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Background: The glenoid labrum is a fibrocartilaginous ring that affixes the joint capsule and ligaments of the glenohumeral joint. Superior labrum anterior to posterior (SLAP) lesions are a subset of injuries that affect the superior glenoid labrum, most common in laborers and overhead-throwing athletes. In 1990, Snyder et al classified SLAP lesions into one of four types. Later, Maffet et al expanded this scale to include three additional subclassifications. At present, arthroscopy is considered the gold standard for SLAP tear diagnosis. Classification under arthroscopy has demonstrated low to moderate inter-rater reliability. Magnetic resonance arthrography (MRa) is an alternate, less invasive test for diagnosing SLAP lesions. The reliability of MRa for diagnosing slap tears is uncertain. Methods: Magnetic resonance arthrograms were identified using the Picture Archiving and Communication System (PACS). In total, 273 shoulder arthrograms were reviewed, and 20 were selected with the desired pathology. Three orthopedic surgeons and three musculoskeletal radiologists were asked to classify the SLAP lesions into one of seven categories (Snyder & Maffet classification systems). Data was collected on two separate occasions at an interval of at least two months. Inter-rater and intrarater reliability were calculated using Fleiss Kappa and Cohen's Kappa, respectively. Results: Between all raters, there was poor inter-rater reliability for each round of data collection (κ = .177, κ = .124 for rounds 1 and 2, respectively). Between orthopedic surgeons, there were poor levels of agreement (κ = -.056, κ = .114), whereas, between radiologists, there was fair to moderate agreement (κ = 0.479, κ = 0.340). Within orthopedic raters, κ values ranged from -0.059 to 0.125, indicating, at best, poor intrarater reliability. Within radiologists, κ values ranged from 0.545 to 0.553, indicating moderate agreement within raters. The analysis determined that none of the orthopedic values for inter or intrarater reliability could be deemed statistically different from zero. Conclusion: Overall, classification using MRa resulted in significant disagreement between and within raters. Trained radiologists demonstrated higher overall levels of agreement than orthopedic surgeons. In summary, when using MRa to assess SLAP lesions, Snyder and Maffet classification demonstrates poor reliability by orthopedic surgeons and moderate reliability when used by musculoskeletal radiologists.

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PURPOSE: The current subclassifications of dry eye disease (DED) are aqueous deficient (ADDE) and evaporative (EDE) forms, but there lacks consistency in the clinical characteristics used to define each of these. This study used clinical data to inform cut-off values for the subclassification of ADDE and EDE, to allow more consistent study of the epidemiology of both DED subtypes. METHODS: The study enrolled 261 residents from the UK, extracted from a cohort with demographics representing the population (mean 42.4 ± 18.7 years, 56 % females). The TFOS DEWS II diagnostic criteria were used to identify those with DED. Meibomian gland loss/drop-out (from meibography), lipid layer thickness (LLT - from interferometry graded on the Guillon-Keeler scale), and tear meniscus height (TMH - Keratograph 5M) along with tear evaporation (Delfin Vapometer) were used to characterise the subclassification. The Dry Eye Risk Factor Survey was used to assess risk factors associated with each DED subtype. RESULTS: Compared to individuals who were not diagnosed with DED, EDE was characterized by signs of meibomian gland loss of > 28 %, LLT grade < 3 and tear evaporation > 46 g/m2/h. In contrast, ADDE was best characterized by a reduced TMH < 0.2 mm. Based on these criteria, the prevalence of ADDE was 6.2 %, EDE was 64.2 %, and 11.1 % exhibited features of both ADDE and EDE, with 18.5 % unclassified despite having a DED diagnosis. Contact lens wear and computer use were risk factors for ADDE (p < 0.05), whereas age was a positive risk factor for EDE (p < 0.01). Meibomian gland loss (occurring in 27.9 %) was the most commonly observed sign in EDE. CONCLUSIONS: Data driven-classification of DED confirms that the evaporative form is most prevalent and identified that in a generalisable UK population, ADDE alone occurs only in approximately 1 in 16 cases of DED.

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Síndromes de Ojo Seco , Glándulas Tarsales , Lágrimas , Humanos , Síndromes de Ojo Seco/epidemiología , Síndromes de Ojo Seco/diagnóstico , Síndromes de Ojo Seco/clasificación , Femenino , Masculino , Adulto , Persona de Mediana Edad , Glándulas Tarsales/patología , Factores de Riesgo , Reino Unido/epidemiología , Anciano , Adulto Joven , Prevalencia

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INTRODUCTION: Current molecular research has shown the several oncogenic pathways that give rise to the peripheral T-cell lymphoma, not otherwise defined (PTCL, NOS) subtypes, which alter prognosis and might have predictive value. This study was conducted to assess the immunohistochemistry (IHC) algorithm by Amador et al for the subtyping of PTCL, NOS and determine its applicability in relation to the clinicopathological profile. METHODS: This study included 43 patients with PTCL, NOS diagnosis. Following the use of IHC for the transcription factors GATA3, TBX21, CCR4, and CXCR3, two pathologists subtyped the samples. Comprehensive clinicopathological correlation was carried out. RESULTS: Applying the algorithm of Amador et al., cases were classified into GATA3 (20), TBX21 (15), and unclassified (8) subtypes. No significant association with clinical parameters of subtypes or CD4/ CD8 positivity was observed. Although a higher proportion of cases in the TBX21 subgroup showed a polymorphic population compared with the GATA3 subgroup, which had a monomorphic population, no significant p-value (0.111) was observed. Two Lennert lymphomas were classified into the GATA3 subgroup. Multivariate analysis showed no significant difference in overall survival (p-value = 0.105) and progression-free survival (p-value = 0.0509) between IHC-defined subtypes; trends indicate that overall survival and progression-free survival are worse in the GATA3 subgroup. CONCLUSION: Although the algorithm is reproducible, a proportion of cases remains unclassifiable and may require additional investigation and gene expression profiling. The GATA3 subgroup was found to have a monomorphic population with a poor overall prognosis and thus requires a larger sample size for validation.

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The GeneCaRNA human gene database is a member of the GeneCards Suite. It presents ~280,000 human non-coding RNA genes, identified algorithmically from ~690,000 RNAcentral transcripts. This expands by ~tenfold the ncRNA gene count relative to other sources. GeneCaRNA thus contains ~120,000 long non-coding RNAs (LncRNAs, >200 bases long), including ~100,000 novel genes. The latter have sparse functional information, a vast terra incognita for future research. LncRNA genes are uniformly represented on all nuclear chromosomes, with 10 genes on mitochondrial DNA. Data obtained from MalaCards, another GeneCards Suite member, finds 1547 genes associated with 1 to 50 diseases. About 15% of the associations portray experimental evidence, with cancers tending to be multigenic. Preliminary text mining within GeneCaRNA discovers interactions of lncRNA transcripts with target gene products, with 25% being ncRNAs and 75% proteins. GeneCaRNA has a biological pathways section, which at present shows 131 pathways for 38 lncRNA genes, a basis for future expansion. Finally, our GeneHancer database provides regulatory elements for ~110,000 lncRNA genes, offering pointers for co-regulated genes and genetic linkages from enhancers to diseases. We anticipate that the broad vista provided by GeneCaRNA will serve as an essential guide for further lncRNA research in disease decipherment.

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Extracellular vesicles (EVs) in biofluids are highly heterogeneous entities in terms of their origins and physicochemical properties. Considering the application of EVs in diagnostic and therapeutic fields, it is of extreme importance to establish differentiating methods by which focused EV subclasses are operationally defined. Several differentiation protocols have been proposed; however, they have mainly focused on smaller types of EVs, and the heterogeneous nature of large EVs has not yet been fully explored. In this report, to classify large EVs into subgroups based on their physicochemical properties, we have developed a protocol, named EV differentiation by sedimentation patterns (ESP), in which entities in the crude large EV fraction are first moved through a density gradient of iodixanol with small centrifugation forces, and then the migration patterns of molecules through the gradients are analysed using a non-hierarchical data clustering algorithm. Based on this method, proteins in the large EV fractions of oral fluids clustered into three groups: proteins shared with small EV cargos and enriched in immuno-related proteins (Group 1), proteins involved in energy metabolism and protein synthesis (Group 2), and proteins required for vesicle trafficking (Group 3). These observations indicate that the physiochemical properties of EVs, which are defined through low-speed gradient centrifugation, are well associated with their functions within cells. This protocol enables the detailed subclassification of EV populations that are difficult to differentiate using conventional separation methods.

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Intraductal papillary neoplasm of the bile duct (IPNB) is a heterogeneous disease similar to intraductal papillary mucinous neoplasm of the pancreas. These lesions have been recognized as one of the three major precancerous lesions in the biliary tract since 2010. In 2018, Japanese and Korean pathologists reached a consensus, classifying IPNBs into type l and type 2 IPNBs. IPNBs are more prevalent in male patients in East Asia and are closely related to diseases such as cholelithiasis and schistosomiasis. From a molecular genetic perspective, IPNBs exhibit early genetic variations, and different molecular pathways may be involved in the tumorigenesis of type 1 and type 2 IPNBs. The histological subtypes of IPNBs include gastric, intestinal, pancreaticobiliary, or oncocytic subtypes, but type 1 IPNBs typically exhibit more regular and well-organized histological features than type 2 IPNBs and are more commonly found in the intrahepatic bile ducts with abundant mucin. Due to the rarity of these lesions and the absence of specific clinical and laboratory features, imaging is crucial for the preoperative diagnosis of IPNB, with local bile duct dilation and growth along the bile ducts being the main imaging features. Surgical resection remains the optimal treatment for IPNBs, but negative bile duct margins and the removal of lymph nodes in the hepatic hilum significantly improve the postoperative survival rates for patients with IPNBs.

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Neoplasias de los Conductos Biliares , Humanos , Neoplasias de los Conductos Biliares/patología , Neoplasias de los Conductos Biliares/genética , Carcinoma Papilar/patología , Carcinoma Papilar/genética , Masculino , Conductos Biliares Intrahepáticos/patología , Conductos Biliares/patología

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Lung cancer is still one of the deadliest malignancies today, and most patients with advanced lung cancer pass away from disease progression that is uncontrollable by medications. Super-enhancers (SEs) are large clusters of enhancers in the genome's non-coding sequences that actively trigger transcription. Although SEs have just been identified over the past 10 years, their intricate structure and crucial role in determining cell identity and promoting tumorigenesis and progression are increasingly coming to light. Here, we review the structural composition of SEs, the auto-regulatory circuits, the control mechanisms of downstream genes and pathways, and the characterization of subgroups classified according to SEs in lung cancer. Additionally, we discuss the therapeutic targets, several small-molecule inhibitors, and available treatment options for SEs in lung cancer. Combination therapies have demonstrated considerable advantages in preclinical models, and we anticipate that these drugs will soon enter clinical studies and benefit patients.

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Evidence from the Oxford IgA nephropathy (IgAN) cohort supports the clinical value of subclassifying focal segmental glomerulosclerosis lesions (S1). Using the larger Validation in IgA (VALIGA) study cohort, we investigated the association between podocytopathic changes and higher proteinuria, kidney outcome and response to immunosuppressive therapy. All biopsies were evaluated for glomeruli with segmental capillary occlusion by matrix ("not otherwise specified", NOS lesion), simple capsular adhesion without capillary occlusion (Adh), tip lesions, and podocyte hypertrophy (PH). S1 required a NOS lesion and/or Adh. A Chi-Squared Automatic Interaction Detection method was used to identify subgroups of FSGS lesions associated with distinctive proteinuria at biopsy. We assessed survival from a combined event (kidney failure or 50% decline in estimated glomerular filtration rate). Finally, we evaluated within each subgroup if immunosuppression was associated with a favorable outcome using propensity analysis. In 1147 patients, S1 was found in 70% of biopsies. Subclassification found NOS lesions in 44%, Adh in 59%, PH in 13%, and tip lesions in 3%, with much overlap. Four subgroups were identified with progressively higher proteinuria: from lowest, S1 without NOS, S1 with NOS but without Adh/PH, to highest, S1 with NOS and Adh but without PH, and S1 with NOS and PH. These four subgroups showed progressively worse kidney survival. Immunosuppression was associated with a better outcome only in the two highest proteinuria subgroups. Propensity analysis in these two groups, adjusted for clinical and pathological findings, found a significantly reduced time-dependent hazard of combined outcome with corticosteroids. Podocyte hypertrophy and glomeruli with simple adhesions appeared to reflect active lesions associated with a response to corticosteroids, while other S1 lesions defined chronicity. Thus, our findings support subclassifying S1 lesions in IgAN.

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Tasa de Filtración Glomerular , Glomerulonefritis por IGA , Glomeruloesclerosis Focal y Segmentaria , Inmunosupresores , Proteinuria , Humanos , Glomerulonefritis por IGA/patología , Glomerulonefritis por IGA/clasificación , Glomerulonefritis por IGA/diagnóstico , Glomerulonefritis por IGA/inmunología , Glomeruloesclerosis Focal y Segmentaria/patología , Glomeruloesclerosis Focal y Segmentaria/clasificación , Glomeruloesclerosis Focal y Segmentaria/inmunología , Masculino , Femenino , Adulto , Proteinuria/etiología , Proteinuria/patología , Biopsia , Persona de Mediana Edad , Inmunosupresores/uso terapéutico , Podocitos/patología , Podocitos/inmunología , Glomérulos Renales/patología , Glomérulos Renales/inmunología , Hipertrofia , Progresión de la Enfermedad , Resultado del Tratamiento

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BACKGROUND: Whether T2 esophageal squamous cell carcinoma should be subclassified remains controversial. We aimed to investigate the impact of the depth of muscularis propria invasion on nodal status and survival outcomes. METHODS: We identified patients with pT2 esophageal squamous cell carcinoma who underwent primary surgery from January 2009 to June 2017. Clinical data were extracted from prospectively maintained databases. Tumor muscularis propria invasion was stratified into superficial or deep. Binary logistic regression was used to determine risk factors for lymph node metastases. The impact of the depth of muscularis propria invasion on survival was investigated using Kaplan‒Meier analysis and a Cox proportional hazard regression model. RESULTS: A total of 750 patients from three institutes were investigated. The depth of muscularis propria invasion (odds ratio [OR]: 3.95, 95% confidence interval [CI]: 2.46-6.35; p < 0.001) was correlated with lymph node metastases using logistic regression. T substage (hazard ratio [HR]: 1.37, 95% CI: 1.05-1.79; p < 0.001) and N status (HR: 1.51, 95% CI: 1.05-2.17; p < 0.001) were independent risk factors in multivariate Cox regression analysis. The deep muscle invasion was associated with worse overall survival (HR: 1.52, 95% CI: 1.19-1.94; p = 0.001) than superficial, specifically in T2N0 patients (HR: 1.38, 95% CI: 1.08-1.94; p = 0.035). CONCLUSIONS: We found that deep muscle invasion was associated with significantly worse outcomes and recommended the substaging of pT2 esophageal squamous cell carcinoma in routine pathological examination.

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Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Metástasis Linfática , Invasividad Neoplásica , Humanos , Masculino , Femenino , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/mortalidad , Neoplasias Esofágicas/cirugía , Persona de Mediana Edad , Carcinoma de Células Escamosas de Esófago/patología , Carcinoma de Células Escamosas de Esófago/cirugía , Carcinoma de Células Escamosas de Esófago/mortalidad , Anciano , Tasa de Supervivencia , Estudios Retrospectivos , Esofagectomía , Estadificación de Neoplasias , Estudios de Seguimiento , Pronóstico , Ganglios Linfáticos/patología , Ganglios Linfáticos/cirugía , Estudios Prospectivos

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Background and purpose: Perforator artery disease (PAD) is an important subtype of ischemic stroke. The risk factors affecting the prognosis of patients with PAD are unclear. This study aimed to investigate the risk factors affecting the unfavorable prognosis of PAD. Methods: Patients with PAD were enrolled from Dushu Lake Hospital Affiliated to Soochow University and diagnosed as stroke with PAD during the period from September 2021 to July 2023 and followed up with a modified Rankin Scale (mRS) after 90 days, defining the mRS of 0-2 as a group with favorable prognosis, and 3-6 as a group with unfavorable functional outcome. Logistic regression was used to identify predictors for PAD. Multiple logistic regression analysis and receiver operating characteristics (ROC) were used to identify predictors of unfavorable prognosis. Results: Of the 181 enrolled patients, 48 (26.5%) were identified with unfavorable prognosis. On multivariate analysis, increased age (OR = 1.076, 95% CI: 1.012 ~ 1.144, p = 0.019), higher National Institutes of Health Stroke Scale (NIHSS) score at admission (OR = 2.930, 95% CI: 1. 905 ~ 4.508, p < 0.001), and increased neutrophil-to-lymphocyte ratio (NLR) (OR = 3.028, 95% CI: 1.615 ~ 5.675, p = 0.001) were independent risk factors for unfavorable prognosis in patients with PAD, and the area under the receiver operating characteristic curve was 0.590, 0.905, and 0.798, and the multi-factor diagnostic model (Model 2) showed reliable diagnostic specificity and sensitivity (area under the curve = 0.956, p < 0.001, specificity 0.805, sensitivity 0.958, accuracy 0.845). Conclusion: Increased baseline NLR and NIHSS score and aging may be independent risk factors for unfavorable prognosis of patients with PAD. NLR can be used as a potential biological indicator to predict the prognosis of stroke with PAD.

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BACKGROUND: Intermediate-stage hepatocellular carcinoma (BCLC B HCC) occurs in a heterogeneous group of patients and can be addressed with a wide spectrum of treatments. Consequently, survival significantly varies among patients. In recent years, several subclassification systems have been proposed to stratify patients' prognosis. We analyzed and compared these systems (Bolondi, Yamakado, Kinki, Wang, Lee, and Kim criteria) in patients undergoing systemic therapy. METHODS: We considered 171 patients with BCLC B HCC treated with sorafenib as first-line systemic therapy in six Italian centers from 2010 to 2021 and retrospectively applied the criteria of six different subclassification systems. RESULTS: Except for the Yamakado criteria, all the subclassification systems showed a statistically significant correlation to overall survival (OS). In the postestimation analysis, the Bolondi criteria (OS of subgroups 22.5, 11.9, and 6.6 mo, respectively; C-index 0.586; AIC 1338; BIC 1344) and the Wang criteria (OS of subgroups 20.6, 11.9, and 7.0, respectively; C-index 0.607; AIC 1337; BIC 1344) presented the best accuracy. Further analyses of these two subclassification systems implemented with the prognostic factor of alpha-fetoprotein (AFP) > 400 ng/mL have shown an increase in accuracy for both systems (C-index 0.599 and 0.624, respectively). CONCLUSIONS: Intermediate-stage subclassification systems maintain their predictive value also in the setting of systemic therapy. The Bolondi and Wang criteria showed the highest accuracy. AFP > 400 ng/mL enhances the performance of these systems.

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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , alfa-Fetoproteínas , Estudios Retrospectivos , Estadificación de Neoplasias

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BACKGROUND: Intravascular inflammation and an antiangiogenic state have been implicated in the pathophysiology of preeclampsia. On the basis of the profiles of their angiogenic/antiangiogenic factors, women with preeclampsia at term may be classified into 2 subgroups with different characteristics and prevalence of adverse outcomes. This study was undertaken to examine whether these 2 subgroups of preeclampsia at term also show differences in their profiles of intravascular inflammation. OBJECTIVE: This study aimed to determine the plasma profiles of cytokines and chemokines in women with preeclampsia at term who had a normal or an abnormal angiogenic profile. STUDY DESIGN: A nested case-control study was conducted to include women classified into 3 groups: women with an uncomplicated pregnancy (n=213) and women with preeclampsia at term with a normal (n=55) or an abnormal (n=41) angiogenic profile. An abnormal angiogenic profile was defined as a plasma ratio of placental growth factor and soluble fms-like tyrosine kinase-1 multiple of the median <10th percentile for gestational age. Concentrations of cytokines were measured by multiplex immunoassays. RESULTS: Women with preeclampsia at term and an abnormal angiogenic profile showed evidence of the greatest intravascular inflammation among the study groups. These women had higher plasma concentrations of 5 cytokines (interleukin-6, interleukin-8, interleukin-12/interleukin-23p40, interleukin-15, and interleukin-16) and 7 chemokines (eotaxin, eotaxin-3, interferon-γ inducible protein-10, monocyte chemotactic protein-4, macrophage inflammatory protein-1ß, macrophage-derived chemokine, and thymus and activation-regulated chemokine compared to women with an uncomplicated pregnancy. By contrast, women with preeclampsia at term and a normal angiogenic profile, compared to women with an uncomplicated pregnancy, had only a higher plasma concentration of monocyte chemotactic protein-4. A correlation between severity of the antiangiogenic state, blood pressure, and plasma concentrations of a subset of cytokines was observed. CONCLUSION: Term preeclampsia can be classified into 2 clusters. One is characterized by an antiangiogenic state coupled with an excessive inflammatory process, whereas the other has neither of these features. These findings further support the heterogeneity of preeclampsia at term and may explain the distinct clinical outcomes.

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Preeclampsia , Embarazo , Femenino , Humanos , Factor de Crecimiento Placentario , Citocinas , Estudios de Casos y Controles , Inductores de la Angiogénesis , Biomarcadores , Inflamación , Proteínas Quimioatrayentes de Monocitos , Receptor 1 de Factores de Crecimiento Endotelial Vascular

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OBJECTIVE: The population with pathological T3 (pT3) upper tract urothelial carcinoma (UTUC) is heterogeneous, thereby making prognostication challenging. We assessed the clinical ramifications of subclassifying pT3 UTUC after nephroureterectomy. METHODS: We conducted a retrospective analysis including 308 patients who underwent nephroureterectomy for pT3N0-1M0 UTUC. pT3 was subclassified into pT3a and pT3b based on invasion of the peripelvic and/or periureteral fat. Cox's proportional hazard models were utilized to determine the significant prognosticators of oncological outcomes, encompassing intravesical recurrence-free survival, recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival. RESULTS: Multivariate analysis elucidated that pT3b status, pathological N1 status, and lymphovascular invasion status were independent risk factors for an unfavorable RFS and CSS. Although the RFS and CSS of patients with pT3b UTUC were superior to those in patients with pT4 UTUC, no significant disparities were detected between patients with pT3a and pT2. CONCLUSION: Our findings demonstrate that pT3 UTUC with peripelvic/periureteral fat invasion is independently associated with metastasis and cancer-specific death after nephroureterectomy. These findings provide patients and physicians with invaluable insight into the risk for disease progression in pT3 UTUC patients.

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Carcinoma de Células Transicionales , Neoplasias de la Vejiga Urinaria , Neoplasias Urológicas , Humanos , Pronóstico , Carcinoma de Células Transicionales/patología , Estudios Retrospectivos , Nefroureterectomía/métodos , Neoplasias Urológicas/patología

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INTRODUCTION: Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous entity. Lately, several algorithms achieving therapeutically and prognostically relevant DLBCL subclassification have been published. METHODS: A cohort of 74 routine DLBCL cases was broadly characterized by immunohistochemistry (IHC), fluorescence in situ hybridization (FISH) of the BCL2, BCL6, and MYC loci, and comprehensive high-throughput sequencing (HTS). Based on the genetic alterations found, cases were reclassified using two probabilistic tools - LymphGen and Two-step classifier, allowing for comparison of the two models. RESULTS: Hans and Tally's overall IHC-based subclassification success rate was 96% and 82%, respectively. HTS and FISH data allowed the LymphGen algorithm to successfully classify 11/55 cases (1 - BN2, 7 - EZB, 1 - MCD, and 2 - genetically composite EZB/N1). The total subclassification rate was 20%. On the other hand, the Two-step classifier categorized 36/55 cases, with 65.5% success (9 - BN2, 12 - EZB, 9 - MCD, 2 - N1, and 4 - ST2). Clinical correlations highlighted MCD as an aggressive subtype associated with higher relapse and mortality. CONCLUSIONS: The Two-step algorithm has a better success rate at subclassifying DLBCL cases based on genetic differences. Further improvement of the classifiers is required to increase the number of classifiable cases and thus prove their applicability in routine diagnostics.

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Secuenciación de Nucleótidos de Alto Rendimiento , Hibridación Fluorescente in Situ , Linfoma de Células B Grandes Difuso , Humanos , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/clasificación , Linfoma de Células B Grandes Difuso/patología , Masculino , Femenino , Persona de Mediana Edad , Anciano , Adulto , Inmunohistoquímica , Proteínas Proto-Oncogénicas c-bcl-2/genética , Anciano de 80 o más Años , Algoritmos , Proteínas Proto-Oncogénicas c-bcl-6/genética , Biomarcadores de Tumor/genética , Estudios de Cohortes , Pronóstico , Proteínas Proto-Oncogénicas c-myc/genética

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BACKGROUND: Sepsis is a highly heterogeneous syndrome, which has hindered the development of effective therapies. This has prompted investigators to develop a precision medicine approach aimed at identifying biologically homogenous subgroups of patients with septic shock and critical illnesses. Transcriptomic analysis can identify subclasses derived from differences in underlying pathophysiological processes that may provide the basis for new targeted therapies. The goal of this study was to elucidate pathophysiological pathways and identify pediatric septic shock subclasses based on whole blood RNA expression profiles. METHODS: The subjects were critically ill children with cardiopulmonary failure who were a part of a prospective randomized insulin titration trial to treat hyperglycemia. Genome-wide expression profiling was conducted using RNA sequencing from whole blood samples obtained from 46 children with septic shock and 52 mechanically ventilated noninfected controls without shock. Patients with septic shock were allocated to subclasses based on hierarchical clustering of gene expression profiles, and we then compared clinical characteristics, plasma inflammatory markers, cell compositions using GEDIT, and immune repertoires using Imrep between the two subclasses. RESULTS: Patients with septic shock depicted alterations in innate and adaptive immune pathways. Among patients with septic shock, we identified two subtypes based on gene expression patterns. Compared with Subclass 2, Subclass 1 was characterized by upregulation of innate immunity pathways and downregulation of adaptive immunity pathways. Subclass 1 had significantly worse clinical outcomes despite the two classes having similar illness severity on initial clinical presentation. Subclass 1 had elevated levels of plasma inflammatory cytokines and endothelial injury biomarkers and demonstrated decreased percentages of CD4 T cells and B cells and less diverse T cell receptor repertoires. CONCLUSIONS: Two subclasses of pediatric septic shock patients were discovered through genome-wide expression profiling based on whole blood RNA sequencing with major biological and clinical differences. Trial Registration This is a secondary analysis of data generated as part of the observational CAF-PINT ancillary of the HALF-PINT study (NCT01565941). Registered March 29, 2012.

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Sepsis , Choque Séptico , Niño , Humanos , Perfilación de la Expresión Génica , Estudios Prospectivos , Sepsis/genética , Choque Séptico/terapia , Transcriptoma , Ensayos Clínicos Controlados Aleatorios como Asunto , Estudios Observacionales como Asunto

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Background: Sepsis is a highly heterogeneous syndrome, that has hindered the development of effective therapies. This has prompted investigators to develop a precision medicine approach aimed at identifying biologically homogenous subgroups of patients with septic shock and critical illnesses. Transcriptomic analysis can identify subclasses derived from differences in underlying pathophysiological processes that may provide the basis for new targeted therapies. The goal of this study was to elucidate pathophysiological pathways and identify pediatric septic shock subclasses based on whole blood RNA expression profiles. Methods: The subjects were critically ill children with cardiopulmonary failure who were a part of a prospective randomized insulin titration trial to treat hyperglycemia. Genome-wide expression profiling was conducted using RNA-sequencing from whole blood samples obtained from 46 children with septic shock and 52 mechanically ventilated noninfected controls without shock. Patients with septic shock were allocated to subclasses based on hierarchical clustering of gene expression profiles, and we then compared clinical characteristics, plasma inflammatory markers, cell compositions using GEDIT, and immune repertoires using Imrep between the two subclasses. Results: Patients with septic shock depicted alterations in innate and adaptive immune pathways. Among patients with septic shock, we identified two subtypes based on gene expression patterns. Compared with Subclass 2, Subclass 1 was characterized by upregulation of innate immunity pathways and downregulation of adaptive immunity pathways. Subclass 1 had significantly worse clinical outcomes despite the two classes having similar illness severity on initial clinical presentation. Subclass 1 had elevated levels of plasma inflammatory cytokines and endothelial injury biomarkers and demonstrated decreased percentages of CD4 T cells and B cells, and less diverse T-Cell receptor repertoires. Conclusions: Two subclasses of pediatric septic shock patients were discovered through genome-wide expression profiling based on whole blood RNA sequencing with major biological and clinical differences. Trial Registration: This is a secondary analysis of data generated as part of the observational CAF PINT ancillary of the HALF PINT study (NCT01565941). Registered 29 March 2012.

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BACKGROUND: Heterogeneity in clinical manifestation and underlying neuro-biological mechanisms are major obstacles to providing personalized interventions for individuals with autism spectrum disorder (ASD). Despite various efforts to unify disparate data modalities and machine learning techniques for subclassification, replicable ASD clusters remain elusive. Our study aims to introduce a novel method, utilizing the objective behavioral biomarker of gaze patterns during joint attention, to subclassify ASD. We will assess whether behavior-based subgrouping yields clinically, genetically, and neurologically distinct ASD groups. METHODS: We propose a study involving 60 individuals with ASD recruited from a specialized psychiatric clinic to perform joint attention tasks. Through the examination of gaze patterns in social contexts, we will conduct a semi-supervised clustering analysis, yielding two primary clusters: good gaze response group and poor gaze response group. Subsequent comparison will occur across these clusters, scrutinizing neuroanatomical structure and connectivity using structural as well as functional brain imaging studies, genetic predisposition through single nucleotide polymorphism data, and assorted socio-demographic and clinical information. CONCLUSIONS: The aim of the study is to investigate the discriminative properties and the validity of the joint attention-based subclassification of ASD using multi-modality data. TRIAL REGISTRATION: Clinical trial, KCT0008530, Registered 16 June 2023, https://cris.nih.go.kr/cris/index/index.do .

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Trastorno del Espectro Autista , Humanos , Trastorno del Espectro Autista/diagnóstico , Trastorno del Espectro Autista/psicología , Biomarcadores , Señales (Psicología) , Medio Social , Neuroimagen Funcional

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Preclinical meningioma models offer a setting to test molecular mechanisms of tumor development and targeted treatment options but historically have been challenging to generate. Few spontaneous tumor models in rodents have been established, but cell culture and in vivo rodent models have emerged along with artificial intelligence, radiomics, and neural networks to differentiate the clinical heterogeneity of meningiomas. We reviewed 127 studies using PRISMA guideline methodology, including laboratory and animal studies, that addressed preclinical modeling. Our evaluation identified that meningioma preclinical models provide valuable molecular insight into disease progression and effective chemotherapeutic and radiation approaches for specific tumor types.

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Neoplasias Meníngeas , Meningioma , Animales , Humanos , Meningioma/terapia , Neoplasias Meníngeas/terapia , Inteligencia Artificial , Progresión de la Enfermedad

RESUMEN

INTRODUCTION: This study aims to investigate the feasibility and reliability of ThinPrep slides in detecting the subclassification of lung cancer and develop a process for immunocytochemistry (ICC) with optimized staining steps of an automated immunostainer. METHODS: Cytomorphology and ancillary ICC by automated immunostainer on ThinPrep slides were performed to subclassify 271 cytology cases of pulmonary tumor, which were stained with 2 or more of the following antibodies: p40, p63, thyroid transcription factor-1 (TTF-1), Napsin A, synaptophysin (Syn), and CD56. RESULTS: The accuracy of cytological subtyping was improved from 67.2% to 92.7% (p < .0001) after ICC. The accuracy of cytomorphology combined with ICC results for lung squamous-cell carcinoma (LUSC), lung adenocarcinomas (LUAD), and small cell carcinoma (SCLC) was 89.5% (51 of 57), 97.8% (90 of 92), and 98.8% (85 of 86), respectively. The sensitivity and specificity of 6 antibodies were as follows: p63 (91.2%, 90.4%) and p40 (84.2%, 95.1%) for LUSC, TTF-1(95.6%, 64.6%) and Napsin A (89.7%, 96.7%) for LUAD and Syn (90.7%, 60.0%) and CD56 (97.7%, 50.0%) for SCLC, respectively. P40 expression on ThinPrep slides had the highest agreement (κ = 0.881) with immunohistochemistry (IHC) results, followed by p63 (κ = 0.873), Napsin A (κ = 0.795), TTF-1 (κ = 0.713), CD56 (κ = 0.576), and Syn (κ = 0.491). CONCLUSION: The result of ancillary ICC on ThinPrep slides by fully automated immunostainer was in good agreement with the gold standard in pulmonary tumors subtype and immunoreactivity, objectively achieving accurate subtyping in cytology.

Asunto(s)

Adenocarcinoma del Pulmón , Carcinoma de Pulmón de Células no Pequeñas , Carcinoma de Células Pequeñas , Carcinoma de Células Escamosas , Neoplasias Pulmonares , Carcinoma Pulmonar de Células Pequeñas , Humanos , Reproducibilidad de los Resultados , Factores de Transcripción/metabolismo , Biomarcadores de Tumor/metabolismo , Neoplasias Pulmonares/patología , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma Pulmonar de Células Pequeñas/patología , Carcinoma de Células Escamosas/patología

RESUMEN

Introduction: Papillary thyroid cancer (PTC) is the most common endocrine malignancy. However, different PTC variants reveal high heterogeneity at histological, cytological, molecular and clinicopathological levels, which complicates the precise diagnosis and management of PTC. Alternative splicing (AS) has been reported to be potential cancer biomarkers and therapeutic targets. Method: Here, we aim to find a more sophisticated molecular subclassification and characterization for PTC by integrating AS profiling. Based on six differentially expressed alternative splicing (DEAS) events, a new molecular subclassification was proposed to reclassify PTC into three new groups named as Cluster0, Cluster1 and Cluster2 respectively. Results: An in silico prediction was performed for accurate recognition of new groups with the average accuracy of 91.2%. Moreover, series of analyses were implemented to explore the differences of clinicopathology, molecular and immune characteristics across them. It suggests that there are remarkable differences among them, but Cluster2 was characterized by poor prognosis, higher immune heterogeneity and more sensitive to anti-PD1 therapy. The splicing correlation networks proved the complicated regulation relationships between AS events and splicing factors (SFs). An independent prognostic indicator for PTC overall survival (OS) was established. Finally, three compounds (orantinib, tyrphostin-AG-1295 and AG-370) were discovered to be the potential therapeutic agents. Discussion: Overall, the six DEAS events are not only potential biomarkers for precise diagnosis of PTC, but also the probable prognostic predictors. This research would be expected to highlight the effect of AS events on PTC characterization and also provide new insights into refining precise subclassification and improving medical therapy for PTC patients.