Chordoma: Genetics and Contemporary Management.

Chordomas, arising from notochord remnants, are rare neoplasms with aggressive growth patterns despite their histologically low-grade nature. This review explores their embryological origins, molecular markers like brachyury, and genetic alterations driving pathogenesis. Diagnosis relies on advanced imaging and biopsy confirmation due to overlapping features with chondrosarcoma. The WHO classification distinguishes conventional, dedifferentiated, and poorly differentiated chordomas, each with distinct prognostic implications. Recent genomic analyses uncovered recurrent mutations in PI3K signaling pathways and chromatin remodeling genes, informing prognostic models. Surgery remains the cornerstone of treatment, though adjuvant radiation complements surgical resection. Although chordomas are generally considered refractory to medical therapy, emerging targeted molecular strategies show potential promise in ongoing trials. This review aims to provide a concise yet comprehensive overview of chordomas, guiding clinicians in diagnosis, treatment, and prognostication for improved patient outcomes.

Clinical Research Primer for Medical Students: Overview and Illustrative Experiences.

Background The ability to participate in clinical scholarship is a foundational component of modern evidence-based medical practice, empowering improvement across essentially every aspect of clinical care. In tandem, the need for comprehensive exposure to clinical research has been identified as a critical component of medical student training and preparation for residency that is underserved by traditional undergraduate medical education models. The goal of the current work was to provide guidelines and recommendations to assist novice medical students in taking ownership of their research education. Methods The Clinical Research Primer was composed from pooled research documents compiled by the study authors and our institutional neurosurgery student research group. The Primer was then structured as the natural evolution of a research project from its inception through the submission process. Results We divided the foundational components of the Clinical Research Primer into seven domains, each representing a landmark in the development of a peer-reviewed study, and a set of skills critical for junior scholars to develop. These vital components included the following: pitching and designing clinical studies, developing a research workflow, navigating the Institutional Review Board, data collection and analysis, manuscript writing and editing, submission mechanics, and tracking research projects for career development. Conclusion We anticipate that the tools included in the Clinical Research Primer will increase student research productivity and preparedness for residency. Although our recommendations are informed by our experiences within neurosurgery, they have been written in a manner that should generalize to almost any field of clinical study.

Mixed Continuous and Categorical Flow Matching for 3D De Novo Molecule Generation.

Deep generative models that produce novel molecular structures have the potential to facilitate chemical discovery. Diffusion models currently achieve state of the art performance for 3D molecule generation. In this work, we explore the use of flow matching, a recently proposed generative modeling framework that generalizes diffusion models, for the task of de novo molecule generation. Flow matching provides flexibility in model design; however, the framework is predicated on the assumption of continuously-valued data. 3D de novo molecule generation requires jointly sampling continuous and categorical variables such as atom position and atom type. We extend the flow matching framework to categorical data by constructing flows that are constrained to exist on a continuous representation of categorical data known as the probability simplex. We call this extension SimplexFlow. We explore the use of SimplexFlow for de novo molecule generation. However, we find that, in practice, a simpler approach that makes no accommodations for the categorical nature of the data yields equivalent or superior performance. As a result of these experiments, we present FlowMol, a flow matching model for 3D de novo generative model that achieves improved performance over prior flow matching methods, and we raise important questions about the design of prior distributions for achieving strong performance in flow matching models. Code and trained models for reproducing this work are available at https://github.com/dunni3/FlowMol.

Accelerating Inference in Molecular Diffusion Models with Latent Representations of Protein Structure.

Diffusion generative models have emerged as a powerful framework for addressing problems in structural biology and structure-based drug design. These models operate directly on 3D molecular structures. Due to the unfavorable scaling of graph neural networks (GNNs) with graph size as well as the relatively slow inference speeds inherent to diffusion models, many existing molecular diffusion models rely on coarse-grained representations of protein structure to make training and inference feasible. However, such coarse-grained representations discard essential information for modeling molecular interactions and impair the quality of generated structures. In this work, we present a novel GNN-based architecture for learning latent representations of molecular structure. When trained end-to-end with a diffusion model for de novo ligand design, our model achieves comparable performance to one with an all-atom protein representation while exhibiting a 3-fold reduction in inference time.

The experience of caregiving for adults with benign brain tumors: An integrative review.

Background: Caregiving for the adult benign brain tumor (aBBT) population is unique, as patients' extended period of survivorship poses significant challenges related to the long-term sequelae of the disease and the foreboding possibility of recurrence. In this integrative review, we examined the caregiving experience across the spectrum of the aBBT population. Methods: We searched OVID, CINAHL, and PubMed databases from 2000 to 2022. We included studies primarily focused on caregivers of aBBT and written in English. Results: Among 594 papers identified in the initial review, we included a final list of 7 papers. Among these 7 papers, 5 central themes emerged. First, we identified a theme surrounding psychosocial and emotional needs, which included the social isolation of caregiving. The second theme related to informational care needs, including what is considered to be the normal course of recovery after surgery. The third theme focused on access to services, including specialist neurosurgical care, and the fourth theme related to financial strain and the economic burdens associated with long-term follow-up. Lastly, we found a theme surrounding family role changes, which included the shift from spouse to caregiver. Conclusions: In this review, we identified themes highlighting similarities to the high-grade glioma population. However, we uncovered distinct differences in terms of caregiver characteristics, length of survivorship, and the burden of caregiving over time. Collectively, our findings underscore the incomplete understanding of the caregiving experience across the spectrum of the aBBT population.

Meningioma: International Consortium on Meningiomas (ICOM) consensus review on scientific advances & treatment paradigms for clinicians, researchers, and patients.

Meningiomas are the most common primary intracranial tumors in adults and are increasing in incidence due to the aging population and the rising availability of neuroimaging. While most exhibit non-malignant behaviour, a subset of meningiomas are biologically aggressive and lead to significant neurological morbidity and mortality. In recent years, meaningful advances in our understanding of the biology of these tumors have led to the incorporation of molecular biomarkers into their grading and prognostication. However, unlike other central nervous system tumors, a unified molecular taxonomy for meningiomas has not yet been established and remains an overarching goal of the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy-Not Official WHO (cIMPACT-NOW) working group. There also remains clinical equipoise on how specific meningioma cases and patient populations should be optimally managed. To address these existing gaps, members of the International Consortium on Meningiomas (ICOM) including field-leading experts, have prepared a comprehensive consensus narrative review directed towards clinicians, researchers, and patients. Included in this manuscript are detailed overviews of proposed molecular classifications, novel biomarkers, contemporary treatment strategies, trials on systemic therapies, health-related quality of life studies, and management strategies for unique meningioma patient populations. In each section we discuss the current state of knowledge as well as ongoing clinical and research challenges to road map future directions for further investigation.

Improved optic nerve visualization and treatment planning through a dedicated optic nerve MRI protocol.

OBJECTIVE: This study describes an innovative optic nerve MRI protocol for better delineating optic nerve anatomy from neighboring pathology. METHODS: Twenty-two patients undergoing MRI examination of the optic nerve with the dedicated protocol were identified and included for analysis of imaging, surgical strategy, and outcomes. T2-weighted and fat-suppressed T1-weighted gadolinium-enhanced images were acquired perpendicular and parallel to the long axis of the optic nerve to achieve en face and in-line views along the course of the nerve. RESULTS: Dedicated optic nerve MRI sequences provided enhanced visualization of the nerve, CSF within the nerve sheath, and local pathology. Optic nerve sequences leveraged the "CSF ring" within the optic nerve sheath to create contrast between pathology and normal tissue, highlighting areas of compression. Tumor was readily tracked along the longitudinal axis of the nerve by images obtained parallel to the nerve. The findings augmented treatment planning. CONCLUSIONS: The authors present a dedicated optic nerve MRI protocol that is simple to use and affords improved cross-sectional and longitudinal visualization of the nerve, surrounding CSF, and pathology. This improved visualization enhances radiological evaluation and treatment planning for optic nerve lesions.

Genetically Distinct Oligosarcoma Arising from Oligodendroglioma: Systematic Review & Illustrative Case Example.

BACKGROUND: Oligosarcoma is a rare central nervous system (CNS) neoplasm that may arise following oligodendroglioma resection, which demonstrates a unique genetic profile and aggressive clinical phenotype. We present a systematic review and illustrative case example emphasizing the clinical and prognostic features of this unusual and unfavorable neuro-oncologic disease. METHODS: Systematic literature review and illustrative case report. RESULTS: A 41-year-old man who had undergone 2 neurosurgical resections for a World Health Organization grade II oligodendroglioma (Ki-67 = 5-10%, 1p/19q codeleted, IDH2 mutated), without adjuvant chemoradiation, presented with seizures seven years after resection. An extra-axial mass was identified adjacent to the resection cavity, in which gross total resection was achieved. Pathology confirmed World Health Organization grade IV oligosarcoma (Ki-67 = 20%). Adjuvant chemoradiation was initiated, with disease control observed over 6 months of follow-up. Seven publications met inclusion criteria. Oligosarcoma has been confirmed in 36 lesions, arising in 35 patients; 5 were primary oligosarcoma, while 31 occurred in the setting of prior resected oligodendroglioma or oligoastrocytoma. Features shared by these lesions include regain of H3K27me3 expression, 1p/19q codeletion, homozygous deletion of CDKN2A/B, loss of 6q, loss of NF1 and YAP1, and attenuation of CpG island methylator. Median survival after oligosarcoma diagnosis was 1.3 years (range, 0-5.2; n = 35). CONCLUSIONS: Oligosarcoma is a prognostically unfavorable CNS neoplasm with characteristic imaging and pathologic features, and a strong association with previously resected oligodendroglioma. Aggressive treatment is recommended, including gross total resection and adjuvant chemoradiation. Further study is required to define optimal treatment protocol for this CNS malignancy.

Dialysis disequilibrium syndrome in neurosurgery: literature review and illustrative case example.

INTRODUCTION: The dialysis disequilibrium syndrome (DDS) is a complication in those undergoing dialysis for chronic kidney disease (CKD) or acute kidney injury (AKI), characterized by nonspecific symptoms that may progress to coma and death secondary to cerebral edema. This syndrome is associated with rapid change in electrolytes during dialysis with changes in intracranial pressure (ICP) and may have a higher incidence in the elderly neurosurgical patient population. METHODS: Literature review and illustrative case example. RESULTS: A 62-year-old female presented with acute mental status change during hemodialysis (HD), with a history of a nonsurgical acute subdural hematoma (SDH) 10 days prior. Imaging showed a conversion of the acute SDH to chronic SDH of 12.2 mm in size with a 14.1 midline shift, for which she underwent a hemicraniectomy with SDH evacuation, with a gradual return to baseline. The literature review identified 5 publications meeting the inclusion criteria. Major theories of DDS include a reverse urea effect, intracerebral acidosis, idiogenic osmoles, and local inflammation. This complication may occur more frequently in the elderly neurosurgical patient population, likely due to age-related comorbidities, preexisting neurological insult, and increased permeability of the blood-brain barrier (BBB), leading to cerebral edema. CONCLUSION: DDS is a rare and potentially fatal complication of HD that may have a higher incidence in the elderly neurosurgical patient population, yet remains to be fully understood. Further study is recommended to characterize the pathophysiological mechanism and incidence of DDS in neurosurgical patients.

Post-pandemic paradigm shift toward telemedicine and tele-education; an updated survey of the impact of Covid-19 pandemic on neurosurgery residents in United States.

Background: Several strategies were implemented during the Covid-19 pandemic to enhance residency training and patient care. Objective: This study aims to assess the post-pandemic landscape of neurosurgical training and practice. Method: A survey consisting of 28 questions examining the challenges faced in neurosurgery and the adaptive measures was conducted among US neurosurgery residents from May 2022 to May 2023. Results: This study encompassed 59 neurosurgical residents, predominantly male (72.9%) and in later years of training (66.1%) and were distributed across 25 states. Telemedicine and tele-education were pivotal during the pandemic, with virtual lecture series, standalone lectures, and virtual discussions highly favored. Remote didactic learning increased for nearly half of the residents, while 54.2% resumed in-person instruction. Telemedicine was deemed effective by 86.4% for evaluating neurosurgical patients. Access to teaching environments was restricted for 61.0% of residents, impacting their training. The pandemic significantly influenced elective surgeries, with complete cancellations reported by 42.4%. Reduced faculty engagement was noted by 35.6% of residents, while 47.5% reported a negative impact on the overall resident experience. The majority (76.3%) considered changes to their training reasonable given the global health situation. Conclusions: Strategies implemented during the peak of the pandemic remain crucial in shaping neurosurgery training. Telemedicine has become indispensable, with widespread adoption. Tele-education has also expanded, providing additional learning opportunities. However, traditional didactic courses and hands-on experiences remain essential for comprehensive training. Balancing technology-driven methods with established approaches is crucial for optimizing neurosurgical education and maintaining high-quality patient care.

Cold atmospheric pressure air plasma jet disinfection of table eggs: Inactivation of Salmonella enterica, cuticle integrity and egg quality.

Eggshell cuticles are first lines of defense against egg-associated pathogens, such as Salmonella enterica serovar Enteritidis (SE). Infections from eggs contaminated with this strain remain a significant risk. In addition, changes in the cuticle are closely related to changes in egg safety. The emerging non-thermal atmospheric pressure plasma technology enables a high rate of microbial inactivation at near-ambient temperatures, making it ideal for food safety applications. This study examines the effects of a cold atmospheric pressure air plasma jet (CAAP-J) on eggshell cuticle and egg quality whilst inactivating SE. Shell eggs inoculated with SE (7 log10 cfu/egg) were used as the samples to test the decontamination performance of the device. The tests were conducted using an industrial CAAP-J with different power levels (600-800 W), exposure times (60-120 s), at a fixeddistance of 20 mm from the plasma jet and an air flow rate of 3600 L/h. It was found that the best results were obtained after 120 s at maximum plasma power (800 W). Subsequent to the implementation of this plasma procedure, it was determined that no viable cells could be detected. After CAAP-J treatment, the temperature remains below 50.5 °C, thereby minimizing the risk of altering egg quality. All specific measurements (egg white pH, yolk pH, yolk color, HU, and eggshell breaking strength) have shown that CAAP-J treatment has no negative effect on egg quality. No changes in eggshell cuticle quality after CAAP-J treatment was confirmed through scanning electron microscope (SEM).

An institutional experience in applying quality improvement measures to pituitary surgery: clinical and resource implications.

OBJECTIVE: The aim of this study was to report the authors' experience developing a Lean Six Sigma clinical care pathway (CCP) for endoscopic endonasal transsphenoidal operations. METHODS: Using Lean Six Sigma quality improvement principles-including the define, measure, analyze, improve, and control framework-the authors developed a CCP for endoscopic endonasal transsphenoidal operations, incorporating preoperative, intraoperative, and inpatient and outpatient postoperative phases of care. Efficacy and quality metrics were defined as postoperative length of stay (LOS), presentation to the emergency department (ED) or readmission within 30 days of discharge, and hospital charges. The study included all adult patients who underwent elective endoscopic endonasal resection for pituitary adenoma, Rathke's cleft cyst, craniopharyngioma, pituicytoma, or arachnoid cyst during the sampling period (April 1, 2018, to December 31, 2022). RESULTS: Two hundred twenty-eight patients met criteria and were included; 94 were treated before and 134 were treated after implementation of the CCP. Differences between groups in age, gender, race, BMI, American Society of Anesthesiologists classification, geographic distribution, preoperative serum sodium, tumor size, adenoma functional status, and prior surgery were not significant. The mean postoperative LOS significantly decreased from 4.5 to 1.7 days following CCP implementation (p < 0.0001); LOS variability also decreased, with the standard deviation declining from 3.1 to 1.5 days. The proportion of patients discharged on postoperative day (POD) 1 significantly increased from 0% to 61.9% (p < 0.0001). Fewer than one-quarter of the patients (23.4%) were discharged by POD 2 prior to the CCP, while 88.8% of were discharged by POD 2 after CCP implementation (p < 0.0001). Rates of 30-day ED presentations or readmissions were not significantly different (2.1% vs 6.0%, p = 0.20, and 7.5% vs 6.7%, p > 0.99, respectively). Mean per-patient hospital costs declined from $38,326 to $26,289 (p < 0.0001), with an associated change in cost variability from a standard deviation of $16,716 to $12,498. CONCLUSIONS: CCP implementation significantly improved LOS and costs of endoscopic endonasal resection, without adversely impacting postoperative ED presentations or readmissions.

Decision-Making in Clival Mass Lesions: Risk Factors for Malignant Disease and an Illustrative Case Example.

Introduction Clival tumors are rare and heterogeneous. Although some benign prototypical sellar lesions may present as clival tumors, the likelihood of malignant disease is higher. Here we define a novel algorithm for the workup and management of clival masses through an illustrative case of colorectal adenocarcinoma metastasis to the clivus. Methods In this case report, the best practice guidelines for managing clival masses are described through a literature review and refined by senior author consensus. We conducted a focused systematic review to characterize the present case in the context of clival metastasis from gastrointestinal malignancy. Results An 83-year-old woman presented with 4 weeks of headaches and blurry vision. Examination revealed partial right abducens and left oculomotor palsies. Magnetic resonance imaging (MRI) identified a large, weakly enhancing sellar and clival mass with sphenoid sinus extension. An aggressive subtotal endoscopic endonasal resection was performed with removal of all sphenoid, clival, and sellar disease without cavernous sinus wall resection. Pathology confirmed colorectal adenocarcinoma; computed tomography (CT) imaging identified an ascending colon mass with metastases to the liver and mesenteric nodes. Palliative oncologic therapies were recommended, but she elected hospice, and died 3 months after initial presentation. Gastrointestinal clival metastases are exceedingly rare among sellar and clival pathologies, with eight prior cases reported, most of which presented with diplopia from abducens nerve involvement. Conclusion Clival masses are uncommon skull base lesions that are associated with more aggressive diseases. We present a consolidated framework for decision-making in these challenging patients, alongside an unusual case example that illustrates the importance of increased suspicion for malignant clinical entities in this setting.

Comparative analyses of dynamic transcriptome profiles highlight key response genes and dominant isoforms for muscle development and growth in chicken.

BACKGROUND: Modern breeding strategies have resulted in significant differences in muscle mass between indigenous chicken and specialized broiler. However, the molecular regulatory mechanisms that underlie these differences remain elusive. The aim of this study was to identify key genes and regulatory mechanisms underlying differences in breast muscle development between indigenous chicken and specialized broiler. RESULTS: Two time-series RNA-sequencing profiles of breast muscles were generated from commercial Arbor Acres (AA) broiler (fast-growing) and Chinese indigenous Lushi blue-shelled-egg (LS) chicken (slow-growing) at embryonic days 10, 14, and 18, and post-hatching day 1 and weeks 1, 3, and 5. Principal component analysis of the transcriptome profiles showed that the top four principal components accounted for more than 80% of the total variance in each breed. The developmental axes between the AA and LS chicken overlapped at the embryonic stages but gradually separated at the adult stages. Integrative investigation of differentially-expressed transcripts contained in the top four principal components identified 44 genes that formed a molecular network associated with differences in breast muscle mass between the two breeds. In addition, alternative splicing analysis revealed that genes with multiple isoforms always had one dominant transcript that exhibited a significantly higher expression level than the others. Among the 44 genes, the TNFRSF6B gene, a mediator of signal transduction pathways and cell proliferation, harbored two alternative splicing isoforms, TNFRSF6B-X1 and TNFRSF6B-X2. TNFRSF6B-X1 was the dominant isoform in both breeds before the age of one week. A switching event of the dominant isoform occurred at one week of age, resulting in TNFRSF6B-X2 being the dominant isoform in AA broiler, whereas TNFRSF6B-X1 remained the dominant isoform in LS chicken. Gain-of-function assays demonstrated that both isoforms promoted the proliferation of chicken primary myoblasts, but only TNFRSF6B-X2 augmented the differentiation and intracellular protein content of chicken primary myoblasts. CONCLUSIONS: For the first time, we identified several key genes and dominant isoforms that may be responsible for differences in muscle mass between slow-growing indigenous chicken and fast-growing commercial broiler. These findings provide new insights into the regulatory mechanisms underlying breast muscle development in chicken.

CBX7 reprograms metabolic flux to protect against meningioma progression by modulating the USP44/c-MYC/LDHA axis.

Meningioma is one of the most common primary neoplasms in the central nervous system, whereas there is still no specific molecularly targeted therapy that has been approved for the clinical treatment of aggressive meningiomas. There is therefore an urgent demand to decrypt the biological and molecular landscape of malignant meningioma. Here, through the in-silica prescreening and 10-year follow-up of 445 meningioma patients, we uncovered that CBX7 is progressively decreased with malignancy grade and neoplasia stage in meningioma and a high CBX7 expression level predicts a favorable prognosis in meningioma patients. CBX7 restoration significantly induces cell cycle arrest and inhibits meningioma cell proliferation. iTRAQ-based proteomics analysis indicated that CBX7 restoration triggers the metabolic shift from glycolysis to oxidative phosphorylation. The mechanistic study demonstrated that CBX7 promotes the proteasome-dependent degradation of c-MYC proteins by transcriptionally inhibiting the expression of a c-MYC deubiquitinase, USP44, which attenuates c-MYC-mediated transactivation of LDHA transcripts and further inhibits glycolysis and subsequent cellular proliferation. More importantly, the functional role of CBX7 was further confirmed in both subcutaneous and orthotopic meningioma xenografts mouse models and human meningioma patients. Together, our results shed light on the critical role of CBX7 during meningioma malignancy progression and identified the CBX7/USP44/c-MYC/LDHA axis as a promising therapeutic target against meningioma progression.

Molecular and clinicopathological implications of PRAME expression in adult glioma.

BACKGROUND: PRAME (PReferentially expressed Antigen in MElanoma) is a biomarker studied in various human cancers. Little is known about the biological implications of PRAME in glioma. We aimed to perform a comprehensive analysis to explore PRAME gene expression and its biological and clinicopathological significance in gliomas. METHODS AND MATERIALS: We accessed the human cancer atlas (TCGA) database to collect glioma patients (n = 668) with primary tumors and gene expression data. Single nucleotide variants, copy number variation, DNA methylation data, and other clinicopathological factors were also extracted for the analysis. RESULTS: Overall, 170, 484, and 14 tumors showed no expression, low expression (FPKM≤1), and overexpression (FPKM>1) of the PRAME gene, respectively. The principal component analysis and pathway analyses showed that PRAME-positive gliomas (n = 498), which consisted of tumors with PRAME low expression and overexpression, expressed different oncogenic profiles, possessing higher activity of Hedgehog, P3IK-AKT-mTOR, and Wnt/ß-catenin pathways (p<0.001). DNA methylation analysis also illustrated that PRAME-positive tumors were distributed more densely within a grade 4-related cluster (p<0.001). PRAME positivity was an independent prognostic factor for poor outcomes in a multivariate cox analysis adjusted for clinical characteristics and genetic events. Kaplan-Meier analysis stratified by revised classification showed that PRAME positivity was solely associated with IDH-wildtype glioblastoma, grade 4. Finally, PRAME-overexpressing cases (n = 14) had the worst clinical outcome compared to the PRAME-negative and PRAME-low cohorts (adjusted p<0.001) in pairwise comparisons. CONCLUSION: PRAME expression statuses may dictate different biological and clinicopathological profiles in IDH-wildtype glioblastoma.

High-Throughput Splicing Assays Identify Known and Novel WT1 Exon 9 Variants in Nephrotic Syndrome.

Introduction: Frasier syndrome (FS) is a rare Mendelian form of nephrotic syndrome (NS) caused by variants which disrupt the proper splicing of WT1. This key transcription factor gene is alternatively spliced at exon 9 to produce 2 isoforms ("KTS+" and "KTS-"), which are normally expressed in the kidney at a ∼2:1 (KTS+:KTS-) ratio. FS results from variants that reduce this ratio by disrupting the splice donor of the KTS+ isoform. FS is extremely rare, and it is unclear whether any variants beyond the 8 already known could cause FS. Methods: To prospectively identify other splicing-disruptive variants, we leveraged a massively parallel splicing assay. We tested every possible single nucleotide variant (n = 519) in and around WT1 exon 9 for effects upon exon inclusion and KTS+/- ratio. Results: Splice disruptive variants (SDVs) made up 11% of the tested point variants overall and were tightly concentrated near the canonical acceptor and the KTS+/- alternate donors. Our map successfully identified all 8 known FS or focal segmental glomerulosclerosis (FSGS) variants and 16 additional novel variants which were comparably disruptive to these known pathogenic variants. We also identified 19 variants that, conversely, increased the KTS+/KTS- ratio, of which 2 are observed in unrelated individuals with 46,XX ovotesticular disorder of sex development (46,XX OTDSD). Conclusion: This splicing effect map can serve as functional evidence to guide the clinical interpretation of newly observed variants in and around WT1 exon 9.

Clinical and prognostic significance of granulation patterns in somatotroph adenomas/tumors of the pituitary: a meta-analysis.

INTRODUCTION: Sparsely granulated somatotroph adenoma/tumor (SGST) is thought to be more clinically aggressive than densely granulated somatotroph adenoma/tumor (DGST). However, the literature is not entirely consistent as to the disparate demographic and behavioral features of these subtypes. In this study, we conducted a meta-analysis to further clarify the demographic, clinicopathological, prognostic, and molecular characteristics of SGST versus DGST. METHODS: We accessed two electronic databases to search for potential data. Pooled estimates of odds ratio (OR), mean difference (MD), and corresponding 95% confidence interval (CI) were calculated using the random-effect model. RESULTS: SGST was associated with younger patient age and lower male-to-female ratio (p < 0.001) compared to DGST. Clinically, SGST had larger tumor size and high rate of cavernous sinus and suprasellar extension (p < 0.001) than DGST. During postoperative follow-up, SGST was associated with a lower endocrinological remission rate (OR 0.60; 95% CI 0.40 to 0.90; p = 0.01) and a poorer response rate to SRL (OR 0.16; 95% CI 0.08-0.35; p < 0.001) in comparison to DGST. The prevalence of GSP mutations was significantly lower in SGST (OR 0.36; 95% CI 0.17 to 0.79; p = 0.01). CONCLUSION: SGST and DGST were demographically, clinicopathologically, and molecularly different from each other with the former associated with adverse treatment outcomes and poor response to medical therapy. There are still gaps in translational studies that could help us better understand the behavior of these tumors and identify potential targets in the treatment of sparsely granulated tumors.

Genome wide association analysis of cuticle deposition in laying hens.

The cuticle is an invisible barrier that protects the internal egg contents from microorganisms entering through gas exchange pores. Eggs which have a good cuticle are least likely to be penetrated by microorganisms and improved cuticle cover should reduce vertical transmission of microorganisms and improve biosecurity. The aim was to carry out a genome wide association study for cuticle deposition in 3 independent populations of laying hens using tartrazine and lissamine green staining. Eggs from ∼8,000 hens represented 2 White Leghorn and 1 Rhode Island Red breed. Estimates of heritability using pedigree or genomic relationship matrices were in the 0.2 to 0.3 range. The results were breed specific. Across the populations, genomic regions on chromosomes 1, 2, 4, 5, and 8 were identified as significantly associated with cuticle deposition. No single loci had a large effect. A comparison was made with genes differentially expressed in the shell gland when cuticle deposition was manipulated, however none were obvious candidates for cuticle deposition. The results support the polygenic nature of the trait and the information will help in the future to understand the genetic variance and what might control cuticle deposition and the microbiological safety of the egg.

TRAF7 is an essential regulator of blood vessel integrity during mouse embryonic and neonatal development.

Targeted deletion of TRAF7 revealed that it is a crucial part of shear stress-responsive MEKK3-MEK5-ERK5 signaling pathway induced in endothelial cells by blood flow. Similar to Mekk3-, Mek5- or Erk5-deficient mice, Traf7-deficient embryos died in utero around midgestation due to impaired endothelium integrity. They displayed significantly lower expression of transcription factor Klf2, an essential regulator of vascular hemodynamic forces downstream of the MEKK3-MEK-ERK5 signaling pathway. In addition, deletion of Traf7 in endothelial cells of postnatal mice was associated with severe cerebral hemorrhage. Here, we show that besides MEKK3 and MEK5, TRAF7 associates with a planar cell polarity protein SCRIB. SCRIB binds with an N-terminal region of TRAF7, while MEKK3 associates with the C-terminal WD40 domain. Downregulation of TRAF7 as well as SCRIB inhibited fluid shear stress-induced phosphorylation of ERK5 in cultured endothelial cells. These findings suggest that TRAF7 and SCRIB may comprise an upstream part of the MEKK3-MEK5-ERK5 signaling pathway.