RÉSUMÉ
Japan is one of the world's most aging societies and the number of elderly patients taking antithrombotic drugs is increasing. In recent years, dual antiplatelet therapy (DAPT), in which two antiplatelet drugs are administered, has become common in anticipation of its high therapeutic efficacy. However, there are concerns about increased bleeding complications in use of DAPT. Therefore, the goal of this study was to investigate the effects of DAPT in patients with traumatic brain injury (TBI). A prospective, multicenter, observational study was conducted from December 2019 to May 2021 to examine the effects of antithrombotic drugs and reversal drugs in 721 elderly patients with TBI. In the current study, the effect of DAPT on TBI was examined in a secondary analysis. Among the registered patients, 132 patients taking antiplatelet drugs only were divided into those treated with single antiplatelet therapy (SAPT) (n=106) and those treated with DAPT (n=26) prior to TBI. Glasgow Coma Scale (GCS) on admission, pupillary findings, course during hospitalization, and outcome were compared in the two groups. A similar analysis was performed in patients with a mild GCS of 13-15 (n=95) and a moderate to severe GCS of 3-12 (n=37) on admission. The DAPT group had significantly more males (67.0â¯% vs. 96.2â¯%), a higher severity of illness on admission, and a higher frequency of brain herniation findings on head CT (21.7â¯% vs. 46.2â¯%), resulting in significantly higher mortality (12.3â¯% vs. 30.8â¯%). The only significant factor for mortality was severity on admission. The rate of DAPT was significantly higher in patients with a moderate to severe GCS on admission, and DAPT was the only significant factor related to severity on admission. These findings suggest that the severity of injury on admission influences the outcome six months after injury, and that patients with more severe TBI on admission are more likely to have been treated with DAPT compared to SAPT.
Sujet(s)
Lésions traumatiques de l'encéphale , Bithérapie antiplaquettaire , Antiagrégants plaquettaires , Humains , Lésions traumatiques de l'encéphale/traitement médicamenteux , Lésions traumatiques de l'encéphale/complications , Mâle , Femelle , Antiagrégants plaquettaires/usage thérapeutique , Antiagrégants plaquettaires/administration et posologie , Sujet âgé , Études prospectives , Sujet âgé de 80 ans ou plus , Bithérapie antiplaquettaire/méthodes , Résultat thérapeutique , Échelle de coma de Glasgow , Adulte d'âge moyenRÉSUMÉ
The diagnosis of hereditary skin tumors is difficult for "old" diagnostic tools such as immunohistochemistry. Whole-exome sequencing analysis as a "new" diagnostic tool enables us to make a final diagnosis in spite of unknown hereditary diseases in the past. Hereditary leiomyomatosis and renal cell cancer are autosomal dominant hereditary cancer syndromes characterized by uterine myomas, cutaneous leiomyomas, and aggressive renal cell cancer. The syndrome is associated with pathogenic germline variants in the fumarate hydratase gene. Herein, we demonstrate a pathogenic germline variant of the fumarate hydratase gene in a 60-year-old woman with multiple cutaneous leiomyomas, leading to the diagnosis of hereditary leiomyomatosis and renal cell cancer. Whole-exome sequencing analysis using genomic DNA extracted from peripheral blood leukocytes revealed one germline variant in the FH gene on chromosome 1 (c.290G>A, p.Gly97Asp). She received total hysterectomy due to uterine myoma, which strongly supported the diagnosis. No tumor was detected in her kidney by computed tomography and ultrasound examination. Genetic examination for the mutation of the fumarate hydratase gene is important in order to reach the correct diagnosis and to detect renal cancer at its early stage.
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In forensic cases, detailed identification of pneumonia is important. Our objective was to statistically determine the applicability of three interstitial lung disease (ILD) markers for forensic diagnosis using serum collected from dead bodies with various postmortem intervals (PMIs). We retrospectively analyzed the levels of postmortem serum Krebs von den Lungen-6 (KL-6) and pulmonary surfactant-associated proteins A and D (SP-A and SP-D) using 221 samples obtained during forensic autopsy at our facility from 2019 to 2023. We evaluated the diagnostic efficacy of ILD markers for various pneumonias against the pathological diagnosis, and examined the assessment of the severity of ILD. When comparing the ILD group with bacterial pneumonia (BP) versus the control group, there was a significant increase in KL-6 in the ILD group. When comparing the severe ILD (SILD) group with the mild ILD (MILD) group, there was a significant increase in KL-6 and SP-D in the SILD group. The optimal cutoff values for differentiating SILD were 607.0 U/mL for KL-6, 55.5 ng/mL for SP-A, and 160.0 ng/mL for SP-D, and the sensitivity/specificity (%) of KL-6, SP-A, and SP-D for SILD were 84.1/95.2, 55.6/85.7, and 66.7/74.6, respectively. This is the first study to examine KL-6 in postmortem serum in forensic medicine. By analyzing dead bodies with various PMIs, our results confirmed statistically that postmortem serum KL-6 specifically detects ILD, postmortem serum SP-A has high sensitivity to lung injury, and postmortem serum SP-D is potentially useful in assessing the severity of ILD.
Sujet(s)
Marqueurs biologiques , Pneumopathies interstitielles , Mucine-1 , Protéine A associée au surfactant pulmonaire , Protéine D associée au surfactant pulmonaire , Humains , Mucine-1/sang , Pneumopathies interstitielles/sang , Protéine D associée au surfactant pulmonaire/sang , Marqueurs biologiques/sang , Mâle , Femelle , Adulte d'âge moyen , Études rétrospectives , Protéine A associée au surfactant pulmonaire/sang , Sujet âgé , Adulte , Sensibilité et spécificité , Sujet âgé de 80 ans ou plus , Pneumopathie infectieuse/sang , Anatomopathologie légale , Pneumopathie bactérienne/sang , Pneumopathie bactérienne/diagnosticRÉSUMÉ
â¢We report the first case of IgG4-related pachyleptomeningitis.â¢Our case showed also an inflammatory pseudotumor on the side ipsilateral to the pachyleptomeningitis.â¢The pachyleptomeningitis is probably due to inflammation from the dural pseudotumor spreading along the adjacent meninges.
RÉSUMÉ
A case of cytoplasmic anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) initially involving the skin in a 44-year-old Japanese female is reported. The patient had a hemorrhagic erythematous tumor on the right thigh without any systemic symptoms. Pathology showed diffuse infiltration of CD30-positive anaplastic large cells positive for epithelial membrane antigen and cytoplasmic ALK. The right inguinal lymph node showed infiltration of tumor cells in the marginal sinus. Only 2 weeks after radiation therapy, the patient developed multiple subcutaneous nodules and lung involvement. Even after subsequent multichemotherapy sessions, cutaneous recurrence occurred. Literature review of cytoplasmic ALK-positive ALCL initially involving in the skin revealed that skin lesions were mostly seen in the extremities and that half of the cases developed extracutaneous lesions. Radiation and chemotherapy were effective for most cases. Inverse RT-PCR identified a tumor necrosis factor receptor-associated factor (TRAF)1-ALK fusion in our case. Most reported cases with this translocation experienced repeated changes in chemotherapy, suggesting poorer prognosis. Although ALK-positive ALCL generally responds well to chemotherapy, the presence of a TRAF1-ALK fusion may suggest resistance to treatment. Detection of fusion partners of ALK is important for predicting clinical courses and deciding treatment options.
Sujet(s)
Lymphome à grandes cellules anaplasiques , Humains , Femelle , Adulte , Lymphome à grandes cellules anaplasiques/diagnostic , Lymphome à grandes cellules anaplasiques/génétique , Kinase du lymphome anaplasique/génétique , Récepteurs à activité tyrosine kinase/génétique , Récepteurs à activité tyrosine kinase/métabolisme , Récepteurs à activité tyrosine kinase/usage thérapeutique , Facteur-1 associé aux récepteurs de TNF/métabolisme , Noeuds lymphatiques/anatomopathologieRÉSUMÉ
Background: This study investigates the pulmonary arterial histopathology in patients with idiopathic pulmonary arterial hypertension (IPAH) and acute vasoreactive phenotype, who demonstrated long-term survival (>30 years) and incidental death from causes other than PAH progression. The pathological changes observed in these patients were compared with those in patients with bone morphogenetic protein receptor type 2 (BMPR2) mutation. Case Presentation: We present two cases of patients with pulmonary arterial hypertension (PAH) who died incidentally from causes unrelated to PAH progression. We report compares pulmonary arterial histopathology in long-term survivors of CCB-responsive PAH patient and a hereditary PAH patient with a BMPR2 mutation. Lung specimens were analyzed using the Heath and Edwards (HE) classification and percentage muscular wall thickness (%MWT) of pulmonary arterioles. A significant difference in the severity of grading (p = 0.0001) and distribution between grades 1-2, 4 (p = 0.001), and 5 (p = 0.014) was observed between both patients. These findings suggest differential vascular pathology between the two cases, with CCB responders displaying more mild illness lesions compared to BMPR2 mutant patients. Conclusion: The study revealed that CCB responders exhibit more mild illness vascular lesions than BMPR2 mutant patients despite their long-term survival, suggesting a difference in vascular pathology between the two phenotypes.
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Fibrocystic breast disease is the most common benign condition and is important for differentiating breast cancer. We present the case of a 27-year-old female patient with pleomorphic calcifications and segmental distribution on mammography, which was highly suggestive of breast cancer; however, the pathological findings were fibrocystic disease. Although fibrocystic breast disease does not require treatment, appropriate follow-up is necessary after assessing the risk of breast cancer.
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Late relapse (LR) of testicular cancer is often associated with chemoresistance, and thus the first choice of therapy is surgery if complete resection is possible. In some LR cases (including our patient, a 31-year-old Japanese man), elevation of alpha-fetoprotein (AFP) may precede the radiologic detection of LR. Approximately 500 days after the start of our patient's AFP elevation, 18F-fluordeoxyglucose positron emission tomography (FDG-PET) revealed strong FDG uptake in an equivocally enlarged external iliac lymph node. The lymphadenectomy as salvage surgery resulted in long-term complete remission without further treatment. Using FDG-PET made it possible to perform effective salvage surgery.
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Chronic expanding hematomas (CEHs) in the retroperitoneal space are rare disease. Since CEHs often develop huge masses, it is difficult to differentiated from malignant tumor. Here, we present a case of CEH in the retroperitoneal space. The lesion exhibited increased activity on 18F-fluordeoxyglucose positron emission tomography (FDG-PET). In the present case, the increased FDG uptake was showed only in the peripheral rim of the mass, and no other abnormal uptake was observed. The findings of our case and previously reported cases suggest that FDG uptake observed only in peripheral rim of the mass might be characteristic findings of CEHs.
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Tuberous sclerosis complex (TSC) tumors are presently incurable despite a cytostatic response to mTOR pathway inhibition because recurrence of disease occurs after treatment is discontinued. Here, we explored the hypothesis that inhibiting tyrosine kinase activity in mesenchymal lineage-specific platelet-derived growth factor receptor ß (PDGFRß) signaling in TSC tumors is cytocidal and attenuates tumorigenesis at significantly higher levels than treatment with an mTOR inhibitor. Rapamycin-induced versus tyrosine kinase inhibitor (TKI)-induced renal angiomyolipoma (AML) and pulmonary lymphangioleiomyomatosis (LAM) tumor cells were comparatively analyzed using cell survival assays, RNA sequencing, and bioinformatics to distinguish tumoricidal mechanisms adopted by each drug type. The efficacy of imatinib therapy was validated against spontaneously developing renal cystadenomas in tuberous sclerosis Tsc2+/- mouse models (C57BL/6J mice; N = 6; 400 mg/kg/d; oral gavage) compared with Tsc2+/- mice treated with PBS (C57BL/6J mice; N = 6). Our study revealed that TKIs imatinib and nilotinib were cytocidal to both pulmonary LAM and renal AML cell cultures through the downregulation of the glycoprotein GPVI pathway and resultant disruption in mitochondrial permeability, increased cytosolic cytochrome C, and caspase 3 activation. Importantly, renal tumor growth was significantly attenuated in imatinib-treated Tsc2+/- mice compared with PBS treatment. The preclinical studies reported here provide evidence documenting the effectiveness of TKIs in limiting LAM and AML cell growth and viability with important clinical potential. Furthermore, these drugs elicit their effects by targeting a PDGF pathway-dependent apoptotic mechanism supporting the investigation of these drugs as a novel class of TSC therapeutics.
Sujet(s)
Angiomyolipome , Tumeurs du rein , Leucémie aigüe myéloïde , Complexe de la sclérose tubéreuse , Souris , Animaux , Complexe de la sclérose tubéreuse/traitement médicamenteux , Complexe de la sclérose tubéreuse/génétique , Complexe de la sclérose tubéreuse/métabolisme , Angiomyolipome/traitement médicamenteux , Angiomyolipome/génétique , Angiomyolipome/métabolisme , Protéines suppresseurs de tumeurs/génétique , Tumeurs du rein/anatomopathologie , Mésilate d'imatinib/pharmacologie , Souris de lignée C57BL , Sérine-thréonine kinases TOR/métabolisme , ApoptoseRÉSUMÉ
Insulinoma-associated protein 1 (INSM1) is a representative diagnostic marker of neuroendocrine neoplasms (NENs); however, it has not yet been used to diagnose pituitary neuroendocrine tumors (PitNETs), according to the 2022 World Health Organization (WHO) classification of pituitary tumors. This study aimed to examine the expression of INSM1 using immunohistochemistry, in the various cell lineages of PitNET classified by hormone secretion and transcription factor expression. INSM1 expression in PitNETs (different subtypes) and normal pituitary tissues was immunohistochemically assessed. The results were interpreted as scores of 0 (negative), 1 (focally positive), or 2 (frankly positive), depending on the proportion of cell staining. Twenty-eight of 35 PitNET cases (80%) showed INSM1 positivity in their nuclei. The staining in each histological subtype of PitNETs was as follows: somatotroph tumors, score 0 = 3/5, score 1 = 1/5, score 2 = 1/5; lactotroph tumors, score 0 = 2/5, score 1 = 1/5, score 2 = 2/5; thyrotroph tumors, score 2 = 5/5; corticotroph tumors: score 1 = 1/9, score 2 = 8/9; gonadotroph tumors, score 0 = 2/10, score 1 = 0/10, score 2 = 8/10; and unclassifiable tumor, score 1 = 1/1. INSM1 expression in most PitNETs was obtained, similar to that in the normal pituitary gland; thus, INSM1 may maintain the characteristics of anterior pituitary cells and pituitary tumors.
RÉSUMÉ
Current therapeutic modalities for pituitary neuroendocrine tumors (PitNETs) include medication, surgery, and radiotherapy. Some patients have tumors that are refractory to current modalities. Therefore, novel treatment options are needed for patients with intractable diseases. Consequently, we examined the pathological data of PitNETs to study medical therapies. We retrospectively studied 120 patients with histologically diagnosed PitNETs. We used the data for the histopathological examination of hormones, such as growth hormone (GH), prolactin (PRL), adrenocorticotropic hormone, thyroid stimulating hormone, luteinizing hormone, follicle-stimulating hormone, and α-subunit, together with the immunohistochemical studies of the phospho-mammalian target of rapamycin (mTOR), cytokeratin (CAM5.2), somatostatin receptor (SSTR) type 2 and 5, Pit-1 (POU1F1/GHF-1), steroidogenic factor-1 (SF-1), and Tpit. GH-, PRL-, and SSTR5-immunopositive PitNETs had significantly higher percentage of mTOR-positivity, compared with GH-, PRL-, and SSTR5-immunonegative Pit NETs. Our results show that activation of the AKT/phosphatidylinositol-3-kinase pathway, including mTOR activation, might be related the development of PitNETs, especially GH- and PRL-producing PitNETs. Thus, mTOR is a potential target for treating functional PitNETs.
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Coronavirus disease 2019 (COVID-19) is a novel emerging disease and a major risk factor for postoperative complications, especially in thoracic surgery. However, it is unclear how previous COVID-19 infection may affect perioperative management of lung resection patients. A 70-year-old woman visited her primary doctor complaining of chest pain. Chest computed tomography (CT) revealed three abnormal nodules in the right upper and middle lung lobes and synchronous triple primary cancer was suspected. Before we could assess the patient for surgery, she developed a persistent fever. A second chest CT scan revealed newly emerged subpleural ground-glass opacities (GGO) in the right lung. The patient was diagnosed with COVID-19 pneumonia and hospitalized. She was treated for COVID-19 (Clinical Trial: jRCTs031200196) and discharged in a satisfactory condition 10 days later. A right upper and middle bilobectomy was performed 60 days after the patient's initial COVID-19 diagnosis without any complications. Histopathological examination of the nodules identified synchronous triple primary lung cancer. The subpleural right upper and middle lung lobe tissue showed peribronchial lymphocyte infiltration and interstitial thickening. However, immunohistochemical staining for the SARS-CoV-2 antigen and PCR testing for SARS-CoV-2 were both negative. In this case, bilobectomy for triple primary lung cancer was performed safely after COVID-19 pneumonia. Further studies are needed to establish a safe and appropriate perioperative management system for thoracic surgery in patients recovering from COVID-19 pneumonia.
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We report findings from an autopsy case who died from massive bleeding because of splenic peliosis. The case subject was an 80-year-old man who had diabetes mellitus and who was receiving hemodialysis and anticoagulant therapy. Postmortem computed tomography demonstrated massive intra-abdominal hemorrhage especially seen around the spleen. At autopsy, we found abundant hemorrhagic ascites, including a large number of clots, in the abdominal cavity. The spleen had several distinct dark red areas ranging in size from 1.5 to 2.5 cm and showed spontaneous rupture along with hematoma formation on the outside of the splenic capsule on the anterior side. From these findings, we concluded that the cause of death in this case was massive hemorrhage owing to spontaneous rupture of splenic peliosis. Although peliosis itself rarely causes death, but when it is destroyed, massive bleeding leads to death. Thus, it is necessary to know the histopathological characteristics of peliosis, in forensics.
Sujet(s)
Rupture de rate , Sujet âgé de 80 ans ou plus , Autopsie , Hémopéritoine/étiologie , Humains , Mâle , Rupture spontanée , Rupture de rate/imagerie diagnostiqueRÉSUMÉ
Tuberous sclerosis (TS) is a rare disorder exhibiting multi-systemic benign neoplasms. We hypothesized the origin of TS neoplastic cells derived from the neural crest given the heterogeneous ecto-mesenchymal phenotype of the most common TS neoplasms. To test this hypothesis, we employed Cre-loxP lineage tracing of myelin protein zero (Mpz)-expressing neural crest cells (NCCs) in spontaneously developing renal tumors of Tsc2 +/- /Mpz(Cre)/TdT fl/fl reporter mice. In these mice, ectopic renal tumor onset was detected at 4 months of age increasing in volume by 16 months of age with concomitant increase in the subpopulation of tdTomato+ NCCs from 0% to 6.45% of the total number of renal tumor cells. Our results suggest that Tsc2 +/- mouse renal tumors arise from domiciled proliferative progenitor cell populations of neural crest origin that co-opt tumorigenesis due to mutations in Tsc2 loci. Targeting neural crest antigenic determinants will provide a potential alternative therapeutic approach for TS pathogenesis.
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Globally, COPD remains a major cause of disability and death. In the United States alone, it is estimated that approximately 14 million people suffer from the disease. Given the high disease burden and requirement for chronic, long-term medical care associated with COPD, it is essential that new disease modifying agents are developed to complement the symptomatic therapeutics currently available. In the present report, we have identified a potentially novel therapeutic agent through the use of a high throughput screen based on the knowledge that cigarette smoke induces the proteolytic enzyme MMP1 leading to destruction of the lung in COPD. A construct utilizing the cigarette responsive promoter element of MMP-1 was conjugated to a luciferase reporter and utilized in an in vitro assay to screen the NIH Molecular Libraries Small Molecule Repository to identify putative targets that suppressed luciferase expression in response to cigarette smoke extract (CSE). Selective serotonin reuptake inhibitors potently inhibited luciferase expression and were further validated. SSRI treatment suppressed MMP-1 production in small airway epithelial cells exposed to (CSE) in vitro as well as in smoke exposed rabbits. In addition, SSRI treatment inhibited inflammatory cytokine production while rescuing cigarette smoke induced downregulation in vivo of the anti-inflammatory lipid transporter ABCA1, previously shown by our laboratory to be lung protective. Importantly, SSRI treatment prevented lung destruction in smoke exposed rabbits as measured by morphometry. These studies support further investigation into SSRIs as a novel therapeutic for COPD may be warranted.
Sujet(s)
Fumer des cigarettes/effets indésirables , Cellules épithéliales/effets des médicaments et des substances chimiques , Poumon/effets des médicaments et des substances chimiques , Matrix metalloproteinase 1/composition chimique , Pneumopathie infectieuse/traitement médicamenteux , Emphysème pulmonaire/traitement médicamenteux , Inbiteurs sélectifs de la recapture de la sérotonine/pharmacologie , Animaux , Cellules cultivées , Cellules épithéliales/métabolisme , Cellules épithéliales/anatomopathologie , Femelle , Poumon/métabolisme , Poumon/anatomopathologie , Pneumopathie infectieuse/induit chimiquement , Pneumopathie infectieuse/enzymologie , Pneumopathie infectieuse/anatomopathologie , Emphysème pulmonaire/induit chimiquement , Emphysème pulmonaire/enzymologie , Emphysème pulmonaire/anatomopathologie , Lapins , Sérotonine/métabolismeRÉSUMÉ
BACKGROUND: Redox dysregulation originating from metabolic alterations in cancer cells contributes to their proliferation, invasion, and resistance to therapy. Conversely, these features represent a specific vulnerability of malignant cells that can be selectively targeted by redox chemotherapeutics. Amongst them, Vitamin K (VitK) carries the potential against cancer stem cells, in addition to the rest of tumor mass. OBJECTIVES: To assess the possible benefits and safety of VitK for cancer treatment using a systematic review and meta-analysis with a mixed-methods approach. METHODS: We performed a systematic search on several electronic databases for studies comparing VitK treatment with and without combination to the control groups. For quantitative studies, fully or partially reported clinical outcomes such as recurrence rates, survival, overall response and adverse reactions were assessed. For qualitative studies, a narrative synthesis was accomplished. RESULTS: Our analysis suggested that the clinical outcome of efficacy, the pooled hazard ratio for progression-free survival, and the pooled relative risk for overall survival, and overall response were significantly higher in the VitK therapy group compared to the placebo group (p<0.05). We did not observe any significant difference in the occurrence of adverse events between groups. Among qualitative studies, VitK treatment targeting myelodysplastic syndrome and advanced solid tumors resulted in 24.1% and 10% of clinical response, respectively. CONCLUSION: VitK not only exerts antitumor effects against a wide range of tumor types, but it also has excellent synergism with other therapeutic agents.
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Tumeurs , Vitamine K , Humains , Tumeurs/traitement médicamenteuxRÉSUMÉ
Recent studies of leukemic tumors in individual extramedullary sites showed they adopt the clinical and metastatic behavior of solid cancers originating in those sites. To elucidate features of leukemic tumors that render them resistant to agents effective against marrow leukemia, we analyzed a series of AML breast tumors by histology, immunohistochemistry, and RNA sequencing. Striking histologic similarities to solid cancers were found: a single-filing architectural pattern virtually identical to that of invasive lobular breast carcinoma and dense desmoplastic keloid-like fibrosis similar to colon, gallbladder, and pancreas carcinomas. Sequencing found 2157 genes significantly downregulated in AML breast tumors compared to normal breast. Comparison to triple-negative breast cancer found 859 genes similarly downregulated. At least 30 of these genes have been associated with poor prognosis in breast cancers. Five were reported in AML marrow studies to correlate with poor prognosis. The findings of this pilot study suggest the seed-and-soil interaction recognized in solid cancer growth may help explain how leukemic cells, in some patients, adopt solid tumor behavior in non-marrow sites. Transformed cells that metastasize from tumor to marrow can impart chemoresistance and be an unrecognized cause of treatment failure and death. Further studies comparing leukemic tumor to simultaneous marrow could potentially identify biomarkers that predict extramedullary resistance and lead to new therapeutic targets. Recognizing the potential for leukemia to adopt solid tumor phenotype, and implementation of body scanning and ablative tumor treatment, could decrease the persistently high rates of marrow resistance and treatment failure.
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Région mammaire/anatomopathologie , Leucémie aigüe myéloïde/anatomopathologie , Sarcome myéloïde/anatomopathologie , Protocoles de polychimiothérapie antinéoplasique/usage thérapeutique , Marqueurs biologiques tumoraux , Région mammaire/composition chimique , Tumeurs du sein/composition chimique , Tumeurs du sein/anatomopathologie , Carcinomes/anatomopathologie , Association thérapeutique , Résistance aux médicaments antinéoplasiques , Femelle , Analyse de profil d'expression de gènes , Réseaux de régulation génique , Transplantation de cellules souches hématopoïétiques , Humains , Leucémie aigüe myéloïde/génétique , Leucémie aigüe myéloïde/métabolisme , Leucémie aigüe myéloïde/thérapie , Protéines tumorales/biosynthèse , Protéines tumorales/génétique , Spécificité d'organe , Projets pilotes , Pronostic , ARN messager/analyse , ARN tumoral/analyse , Sarcome myéloïde/traitement médicamenteux , Sarcome myéloïde/génétique , Sarcome myéloïde/métabolisme , Tumeurs du sein triple-négatives/anatomopathologieRÉSUMÉ
ADAMs (a disintegrin and metalloproteinases) are involved in various biological events such as cell adhesion, migration and invasion, membrane protein shedding and proteolysis. However, there have been no systematic studies on the expression of ADAMs in human ovarian carcinomas. We therefore examined mRNA expression of all the proteolytic ADAM species including ADAM8, 9, 10, 12, 15, 17, 19, 20, 21, 28, 30, 33 and ADAMDEC1 in human ovarian carcinomas, and found that prototype membrane-anchored ADAM9m, but not secreted isoform ADAM9s, is significantly over-expressed in carcinomas than in control non-neoplastic ovarian tissue. Among the histological subtypes of serous, endometrioid, mucinous and clear cell carcinomas, ADAM9m expression was highest in clear cell carcinomas. Immunohistochemistry showed that all the clear cell carcinoma samples displayed ADAM9m primarily on the carcinoma cell membrane. By immunoblotting, ADAM9m was detected mainly in an active form in the clear cell carcinoma tissues. When two clear cell carcinoma cell lines (RMG-I and TOV21G cells) with ADAM9m expression were treated with cisplatin, viability was significantly reduced and apoptosis increased in ADAM9m knockdown cells compared with mock transfectants. In addition, treatment of the cells with neutralizing anti-ADAM9m antibody significantly decreased viability compared with non-immune IgG, whereas ADAM9m over-expression significantly increased viability compared with mock transfectants. Our data show, to the best of our knowledge, for the first time, that ADAM9m is over-expressed in an activated form in human ovarian clear cell carcinomas, and suggest that ADAM9m plays a key role in cisplatin resistance.
Sujet(s)
Protéines ADAM/génétique , Adénocarcinome à cellules claires/génétique , Antinéoplasiques/pharmacologie , Cisplatine/pharmacologie , Résistance aux médicaments antinéoplasiques , Protéines membranaires/génétique , Tumeurs de l'ovaire/génétique , Protéines ADAM/métabolisme , Adénocarcinome à cellules claires/métabolisme , Apoptose/effets des médicaments et des substances chimiques , Lignée cellulaire tumorale , Mouvement cellulaire/effets des médicaments et des substances chimiques , Femelle , Régulation de l'expression des gènes tumoraux , Techniques de knock-down de gènes , Humains , Protéines membranaires/métabolisme , Tumeurs de l'ovaire/métabolisme , Régulation positiveRÉSUMÉ
OBJECTIVE: To review studies on structural pulmonary and cardiac changes in SUDEP cases as well as studies showing pulmonary or cardiac structural changes in living epilepsy patients. METHODS: We conducted electronic literature searches using the PubMed database for articles published in English, regardless of publication year, that included data on cardiac and/or pulmonary structural abnormalities in SUDEP cases or in living epilepsy patients during the postictal period. RESULTS: Fourteen postmortem studies reported pulmonary findings in SUDEP cases. Two focused mainly on assessing lung weights in SUDEP cases versus controls; no group difference was found. The other 12 reported descriptive autopsy findings. Among all SUDEP cases with available descriptive postmortem pulmonary examination, 72% had pulmonary changes, most often pulmonary edema/congestion, and, less frequently, intraalveolar hemorrhage. Eleven studies reported on cardiac pathology in SUDEP. Cardiac abnormalities were found in approximately one-fourth of cases. The most common findings were myocyte hypertrophy and myocardial fibrosis of various degrees. Among living epilepsy patients, postictal pulmonary pathology was the most commonly reported pulmonary abnormality and the most common postictal cardiac abnormality was transient left ventricular dysfunction - Takotsubo or neurogenic stunned myocardium. SIGNIFICANCE: Cardiac and pulmonary pathological abnormalities are frequent among SUDEP cases, most commonly pulmonary edema/congestion and focal interstitial myocardial fibrosis. Most findings are not quantified, with subjective elements and undefined interobserver reliability, and lack of controls such as matched epilepsy patients who died from other causes. Further, studies have not systematically evaluated potential confounding factors, including postmortem interval to autopsy, paramedic resuscitation and IV fluids administration, underlying heart/lung disease, and risk factors for cardiac or pulmonary disease. Prospective studies with controls are needed to define the heart and lung changes in SUDEP and understand their potential relationship to mechanisms of death in SUDEP.