Tranilast Treatment Prevents Chronic Radiation-Induced Colitis in Rats by Inhibiting Mast Cell Infiltration.

INTRODUCTION: Mast cells are the principal cells involved in acute and chronic colitis due to radiation, known as radiation-induced colitis (RIC). In this study, we investigated whether pretreatment with tranilast, a mast cell inhibitor, could alleviate chronic RIC. METHODS: A total of 23 Sprague-Dawley rats were randomly divided into three groups: control group (n = 5), radiation group (RG, n = 9), and tranilast-pretreated radiation group (TG, n = 9). The rats in the RG and the TG were irradiated in the pelvic area (1.5 cm from the anus) with a single dose of 20 Gy under general anesthesia. Tranilast (100 mg/kg) was administered intraperitoneally to the rats of the TG for 10 days, starting from the day of pelvic radiation. Ten weeks after radiation, the rats were euthanized. Rectal tissue samples were histologically evaluated for the total inflammation score (TIS) and mast cell count. The expression of MUC2, MUC5AC, and matrix metalloproteinase-9 (MMP-9) was also assessed immunohistochemically. RESULTS: Both the TIS and specific components of TIS such as epithelial atypia, vascular sclerosis, and colitis cystica profunda (CCP) were significantly higher in the RG than in the TG (p = 0.02, 0.038, 0.025, and 0.01, respectively). Thein number of infiltrating mast cells was significantly higher in the RG than in the TG (median [range]: 20 [3-54] versus 6 [3-25], respectively; p = 0.034). Quantitatively, the number of MMP-9-positive cells was significantly higher in the RG (23.67 ± 19.00) than in the TG (10.25 ± 8.45) (mean ± standard deviation; p < 0.05). TIS and MMP-9 exhibited a strong association (correlation coefficient r = 0.56, p < 0.05). Immunohistochemically, the mucin-lake of CCP showed no staining for MUC5AC but was stained positive for MUC2. CONCLUSION: Tranilast pretreatment of chronic RIC showed an anti-inflammatory effect associated with the reduction of mast cell infiltration and MMP-9 expression.

Collision Tumor of the Ovary: Adult Granulosa Cell Tumor and Mesonephric-like Adenocarcinoma.

Collision tumors of the ovaries are rare, with only a few reports in the literature. Adult granulosa cell tumors are a relatively common primary tumor component of previously reported collision tumors. The combination of serous and mucinous tumors with adult granulosa cell tumors has been reported in several cases. On the other hand, mesonephric-like adenocarcinomas are rare neoplasms that commonly arise in the uterine corpus and ovaries. In this report, we present the case of a collision tumor composed of an adult granulosa cell tumor and mesonephric-like adenocarcinoma of the ovary in a 63-year-old woman. The initial magnetic resonance imaging findings showed a cystic mass with an internal hemorrhage, which suggested an adult granulosa cell tumor, and a solid mass with different enhancements. Microscopically, the tumor had two distinct components: An adult granulosa cell tumor and a mesonephric-like adenocarcinoma. Recognizing collision tumors consisting of slow-growing and aggressive tumors may prove beneficial in future diagnostic and treatment strategies.

Improved Diagnostic Accuracy of Thyroid Fine-Needle Aspiration Cytology with Artificial Intelligence Technology.

Background: Artificial intelligence (AI) is increasingly being applied in pathology and cytology, showing promising results. We collected a large dataset of whole slide images (WSIs) of thyroid fine-needle aspiration cytology (FNA), incorporating z-stacking, from institutions across the nation to develop an AI model. Methods: We conducted a multicenter retrospective diagnostic accuracy study using thyroid FNA dataset from the Open AI Dataset Project that consists of digitalized images samples collected from 3 university hospitals and 215 Korean institutions through extensive quality check during the case selection, scanning, labeling, and reviewing process. Multiple z-layer images were captured using three different scanners and image patches were extracted from WSIs and resized after focus fusion and color normalization. We pretested six AI models, determining Inception ResNet v2 as the best model using a subset of dataset, and subsequently tested the final model with total datasets. Additionally, we compared the performance of AI and cytopathologists using randomly selected 1031 image patches and reevaluated the cytopathologists' performance after reference to AI results. Results: A total of 10,332 image patches from 306 thyroid FNAs, comprising 78 malignant (papillary thyroid carcinoma) and 228 benign from 86 institutions were used for the AI training. Inception ResNet v2 achieved highest accuracy of 99.7%, 97.7%, and 94.9% for training, validation, and test dataset, respectively (sensitivity 99.9%, 99.6%, and 100% and specificity 99.6%, 96.4%, and 90.4% for training, validation, and test dataset, respectively). In the comparison between AI and human, AI model showed higher accuracy and specificity than the average expert cytopathologists beyond the two-standard deviation (accuracy 99.71% [95% confidence interval (CI), 99.38-100.00%] vs. 88.91% [95% CI, 86.99-90.83%], sensitivity 99.81% [95% CI, 99.54-100.00%] vs. 87.26% [95% CI, 85.22-89.30%], and specificity 99.61% [95% CI, 99.23-99.99%] vs. 90.58% [95% CI, 88.80-92.36%]). Moreover, after referring to the AI results, the performance of all the experts (accuracy 96%, 95%, and 96%, respectively) and the diagnostic agreement (from 0.64 to 0.84) increased. Conclusions: These results suggest that the application of AI technology to thyroid FNA cytology may improve the diagnostic accuracy as well as intra- and inter-observer variability among pathologists. Further confirmatory research is needed.

Immunoglobulin G4-related disease mimicking an appendiceal neoplasm: a case report.

Immunoglobulin G4-related disease (IgG4-RD) is a fibroinflammatory condition characterized by chronic activation of the immune system and a tendency to form tumorous lesions. IgG4-RD is frequently characterized by the presence of tumor-like masses affecting multiple organs and is easily mistaken for a malignant neoplasm. However, IgG4-RD affecting the appendix is extremely rare, with only seven cases reported previously. We report the case of a woman in her early 60s who presented with insidious abdominal pain and radiological findings mimicking appendiceal neoplasms. After diagnosing appendiceal neoplasms, surgery was performed. The patient had a serum IgG4 concentration of <1.35 g/L, which did not satisfy one of the three revised comprehensive diagnostic criteria for IgG4-RD. A pathological examination was conducted, and the patient was diagnosed with appendiceal IgG4-RD. To the best of our knowledge, there have been no previously reported cases of IgG4-RD affecting the appendix in patients with low serum IgG4 concentrations. This report may prove beneficial for the future understanding of IgG4-RD and for the revision of diagnostic and treatment strategies.

Poly (Adp-Ribose) Polymerase-1 (PARP-1) Is a Good Prognostic Marker for Pancreatic/Periampullary Cancers.

BACKGROUND: Periampullary cancer (PAC) is highly aggressive with no effective adjuvant therapy or prognostic markers. Recently, poly (ADP-ribose) polymerase-1 (PARP-1) has emerged as a target in solid cancers, and its relationship with epithelial-mesenchymal transition (EMT) has been observed. However, the relationship between PARP-1 and EMT in PAC has not explored well. MATERIALS AND METHODS: We assessed the prognostic significance of PARP-1 in 190 PACs patients and correlated it with EMT markers, including FGF8, FGFR4, MMP2, MMP3, Snail, and ZEB1. Immunohistochemistry for PARP-1 and EMT markers was performed using a tissue microarray. RESULTS: PARP-1 and FGF8 expression were associated with better survival unlike other solid cancers ( P = 0.006 and P = 0.003), and MMP3 and ZEB1 expression were associated with poor prognosis in multivariate and survival analyses ( P = 0.009 and P < 0.001). In addition, PARP-1 is related negatively to Snail but not related with other EMT markers, implying an independent mechanism between PARP-1 and EMT in PACs. PARP-1 and FGF8 are independent good survival markers in PACs unlike other solid cancers. CONCLUSIONS: PARP-1 and FGF8 in PACs could not be related to the EMT pathway but must be rather understood in light of similar cancer-protective roles. Further studies are required on EMT-associated immune markers in PACs.

AGE-RAGE axis culminates into multiple pathogenic processes: a central road to neurodegeneration.

Advanced glycation end-products (AGEs; e.g., glyoxal, methylglyoxal or carboxymethyl-lysine) are heterogenous group of toxic compounds synthesized in the body through both exogenous and endogenous pathways. AGEs are known to covalently modify proteins bringing about loss of functional alteration in the proteins. AGEs also interact with their receptor, receptor for AGE (RAGE) and such interactions influence different biological processes including oxidative stress and apoptosis. Previously, AGE-RAGE axis has long been considered to be the maligning factor for various human diseases including, diabetes, obesity, cardiovascular, aging, etc. Recent developments have revealed the involvement of AGE-RAGE axis in different pathological consequences associated with the onset of neurodegeneration including, disruption of blood brain barrier, neuroinflammation, remodeling of extracellular matrix, dysregulation of polyol pathway and antioxidant enzymes, etc. In the present article, we attempted to describe a new avenue that AGE-RAGE axis culminates to different pathological consequences in brain and therefore, is a central instigating component to several neurodegenerative diseases (NGDs). We also invoke that specific inhibitors of TIR domains of TLR or RAGE receptors are crucial molecules for the therapeutic intervention of NGDs. Clinical perspectives have also been appropriately discussed.

Recent application of artificial intelligence on histopathologic image-based prediction of gene mutation in solid cancers.

PURPOSE: Evaluation of genetic mutations in cancers is important because distinct mutational profiles help determine individualized drug therapy. However, molecular analyses are not routinely performed in all cancers because they are expensive, time-consuming and not universally available. Artificial intelligence (AI) has shown the potential to determine a wide range of genetic mutations on histologic image analysis. Here, we assessed the status of mutation prediction AI models on histologic images by a systematic review. METHODS: A literature search using the MEDLINE, Embase and Cochrane databases was conducted in August 2021. The articles were shortlisted by titles and abstracts. After a full-text review, publication trends, study characteristic analysis and comparison of performance metrics were performed. RESULTS: Twenty-four studies were found mostly from developed countries, and their number is increasing. The major targets were gastrointestinal, genitourinary, gynecological, lung and head and neck cancers. Most studies used the Cancer Genome Atlas, with a few using an in-house dataset. The area under the curve of some of the cancer driver gene mutations in particular organs was satisfactory, such as 0.92 of BRAF in thyroid cancers and 0.79 of EGFR in lung cancers, whereas the average of all gene mutations was 0.64, which is still suboptimal. CONCLUSION: AI has the potential to predict gene mutations on histologic images with appropriate caution. Further validation with larger datasets is still required before AI models can be used in clinical practice to predict gene mutations.

Recent Application of Artificial Intelligence in Non-Gynecological Cancer Cytopathology: A Systematic Review.

State-of-the-art artificial intelligence (AI) has recently gained considerable interest in the healthcare sector and has provided solutions to problems through automated diagnosis. Cytological examination is a crucial step in the initial diagnosis of cancer, although it shows limited diagnostic efficacy. Recently, AI applications in the processing of cytopathological images have shown promising results despite the elementary level of the technology. Here, we performed a systematic review with a quantitative analysis of recent AI applications in non-gynecological (non-GYN) cancer cytology to understand the current technical status. We searched the major online databases, including MEDLINE, Cochrane Library, and EMBASE, for relevant English articles published from January 2010 to January 2021. The searched query terms were: "artificial intelligence", "image processing", "deep learning", "cytopathology", and "fine-needle aspiration cytology." Out of 17,000 studies, only 26 studies (26 models) were included in the full-text review, whereas 13 studies were included for quantitative analysis. There were eight classes of AI models treated of according to target organs: thyroid (n = 11, 39%), urinary bladder (n = 6, 21%), lung (n = 4, 14%), breast (n = 2, 7%), pleural effusion (n = 2, 7%), ovary (n = 1, 4%), pancreas (n = 1, 4%), and prostate (n = 1, 4). Most of the studies focused on classification and segmentation tasks. Although most of the studies showed impressive results, the sizes of the training and validation datasets were limited. Overall, AI is also promising for non-GYN cancer cytopathology analysis, such as pathology or gynecological cytology. However, the lack of well-annotated, large-scale datasets with Z-stacking and external cross-validation was the major limitation found across all studies. Future studies with larger datasets with high-quality annotations and external validation are required.

Recent Applications of Artificial Intelligence from Histopathologic Image-Based Prediction of Microsatellite Instability in Solid Cancers: A Systematic Review.

Cancers with high microsatellite instability (MSI-H) have a better prognosis and respond well to immunotherapy. However, MSI is not tested in all cancers because of the additional costs and time of diagnosis. Therefore, artificial intelligence (AI)-based models have been recently developed to evaluate MSI from whole slide images (WSIs). Here, we aimed to assess the current state of AI application to predict MSI based on WSIs analysis in MSI-related cancers and suggest a better study design for future studies. Studies were searched in online databases and screened by reference type, and only the full texts of eligible studies were reviewed. The included 14 studies were published between 2018 and 2021, and most of the publications were from developed countries. The commonly used dataset is The Cancer Genome Atlas dataset. Colorectal cancer (CRC) was the most common type of cancer studied, followed by endometrial, gastric, and ovarian cancers. The AI models have shown the potential to predict MSI with the highest AUC of 0.93 in the case of CRC. The relatively limited scale of datasets and lack of external validation were the limitations of most studies. Future studies with larger datasets are required to implicate AI models in routine diagnostic practice for MSI prediction.

Pure Autonomic Failure: A Case Report of Recurrent Orthostatic Hypotension.

Pure autonomic failure is a neurodegenerative disorder affecting the autonomic nervous system which clinically presents with orthostatic hypotension. It is a diagnosis of exclusion after detailed clinical examinations and relevant investigations. Here, we discuss a case of 68 years old male who had complaints of multiple episodes of loss of consciousness on standing from a sitting position for the last 3 years. The diagnosis was considered by clinical examinations revealing autonomic dysfunctions with normal appropriate investigations. The patient was treated successfully with midodrine, fludrocortisone, and other non-pharmacological interventions. We focused on doing various autonomic dysfunction tests in the evaluation of a patient with recurrent orthostatic hypotension. We suspect that pure autonomic failure might not have been considered in the differential diagnosis of recurrent orthostatic hypotension and suggest that it is to be kept as a differential in such a scenario. Midodrine has an effective role in syncope due to sympathetic vasoconstrictor failure.

Differences in the mitochondrial microsatellite instability of Keratoacanthoma and cutaneous squamous cell carcinoma.

Keratoacanthoma (KA) is a common cutaneous neoplasm which often resembles typical squamous cell carcinoma (SCC) in both its clinical and historical presentation. Several studies have attempted to identify methods for distinguishing between KA and SCC, however, none of these have proven to play any obvious roles in these tumors. Given this we went on to evaluate mitochondrial microsatellite instability (mtMSI) in KA and SCC in an effort to understand these tumors better. DNA was isolated from paired normal and tumoral tissues donated by 57 KA patients and 43 SCC patients. MtMSI was then analyzed using eight microsatellite markers and was observed in 2 (3.5%) of the 57 KA patients and 8 (18.6%) of the 43 SCC patients, respectively. MtMSI was also shown to affect different locations depending on tumor type. In KA patients, mtMSI was detected at mitochondrial D514 D-loop and presented with (CA) n repeats, in contrast, all of the SCC patient experienced mtMSI at the D310 with (C)n repeats of the D-loop region. These differences in location were found to be significant, which may support the hypothesis that KA and SCC have different pathogenetic pathways. Our results also suggest that mtMSI may be a candidate for developing novel differential diagnostic methods for KA and SCC.

Alterations in telomere length and mitochondrial DNA copy number in human lymphocytes on short-term exposure to moderate hypoxia.

Hypoxia is related to a variety of diseases, such as cardiovascular and inflammatory diseases and various cancers. Telomere length (TL) may vary according to the hypoxia level and cell types. To the best of our knowledge, no study has investigated the effect of moderate hypoxia on TL and mitochondrial DNA copy number (mtDNAcn) in human lymphocytes. Therefore, in this study, we analyzed the effect of moderate hypoxia on TL in correlation with mtDNAcn. This study included 32 healthy male nonsmoker's subjects; in this cohort, we had previously studied sister chromatid exchange and microsatellite instability. Blood samples from each subject were divided into three groups: a control group and two experimental groups exposed to moderate hypoxia for 12 or 24 h. Relative TL and mtDNAcn were measured by a quantitative real-time polymerase chain reaction. The TL in the control group did not significantly differ from that in the experimental group subjected to hypoxia for 12 h; however, the TL in the 24 h hypoxia-treated experimental group was significantly higher than that in the control group. The correlation between TL and mtDNAcn was not statistically significant in the two hypoxic states. The increase in TL was observed on exposure to hypoxia for 24 h and not for 12 h; thus, the findings suggest that telomere elongation is related to hypoxia exposure duration. The mtDNAcn in the two experimental groups did not significantly differ from that in the control group. These observations suggest that mtDNAcn alterations show more genetic stability than TL alterations. To the best of our knowledge, this is the first in vitro study on human lymphocytes reporting an increase in TL and no alteration in mtDNAcn after short-time exposure to moderate hypoxia.

Alzheimer's Disease: An Overview of Major Hypotheses and Therapeutic Options in Nanotechnology.

Alzheimer's disease (AD), a progressively fatal neurodegenerative disorder, is the most prominent form of dementia found today. Patients suffering from Alzheimer's begin to show the signs and symptoms, like decline in memory and cognition, long after the cellular damage has been initiated in their brain. There are several hypothesis for the neurodegeneration process; however, the lack of availability of in vivo models makes the recapitulation of AD in humans impossible. Moreover, the drugs currently available in the market serve to alleviate the symptoms and there is no cure for the disease. There have been two major hurdles in the process of finding the same-the inefficiency in cracking the complexity of the disease pathogenesis and the inefficiency in delivery of drugs targeted for AD. This review discusses the different drugs that have been designed over the recent years and the drug delivery options in the field of nanotechnology that have been found most feasible in surpassing the blood-brain barrier (BBB) and reaching the brain.