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PURPOSE: In Japan, immunohistochemistry for mismatch repair (MMR) proteins targeted at stage II and III colorectal cancers (CRCs) has been covered by national insurance since October, 2022. This study aimed to clarify the long-term outcomes of patients with stage II and III CRCs receiving postoperative adjuvant chemotherapy based on their MMR status. METHODS: The outcomes of 640 patients who underwent radical surgery for stage II and III CRCs were analyzed retrospectively. RESULTS: Deficient MMR (dMMR) was diagnosed in 41 (13.3%) patients with stage II and 28 (9.1%) patients with stage III CRC. The overall survival and recurrence rates were not significantly different between the patients with stage II and those with stage III CRC. The risk factors for recurrence among those with stage II CRC were tumors on the left side, T4 disease, and the presence of BRAF wild type. The recurrence rates were lower in the stage II CRC patients with sporadic dMMR than in those with suspected Lynch syndrome (LS). The first site of recurrence was more frequently the peritoneum or distant lymph node in patients with dMMR. CONCLUSIONS: Stage II CRC patients with sporadic dMMR were found to have a very good prognosis. On the other hand, peritoneal dissemination or distant lymph node metastasis tended to develop in patients with dMMR.
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Background: Young children are susceptible to enterovirus (EV) infections, which cause significant morbidity in this age group. Objective: This study investigated the characteristics of virus strains and the epidemiology of EVs circulating among young children in Taiwan from 2011 to 2020. Methods: Children diagnosed with EV infections from 2011 to 2020 were identified from the routine national health insurance data monitoring disease system, real-time outbreak and disease surveillance system, national laboratory surveillance system, and Statistics of Communicable Diseases and Surveillance Report, a data set (secondary data) of the Taiwan Centers for Disease and Control. Four primary outcomes were identified: epidemic features, characteristics of sporadic and cluster cases of EV infections, and main cluster institutions. Results: From 2011 to 2020, between 10 and 7600 person-times visited the hospitals for EV infections on an outpatient basis daily. Based on 2011 to 2020 emergency department EV infection surveillance data, the permillage of EV visits throughout the year ranged from 0.07 and 25.45. After typing by immunofluorescence assays, the dominant type was coxsackie A virus (CVA; 8844/12,829, 68.9%), with most constituting types CVA10 (n=2972), CVA2 (n=1404), CVA6 (n=1308), CVA4 (n=1243), CVA16 (n=875), and CVA5 (n=680); coxsackie B virus CVB (n=819); echovirus (n=508); EV-A71 (n=1694); and EV-D68 (n=10). There were statistically significant differences (P<.001) in case numbers of EV infections among EV strains from 2011 to 2020. Cases in 2012 had 15.088 times the odds of being EV-A71, cases in 2014 had 2.103 times the odds of being CVA, cases in 2015 had 1.569 times the odds of being echovirus, and cases in 2018 had 2.274 times the odds of being CVB as cases in other years. From 2011 to 2020, in an epidemic analysis of EV clusters, 57 EV clusters were reported. Clusters that tested positive included 53 (53/57, 93%) CVA cases (the major causes were CVA6, n=32, and CVA10, n=8). Populous institutions had the highest proportion (7 of 10) of EV clusters. Conclusions: This study is the first report of sporadic and cluster cases of EV infections from surveillance data (Taiwan Centers for Disease and Control, 2011-2020). This information will be useful for policy makers and clinical experts to direct prevention and control activities to EV infections that cause the most severe illness and greatest burden to the Taiwanese.
Subject(s)
Enterovirus Infections , Humans , Taiwan/epidemiology , Enterovirus Infections/epidemiology , Child, Preschool , Infant , Male , Retrospective Studies , Female , Child , Infant, Newborn , Enterovirus/isolation & purification , Enterovirus/classification , Disease OutbreaksABSTRACT
BACKGROUND: Clinicopathological differences exist between ulcerative colitis-associated colorectal cancer (UC-CRC) and sporadic colorectal cancer (S-CRC). However, differences in the prognosis remain controversial, and the reason for these differences remains unclear. We therefore assessed the differences between patients with UC-CRC and S-CRC. PATIENTS AND METHODS: This was a matched-pair analysis of the clinicopathological characteristics and prognosis of patients with UC-CRC and S-CRC who underwent colorectal resection between January 2000 and December 2021 at two institutions. Patients were matched according to age, sex, date of surgery, tumor location, and Union for International Cancer Control (UICC) stage. RESULTS: A total of 5992 patients underwent surgery for CRC at the two institutions, and 288 patients (48 with UC-CRC and 240 with S-CRC) were matched in this study. Patients with UC-CRC underwent more invasive surgery and had a longer operative time than those with S-CRC, but there was no marked difference in postoperative complications or perioperative mortality. Long-term outcomes showed a similar 5-year overall survival (OS) for UC-CRC and S-CRC (86.5% versus 88.8%, p = 0.742); however, in stage 3 patients, patients with UC-CRC had a poorer 5-year OS than those with S-CRC (51.4% versus 83.8%, p = 0.032). The first recurrence sites in stage 3 UC-CRC were peritoneal dissemination followed by the bones, while those in S-CRC were the liver and pulmonary system. CONCLUSIONS: Despite no significant differences in surgical outcomes, patients with UC-CRC had a poorer prognosis than those with S-CRC at stage 3. The recurrence patterns in UC-CRC differed from those in S-CRC, suggesting a possible prognostic difference.
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This research aims to compare and assess the clinical and radiological presentations of tuberous sclerosis complex (TSC)-associated lymphangioleiomyomatosis (LAM) and sporadic LAM. A retrospective medical record review was conducted for 90 patients with confirmed LAM diagnoses. Radiologists who were blinded to the LAM type evaluated CT images of the chest and abdomen for the presence of four CT phenotypes: multiple sclerotic bone lesions (SBLs), multifocal micronodular pneumocyte hyperplasia (MMPH), hepatic fat-containing lesions, and cardiac fat-containing lesions. Statistical analyses were then completed to analyze the differences between TSC-LAM and sporadic LAM. Sporadic LAM patients reported a greater number of clinical symptoms at the time of diagnosis than TSC-LAM patients. All four CT phenotypes were present among the TSC-LAM patient population, whereas hepatic fat containing lesions were the only phenotype present in sporadic LAM patients evaluated in this study. The clinical and radiological presentations of sporadic LAM and TSC-LAM differ significantly, suggesting that the diagnostic criteria for sporadic LAM and/or TSC itself could be adapted accordingly. However, the similarities in the presentation of the LAM types are also important to note as these trends inform theories surrounding the potential underlying pathogenic mechanisms of sporadic LAM.
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Nonsyndromic sporadic thoracic aortic aneurysm (nssTAA) is characterized by diverse genetic variants that may vary in different populations. Our aim was to identify clinically relevant variants in genes implicated in hereditary aneurysms in Russian patients with nssTAA. Forty-one patients with nssTAA without dissection were analyzed. Using massive parallel sequencing, we searched for variants in exons of 53 known disease-causing genes. Patients were found to have no (likely) pathogenic variants in the genes of hereditary TAA. Six variants of uncertain significance (VUSs) were identified in four (9.8%) patients. Three VUSs [FBN1 c.7841C>T (p.Ala2614Val), COL3A1 c.2498A>T (p.Lys833Ile), and MYH11 c.4993C>T (p.Arg1665Cys)] are located in genes with "definitive" disease association (ClinGen). The remaining variants are in "potentially diagnostic" genes or genes with experimental evidence of disease association [NOTCH1 c.964G>A (p.Val322Met), COL4A5 c.953C>G (p.Pro318Arg), and PLOD3 c.833G>A (p.Gly278Asp)]. Russian patients with nssTAA without dissection examined in this study have ≥1 VUSs in six known genes of hereditary TAA (FBN1, COL3A1, MYH11, NOTCH1, COL4A5, or PLOD3). Experimental studies expanded genetic testing, and clinical examination of patients and first/second-degree relatives may shift VUSs to the pathogenic (benign) category or to a new class of rare "predisposing" low-penetrance variants causing the pathology if combined with other risk factors.
Subject(s)
Aortic Aneurysm, Thoracic , Genetic Predisposition to Disease , Humans , Female , Male , Russia/epidemiology , Aortic Aneurysm, Thoracic/genetics , Middle Aged , Adult , Myosin Heavy Chains/genetics , Fibrillin-1/genetics , Collagen Type III/genetics , Aged , Cardiac Myosins/genetics , High-Throughput Nucleotide Sequencing , Mutation , Genetic Variation , AdipokinesABSTRACT
Osteogenesis imperfecta (OI) arises from a collagen type 1 defect due to several gene mutations, particularly COL1A1 and COL1A2. Its inheritance pattern is typically autosomal dominant, which is more common, or autosomal recessive, although sporadic cases also occur. Prenatal ultrasound can detect severe types, but genetic testing is necessary for confirmation, often at birth or in early childhood. We present a rare case of sporadic OI type III involving a three-year-old boy. Prenatal ultrasound initially revealed limb deformities and skeletal dysplasia, with subsequent confirmation at birth through bone deformities and multiple fractures. Exome sequencing confirmed the diagnosis at 15 months, revealing a new, rare variant in the COL1A2 gene. Pamidronate treatment began at seven months.
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Holt-Oram syndrome is an autosomal dominant condition marked by heart and upper limb defects. Holt and Oram were the first to narrate this in 1960. Holt-Oram syndrome is the prototype of heart-hand syndromes and has recently been mapped to the long arm of chromosome 12 (12q2). This syndrome was described in 1960 by Dr Mary Holt and Dr Samuel Oram. It is an autosomal dominant condition resulting from a mutation in TBX5 located on chromosome 12q24.1, which regulates cardiac and limb morphogenesis. It must be differentiated from heart-hand syndrome type II (Tobatznik's syndrome) and heart-hand syndrome type III (MIM No. 140450), which are phenotypically similar. The latter do not map to 12q2, and atrial septal defects do not occur in these conditions. This syndrome is distinguished by heart problems as well as thumb aplasia or hypoplasia. It is sometimes referred to as atriodigital syndrome, upper limb-cardiovascular syndrome, heart-hand syndrome, cardiomelic syndrome, or cardiac limb syndrome. Other upper-limb anomalies include aplasia or hypoplasia of the radius, arm length variation, atypical forearm pronation and supination, uncommon thumb resistance, sloping shoulders, and restricted shoulder movement. All those who are affected have an aberrant carpal bone, which might be the only sign of the illness. Seventy-five percent of those with Holt-Oram syndrome have a congenital cardiac defect, which most frequently affects the septum. In this case, we report a girl who is 4 years and 6 months old and is a known case of Holt-Oram syndrome with an atrial septal defect. She underwent device closure and had come to the pediatric op with fever and cough.
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BACKGROUND: Sporadic Creutzfeldt-Jakob Disease (SCJD) is a severe neurodegenerative disorder characterized by rapid progression and extensive neuronal loss. Disulfidptosis is an innovative type of programmed cell demise characterized by an accumulation of disulfide bonds within the cellular cytoplasm, subsequently triggering functional disruption and cell demise. METHODS: Through literature review and analysis, we identified 18 candidate disulfidptosis-related genes (DRGs) involved in cellular processes. The dataset used for analysis, GSE124571, was obtained from the GEO database. Gene-gene and protein-protein interactions were analyzed using the GeneMANIA and STRING databases, respectively. We also performed enrichment analysis, DEGs analysis, WGCNA analysis, immune infiltration, consensus clustering and matrix correlation. RESULTS: The analysis showed that 12 out of 18 DRGs were significantly changed between SCJD and control groups. The DRGs had strong interactions such as physical interactions, co-expression and genetic interactions and were enriched in biological processes and pathways related to actin cytoskeletal regulation. The study most notably identified three hub genes (WASF2, TLN1 and G6PD) important for SCJD and emphasized the functional significance of the identified hub genes. The role of the immune system in the pathogenesis of SCJD The study found that the composition of immune cells in SCJD brain tissue is altered. Consensus clustering provided insights into immune infiltration and hub gene expression in SCJD subgroup. CONCLUSION: Our study reveals the possible involvement of disulfidptosis in SCJD and highlights the significance of identified hub genes as potential biomarkers and therapeutic targets for SCJD.
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BACKGROUND: Inclusion body myositis (IBM) is a progressive myopathy occurring in patients over 45 years of age, with heterogeneous and variable clinical features. This study aimed to determine the influence of autoantibodies, gender, and age of onset on the clinical features of IBM. METHODS: Medical records and muscle histology findings of 570 participants with suspected IBM were reviewed. Various characteristics of patients who met the 2011 ENMC IBM diagnostic criteria were compared based on the presence of anti-cytosolic 5'-nucleotidase 1 A (cN1A) autoantibodies, gender, age of onset, and disease duration. RESULTS: Of the 353 patients who met the criteria, 41.6% were female. The mean age at onset was 64.6 ± 9.3 years, and the mean duration from onset to diagnosis was 5.7 ± 4.7 years. 196 of the 353 patients (55.5%) were positive for anti-cN1A autoantibodies and 157 were negative. Logistic regression showed that patients with anti-cN1A autoantibodies had a higher frequency of finger flexion weakness. Multiple regression showed that patients with later age of onset had shorter disease duration, lower BMI, and lower serum CK levels. Male patients had a higher frequency of onset with finger weakness and female patients had a lower BMI. CONCLUSION: Autoantibodies, gender, age of onset, and disease duration may influence the clinical presentation of IBM, highlighting the need for a precision medicine approach that considers these factors along with the underlying mechanisms of the disease.
Subject(s)
5'-Nucleotidase , Age of Onset , Autoantibodies , Myositis, Inclusion Body , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , 5'-Nucleotidase/immunology , Autoantibodies/blood , Myositis, Inclusion Body/immunology , Myositis, Inclusion Body/blood , Myositis, Inclusion Body/diagnosis , Retrospective Studies , Sex CharacteristicsABSTRACT
MicroRNAs (miRNAs) are critical post-transcriptional gene regulators and their involvement in sporadic colon cancer (CRC) tumorigenesis has been confirmed. In this study we investigated differences in miRNA expression in microsatellite stable (MSS/EMAST-S), microsatellite unstable marked by high elevated microsatellite alterations at selected tetranucleotide repeats (MSS/EMAST-H), and high microsatellite unstable (MSI-H/EMAST-H) tumor subgroups as well as in tumors with different clinicopathologic characteristics. An RT-qPCR analysis of miRNA expression was carried out on 45 colon cancer and adjacent normal tissue samples (15 of each group). Overall, we found three differentially expressed miRNAs between the subgroups. miR-92a-3p and miR-224-5p were significantly downregulated in MSI-H/EMAST-H tumors in comparison to other subgroups. miR-518c-3p was significantly upregulated in MSS/EMAST-H tumors in comparison to stable and highly unstable tumors. Furthermore, we showed that miR-143-3p and miR-145-5p were downregulated in tumors in comparison to normal tissues in all subgroups. In addition, we showed overexpression of miR-125b-5p in well-differentiated tumors and miR-451a in less advanced tumors. This is the first report on differences in miRNA expression profiles between MSS/EMAST-S, MSS/EMAST-H, and MSI-H/EMAST-H colorectal cancers. Our findings indicate that the miRNA expression signatures differ in CRC subgroups based on their instability status.
Subject(s)
Colonic Neoplasms , Gene Expression Regulation, Neoplastic , MicroRNAs , Microsatellite Instability , Humans , MicroRNAs/genetics , Colonic Neoplasms/genetics , Colonic Neoplasms/pathology , Female , Male , Middle Aged , Aged , Gene Expression Profiling/methods , Microsatellite Repeats/genetics , Transcriptome/geneticsABSTRACT
Key Clinical Message: Creutzfeldt-Jakob disease (CJD) is a rapidly progressive, fatal neurodegenerative disorder. This case highlights parkinsonism as a rare initial manifestation of sporadic CJD (sCJD), emphasizing the need for heightened clinical awareness to prevent misdiagnosis. Early and accurate diagnosis of sCJD is crucial for preventing potential iatrogenic transmission and optimizing patient management. Abstract: Creutzfeldt-Jakob disease (CJD) is a fatal neurodegenerative illness. While movement disorders may be present at the onset of the disease in about half of those with sporadic CJD (sCJD), parkinsonism is a rare initial presentation. In this article, we report a case of CJD with parkinsonism as the initial presentation of the disease. We report a 69-year-old lady with initial symptoms of gait difficulty, tremor, and bradykinesia. Later, she developed cognitive impairment, ataxia, chin tremor, and myoclonic jerks. Her condition worsened to the point of akinetic mutism. She was diagnosed with probable sCJD after detecting protein 14-3-3 in her cerebrospinal fluid and observing typical imaging features.This case report illustrates important aspects of an inevitably fatal and rapidly progressing disease's early presentation and clinical features. The uncommon initial presentations of sCJD should be considered with the intent of preventing misdiagnosis in the future. Early diagnosis of sCJD can prevent possible iatrogenic disease transmission and improve patient care.
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Anatomical variations are observed at times during a routine dissection process and some of them are clinically relevant as they can lead to certain clinical presentations or situations that are difficult to anticipate without the knowledge about their possibility. The unilateral non-syndromic complete absence of pectoral muscles is very rare. Their absence is always found to be associated with syndromes like Poland syndrome or Sprengel's deformity. During the routine anatomical dissection, we encountered two cases of non-syndromic complete unilateral absence of the pectoralis minor muscle. On further inspection of the cadaver in both the cases, no other bony (ribs, scapula), vascular, breast abnormalities, or muscular aplasia (fibers of the serratus anterior or pectoralis major) was noted. As the pectoralis minor muscle serves as the potential surgical landmark and can also be used as the myo-cutaneous flaps for facial reanimation surgeries and in thumb opponensplasty, the absence of the pectoralis minor muscle would come as a surprise for the surgeons during the process of harvesting the flap for these procedures, so the possibility of this kind of rare variation should be documented.
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PURPOSE: Family history is one of the strongest risk factors for inflammatory bowel diseases (IBD) while studies about the clinical phenotype of familial IBD are limited. This study aimed to compare the phenotypic features of familial Crohn's disease (CD) with sporadic CD. METHODS: Familial CD was defined as CD patients having one or more first, second, third, fourth degree, or above relatives with CD. Sporadic CD patients hospitalized during the same period were matched 1:3 by age and gender. Differences in clinical characteristics, phenotype distribution, extraintestinal manifestations, and complications at diagnosis, as well as treatment regimen and surgery, were compared between familial and sporadic CD. RESULTS: The familial CD was associated with a higher rate of past appendectomy history (P = 0.009), more intestinal perforation at onset (P = 0.012), more MRI results of anal lesion (P = 0.023), and gastrointestinal perforation (P = 0.040) at diagnosis, higher rate of past intestinal surgery history (P = 0.007), more number of intestinal surgeries (P = 0.037), longer duration of follow-up (P = 0.017), lower rate of taking biologicals for current maintenance (P = 0.043), lower tendency to upgrade to biologicals during follow-up (P = 0.013), higher possibility to experience gastrointestinal obstruction (P = 0.047), and abdominal abscess during follow-up (P = 0.045). CONCLUSION: Familial CD is associated with a more aggressive clinical phenotype.
Subject(s)
Crohn Disease , Phenotype , Humans , Crohn Disease/genetics , Crohn Disease/complications , Crohn Disease/pathology , Male , Female , China , Adult , Young Adult , Middle Aged , Genetic Predisposition to Disease , Risk Factors , AdolescentABSTRACT
Background: Finding successful therapies for individuals with Alzheimer's disease (AD) remains an ongoing challenge. One contributing factor is that the mouse models commonly used in preclinical research primarily mimic the familial form of AD, whereas the vast majority of human cases are sporadic. Accordingly, for a sporadic mouse model of AD, incorporating the multifactorial aspects of the disease is of utmost importance. Methods: In the current study, we exposed humanized Aß knock-in mice (hAß-KI) to weekly low-dose lipopolysaccharide (LPS) injections until 24 weeks of age and compared the development of AD pathologies to the familial AD mouse model known as the J20 mice. Results: At the early time point of 24 weeks, hAß-KI mice and J20 mice exhibited spatial memory impairments in the Barnes maze. Strikingly, both hAß-KI mice and J20 mice showed significant loss of dendritic spines when compared to WT controls, despite the absence of Aß plaques in hAß-KI mice at 24 weeks of age. Glial cell numbers remained unchanged in hAß-KI mice compared to WT, and LPS exposure in hAß-KI mice did not result in memory deficits and failed to exacerbate any other examined AD pathology. Conclusion: The study highlights the potential of hAß-KI mice as a model for sporadic AD, demonstrating early cognitive deficits and synaptic alterations despite no evidence of Aß plaque formation. These findings underscore the importance of considering multifactorial influences in sporadic AD pathogenesis and the need for innovative models to advance our understanding and treatment strategies for this complex disease.
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Sporadic late-onset cerebellar ataxias (SLOCA) present a diagnostic challenge due to their heterogeneous etiologies and complex clinical manifestations. This retrospective study aimed to conduct a comprehensive evaluation of six male patients diagnosed with SLOCA, with a mean age of 55 years and an average symptom onset at 47 years. All patients presented with gait and balance disturbances, with additional sensory abnormalities observed in two cases. Neurological examinations revealed varied cerebellar syndromes, including static and static-kinetic presentations, accompanied by peripheral neurogenic syndromes in some instances. Brain MRI findings showed cerebellar atrophy, predominantly involving the vermis, in a subset of patients. Biochemical and serological investigations yielded mostly unremarkable results, although two patients exhibited significant vitamin E deficiency and anti-Hu antibodies (anti-neuronal nuclear antibody type 1). Electromyography confirmed sensory axonal neuropathy in those with peripheral neurogenic syndromes. Treatment with TOCO 500 mg (Vitamin E) was administered to four patients, with follow-up indicating stable disease progression in two cases. This study underscores the complexity of SLOCA and the need for a multidisciplinary approach to diagnosis and management. Further research is warranted to elucidate the underlying mechanisms and improve clinical outcomes for affected individuals.
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Sporadic Creutzfeldt-Jakob disease (sCJD) is a rare and fatal neurodegenerative disorder belonging to a group of diseases known as prion disease. Characterized by the formation of abnormal prion proteins in the brain, these conditions lead to tissue damage and vacuolation, giving the brain a sponge-like appearance. sCJD represents the most prevalent form of CJD, accounting for roughly 85% of all CJD cases. We report a case with unusual clinical manifestations. The patient experienced progressive neurological symptoms and MRI progression.
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A 19-year-old male suffered from sporadic hemiplegic migraine (SHM) for several years and experienced significant pain and disability with sensory and motor disturbances during the migraine headaches. Weakness, abnormal vision, abnormal sensation, one-sided disabling motor weakness, and other signs of SHM were diagnosed. The patient had received previous physical therapy, chiropractic and over-the-counter medications, as well as migraine-specific prescriptions without lasting improvements. Chiropractic BioPhysics® (CBP®) spinal structural rehabilitation protocols were used to increase cervical lordosis and improve cervical muscular strength, mobility, and posture. These protocols include spine-specific prescriptions for Mirror Image® postural exercises, traction, and spinal manipulative therapy. After 24 treatments over eight weeks, all subjective and objective outcomes improved dramatically with a near resolution of all initial symptoms of SHM. There were a significant increase in cervical lordosis and a reduction in forward head posture. The neck disability index improved from 26% to 6%, and all pain scores for all regions improved following treatment. A 10-month follow-up exam showed the outcomes were maintained. SHM is rare and debilitating, is part of the global burden of disease, and is a major cause of disability in the world. Reports of successful conservative and non-conservative long-term treatments for SHM are rare, and there are no clinical trials showing successful treatments for SHM. This successful case demonstrates preliminary evidence that CBP spinal structural rehabilitation may serve as a treatment option for SHM. Future studies are needed to replicate the findings from this case.
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INTRODUCTION: Hemangioblastoma (HB) is a benign tumor of the central nervous system, associated with von Hippel-Lindau disease (VHL), or sporadic. The aim of this study was to compare and examine the clinical-pathological profile of patients with spinal hemangioblastoma and YAP expression. METHODS: A retrospective, descriptive, comparative study. All patients who underwent surgery for spinal HB between 2016 and 2023 were included. Clinical and radiological data were collected and analyzed. An immunohistochemistry panel including NeuN, neurofilaments (NF), and YAP-1, was performed. RESULTS: Nine patients were studied, six women and three men. Four patients had previously diagnosed VHL. The tumor location included: four cervical (44.44%), two thoracic (22.22%), two pontine with cervical extension (22.22%) and one patient with two lesions, one cervical and one thoracic (11.11%). Non-significant clinical differences were identified between VHL and sporadic patients. Imaging evidenced seven extramedullary and three intramedullary tumors. Histologically, intra-tumoral and perivascular axonal tracts were observed in all cases. One third of the tumors (two with VHL and one sporadic) presented extramedullary hematopoiesis. Seven cases (77.8%) expressed nuclear YAP (three with VHL and four sporadic HBs). The surgical outcome was good and only one patient with VHL undergoing subtotal resection had recurrence. CONCLUSIONS: Spinal HBs can be associated with VHL or be sporadic. To the best of our knowledge, this is the first study to describe YAP expression in HB. It is important to investigate the involvement of the Hippo pathway in HBs as a possible therapeutic target.
Subject(s)
Hemangioblastoma , Transcription Factors , YAP-Signaling Proteins , von Hippel-Lindau Disease , Adult , Aged , Female , Humans , Male , Middle Aged , Young Adult , Adaptor Proteins, Signal Transducing/analysis , Hemangioblastoma/pathology , Hemangioblastoma/chemistry , Retrospective Studies , Spinal Cord Neoplasms/pathology , Spinal Cord Neoplasms/chemistry , Spinal Cord Neoplasms/surgery , Spinal Neoplasms/pathology , Spinal Neoplasms/chemistry , Transcription Factors/analysis , von Hippel-Lindau Disease/complications , von Hippel-Lindau Disease/pathologyABSTRACT
Abnormalities in mucosal immunity are involved in the onset and progression of ulcerative colitis (UC), resulting in a high incidence of colorectal cancer (CRC). While high-mobility group box-1 (HMGB1) is overexpressed during colorectal carcinogenesis, its role in UC-related carcinogenesis remains unclear. In the present study, we investigated the role of HMGB1 in UC-related carcinogenesis and sporadic CRC. Both the azoxymethane colon carcinogenesis and dextran sulfate sodium colitis carcinogenesis models demonstrated temporal increases in mucosal HMGB1 levels. Activated CD8+ cells initially increased and then decreased, whereas exhausted CD8+ cells increased. Additionally, we observed increased regulatory CD8+ cells, decreased naïve CD8+ cells, and decreased mucosal epithelial differentiation. In the in vitro study, HMGB1 induced energy reprogramming from oxidative phosphorylation to glycolysis in CD8+ cells and intestinal epithelial cells. Furthermore, in UC dysplasia, UC-related CRC, and hyperplastic mucosa surrounding human sporadic CRC, we found increased mucosal HMGB1, decreased activated CD8+ cells, and suppressed mucosal epithelial differentiation. However, we observed increased activated CD8+ cells in active UC mucosa. These findings indicate that HMGB1 plays an important role in modulating mucosal immunity and epithelial dedifferentiation in both UC-related carcinogenesis and sporadic CRC.
Subject(s)
CD8-Positive T-Lymphocytes , Cell Differentiation , Colitis, Ulcerative , HMGB1 Protein , Immunity, Mucosal , Intestinal Mucosa , HMGB1 Protein/metabolism , Humans , Intestinal Mucosa/metabolism , Intestinal Mucosa/immunology , Intestinal Mucosa/pathology , Colitis, Ulcerative/pathology , Colitis, Ulcerative/immunology , Colitis, Ulcerative/metabolism , Colitis, Ulcerative/chemically induced , Animals , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , Mice , Male , Epithelial Cells/metabolism , Epithelial Cells/pathology , Colorectal Neoplasms/pathology , Colorectal Neoplasms/metabolism , Colorectal Neoplasms/immunology , Mice, Inbred C57BL , Carcinogenesis/immunology , Carcinogenesis/pathology , Carcinogenesis/metabolismABSTRACT
BACKGROUND: Atypical/Nor98 scrapie (AS) is an idiopathic infectious prion disease affecting sheep and goats. Recent findings suggest that zoonotic prions from classical bovine spongiform encephalopathy (C-BSE) may copropagate with atypical/Nor98 prions in AS sheep brains. Investigating the risk AS poses to humans is crucial. METHODS: To assess the risk of sheep/goat-to-human transmission of AS, we serially inoculated brain tissue from field and laboratory isolates into transgenic mice overexpressing human prion protein (Met129 allele). We studied clinical outcomes as well as presence of prions in brains and spleens. RESULTS: No transmission occurred on the primary passage, with no clinical disease or pathological prion protein in brains and spleens. On subsequent passages, 1 isolate gradually adapted, manifesting as prions with a phenotype resembling those causing MM1-type sporadic Creutzfeldt-Jakob disease in humans. However, further characterization using in vivo and in vitro techniques confirmed both prion agents as different strains, revealing a case of phenotypic convergence. Importantly, no C-BSE prions emerged in these mice, especially in the spleen, which is more permissive than the brain for C-BSE cross-species transmission. CONCLUSIONS: The results obtained suggest a low zoonotic potential for AS. Rare adaptation may allow the emergence of prions phenotypically resembling those spontaneously forming in humans.