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Endothelin receptors: receptor classification, novel receptor antagonists, and potential therapeutic targets.

The development of endothelin receptor antagonists has progressed rapidly since the initial discovery of endothelin. Highly potent, orally active nonpeptide endothelin receptor antagonists have been identified, and are being used as pharmacological tools to elucidate the role of endothelin in pathological disorders. Subtype selective endothelin receptor antagonists will also be useful in understanding the physiological and pathological roles of the different subtypes of the endothelin receptors. The selectivity profile for the ideal endothelin receptor antagonist is presently unknown, and it may actually be that the optimal profile for a compound may depend on the clinical indication. In the near future, data from clinical trials with endothelin receptor antagonists will become available and will help to establish the role of endothelin in the etiology of human disease, as well as to provide valuable information concerning the optimum endothelin receptor subtype selectivity for antagonists needed for therapeutic agents.

Amino Acid Sequence↗

Automated Classification of Lymphoma Subtypes From Histopathological Images Using a U-Net Deep Learning Model: Comparative Evaluation Study.

BACKGROUND: Accurate classification and grading of lymphoma subtypes are essential for treatment planning. Traditional diagnostic methods face challenges of subjectivity and inefficiency, highlighting the need for automated solutions based on deep learning techniques. OBJECTIVE: This study aimed to investigate the application of deep learning technology, specifically the U-Net model, in classifying and grading lymphoma subtypes to enhance diagnostic precision and efficiency. METHODS: In this study, the U-Net model was used as the primary tool for image segmentation integrated with attention mechanisms and residual networks for feature extraction and classification. A total of 620 high-quality histopathological images representing 3 major lymphoma subtypes were collected from The Cancer Genome Atlas and the Cancer Imaging Archive. All images underwent standardized preprocessing, including Gaussian filtering for noise reduction, histogram equalization, and normalization. Data augmentation techniques such as rotation, flipping, and scaling were applied to improve the model's generalization capability. The dataset was divided into training (70%), validation (15%), and test (15%) subsets. Five-fold cross-validation was used to assess model robustness. Performance was benchmarked against mainstream convolutional neural network architectures, including fully convolutional network, SegNet, and DeepLabv3+. RESULTS: The U-Net model achieved high segmentation accuracy, effectively delineating lesion regions and improving the quality of input for classification and grading. The incorporation of attention mechanisms further improved the model's ability to extract key features, whereas the residual structure of the residual network enhanced classification accuracy for complex images. In the test set (N=1250), the proposed fusion model achieved an accuracy of 92% (1150/1250), a sensitivity of 91.04% (1138/1250), a specificity of 89.04% (1113/1250), and an F1-score of 90% (1125/1250) for the classification of the 3 lymphoma subtypes, with an area under the receiver operating characteristic curve of 0.95 (95% CI 0.93-0.97). The high sensitivity and specificity of the model indicate strong clinical applicability, particularly as an assistive diagnostic tool. CONCLUSIONS: Deep learning techniques based on the U-Net architecture offer considerable advantages in the automated classification and grading of lymphoma subtypes. The proposed model significantly improved diagnostic accuracy and accelerated pathological evaluation, providing efficient and precise support for clinical decision-making. Future work may focus on enhancing model robustness through integration with advanced algorithms and validating performance across multicenter clinical datasets. The model also holds promise for deployment in digital pathology platforms and artificial intelligence-assisted diagnostic workflows, improving screening efficiency and promoting consistency in pathological classification.

Humans↗

Basal cell adenoma of the parotid gland: characteristics of 2-phase helical computed tomography and magnetic resonance imaging.

OBJECTIVE: The goal of this study was to report the radiologic characteristics of basal cell adenoma of the parotid gland, which is a relatively rare neoplasm. METHODS: A radiology and otolaryngology specialist reviewed the 2-phase helical computed tomography (CT) (n = 6) and/or magnetic resonance (MR) imaging (n = 2) scans of 7 patients with basal cell adenoma. The authors evaluated the imaging characteristics, including tumor size, location, contour and margin, internal density or signal intensity, contrast enhancement pattern, and presence of calcification. The imaging features were then analyzed and correlated with the pathologic findings. RESULTS: All the tumors presented as small (less than 3 cm), well-encapsulated, round or oval masses on CT or MR imaging. On the 2-phase CT scan, the mostly solid-looking tumors (n = 4) showed marked contrast enhancement on the early phase, and there was a subsequent decrease in attenuation on the delayed phase. These tumors were classified as the solid subtype on histologic examination. Meanwhile, the tumors with large cystic areas (n = 2) showed gradual and additional enhancement on the delayed phase and were classified as the tubular or trabecular subtype on pathologic evaluation. There were small spots of low attenuation in the tumors of the solid subtype, which were proved to be intratumoral microcysts in the pathologic correlation. Calcification was found in a tumor. CONCLUSIONS: Basal cell adenomas of the parotid gland present as small well-marginated tumors and appear as masses with central large cysts or solid masses with microcysts on CT and MR imaging scans. Basal cell adenomas of the parotid gland had at least 2 different enhancement patterns on the 2-phase helical CT scans, and the enhancement patterns and imaging architecture were related to the histologic subtype of the tumors.

Adenoma↗

The comparative pathology of severe acute respiratory syndrome and avian influenza A subtype H5N1--a review.

The pathology of 2 zoonotic human viral infections that recently emerged, severe acute respiratory syndrome (SARS) due to coronavirus (SARS-CoV) and avian influenza A subtype H5N1, is reviewed and compared based on the literature and the cases examined by the authors. Pneumocytes are the primary target of infection resulting in diffuse alveolar damage. Systemic cytokine activation results in hemophagocytic syndrome, lymphoid depletion, and skeletal muscle fiber necrosis. Severe acute respiratory syndrome induces a more fibrocellular intra-alveolar organization with a "bronchiolitis obliterans organizing pneumonia"-like pattern and presence of multinucleated histiocytes and pneumocytes. H5N1 causes a more fulminant and necrotizing diffuse alveolar damage with patchy and interstitial paucicellular fibrosis. Severe acute respiratory syndrome associated coronavirus persists in the lung up to the second month, whereas H5N1 persists in the lung up to the third week. Severe acute respiratory syndrome associated coronavirus disseminates to blood, urine, feces, gastrointestinal tract, and liver. There is recent report of possible cerebral involvement by H5N1 and its isolation in the blood, gastrointestinal tract, and cerebrospinal fluid. More pathologic studies are urgently needed.

Coronavirus↗

Understanding the neurotransmitter pathology of schizophrenia: selective deficits of subtypes of cortical GABAergic neurons.

Research aimed at understanding the neurotransmitter pathology of schizophrenia has been underway for half a century, with much emphasis on the dopamine system. Although this approach has advanced our understanding of treatment mechanisms, identification of primary dopaminergic abnormalities in the disease has been elusive. The increasing emphasis on a neuronal pathology of schizophrenia has led to the identification of abnormalities in GABAergic and glutamatergic systems; and we have identified selective deficits in GABAergic interneurons containing the calcium binding proteins parvalbumin and calbindin. Here we report further evidence for a loss of parvalbumin-immunoreactive neurons in both dorsolateral prefrontal and medial temporal cortex, indicating that these deficits are consistent with a subtle neurodevelopmental pathogenesis and hypothesizing that they may contribute to a further degenerative process in schizophrenia.

Bipolar Disorder↗

[Clinico-immunologic subtypes of type I diabetes mellitus].

AIM: To study clinico-immunological characteristics of diabetes mellitus type I. MATERIAL AND METHODS: Clinical examination was made of 333 patients with diabetes mellitus type I with manifestation of carbohydrate metabolism impairment and intoxication syndrome because of diabetic ketoacidosis (group 1) and without it (group 2). Compared to donors (n = 68), T-cell, B-cell and monocytic components of immune system were studied in patients with uncomplicated DM type 1 in both groups (28 and 15 patients, respectively). RESULTS: Patients with different subtypes of the disease differ by the course and rate of progression, defects in T-cell and monocyte components of immunity. CONCLUSION: Type 1 diabetes mellitus is a heterogenous pathology with subtype 1 (rapidly progressive) and subtype 2 (slowly progressive).

Adolescent↗

P300 subcomponent abnormalities in schizophrenia: I. Physiological evidence for gender and subtype specific differences in regional pathology.

BACKGROUND: P300 event-related brain potential (ERP) amplitude is reduced in patients with schizophrenia. Little attention has been paid to gender differences underlying this abnormality, despite clinical differences between male and female schizophrenics. Studies have also largely ignored the fact that the P300 represents the activity of multiple neural generators and have not assessed the separate activity of different subcomponents. METHODS: Auditory P300 ERPs were recorded from 65 patients (42 male, 23 female) and 48 controls (30 male, 18 female). Positive and negative symptoms were assessed with standardized rating scales, and patients were subtyped as deficit or nondeficit. Five P300 subcomponents were identified using current source density measures: frontal (P3f), bilateral parietal (P3pL, P3pR), and bilateral temporal (P3tL, P3tR). RESULTS: Three subcomponents (P3tL, P3f, P3pR) were reduced in patients. The left temporal (P3tL) deficit was common across patient groups, but the overall profile of P300 abnormalities varied by gender and deficit/nondeficit status. Women had greater P3tL and P3f decrements; P3pR was abnormal in men. Deficit and nondeficit patients resembled men and women, respectively, independent of gender. P3f and P3tL amplitudes were correlated and unrelated to symptomatology. P3pR was related to Brief Psychiatric Rating Scale score. CONCLUSIONS: A left temporal abnormality exists in schizophrenia, along with two different profiles of regional pathology, which segregate by gender and deficit/nondeficit status. This supports the hypothesis of two distinct illness subtypes and suggests a physiological basis for phenotypic gender and deficit/nondeficit differences. P300 subcomponent abnormalities may serve as subtype markers. Correlated left temporal and frontal dysfunction is consistent with a frontotemporal neural network disturbance in some schizophrenics. Further investigation of the longitudinal stability and familial inheritance of these subcomponent abnormalities is warranted.

Adult↗

Nocturnal eating: prevalence and features in 120 insomniac referrals.

Pathologic nocturnal eating can be associated with a heterogeneous group of medical and psychiatric disorders. The current study was designed to evaluate the prevalence and clinical features of nocturnal eating syndrome (NES), a major subtype of pathological nocturnal eating. Conducted prospectively over an 18-month period (January 1994-June 1995), the study consisted of clinical, psychological, and polysomnographic assessments of 120 adult subjects (51 males, 69 females; mean age 42.6 years, range 18-86 years) who were either self-referrals (58%) or physician referrals (42%) to our Sleep Disorders Center for insomnia complaints. Nocturnal eating with features that are typical of NES, namely compulsive feeding shortly after a mid-non-rapid eye movement (NREM) sleep awakening, in the absence of daytime eating disorders, occurred in seven subjects (five females, two males; mean age 50.8 +/- 9.5 years; mean age at onset of NES 42 years, range 18-61 years), or 5.8% of the sample. NES accounted for 44.4% of all the nocturnal eating cases observed. The data suggest that an adult, late-onset variety of NES is not infrequent. Several of the clinical features of our NES patient series correspond closely to most of those observed in other descriptions of NES in the literature. Overall, the data reinforce the idea that NES is a distinct syndrome, even though some of its features overlap with sleep-related eating disorders (e.g. associated with sleepwalking, restless legs syndrome, obstructive sleep apnea, etc.) and with eating disorders such as daytime binge eating.

Adolescent↗

Intermediate lymphocytic lymphoma: clinical and pathologic features of a recently characterized subtype of non-Hodgkin's lymphoma.

PURPOSE: We present a comprehensive review of clinical, pathologic, molecular, and prognostic features and therapy of intermediate lymphocytic (mantle cell) lymphoma (ILL/MCL), a recently characterized subtype that represents 2% to 8% of non-Hodgkin's lymphomas (NHLs), but which has not been included in most classification schemes, including the International Working Formulation. DESIGN: The English-language literature encompassing the above aspects, published between 1977 and 1992, is critically reviewed. RESULTS AND CONCLUSION: ILL/MCL is a disease of proliferating B lymphocytes that is characterized by generalized lymphadenopathy and frequent, often extensive, involvement of the spleen, bone marrow, and gastrointestinal tract. The malignant cells usually express the markers CD5 and IgM with or without IgD, but not CD10, on the cell surface, and grow in one of two dominant histologic patterns: mantle zone and diffuse. The characteristic cytogenetic abnormality is a t(11;14)(q13;q32) translocation, which juxtaposes the bcl-1 locus on chromosome 11 with the immunoglobulin (Ig) heavy-chain locus on chromosome 14, and appears to result in dysregulated expression of the gene encoding cyclin D1. Median survival is in the range of 2 to 5 years. While responses to chemotherapy may be seen in up to half the patients, relapses are the rule, and longterm survival is uncommon. The optimal treatment remains undefined, although therapy may be deferred until there are symptoms or complications, at which time judicious administration of alkylating agents and glucocorticoids may result in effective palliation.

Humans↗

Boredom proneness in pathological gambling.

To test the hypothesis that pathological gamblers seek stimulation as a means of reducing aversive under-aroused states of boredom and/or depression, the Beck Depression Inventory, Zuckerman's Sensation Seeking Scale and a Boredom Proneness Scale were administered to 48 diagnosed pathological gamblers and a control group of 40 family physician patients. Analyses of variance showed pathological gamblers obtained significantly higher boredom proneness and depression scores than those of controls. That the Boredom Proneness Scale failed to correlate with the Zuckerman Boredom Susceptibility subscale suggested the two measure differing dimensions. Results indicated the possible existence of three subtypes of pathological gamblers, one group characterized by boredom, another by depression, and a third by a mixture of both depression and boredom.

Adult↗

Plasma cortisol and depression in pathological gamblers.

Basal serum cortisol and dexamethasone suppression test (DST) results were studied in 21 pathological gamblers who varied on the Beck Depression Inventory and selected scales of the Minnesota Multiphasic Personality Inventory, which had previously been shown to be related to depression in gamblers. All subjects were suppressors on the DST. There was a significant relationship between fluctuation in 08.00 h and 16.00 h basal cortisol levels and the psychological measures, suggesting a subtype of pathological gambler with potential clinical significance.

Adult↗

Inactivation of Smad4 in gastric carcinomas.

Allelic loss of chromosome 18q has been noted in intestinal type gastric adenocarcinomas. Smad4 is a gene located at 18q that was recently cloned in humans and found to be significantly altered in pancreatic cancers. We sought to determine whether Smad4 genetic alterations played a significant role in gastric tumorigenesis by studying 35 gastric adenocarcinomas of all histopathological types and pathological stages. Microdissected specimens were used for mutational analysis of Smad4 at the nucleotide level, including the entire coding region and intron/exon boundaries. Allelic imbalance was also analyzed at the Smad4 locus using two nearby microsatellite markers. One case of apparent biallelic inactivation of Smad4 was found in our study of 35 gastric carcinomas. A nonsense point mutation at codon 334 was demonstrated, which, similar to other Smad4 mutations, is predicted to truncate the conserved COOH-terminal domain of this protein. This Smad4 C to T transition mutation was proven to be somatically acquired. Allelic loss was also noted on chromosome 18q at a marker near Smad4 in this mutated gastric cancer, apparently producing complete inactivation of Smad4 in this tumor. Significant 18q allelic loss (56% of 34 informative cases) was noted in our gastric carcinomas using microsatellite markers near the Smad4 locus, regardless of histological subtype or pathological stage. Additionally, three cases of microsatellite instability were observed. Thus, Smad4 inactivation was noted in our gastric carcinomas; however, this event was rare. The frequent loss of chromosomal arm 18q observed in gastric cancers suggests the presence of other tumor suppressor genes in this region that are involved in gastric tumorigenesis. Further studies are needed to identify these other targets of inactivation during gastric cancer development.

Adenocarcinoma↗

Animal models for studying serotonin (5-HT) receptor subtypes: relationship to 5-HT system pathologies.

Despite more than 30 years of intensive research, the specific role of serotonin (5-HT) receptor subtypes in animal models of "anxiety" still remains unclear. The present study focused on the particular role of 5-HT1A receptor subtype in aversive learning, i.e., the passive avoidance (PA) task in the rat. Taken together, the data strongly suggest that: (1) 5-HT1A receptor but not 5-HT2A receptors play a crucial role in PA; (2) the postsynaptic but not presynaptic 5-HT1A receptors are mainly involved in the regulation of PA; (3) 5-HT1A receptors appear to be directly involved both in acquisition and retrieval but not in the consolidation of PA; and (4) besides the "prototypical" 5-HT1A receptor subtype, an additional and yet-unidentified 5-HT receptor subtype seems to play an important modulatory role in PA.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

Epstein-Barr virus in gastric carcinoma in Suzhou, China and Osaka, Japan: association with clinico-pathologic factors and HLA-subtype.

Information on geographic differences of Epstein-Barr virus (EBV) positivity and association with HLA in gastric carcinoma are limited. Therefore, the association of gastric carcinoma with EBV was examined in 118 patients from Suzhou, China, where the incidence of nasopharyngeal carcinoma (NPC) is high, and in 216 patients from Osaka, Japan, where the incidence of NPC is low, NPC being one of the EBV-associated carcinomas. Expression of HLA-A2 was also examined in some of these cases. The EBV genome was evidenced by PCR and in the tumor cells by in situ hybridization in 7/90 and 9/151 of cases from Suzhou and Osaka, respectively. Immunohistochemistry revealed that cancer cells in all cases with EBV did not express latent membrane protein-I. Type A was found in all cases positive for EBV. Among several histologic and clinical factors, only age of patients showed a correlation with EBV positivity: patients over 60 showed a higher frequency than patients below 60 years of age (p < 0.05). Typing of the HLA-A locus was possible in 16 cases positive for the EBV genome: 3 of 4 cases from Suzhou and 4 of 7 from Osaka were positive for HLA-A2 products. Severe lymphoid cell infiltration was found in 2 of 7 cases and 1 of 4 cases with and without the HLA-A2 type, respectively. The reported frequency of EBV positivity in Chinese living in Taiwan and in Japanese living in Hawaii is higher than in Suzhou, China, and Osaka, Japan, respectively. Our findings suggest that EBV association with gastric carcinoma is influenced by environmental and cultural factors.

Adenocarcinoma↗

Distribution, density and heterogeneity of canine mast cells and influence of fixation techniques.

The present study was carried out to determine the physiological distribution of mast cell numbers and types in the dog according to tissue location, staining and fixation methods. Tissue samples from stomach, duodenum, lung, lymph node, skin and uterus were evaluated. Samples were fixed in formalin as well as in Carnoy's fluid. The average number of mast cells was determined using a metachromatic staining method. Protease content of mast cells was examined with a double enzyme-immunohistochemical staining technique, using a histochemical reaction for chloroacetate esterase to detect chymase activity and an immunohistochemical staining method for the detection of tryptase. Canine mast cells can be subdivided into formalin-sensitive and -resistant mast cells. Three subtypes were identified according to their content of the mast cell-specific proteases tryptase (T) and chymase (C): T-, TC- and C-mast cells. Significant differences regarding the distribution of mast cell subtypes as well as the influence of the fixation method can be observed. This underlines the fact that data regarding mast cell heterogeneity from other species, obtained by different fixation methods, are not comparable. This fact has to be taken into consideration when evaluating mast cell subtypes under pathological conditions.

Animals↗

Hrad17 expression in thymoma.

OBJECTIVES: We used palindromic polymerase chain reaction-driven complementary deoxyribonucleic acid differential display to identify and isolate a gene, the human homolog of the Schizosaccharomyces pombe checkpoint gene rad17 (Hrad17), from colon cancer tissue. The loss of checkpoint control in mammalian cells results in genomic instability, leading to the amplification, rearrangement, or loss of chromosomes--events associated with tumor progression. We hypothesized that the Hrad17 may be expressed in thymoma, especially in invasive thymoma. We attempted to determine the influence of Hrad17 expression on clinicopathological features for patients with thymoma who had undergone surgery. METHODS: Expression of Hrad17 messenger ribonucleic acid (RNA) was evaluated by reverse transcription-polymerase chain reaction using a LightCycler in 38 thymomas and 10 adjacent histologically normal thymus samples from patients for whom follow-up data was available. RESULTS: Hrad17 transcripts were detected in all 38 tumor samples (8.789 +/- 7.337) at levels significantly higher than those in normal thymus samples (1.908 +/- 2.267, p < 0.0001). No relationship was seen between Hrad17 gene expression and age, gender, or pathological thymoma subtypes. Hrad17 mRNA expression in invasive thymomas (stage II-IV, 10.067 +/- 5.293) was significantly higher than that in stage I thymomas (5.193 +/- 4.485, p = 0.0168). Immunohistochemistry showed that Hrad17 protein was highly expressed in invasive thymoma tumor tissue but not within the normal thymus tissue. CONCLUSIONS: Hrad17 was highly expressed in invasive thymoma.

Cell Cycle Proteins↗

Anticipation of public speaking in virtual reality reveals a relationship between trait social anxiety and startle reactivity.

BACKGROUND: Startle reflex modification has become valuable to the study of fear and anxiety, but few studies have explored startle reactivity in socially threatening situations. METHODS: Healthy participants ranging in trait social anxiety entered virtual reality (VR) that simulates standing center-stage in front of an audience to anticipate giving a speech and count backward. We measured startle and autonomic reactivity during anticipation of both tasks inside VR after a single baseline recording outside VR. RESULTS: Trait social anxiety, but not general trait anxiety, was positively correlated with startle before entering VR and most clearly during speech anticipation inside VR. Speech anticipation inside VR also elicited stronger physiologic responses relative to anticipation of counting. CONCLUSIONS: Under social-evaluative threat, startle reactivity showed robust relationships with fear of negative evaluation, a central aspect of social anxiety and clinical social phobia. Context-specific startle modification may be an endophenotype for subtypes of pathological anxiety.

Adult↗

Epigenetic inactivation of the RASSF1A tumour suppressor gene in ependymoma.

To investigate the role of aberrant epigenetic events in ependymoma and identify critical genes in its pathogenesis, the methylation status of nine tumour suppressor genes (TSGs: p14(ARF), p15(INK4B), p16(INK4A), CASP8, MGMT, TIMP3, TP73, RB1 and RASSF1A) was assessed. Extensive hypermethylation across the RASSF1A CpG island was detected frequently in ependymomas of all clinical and pathological disease subtypes (86% of cases, n=35), but not in non-neoplastic brain tissues (n=6). Less frequent methylation was observed for CASP8, MGMT and TP73 (5-20%). The remaining TSGs showed no evidence of methylation. RASSF1A hypermethylation represents the most common gene-specific defect identified in ependymoma highlighting the importance of its further investigation in this disease.

Adolescent↗