-three specimens of ACPs, consisting of 71 primary and 22 recurrent tumors, were investigated for the expression of TGF-ß1, SMAD2, SMAD3, and ß-catenin by immunohistochemistry staining. The clinical information of relevant patients, including the extent of resection, hypothalamus invasion, endocrinopathy, complications, and prognosis, was reviewed. The relationships between the expression of these immunopathological markers and clinical factors were analyzed. Results: Endocrinological dysfunctions were more common in recurrent patients and primary patients with hypothalamus invasion in the comparisons. For recurrent patients, the rate of gross total resection (GTR) was significantly lower than for primary patients (63.6% vs. 90.1%, P = 0.007). According to radiological and intraoperative findings, invasive ACPs (IACPs) included 48 (67.6%) cases in primary tumors. The expression of TGF-ß1 and ß-catenin was significantly higher in recurrent tumors (P = 0.021 and P = 0.018, respectively) and IACPs (P = 0.008 and P = 0.004, respectively). The expression level of TGF-ß1 was associated with hypothalamus involvement (Puget grade, P = 0.05; Vile grade, P = 0.002), postoperative endocrinopathy (P = 0.01), and pituitary stalk preservation (P = 0.008) in primary patients. In addition, the extent of resection, treatment history, hypothalamic invasion, and level of TGF-ß1 expression had significant influences on tumor recurrence/progression after surgery separately. Conclusion: Our study demonstrated the potential role of TGF-ß1 in the regulation of hypothalamus invasion in ACPs and the prediction of prognosis after EEA surgery. The TGF-ß signaling pathway may represent a crucial mechanism in the aggressive behavior and progression of ACPs.

Identification of biomarkers associated with the invasion of nonfunctional pituitary neuroendocrine tumors based on the immune microenvironment.

Introduction: The invasive behavior of nonfunctioning pituitary neuroendocrine tumors (NF-PitNEts) affects complete resection and indicates a poor prognosis. Cancer immunotherapy has been experimentally used for the treatment of many tumors, including pituitary tumors. The current study aimed to screen the key immune-related genes in NF-PitNEts with invasion. Methods: We used two cohorts to explore novel biomarkers in NF-PitNEts. The immune infiltration-associated differentially expressed genes (DEGs) were obtained based on high/low immune scores, which were calculated through the ESTIMATE algorithm. The abundance of immune cells was predicted using the ImmuCellAI database. WGCNA was used to construct a coexpression network of immune cell-related genes. Random forest analysis was used to select the candidate genes associated with invasion. The expression of key genes was verified in external validation set using quantitative real-time polymerase chain reaction (qRT‒PCR). Results: The immune and invasion related DEGs was obtained based on the first dataset of NF-PitNEts (n=112). The immune cell-associated modules in NF-PitNEts were calculate by WGCNA. Random forest analysis was performed on 81 common genes intersected by immune-related genes, invasion-related genes, and module genes. Then, 20 of these genes with the highest RF score were selected to construct the invasion and immune-associated classification model. We found that this model had high prediction accuracy for tumor invasion, which had the largest area under the receiver operating characteristic curve (AUC) value in the training dataset from the first dataset (n=78), the self-test dataset from the first dataset (n=34), and the independent test dataset (n=73) (AUC=0.732/0.653/0.619). Functional enrichment analysis revealed that 8 out of the 20 genes were enriched in multiple signaling pathways. Subsequently, the 8-gene (BMP6, CIB2, FABP5, HOMER2, MAML3, NIN, PRKG2 and SIDT2) classification model was constructed and showed good efficiency in the first dataset (AUC=0.671). In addition, the expression levels of these 8 genes were verified by qRT‒PCR. Conclusion: We identified eight key genes associated with invasion and immunity in NF-PitNEts that may play a fundamental role in invasive progression and may provide novel potential immunotherapy targets for NF-PitNEts.

Characteristics and factors influencing hypothalamic pituitary dysfunction in patients with craniopharyngioma.

Background: Craniopharyngioma is a benign tumor originating from the sellar region. Damages in this area caused by the tumor itself, surgery, or radiotherapy may result in severe hypothalamic-pituitary dysfunction (HPD) and eventually lead to a significant impairment in the long-term quality of life of patients. This study aimed to investigate the characteristics of HPD in patients with adamantinomatous craniopharyngioma (ACP) or papillary craniopharyngioma (PCP) and to identify the factors affecting HPD after surgery. Methods: In this single-center retrospective study, a total of 742 patients with craniopharyngioma were included. The neuroendocrine function of these patients before and after surgery was investigated. The differences in hypothalamic-pituitary function between the ACP and PCP groups were compared. The factors influencing the aggravation of HPD after surgery were identified. Results: The median follow-up after surgery was 15 months. Before surgery, the proportion of patients with diabetes insipidus (DI) and hyperprolactinemia in the PCP group was significantly higher than that in the ACP group (P<0.01), and the proportion of patients with adrenocortical hypofunction in the PCP group was significantly lower than that in the ACP group (P=0.03). Most cases of ACP originated in the sellar region, while most cases of PCP originated in the suprasellar region (P<0.01). More patients experienced adenohypophyseal hypofunction, DI, and hypothalamic obesity at postoperative follow-up than at onset in both the ACP and PCP groups (both P<0.01), with a higher increase observed in the ACP group (P<0.01). Older age at CP onset, tumor recurrence or progression, and ACP type were risk factors for postoperative aggravation of HPD in CP patients. Conclusion: Surgical treatment significantly aggravated HPD in both the ACP and PCP groups, but the specific characteristics and risk factors leading to aggravation were different between the two groups.

Effects of elevated ozone and carbon dioxide on the dynamic photosynthesis of Fagus crenata seedlings under variable light conditions.

Ozone (O3) is an air pollutant that is toxic to trees. O3 reduces steady-state net photosynthetic rate (A), and the adverse effects of O3 are mitigated under elevated CO2 condition. However, the combined effects of O3 and elevated CO2 on dynamic photosynthesis under variable light conditions have not yet been clarified. In this study, we investigated the effects of O3 and elevated CO2 on dynamic photosynthesis in the leaves of Fagus crenata seedlings under variable light conditions. The seedlings were grown under four gas treatments comprising two levels of O3 concentration (lower and two times higher than the ambient O3 concentration) and two levels of CO2 concentration (ambient and 700 ppm). Although O3 significantly decreased steady-state A under ambient CO2 concentrations, no significant decrease was observed under elevated CO2 concentrations, indicating the mitigating effect of elevated CO2 on O3-induced adverse effects on steady-state A. During photosynthetic induction, the response of A to the change in photosynthetic photon flux density (PPFD) from 50 (low light) to 1000 µmol m-2 s-1 (high light) showed that the increase in A was slowed by O3 and accelerated by elevated CO2. Under fluctuating light condition of repeating low light for 4 min and high light for 1 min, A at end of each high light period gradually decreased in all treatments, and O3 and elevated CO2 accelerated the reduction of A. In contrast to steady-state A, no mitigating effect of elevated CO2 was observed for any parameters related to dynamic photosynthesis. We conclude that the combined effects of O3 and elevated CO2 on A of F. crenata are different under steady-state and variable light conditions, and the O3-induced decrease in leaf A may not be mitigated by elevated CO2 in the field under variable light conditions.

Analysis of the Prognostic and Immunological Role of HSPB1 in Pituitary Adenoma: A Potential Target for Therapy.

Background and Objectives: The diagnosis and treatment of pituitary adenomas with cavernous sinus invasion pose significant challenges for clinicians. The objective of this study is to investigate the expression profile and prognostic value of HSPB1 (heat shock protein beta-1) in pituitary adenomas with invasive and non-invasive features. Additionally, we aim to explore the potential relationship between HSPB1 expression and immunological functions in pituitary adenoma. Materials and Methods: A total of 159 pituitary adenoma specimens (73 invasive tumours and 86 non-invasive tumours) underwent whole-transcriptome sequencing. Differentially expressed genes and pathways in invasive and non-invasive tumours were analysed. HSPB1 was subjected to adequate bioinformatics analysis using various databases such as TIMER, Xiantao and TISIDB. We investigated the correlation between HSPB1 expression and immune infiltration in cancers and predicted the target drug of HSPB1 using the TISIDB database. Results: HSPB1 expression was upregulated in invasive pituitary adenomas and affected immune cell infiltration. HSPB1 was significantly highly expressed in most tumours compared to normal tissues. High expression of HSPB1 was significantly associated with poorer overall survival. HSPB1 was involved in the regulation of the immune system in most cancers. The drugs DB11638, DB06094 and DB12695 could act as inhibitors of HSPB1. Conclusions: HSPB1 may serve as an important marker for invasive pituitary adenomas and promote tumour progression by modulating the immune system. Inhibitors of HSPB1 expression are currently available, making it a potential target for therapy in invasive pituitary adenoma.

Emotional Problems, Quality of Life and Symptom Burden in Patients with Chordoma.

Chordomas are very rare malignant bone tumors. Following surgery, their effects on neurological, physical, psychological, social, and emotional functioning are substantial and can have a major impact on a patients' quality of life (QOL). In this survey, we aimed to characterize the postoperation health-related QOL and emotional problem in patients with chordoma using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire 30 (EORTC QLQ-C30) and Hamilton Depression Rating Scale (HAMD). The cohort included 100 patients who underwent resection surgery between 2014 and 2020. Being single or divorced, living in a rural area, receiving a diagnosis of sacrococcygeal chordoma, Karnofsky performance status (KPS) ≤ 70, and weight loss were associated with increased likelihood of depression (p < 0.05). Patients who were single or divorced, with KPS ≤ 70, and experiencing weight loss had a higher likelihood of a worse QOL (p < 0.05). The uni- and multivariate logistic regression analyses indicated that the KPS level (p = 0.000) and postoperative radiation therapy (p = 0.009) were related to depression; marital status (p = 0.029), KPS level (p = 0.006), and tumor location (p = 0.033) were related to worse QOL. Certain characteristics placed patients with chordoma at increased risk of emotional problems, which are associated with a lowered QOL and a higher symptom burden. Further knowledge regarding emotional problems is key to improving the QOL for patients with chordoma.

The effect of endoscopic transsphenoidal somatotroph tumors resection on pituitary hormones: systematic review and meta-analysis.

PURPOSE: Currently, endoscopic transsphenoidal surgery is the main treatment for pituitary neuroendocrine tumors (PitNETs). Excision of the tumor may have positive or negative effects on pituitary endocrine function, and the pituitary function of somatotroph tumors is a point of particular concern after the operation. This study aimed to conduct a meta-analysis on the effect of endoscopic transsphenoidal somatotroph tumor resection on pituitary function. METHODS: A systematic literature search was conducted for articles that included the evaluation of pituitary target gland before and after endoscopic transsphenoidal pituitary tumor resection and were published between 1992 and 2022 in PubMed, Cochrane, and Ovid MEDLINE. RESULTS: Sixty-eight studies that included biochemical remission rates in 4524 somatotroph tumors were concluded. According to the 2000 consensus, the biochemical remission rate after transsphenoidal endoscopic surgery was 66.4% (95% CI, 0.622-0.703; P = 0.000), the biochemical remission rate was 56.2% according to the 2010 consensus (95% CI, 0.503-0.620; P = 0.041), and with the rate of biochemical remission ranging from 30.0 to 91.7% with investigator's definition. After endoscopic resection, adrenal axis dysfunction was slightly higher than that before surgery, but the difference was not statistically significant. Hypothyroidism was 0.712 times higher risk than that before surgery (OR = 0.712; 95% CI, 0.527-0.961; P = 0.027). Hypogonadism was 0.541 times higher risk than that before surgery (OR = 0.541; 95% CI, 0.393-0.746; P = 0.000). Hyperprolactinemia was 0.131 times higher risk than that before surgery (OR = 0.131; 95% CI, 0.022-0.783; P = 0.026). The incidence of pituitary insufficiency was 1.344 times the risk before surgery after endoscopic resection of somatotroph tumors, but the difference was not statistically significant. CONCLUSIONS: In patients with somatotroph tumors after undergoing endoscopic surgery, the risk of dysfunction and pituitary insufficiency tend to increase, while preoperative thyroid insufficiency, gonadal insufficiency, and hyperprolactinemia will be partially relieved.