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Cervical intraepithelial neoplasia (CIN) represents a spectrum of preinvasive squamous lesions within the cervical epithelium, whose identification is a diagnostic challenge due to subtle histomorphological differences among its categories. This study explores ORF1p, a nucleic acid-binding protein derived from long interspersed nuclear element-1 (LINE-1), as a potential biomarker for enhancing CIN diagnosis. A comprehensive analysis of 143 cervical specimens, encompassing CIN I (n=20), CIN II (n=46), CIN III (n=14), invasive cancer (n=32), and nondysplastic cases (normal cervical epithelia (n=24) and atrophy (n=7) were conducted. ORF1p, Ki67, and p16 expressions were evaluated using immunohistochemistry. ORF1p immunopositivity was detected in the vast majority [110/112 (98.2%)] of dysplastic and neoplastic (CIN and invasive cancer) specimens, whereas 19/24 (79.2%) of normal cervical specimens lacked ORF1p expression. The observed pattern of ORF1p expression showed a progressively increasing extent and intensity with advancing CIN grades. CIN I exhibited mild ORF1p expression in the lower one or two-thirds of the cervical epithelium [14/16 (87.5%)], whereas CIN II demonstrated moderate to strong ORF1p expression spanning the lower two-thirds [29/46 (63.0%)]. Pronounced transepithelial ORF1p immunopositivity characterized CIN III cases [13/14 (92.8%)] and cervical cancer [30/32 (93.8%)]. These findings propose ORF1p as a valuable indicator even for detecting CIN I, effectively discerning them from normal cervical tissue (p < 0.0001). Our findings underscore the potential of ORF1p as an early diagnostic marker for cervical neoplasia., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Coronavirus disease 2019 (COVID-19) can lead to severe acute respiratory syndrome, and while most individuals recover within weeks, approximately 30-40% experience persistent symptoms collectively known as Long COVID, post-COVID-19 syndrome, or post-acute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (PASC). These enduring symptoms, including fatigue, respiratory difficulties, body pain, short-term memory loss, concentration issues, and sleep disturbances, can persist for months. According to recent studies, SARS-CoV-2 infection causes prolonged disruptions in mitochondrial function, significantly altering cellular energy metabolism. Our research employed transmission electron microscopy to reveal distinct mitochondrial structural abnormalities in Long COVID patients, notably including significant swelling, disrupted cristae, and an overall irregular morphology, which collectively indicates severe mitochondrial distress. We noted increased levels of superoxide dismutase 1 which signals oxidative stress and elevated autophagy-related 4B cysteine peptidase levels, indicating disruptions in mitophagy. Importantly, our analysis also identified reduced levels of circulating cell-free mitochondrial DNA (ccf-mtDNA) in these patients, serving as a novel biomarker for the condition. These findings underscore the crucial role of persistent mitochondrial dysfunction in the pathogenesis of Long COVID. Further exploration of the cellular and molecular mechanisms underlying post-viral mitochondrial dysfunction is critical, particularly to understand the roles of autoimmune reactions and the reactivation of latent viruses in perpetuating these conditions. This comprehensive understanding could pave the way for targeted therapeutic interventions designed to alleviate the chronic impacts of Long COVID. By utilizing circulating ccf-mtDNA and other novel mitochondrial biomarkers, we can enhance our diagnostic capabilities and improve the management of this complex syndrome., (© 2024. The Author(s).)

Background: Obesity is a growing problem worldwide and a major risk factor for many chronic diseases. The accumulation of adipose tissue leads to the release of significant amounts of pro-inflammatory cytokines and adipokines, resulting in a low-grade systemic inflammation. However, the mechanisms behind the development of obesity-related diseases are not fully understood. Therefore, our study aimed to investigate the pathological changes and inflammatory processes at systemic level and in individual organs in two different diet-induced mouse obesity models., Methods: Male C57BL6/J mice were fed by high-fat diet (HFD), high-fat/high-fructose diet (HFD + FR) or normal chow for 21 weeks starting at 3 months of age (n = 15 animals/group). Insulin resistance was tested by oral glucose tolerance test. Pathological changes were investigated on hematoxylin-eosin-stained liver and brown adipose tissue sections. The gene expression levels of adipokines and cytokines were analyzed by qPCR in adipose tissues, whereas serum protein concentrations were determined by multiplex immunoassays. Immunophenotyping of isolated blood, bone marrow and spleen cells was performed by single-cell mass cytometry., Results: Weight gain, glucose intolerance and hepatic steatosis were more severe in the HFD + FR group than in the control and HFD groups. This was accompanied by a higher level of systemic inflammation, as indicated by increased expression of pro-inflammatory genes in visceral white adipose tissue and by a higher serum TNFα level. In addition, immunophenotyping revealed the increase of the surface expressions of CD44 and CD69 on various cell types, such as CD8+ and CD4 + T-cells, B-cells and macrophages, in animals with obesity., Conclusions: The combination of HFD with fructose supplementation promotes more properly the symptoms of metabolic syndrome. Therefore, the combined high-fat/high-fructose nutrition can be a more suitable model of the Western diet. However, despite these differences, both models showed immunophenotypic changes that may be associated with increased risk of obesity-related cancer., (© 2024. The Author(s).)

In recent years a significant demand to develop computer-assisted diagnostic tools to assess prostate cancer using whole slide images has been observed. In this study we develop and validate a machine learning system for cancer assessment, inclusive of detection of perineural invasion and measurement of cancer portion to meet clinical reporting needs. The system analyses the whole slide image in three consecutive stages: tissue detection, classification, and slide level analysis. The whole slide image is divided into smaller regions (patches). The tissue detection stage relies upon traditional machine learning to identify WSI patches containing tissue, which are then further assessed at the classification stage where deep learning algorithms are employed to detect and classify cancer tissue. At the slide level analysis stage, entire slide level information is generated by aggregating all the patch level information of the slide. A total of 2340 haematoxylin and eosin stained slides were used to train and validate the system. A medical team consisting of 11 board certified pathologists with prostatic pathology subspeciality competences working independently in 4 different medical centres performed the annotations. Pixel-level annotation based on an agreed set of 10 annotation terms, determined based on medical relevance and prevalence, was created by the team. The system achieved an accuracy of 99.53% in tissue detection, with sensitivity and specificity respectively of 99.78% and 99.12%. The system achieved an accuracy of 92.80% in classifying tissue terms, with sensitivity and specificity respectively 92.61% and 99.25%, when 5x magnification level was used. For 10x magnification, these values were respectively 91.04%, 90.49%, and 99.07%. For 20x magnification they were 84.71%, 83.95%, 90.13%., (© 2024. The Author(s).)

Introduction: Our working group has previously shown that bile acids (BAs) accelerate carcinogenic processes in pancreatic cancer (PC) in which mucin 4 (MUC4) expression has a central role. However, the role of other mucins in PC is less clear, especially in bile-induced cancer progression. The study aim was to investigate expression of MUC17 in BA- or human serum-treated pancreatic ductal adenocarcinoma (PDAC) cell lines., Methods: Different cell-based assays with RNA silencing/overexpression were used to study the role of MUC17 in cancer progression. Protein expression of MUC17 was evaluated in 55 human pancreatic samples by immunohistochemistry, and Kaplan-Meier survival analysis was used to compare survival curves., Results: Expression of MUC17 increased in PDAC patients, especially in obstructive jaundice (OJ), and the elevated MUC17 expression associated with poorer overall survival (10.66 ± 1.99 vs. 15.05 ± 2.03 months; log-rank: 0.0497). Treatment of Capan-1 and AsPC-1 cells with BAs or with human serum obtained from PDAC + OJ patients enhanced the expression of MUC17, as well as the proliferative potential of the cells, whereas knockdown of MUC17 alone or in combination with MUC4 decreased BAs-induced carcinogenic processes., Conclusion: Our results demonstrated that MUC17 has a central role in bile-induced PC progression, and in addition to MUC4, this isoform also can be used as a novel prognostic biomarker., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Inflammasomes, primarily responsible for the activation of IL-1β, have emerged as critical regulators of the tumor microenvironment. By using in vivo and in vitro brain metastasis models, as well as human samples to study the role of the NLRP3 inflammasome in triple-negative breast cancer (TNBC) brain metastases, we found NLRP3 inflammasome components and IL-1β to be highly and specifically expressed in peritumoral astrocytes. Soluble factors from TNBC cells induced upregulation and activation of NLRP3 and IL-1β in astrocytes, while astrocyte-derived mediators augmented the proliferation of metastatic cells. In addition, inhibition of NLRP3 inflammasome activity using MCC950 or dampening the downstream effect of IL-1β prevented the proliferation increase in cancer cells. In vivo, MCC950 reduced IL-1β expression in peritumoral astrocytes, as well as the levels of inflammasome components and active IL-1β. Most importantly, significantly retarded growth of brain metastatic tumors was observed in mice treated with MCC950. Overall, astrocytes contribute to TNBC progression in the brain through activation of the NLRP3 inflammasome and consequent IL-1β release. We conclude that pharmacological targeting of inflammasomes may become a novel strategy in controlling brain metastatic diseases., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Human pulmonary dirofilariasis (HPD) is rare in Hungary, and it stems from Dirofilaria immitis, mainly transmitted through mosquito bites, with dogs as primary hosts. Despite its prevalence in veterinary settings, human cases are infrequent. Historically, Mediterranean countries report most HPD cases, but sporadic cases occur in temperate European regions. Radiologically, HPD often manifests in a non-specific manner, resembling pulmonary neoplasms, leading to unnecessary surgery and patient distress., Methods: This study presents a notable case series from Hungary, encompassing a 12-year period, documenting 5 instances of HPD with the aim to provide baseline estimate of occurrence for future comparison., Results: Among the patients studied, all were of middle age (median: 52 years, range: 37-69) and exhibited tumor-like lesions, primarily localized to the right lung, necessitating lobectomy or wedge resection. Histological examination consistently revealed a necrotizing granulomatous response characterized by remnants of helminths, without the presence of ovules. Furthermore, rigorous diagnostic procedures excluded other potential infectious agents through specialized staining techniques. Polymerase chain reaction analysis definitively confirmed the diagnosis of HPD in each case., Conclusions: This case series highlights HPD as a seldom zoonosis, with a probable escalation in its occurrence within temperate regions. Therefore, clinicians should maintain a heightened awareness of HPD in the differential diagnosis of pulmonary coin lesions. Early recognition and diagnosis are paramount for appropriate management and prevention of potential complications associated with this increasingly recognized infectious entity., (© 2024. The Author(s).)

A murine colorectal carcinoma (CRC) model was established. CT26 colon carcinoma cells were injected into BALB/c mice's spleen to study the primary tumor and the mechanisms of cell spread of colon cancer to the liver. The CRC was verified by the immunohistochemistry of Pan Cytokeratin and Vimentin expression. Immunophenotyping of leukocytes isolated from CRC-bearing BALB/c mice or healthy controls, such as CD19+ B cells, CD11+ myeloid cells, and CD3+ T cells, was carried out using fluorochrome-labeled lectins. The binding of six lectins to white blood cells, such as galectin-1 (Gal1), siglec-1 (Sig1), Sambucus nigra lectin (SNA), Aleuria aurantia lectin (AAL), Phytolacca americana lectin (PWM), and galectin-3 (Gal3), was assayed. Flow cytometric analysis of the splenocytes revealed the increased binding of SNA, and AAL to CD3 + T cells and CD11b myeloid cells; and increased siglec-1 and AAL binding to CD19 B cells of the tumor-bearing mice. The whole proteomic analysis of the established CRC-bearing liver and spleen versus healthy tissues identified differentially expressed proteins, characteristic of the primary or secondary CRC tissues. KEGG Gene Ontology bioinformatic analysis delineated the established murine CRC characteristic protein interaction networks, biological pathways, and cellular processes involved in CRC. Galectin-1 and S100A4 were identified as upregulated proteins in the primary and secondary CT26 tumor tissues, and these were previously reported to contribute to the poor prognosis of CRC patients. Modelling the development of liver colonization of CRC by the injection of CT26 cells into the spleen may facilitate the understanding of carcinogenesis in human CRC and contribute to the development of novel therapeutic strategies.

Rosai-Dorfman disease (RDD) is a rare, S100-positive histiocytic proliferation, that can cause both nodal and extranodal illness. We present a case of a 53-year-old male patient. Magnetic resonance imaging described a plaque-like meningeal lesion, and the preoperative diagnosis was meningioma. Histologically, dense infiltration of lymphocytes, plasma cells, and histiocytes was seen, furthermore, the presence of emperipolesis in the sample was pronounced. In the histiocytes nuclear and cytoplasmic positivity with S100 protein, and nuclear positivity with Cyclin D1 was observed. The case was concluded as RDD. Morphological appearance of intracranial RDD with imaging procedures can present a differential diagnostic challenge. The correct diagnosis is based on the presence of histiocytes with emperipolesis, and properly defined immunohistochemical characteristics.

Micro-environmental factors, including stromal and immune cells, cytokines, and circulating hormones are well recognized to determine cancer progression. Melanoma cell growth was recently shown to be suppressed by cholecystokinin/gastrin (CCK) receptor antagonists, and our preliminary data suggested that melanoma patients with Helicobacter gastritis (which is associated with elevated serum gastrin) might have an increased risk of cancer progression. Therefore, in the present study, we examined how gastrin may act on melanoma cells. In 89 melanoma patients, we found a statistically significant association between circulating gastrin concentrations and melanoma thickness and metastasis, which are known risk factors of melanoma progression and prognosis. Immunocytochemistry using a validated antibody confirmed weak to moderate CCK2R expression in both primary malignant melanoma cells and the melanoma cell lines SK-MEL-2 and G361. Furthermore, among the 219 tumors in the Skin Cutaneous Melanoma TCGA Pan-Cancer dataset showing gastrin receptor (CCKBR) expression, significantly higher CCKBR mRNA levels were linked to stage III-IV than stage I-II melanomas. In both cell lines, gastrin increased intracellular calcium levels and stimulated cell migration and invasion through mechanisms inhibited by a CCK2 receptor antagonist. Proteomic studies identified increased MMP-2 and reduced TIMP-3 levels in response to gastrin that were likely to contribute to the increased migration of both cell lines. However, the effects of gastrin on tumor cell invasion were relatively weak in the presence of the extracellular matrix. Nevertheless, dermal fibroblasts/myofibroblasts, known also to express CCK2R, increased gastrin-induced cancer cell invasion. Our data suggest that in a subset of melanoma patients, an elevated serum gastrin concentration is a risk factor for melanoma tumor progression, and that gastrin may act on both melanoma and adjacent stromal cells through CCK2 receptors to promote mechanisms of tumor migration and invasion.

Introduction: The effect of platinum-based chemotherapy (Chem.) and second- or multiple- line immune checkpoint PD-1 blocking therapy by Nivolumab or Pembrolizumab (ICI) was assayed in the peripheral blood of non-small cell lung cancer (NSCLC) patients., Methods: Flow cytometry was used to detect NSCLC-related antigen binding IgG antibodies. The Luminex MagPix multiplex bead-based cytokine/chemokine detecting system was used to quantitatively measure 17 soluble markers in the plasma samples. Single-cell mass cytometry was applied for the immunophenotyping of peripheral leukocytes., Results: The incubation of patient derived plasma with human NSCLC tumor cell lines, such as A549, H1975, and H1650, detected NSCLC-specific antibodies reaching a maximum of up to 32% reactive IgG-positive NSCLC cells. The following markers were detected in significantly higher concentration in the plasma of Chem. group versus healthy non-smoker and smoker controls: BTLA, CD27, CD28, CD40, CD80, CD86, GITRL, ICOS, LAG-3, PD-1, PD-L1, and TLR-2. The following markers were detected in significantly higher concentration in the plasma of ICI group versus healthy non-smoker and smoker controls: CD27, CD28, CD40, GITRL, LAG-3, PD-1, PD-L1, and TLR-2. We showed the induction of CD69 and IL-2R on CD4+ CD25+ T-cells upon chemotherapy; the exhaustion of one CD8+ T-cell population was detected by the loss of CD127 and a decrease in CD27. CD19+CD20+, CD79B+, or activated B-cell subtypes showed CD69 increase and downregulation of BTLA, CD27, and IL-2R in NSCLC patients following chemotherapy or ICI., Discussion: Peripheral immunophenotype caused by chemotherapy or PD-1 blocking was shown in the context of advanced NSCLC., Competing Interests: LP is the CEO of Avidin Ltd. and GS an employee of CS-Smartlab-Devices Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Neuperger, Szalontai, Gémes, Balog, Tiszlavicz, Furák, Lázár, Puskás and Szebeni.)

The prognostic markers of lung squamous cell carcinoma (LSCC) are less investigated. The aim of our study was to evaluate tumour budding (TB), minimal cell nest size, nuclear diameter (ND), and spread through air spaces (STAS) among patients with resected LSCC, semi-quantitatively. Furthermore, we aimed to identify a grading system for the best prognostic stratification of LSCC. Patients who underwent surgical resection at the Department of Surgery, University of Szeged between 2010 and 2016 were included. Follow-up data were collected from medical charts. Morphological characteristics were recorded from histologic revision of slides. Kaplan-Meier analysis, log rank test and Cox proportional-hazards model, ROC curve analysis, and intraclass correlation were utilised. Altogether 220 patients were included. In univariate analysis, higher degree of TB, infiltrative tumour border, larger ND, the presence of single cell invasion (SCI) and STAS were associated with adverse prognosis. Based on our results, we proposed an easily applicable grading scheme focusing on TB, ND, and SCI. In multivariate analysis, the proposed grading system (p OS  < 0.001, p RFS  < 0.001) and STAS (p OS  = 0.008, p RFS  < 0.001) were independent prognosticators. Compared to the previously introduced grading systems, ROC curve analysis revealed that the proposed grade had the highest AUC values (AUC OS : 0.83, AUC RFS : 0.78). Each category of the proposed grading system has good (ICC: 0.79-0.88) reproducibility. We validated the prognostic impact of TB, SCI, ND, and STAS in LSCC. We recommend a reproducible grading system combining TB, SCI, and ND for proper prognostic stratification of LSCC patients. Further research is required for validation of this grading scheme., (© 2023. The Author(s).)

The advent of immunotherapy has revolutionized cancer treatments. However, the application of immune checkpoint inhibitors may entail severe side effects, with the risk of therapeutic resistance. The generation of chimeric antigen receptor (CAR) T-cells or CAR-NK cells requires specialized molecular laboratories, is costly, and is difficult to adapt to the rapidly growing number of cancer patients. To provide a simpler but effective immune therapy, a whole-cell tumor vaccine protocol was established based on ultraviolet C (UCV)-irradiated 4T1 triple-negative breast cancer cells. The apoptosis of tumor cells after UVC irradiation was verified using resazurin and Annexin V/propidium iodide flow cytometric assays. Protective immunity was achieved in immunized BALB/c mice, showing partial remission. Adoptive transfer of splenocytes or plasma from the mice in remission showed a protective effect in the naive BALB/c mice that received a living 4T1 tumor cell injection. 4T1-specific IgG antibodies were recorded in the plasma of the mice following immunization with the whole-cell vaccine. Interleukin-2 (IL-2) and oligonucleotide 2006 (ODN2006) adjuvants were used for the transfer of splenocytes from C57BL/6 mice into cyclophosphamide-treated BALB/c mice, resulting in prolonged survival, reduced tumor growth, and remission in 33% of the cases, without the development of the graft-versus-host disease. Our approach offers a simple, cost-effective whole-cell vaccine protocol that can be administered to immunocompetent healthy organisms. The plasma or the adoptive transfer of HLA-matching immunized donor-derived leukocytes could be used as an immune cell therapy for cancer patients.

Patients with recurrent acute pancreatitis (RAP) are at significant risk of developing early chronic pancreatitis (CP), which progresses into irreversible, end-stage CP with severe symptoms. There is no specific therapy in RAP or in early CP that may hinder disease progression. The pathogenesis of CP is complex and involves interactions among multiple cell types, including pancreatic acinar, ductal, and stellate cells (PSC). Therefore, it is pivotal to identify common pathogenic pathways in these cells that could be targeted pharmacologically. The Orai1-mediated store-operated Ca2+ entry (SOCE) is a ubiquitous signaling mechanism that may become overactivated in pathological states resulting in intracellular Ca2+ overload. In this study, we used ex vivo and in vivo preclinical disease models to demonstrate that Orai1 inhibition prevents progression of RAP and early CP. The selective Orai1 inhibitor CM5480 restored the expression of SOCE-associated regulatory factor in acinar cells, prevented uncontrolled Ca2+ elevation, protected acinar and ductal functions, mitigated immune cell infiltration, and diminished PSC activation, proliferation, and migration. We suggest that the overactivation of Orai1 is a crucial pathogenetic event in the progression of early CP and that inhibition of Orai1 could prevent the development of end-stage CP.

The therapeutic approach to brain metastases has changed significantly in the last 30 years. The development of surgical technique, the use of new MRI techniques, preoperative surgical planning and the administration of intraoperative navigation reduced the risks of surgery and improved the results. In the case of aggressive renal cell carcinomas, we detect brain metastases relatively often, which are difficult to treat, but the improved surgical and radiosurgery techniques can also be used with success. In our report, we present the neurosurgical management of metastatic spreading of renal cell carcinoma to the brain. Modern surgical planning and more precise, tailored approach with modern radiosurgery techniques are able to improve the outcome and prolong survival even in aggressive types of renal cell carcinomas that give rise to brain metastases. In more severe cases and even in the case of multiple brain metastases, cranial surgery can be recommended.

The treatment of mixed large cell neuroendocrine carcinoma is less studied due to its low incidence. However, the presence of anaplastic lymphoma kinase (ALK) fusion gene is rare in such tumours, ALK inhibitors may represent a promising therapeutic option instead of cytostatic therapy. Routine chest X-ray and then computed tomography (CT) examination revealed a pulmonary tumour in a 52-year-old asymptomatic woman. The neoplasm was removed by lobectomy. Histological examination confirmed papillary predominant lung adenocarcinoma. The patient was treated with postoperative chemotherapy and irradiation. 3 years later, neurologic symptoms were observed, therefore, brain CT was performed. The evaluation confirmed brain metastases which were removed. Histological examination identified metastasis of large cell neuroendocrine carcinoma. Revision and molecular examination of the metastasis and lung specimen revealed pulmonary mixed large cell neuroendocrine carcinoma with ALK-rearrangement. Alectinib (Alecensa) treatment was initiated resulting in regression of the previously observed liver metastases. Progression has not occurred in the last 3 years since the start of treatment. Detection of ALK fusion genes and research of ALK inhibitor therapy focus primarily on lung adenocarcinomas. Our case report would like to draw attention to the evaluation of driver mutations in pulmonary mixed neuroendocrine carcinoma with adenocarcinoma component because targeted treatment may be an effective alternative. Orv Hetil. 2023; 164(14): 548-554.

Introduction: Therapeutic treatment for advanced-stage (T 2 -T 4 ) gastroesophageal junction (GEJ) and gastric cancer involves neoadjuvant chemotherapy with subsequent surgical intervention., Method: Neoadjuvant oncological treatment for GEJ and gastric cancer previously consisted of the intravenous administration of epirubicin, cisplatin and fluorouracil (ECF) or epirubicin, cisplatin and capecitabine (ECX) combination (Group 1). The new protocol (FLOT, F: 5-FU, L: leucovorin, O: oxaliplatin, T: docetaxel), included patients with resectable GEJ and gastric cancer who had a clinical stage cT 2 or higher nodal positive cN+ disease (Group 2). Between 31 December 2008 and 31 October 2022, the effect of different oncological protocols in terms of surgical outcomes in cases of T 2 -T 4 tumours were retrospectively evaluated. Results of randomly assigned patients from the earlier ECF/ECX protocol ( n  = 36) (Group 1) and the new FLOT protocol ( n  = 52) (Group 2) were compared. Effect of different neoadjuvant therapies on tumour regression, types of possible side effects, type of surgery, and oncological radicality of surgical procedures were analysed., Results: When comparing the two groups, we found that in case of the FLOT neoadjuvant chemotherapy (Group 2, n  = 52), complete regression was achieved in 13.95% of patients, whereas in the case of ECF/ECX (Group 1, n  = 36), complete regression occurred in only 9.10% of patients. Furthermore, in the FLOT group, the mean number of lymph nodes removed was slightly higher (24.69 vs. 20.13 in the ECF/ECX group). In terms of the safety resection margin (proximal), no significant difference was found between the two treatment groups. Nausea and vomiting were the most common side effects. The occurrence of diarrhea was significantly higher in the FLOT group ( p  = 0.006). Leukopenia and nausea occurred more commonly with the old protocol (Group 1). The rate of neutropenia was lower following FLOT treatment ( p  = 0.294), with the lack of grade II and III cases. Anaemia occured at a significantly higher rate ( p  = 0.036) after the ECF/ECX protocol., Conclusions: As a result of the FLOT neoadjuvant oncological protocol for advanced gastro-esophageal junction and gastric cancer, the rate of complete tumour regression increased significantly. The rate of side effects was also appreciably lower following the FLOT protocol. These results strongly suggest a significant advantage of the FLOT neoadjuvant treatment used before surgery., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Paszt, Simonka, Budai, Horvath, Erdos, Vas, Ottlakan, Nyári, Szepes, Uhercsak, Maraz, Torday, Tiszlavicz, Olah and Lazar.)

Malignant mesothelioma (MM) is a rare tumor of mesothelial cells, with an increasing incidence both in developed and developing countries. MM has three major histological subtypes, in order of frequency, according to the World Health Organization (WHO) Classification of 2021: epithelioid, biphasic, and sarcomatoid MM. Distinction may be a challenging task for the pathologist, due to the unspecific morphology. Here, we present two cases of diffuse MM subtypes to emphasize the immunohistochemical (IHC) differences, and to facilitate diagnostic difficulties. In our first case of epithelioid mesothelioma, the neoplastic cells showed cytokeratin 5/6 (CK5/6), calretinin, and Wilms-tumor-1 (WT1) expression, while remaining negative with thyroid transcription factor-1 (TTF-1). BRCA1 associated protein-1 (BAP1) negativity was seen in the neoplastic cells' nucleus, reflecting loss of the tumor suppressor gene. In the second case of biphasic mesothelioma, expression of epithelial membrane antigen (EMA), CKAE1/AE3, and mesothelin was observed, while WT1, BerEP4, CD141, TTF1, p63, CD31, calretinin, and BAP1 expressions were not detected. Due to the absence of specific histological features, the differentiation between MM subtypes could be a challenging task. In routine diagnostic work, IHC may be the proper method in distinction. According to our results and literature data, CK5/6, mesothelin, calretinin, and Ki-67 should be applied in subclassification., (© 2023 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Lipid metabolic disturbances are associated with several diseases, such as type 2 diabetes or malignancy. In the last two decades, high-performance mass spectrometry-based lipidomics has emerged as a valuable tool in various fields of biology. However, the evaluation of macroscopic tissue homogenates leaves often undiscovered the differences arising from micron-scale heterogeneity. Therefore, in this work, we developed a novel laser microdissection-coupled shotgun lipidomic platform, which combines quantitative and broad-range lipidome analysis with reasonable spatial resolution. The multistep approach involves the preparation of successive cryosections from tissue samples, cross-referencing of native and stained images, laser microdissection of regions of interest, in situ lipid extraction, and quantitative shotgun lipidomics. We used mouse liver and kidney as well as a 2D cell culture model to validate the novel workflow in terms of extraction efficiency, reproducibility, and linearity of quantification. We established that the limit of dissectible sample area corresponds to about ten cells while maintaining good lipidome coverage. We demonstrate the performance of the method in recognizing tissue heterogeneity on the example of a mouse hippocampus. By providing topological mapping of lipid metabolism, the novel platform might help to uncover region-specific lipidomic alterations in complex samples, including tumors.

Introduction: The extent of spread through air spaces (STAS) is less investigated among patients with lung adenocarcinoma who underwent sublobar resection. Therefore, we aimed to evaluate the extent of STAS semi-quantitatively, to assess its prognostic impact on overall survival (OS) and recurrence-free survival (RFS), and to investigate the reproducibility of this assessment., Methods: The number of tumour cell clusters and single tumour cells within air spaces was recorded in three different most prominent areas (200x field of view). The extent of STAS was categorized into three groups, and the presence of free tumour cluster (FTC) was recorded., Results: Sixty-one patients were included. Recurrence was more frequent with higher grade (p = 0.003), presence of lymphovascular invasion (p = 0.027), and presence of STAS of any extent (p = 0.007). In multivariate analysis, presence of FTC (HR: 5.89; 95% CI: 1.63-21.26; p = 0.005) and more pronounced STAS (HR: 7.46; 95% CI: 1.60-34.6; p = 0.01) had adverse impact on OS and RFS, respectively. Concerning reproducibility, excellent agreement was found among STAS parameters (ICC range: 0.92-0.94)., Discussion: More extensive STAS is an unfavourable prognostic factor in adenocarcinomas treated with sublobar resection. As the evaluation of extent of STAS is reproducible, further investigation is required to gather more evidence., (© 2022 The Author(s). Published by S. Karger AG, Basel.)

Background: During the last decade, one of the most important treatment options for locally advanced, potencially resectable rectal tumours was neoadjuvant chemoradiotherapy (CRT) followed by surgery. Methods: Effects of the neoadjuvant treatment on surgical outcomes were retrospectively analysed in 185 patients with stage T2-T4 and N0-2, resectable rectal tumour among two patient groups defined by radiosensitizer agents. Group 1 ( n = 94) involved radiotherapy (RT) with 50.4 Gy total dose (25 × 1.8 Gy + 3 × 1.8 Gy tumour bed boost), and intravenous 5-fluorouracil (5-FU) (350 mg/m 2 ) with leucovorin (20 mg/m 2 ) on the 1-5 and 21-25 days, while Group 2 ( n = 91) RT and orally administrated capecitabine (daily 2 × 825 mg/m 2 ) on RT days. Surgery was carried out after 8-10 weeks. Side effects, perioperative complications, type of surgery, number of removed regional lymph nodes, resection margins and tumour regression grade (TRG) were analysed. Results: More favourable side effects were observed in Group 2. Despite the same rate of diarrhoea (Group 1 vs. Group 2: 54.3% vs. 56.0%), Grade 2-3 diarrhoea ratio was lower ( p = 0.0352) after capecitabine (Group 2). Weight loss occurred in 17.0% and 2.2% ( p = 0.00067), while nausea and vomiting was described in 38.3% and 15.4% ( p = 0.00045) with 5-FU treatment and capecitabine respectively. Anaemia was observed in 33.0% and 22.0% ( p = 0.0941). Complete tumour regression occurred in 25.3% after oral- and 13.8% after intravenous treatment ( p = 0.049). Ratio of sphincter preservation was higher with laparoscopy than open surgery (72.3% vs. 39.7%) ( p = 0.00001). Conclusion: The study confirms advantages of neoadjuvant chemoradiotherapy with oral capecitabine for rectal tumours, such as more favourable side effect profile and overall clinical outcome, with increased rate of complete tumour regression., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Paszt, Ottlakan, Abraham, Simonka, Vas, Maraz, Szepes, Tiszlavicz, Nyari, Olah and Lazar.)

Background and Purpose: The aim of the present study was to study the antiarrhythmic effects and cellular mechanisms of desethylamiodarone (DEA), the main metabolite of amiodarone (AMIO), following acute and chronic 4-week oral treatments (25-50 mg·kg -1 ·day -1 )., Experimental Approach: The antiarrhythmic effects of acute iv. (10 mg·kg -1 ) and chronic oral (4 weeks, 25 mg·kg -1 ·day -1 ) administration of DEA were assessed in carbachol and tachypacing-induced dog atrial fibrillation models. Action potentials were recorded from atrial and right ventricular tissue following acute (10 μM) and chronic (p.o. 4 weeks, 50 mg·kg -1 ·day -1 ) DEA application using the conventional microelectrode technique. Ionic currents were measured by the whole cell configuration of the patch clamp technique in isolated left ventricular myocytes. Pharmacokinetic studies were performed following a single intravenous dose (25 mg·kg -1 ) of AMIO and DEA intravenously and orally. In chronic (91-day) toxicological investigations, DEA and AMIO were administered in the oral dose of 25 mg·kg -1 ·day -1 )., Key Results: DEA exerted marked antiarrhythmic effects in both canine atrial fibrillation models. Both acute and chronic DEA administration prolonged action potential duration in atrial and ventricular muscle without any changes detected in Purkinje fibres. DEA decreased the amplitude of several outward potassium currents such as I Kr , I Ks , I K1 , I to , and I KACh , while the I CaL and late I Na inward currents were also significantly depressed. Better drug bioavailability and higher volume of distribution for DEA were observed compared to AMIO. No neutropenia and less severe pulmonary fibrosis was found following DEA compared to that of AMIO administration., Conclusion and Implications: Chronic DEA treatment in animal experiments has marked antiarrhythmic and electrophysiological effects with better pharmacokinetics and lower toxicity than its parent compound. These results suggest that the active metabolite, DEA, should be considered for clinical trials as a possible new, more favourable option for the treatment of cardiac arrhythmias including atrial fibrillation., (© 2022 The British Pharmacological Society.)

Introduction. Recently the therapeutic treatment for advanced, stage T2-T4 gastro-oesophageal junction cancer and those adjacent to the regional lymph nodes involves neoadjuvant chemotherapy with subsequent surgical intervention. Method. Neoadjuvant oncological treatment for gastro-oesophageal junction cancer previously consisted of the intravenous administration of epirubicin, cisplatin and fluorouracil (ECF) or epirubicin, cisplatin and capecitabine (ECX) combination (Group I). In the course of the new protocol (FLOT-, F: 5-FU, L: leucovorin, O: oxaliplatin, T: docetaxel), patients were included with resectable gastro-oesophageal junction cancer who had a clinical-stage cT2 or higher nodal positive cN+ disease (Group II). Between 31st of December 2013 and 1st of June 2021 we retrospectively analyzed the effect of these FLOT oncological protocols in terms of surgical outcomes in cases of T2-T4 tumors (n = 9). We compared the results of the randomly assigned nine patients from earlier ECF/ECX protocol (Group I). We analyzed the effect of the different neoadjuvant therapy on tumor regression, and evaluated the types of possible side effects, type of surgery, and the oncological radicality of surgical procedures (number of removed regional lymph nodes, resection margins). Results. Comparing the two groups we found that in cases of FLOT neoadjuvant chemotherapy complete regression was achieved significantly a higher number like in earlier ECX/ECF therapy. Furthermore, the average number of removed lymph nodes, and the safety resection margins (distal, circumferential) no significant difference was found between the two groups. Neutropenia was the most frequently encountered side effect. Leukopenia, neutropenia and nausea occurred more frequently in cases of the old protocol (Group I). Conclusions. As a result of the FLOT neoadjuvant oncological protocol for advanced gastro-oesophageal junction cancer, the number of cases with complete tumor regression has significantly increased. The present results strongly suggest a significant advantage in favor of FLOT neoadjuvant treatment following surgery. The prevalence of side effects was also appreciably lower in cases of the FLOT protocol.

For the centenary of the Department of Surgery, University of Szeged we have investigated and summarized the results and outcomes of 779 anti-reflux surgery cases between 1. January 2000 – 31. May 2021. The indication for surgery was made in close collaboration with the internal medicine workgroup depending on the results of endoscopy and functional tests. The primer indication for surgery was medical therapy-resistant reflux disease. Based on our clinical practice we performed laparoscopic Nissen fundoplication in 98,2% of the cases. Besides the long- and short-term postoperative complications, we investigated the long-term effect of anti-reflux surgery on acid and bile reflux, and the improvement of the patients' quality of life using the Visick score, and modified GERD-HRLQ score. Our investigations have proven the effect of acid and bile reflux in the pathogenesis of Barrett's esophagus and furthermore we have confirmed that laparoscopic anti-reflux surgery restores the function of the lower esophageal sphincter and eliminates acid and bile reflux, so in certain cases Barrett's esophagus regression can be achieved. But due to the heterogeneity of GERD and Barrett's esophagus long-term and regular endoscopic control is necessary.

Introduction: The COVID-19 (coronavirus disease 2019) caused by SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) is associated with high mortality rates worldwide. Polymerase chain reaction (PCR) is extensively used for virus detection in both infected patients and deceased persons. PCR, however, gives no information about the localization of the virus in cells and tissues. Detection of spike and nucleocapsid proteins and viral ribonucleic acid (RNA) of the SARS-CoV-2 in situ might provide more information and aid in the discovery of the pathomechanism of cellular damage. There are several commercially available anti-spike and anti-nucleocapsid antibodies used to detect immunohistochemical reactions, though each gives different results. Objective: The goal of the present study was to compare the intensity and specificity of several anti-spike and antinucleocapsid antibodies in different dilutions in four Hungarian university departments. Method: Immunohistochemical reactions were performed on coded slides taken from infected lungs of 3 deceased and placenta samples with appropriate negative controls of formalin-fixed paraffin-embedded tissues, scanned, evaluated unanimously and analysed statistically by the assessors. Results: By comparing the intensity, dilution, background and reproducibility of the different primary antibodies, it was possible to select the antibodies with the best results. Conclusion: The antibodies selected with established dilutions can be used in further studies to detect SARS-CoV-2 proteins in surgical materials and in samples obtained during autopsy.

Alcoholic pancreatitis and hepatitis are frequent, potentially lethal diseases with limited treatment options. Our previous study reported that the expression of CFTR Cl - channel is impaired by ethanol in pancreatic ductal cells leading to more severe alcohol-induced pancreatitis. In addition to determining epithelial ion secretion, CFTR has multiple interactions with other proteins, which may influence intracellular Ca 2+ signaling. Thus, we aimed to investigate the impact of ethanol-mediated CFTR damage on intracellular Ca 2+ homeostasis in pancreatic ductal epithelial cells and cholangiocytes. Human and mouse pancreas and liver samples and organoids were used to study ion secretion, intracellular signaling, protein expression and interaction. The effect of PMCA4 inhibition was analyzed in a mouse model of alcohol-induced pancreatitis. The decreased CFTR expression impaired PMCA function and resulted in sustained intracellular Ca 2+ elevation in ethanol-treated and mouse and human pancreatic organoids. Liver samples derived from alcoholic hepatitis patients and ethanol-treated mouse liver organoids showed decreased CFTR expression and function, and impaired PMCA4 activity. PMCA4 co-localizes and physically interacts with CFTR on the apical membrane of polarized epithelial cells, where CFTR-dependent calmodulin recruitment determines PMCA4 activity. The sustained intracellular Ca 2+ elevation in the absence of CFTR inhibited mitochondrial function and was accompanied with increased apoptosis in pancreatic epithelial cells and PMCA4 inhibition increased the severity of alcohol-induced AP in mice. Our results suggest that improving Ca 2+ extrusion in epithelial cells may be a potential novel therapeutic approach to protect the exocrine pancreatic function in alcoholic pancreatitis and prevent the development of cholestasis in alcoholic hepatitis., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

In the present study, the effect of long-term exercise training was investigated on myocardial morphological and functional remodeling and on proarrhythmic sensitivity in a rabbit athlete's heart model. New-Zealand white rabbits were trained during a 12-week long treadmill running protocol and compared with their sedentary controls. At the end of the training protocol, echocardiography, in vivo and in vitro ECG recordings, proarrhythmic sensitivity with dofetilide (nM) were performed in isolated hearts, and action potential duration (APD) measurements at different potassium concentrations (4.5 and 2 mM) were made in the isolated papillary muscles. Expression levels of the slow component of delayed rectifier potassium current and fibrosis synthesis and degradation biomarkers were quantified. Echocardiography showed a significantly dilated left ventricle in the running rabbits. ECG PQ and RR intervals were significantly longer in the exercised group (79 ± 2 vs. 69 ± 2 ms and 325 ± 11 vs. 265 ± 6 ms, p < 0.05, respectively). The in vivo heart rate variability (HRV) (SD of root mean square: 5.2 ± 1.4 ms vs. 1.4 ± 0.2 ms, p < 0.05) and Tpeak-Tend variability were higher in the running rabbits. Bradycardia disappeared in the exercised group in vitro . Dofetilide tended to increase the QTc interval in a greater extent, and significantly increased the number of arrhythmic beats in the trained animals in vitro . APD was longer in the exercised group at a low potassium level. Real-time quantitative PCR (RT-qPCR) showed significantly greater messenger RNA expression of fibrotic biomarkers in the exercised group. Increased repolarization variability and higher arrhythmia incidences, lengthened APD at a low potassium level, increased fibrotic biomarker gene expressions may indicate higher sensitivity of the rabbit "athlete's heart" to life-threatening arrhythmias., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kui, Polyák, Morvay, Tiszlavicz, Nagy, Ördög, Takács, Leprán, Farkas, Papp, Jost, Varró, Baczkó and Farkas.)

Aims: Tumour grading is an essential part of the pathologic assessment that promotes patient management. The International Association for the Study of Lung Cancer (IASLC) proposed a grading system for non-mucinous lung adenocarcinoma in 2020. We aimed to validate the prognostic impact of this novel grading system on overall survival (OS) and recurrence-free survival (RFS) based on literature data., Methods and Results: The review protocol was registered in PROSPERO (CRD42023396059). We aimed to identify randomized or non-randomized controlled trials published after 2020 comparing different IASLC grade categories in Medline, Embase, and CENTRAL. Hazard ratios (HRs) with 95% confidence intervals (CIs) of OS and RFS were pooled and the Quality In Prognosis Studies (QUIPS) tool was used to assess the risk of bias in the included studies. Ten articles were eligible for this review. Regarding OS estimates, grade 1 lung adenocarcinomas were better than grade 3 both in univariate and multivariate analyses (HR OSuni  = 0.19, 95% CI: 0.05-0.66, p = 0.009; HR OSmulti  = 0.21, 95% CI: 0.12-0.38, p < 0.001). Regarding RFS estimates, grade 3 adenocarcinomas had a worse prognosis than grade 1 in multivariate analysis (HR RFSmulti : 0.22, 95% CI: 0.14-0.35, p < 0.001)., Conclusion: The literature data and the result of our meta-analysis demonstrate the prognostic relevance of the IASLC grading system. This supports the inclusion of this prognostic parameter in daily routine worldwide., (© 2024 The Authors. Histopathology published by John Wiley & Sons Ltd.)

Type 1 diabetes is a disease of the endocrine pancreas; however, it also affects exocrine function. Although most studies have examined the effects of diabetes on acinar cells, much less is known regarding ductal cells, despite their important protective function in the pancreas. Therefore, we investigated the effect of diabetes on ductal function. Diabetes was induced in wild-type and cystic fibrosis transmembrane conductance regulator (CFTR) knockout mice following an i.p. administration of streptozotocin. Pancreatic ductal fluid and HCO 3 - secretion were determined using fluid secretion measurements and fluorescence microscopy, respectively. The expression of ion transporters was measured by real-time PCR and immunohistochemistry. Transmission electron microscopy was used for the morphological characterization of the pancreas. Serum secretin and cholecystokinin levels were measured by an enzyme-linked immunosorbent assay. Ductal fluid and HCO 3 - secretion, CFTR activity, and the expression of CFTR, Na + /H + exchanger-1, anoctamine-1 and aquaporin-1 were significantly elevated in diabetic mice. Acute or chronic glucose treatment did not affect HCO 3 - secretion, but increased alkalizing transporter activity. Inhibition of CFTR significantly reduced HCO 3 - secretion in both normal and diabetic mice. Serum levels of secretin and cholecystokinin were unchanged, but the expression of secretin receptors significantly increased in diabetic mice. Diabetes increases fluid and HCO 3 - secretion in pancreatic ductal cells, which is associated with the increased function of ion and water transporters, particularly CFTR. KEY POINTS: There is a lively interaction between the exocrine and endocrine pancreas not only under physiological conditions, but also under pathophysiological conditions The most common disease affecting the endocrine part is type-1 diabetes mellitus (T1DM), which is often associated with pancreatic exocrine insufficiency Compared with acinar cells, there is considerably less information regarding the effect of diabetes on pancreatic ductal epithelial cells, despite the fact that the large amount of fluid and HCO 3 - produced by ductal cells is essential for maintaining normal pancreatic functions Ductal fluid and HCO 3 - secretion increase in T1DM, in which increased cystic fibrosis transmembrane conductance regulator activation plays a central role. We have identified a novel interaction between T1DM and ductal cells. Presumably, the increased ductal secretion represents a defence mechanism in the prevention of diabetes, but further studies are needed to clarify this issue., (© 2024 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Background: The advancement of nanotechnology underscores the imperative need for establishing in silico predictive models to assess safety, particularly in the context of chronic respiratory afflictions such as lung fibrosis, a pathogenic transformation that is irreversible. While the compilation of predictive descriptors is pivotal for in silico model development, key features specifically tailored for predicting lung fibrosis remain elusive. This study aimed to uncover the essential predictive descriptors governing nanoparticle-induced pulmonary fibrosis. Methods: We conducted a comprehensive analysis of the trajectory of metal oxide nanoparticles (MeONPs) within pulmonary systems. Two biological media (simulated lung fluid and phagolysosomal simulated fluid) and two cell lines (macrophages and epithelial cells) were meticulously chosen to scrutinize MeONP behaviors. Their interactions with MeONPs, also referred to as nano-bio interactions, can lead to alterations in the properties of the MeONPs as well as specific cellular responses. Physicochemical properties of MeONPs were assessed in biological media. The impact of MeONPs on cell membranes, lysosomes, mitochondria, and cytoplasmic components was evaluated using fluorescent probes, colorimetric enzyme substrates, and ELISA. The fibrogenic potential of MeONPs in mouse lungs was assessed by examining collagen deposition and growth factor release. Random forest classification was employed for analyzing in chemico, in vitro and in vivo data to identify predictive descriptors. Results: The nano-bio interactions induced diverse changes in the 4 characteristics of MeONPs and had variable effects on the 14 cellular functions, which were quantitatively evaluated in chemico and in vitro. Among these 18 quantitative features, seven features were found to play key roles in predicting the pro-fibrogenic potential of MeONPs. Notably, IL-1β was identified as the most important feature, contributing 27.8% to the model's prediction. Mitochondrial activity (specifically NADH levels) in macrophages followed closely with a contribution of 17.6%. The remaining five key features include TGF-β1 release and NADH levels in epithelial cells, dissolution in lysosomal simulated fluids, zeta potential, and the hydrodynamic size of MeONPs. Conclusions: The pro-fibrogenic potential of MeONPs can be predicted by combination of key features at nano-bio interfaces, simulating their behavior and interactions within the lung environment. Among the 18 quantitative features, a combination of seven in chemico and in vitro descriptors could be leveraged to predict lung fibrosis in animals. Our findings offer crucial insights for developing in silico predictive models for nano-induced pulmonary fibrosis. [ABSTRACT FROM AUTHOR]

Acute pancreatitis (AP) is an inflammatory disease of the pancreas and a complex process involving multiple factors, with mitochondrial damage playing a crucial role. Mitochondrial dysfunction is now considered a key driver in the development of AP. This dysfunction often presents as increased oxidative stress, altered membrane potential and permeability, and mitochondrial DNA damage and mutations. Under stress conditions, mitochondrial dynamics and mitochondrial ROS production increase, leading to decreased mitochondrial membrane potential, imbalanced calcium homeostasis, and activation of the mitochondrial permeability transition pore. The release of mitochondrial DNA (mtDNA), recognized as damage-associated molecular patterns, can activate the cGAS-STING1 and NF-κB pathway and induce pro-inflammatory factor expression. Additionally, mtDNA can activate inflammasomes, leading to interleukin release and subsequent tissue damage and inflammation. This review summarizes the relationship between mitochondria and AP and explores mitochondrial protective strategies in the diagnosis and treatment of this disease. Future research on the treatment of acute pancreatitis can benefit from exploring promising avenues such as antioxidants, mitochondrial inhibitors, and new therapies that target mitochondrial dysfunction. [ABSTRACT FROM AUTHOR]

Introduction: Endotoxemia is a common issue for patients with biliary obstruction. The lung is the most affected organ by endotoxins. Exercise training can alleviate lipopolysaccharide (LPS)-induced lung inflammation and resveratrol has biological effects similar to exercise. In this study, we evaluated the protective effects of exercise preconditioning, resveratrol, and their combination on LPS-induced lung injury and mortality in rats with obstructive jaundice. Methods: Endotoxemia was simulated in rats by common bile duct ligation (CBDL) and intraperitoneal injection of low-dose LPS. The treatment groups were pretreated with exercise and/or resveratrol to assess their effects on lung injury and mortality. Immunohistochemistry, immunofluorescence, and ELISA were subsequently used to evaluate the impact of exercise and/or resveratrol on inflammation in lung tissue and bronchoalveolar lavage fluid. Results: We found that even in the early stages, compared to sham-LPS rats, low-dose LPS induced excessive systemic inflammatory responses in CBDL rats, as evidenced by a significant increase in TNF-α and IL-6, severe lung inflammation, lung injury, and higher mortality rates, indicating that cholestasis increased rats' susceptibility to endotoxins. Exercise training reduced neutrophil infiltration in the lungs of model rats and IL-6 levels in bronchoalveolar lavage fluid. Both exercise training and resveratrol exhibited synergistic effects in reducing macrophage accumulation in lung tissues, lowering TNF-α and IL-6 levels in the lungs, and decreasing TNF-α concentration in bronchoalveolar lavage fluid. Additionally, exercise and combined interventions both significantly increased the expression of IL-10. The interventions induced a marked improvement in lung tissue pathological damage and lung edema in model rats and prolonged the survival time of rats with obstructive jaundice. Discussion: This study demonstrates that exercise preconditioning and/or resveratrol can significantly reduce rats' susceptibility to endotoxins after CBDL and alleviate lung injuries through their anti-inflammatory effects, thereby decreasing the mortality risk. [ABSTRACT FROM AUTHOR]

Background & objectives: Endoscopy is the current gold standard for evaluation of disease activity in ulcerative colitis. The Mayo Endoscopic Subscore (MES) is commonly used for quantifying disease activity, but it has several weaknesses. Numerous new endoscopic indices have been developed but none of these have been widely implemented, likely due to limited feasibility. The primary objective of this study was thus to develop a simple, reliable, endoscopic index for ulcerative colitis. Secondary objectives were to evaluate and compare the MES, the Ulcerative Colitis Endoscopic Index of Severity (UCEIS), and the Ulcerative Colitis Colonoscopic Index of Severity (UCCIS), as well as examining the agreement between full colonoscopy and sigmoidoscopy. Methods: Consecutive adult ulcerative colitis patients had their routine colonoscopies video recorded, each edited into five shorter segment-specific video sequences. In parallel, blood, fecal, and mucosal samples were collected, together with data on symptoms and quality-of-life. The video sequences were scored by three gastroenterologists and one resident gastroenterologist according to a form comprising six endoscopic disease activity descriptors and an overall endoscopic disease severity assessment. Results: One hundred unique video sequences from twenty patients were each evaluated three times by four assessors, generating a total of 7200 unique segment-specific data-points for the six descriptors and 1200 unique assessments of overall endoscopic disease severity. The intra- and interobserver agreement for the individual descriptors were overall moderate to very good. The MES, UCEIS, and UCCIS performed similarly with the latter being slightly superior in terms of reliability and correlation to biomarkers of disease activity. The descriptor vascular pattern was the best discriminator at the lower end of the disease activity spectrum, whereas the descriptor ulcers was the best at the medium to high end. These two descriptors were combined into a new index, the Simple Endoscopic Score for Ulcerative Colitis (SES-UC), which displayed similar levels of reliability and accuracy as the established indices. Finally, comparison of sigmoidoscopy and colonoscopy showed that up to 38% of patients had their most inflamed segment located proximally to the sigmoid colon. Conclusions: We propose a new simplified endoscopic index for ulcerative colitis, the SES-UC, which is based on the two descriptors vascular pattern and ulcers. The performance of the SES-UC was similar to, and in some regards better than, that of the established indices (MES, UCEIS, and UCCIS). This together with its simplicity makes SES-UC a candidate index for use in clinical practice as well as in clinical studies. [ABSTRACT FROM AUTHOR]

Mass spectrometry imaging (MSI) is a well-established technique that allows to determine the distribution of small molecules, such as lipids, metabolites, and drugs, as well as large molecules in tissue sections. Because of the tissue heterogeneity, resulting in different matrix effects, and to the fact that the measured compounds are not entirely "extracted" from the tissue during the measurement, the absolute quantitative aspect of MSI is limited. To combine compound quantification with spatial information on fresh frozen unstained tissue sections, laser (capture) microdissection has been used to isolate tissue sections for compound extraction and LC-MS/MS quantification. Although this method relying on manual ROIs selection is rather sensitive compared to traditional MSI methods, it lacks the throughput needed to screen entire tissue sections. To apply a higher throughput tissue screening approach, we propose herein a workflow for performing indiscriminate and sequential LMD tissue section cuts that can cover up to 96 cuts collected in a 96 well plate on Leica LMD systems, for further extractions and LC-MS/MS analysis. Our workflow relies on the creation and implementation of 96 squares microgrid templates for the LMD cut of different area sizes (30x30 μm2, 50x50 μm2, 100x100 μm2, 200x200 μm2, 270x270 μm2 and 500x500 μm2) using 5 different magnifications (5x, 10x, 20x, 40x and 63x), on fresh frozen tissue sections. The method was applied on 20μm mouse brain and liver tissue sections. The tissue cut collection yields were evaluated visually and by the detection of the sprayed standards on the tissue sections, and found to be ranging from 78% to 91%, and the throughput of the LMD cuts and collection in a 96 well format, was measured to be from 19 to 37 minutes per tissue section, depending on the 96 squares microgrid template and the corresponding magnification lens used. Further extraction and LC-MS/MS analysis of 3 different compounds previously sprayed on a mouse liver tissue section allowed to determine the LLOQ the workflow allows to achieve when using the different templates. [ABSTRACT FROM AUTHOR]

Background: For esophageal squamous cell carcinoma (ESCC), universally accepted pathological criteria for classification by differentiation degree are lacking. Tumor budding, single-cell invasion, and nuclear grade, recognized as prognostic factors in other carcinomas, have rarely been investigated for their correlation with differentiation and prognosis in ESCC. This study aims to determine if pathological findings can predict differentiation degree and prognosis in ESCC. Patients and methods: This study reviewed tumor slides from 326 patients who underwent surgery for ESCC between 2007 and 2012. Tumors were evaluated for subtypes, tumor nest size, tumor stroma, and nuclear grade (nuclear diameter and mitosis) across different differentiation groups. Overall survival (OS) and disease-free survival (DFS) were estimated using the Kaplan-Meier method, with group differences assessed using the stratified log-rank test and Cox proportional hazards model. Results: The mean values of tumor budding invasion margins in well, moderately, and poorly differentiated groups were 25.3%, 30.7%, and 36.3%, respectively. Mean tumor budding/10HPFs were 8.0, 10.3, and 13.0, respectively. Well-differentiated tumors showed more keratinizing subtypes, smaller tumor budding invasion margins, more Grade 1 tumor budding (0-4 cells), absence of single-cell invasion, larger nuclear diameter (≥5 lymphocytes), higher mitotic counts, more submucosal invasion, and less lymphovascular invasion. Conversely, poorly differentiated tumors exhibited opposite characteristics. Multivariate analyses identified the nuclear diameter as independent prognostic factors for OS and DFS. Conclusions: Pathological features can stratify the differentiation landscape in ESCC patients. The nuclear diameter (4 lymphocytes) can help predict prognosis in ESCC than other pathological features. Implications for practice: We first time report the mean values of tumor budding invasion margins and tumor budding/10HPF in well, moderately, and poorly differentiated groups for esophageal squamous cell carcinoma. The landscape of well differentiation was depicted with more keratinizing subtypes, smaller tumor budding invasion margins, more Grade 1 tumor budding (0-4 cells), absence of single-cell invasion, larger nuclear diameter (≥5 lymphocytes), higher mitotic counts, and less lymphovascular invasion. The nuclear diameter as independent prognostic factors for prognosis. The findings indicate that pathological features can stratify the differentiation landscape in ESCC patients and offer novel insight into definition of well or moderately differentiation. [ABSTRACT FROM AUTHOR]

The emergence of new psychoactive substances (NPS) in the global drug market since the 2000s has posed major challenges for regulators and law enforcement agencies. Among these, synthetic cathinones have gained prominence due to their stimulant effects on the central nervous system, leading to widespread recreational use. These compounds, often marketed as alternatives to illicit stimulants such as amphetamines and cocaine, have been linked to numerous cases of intoxication, addiction and death. The structural diversity and enantiomeric forms of synthetic cathinones further complicate their detection and regulation and pose challenges to forensic toxicology. In addition to their psychoactive and toxicological effects, new research suggests that cathinones may have antimicrobial properties. Compounds derived from Catha edulis (khat), including cathinone, have shown antimicrobial activity against multidrug-resistant bacteria such as Staphylococcus aureus and Escherichia coli, highlighting their potential role in the fight against antibiotic resistance. This article provides an overview of the chemistry, pharmacokinetics, pharmacodynamics, toxicological effects and potential antimicrobial applications of synthetic cathinones. The potential therapeutic use of cathinone-derived compounds to combat antimicrobial resistance represents an exciting new frontier in drug development, although further research is needed to balance these benefits with the psychoactive risks. [ABSTRACT FROM AUTHOR]

Simple Summary: Brain metastases represent an unmet medical need in the treatment of breast cancer. Notwithstanding significant achievements in the management of both early and advanced settings, the spread of the disease to the brain is challenging. A multidisciplinary approach allows selection of the most appropriate trajectory. Patients with HER2-positive and triple-negative breast disease are at major risk to develop brain deposits. Local treatment, surgery and radiotherapy are useful in the treatment of brain metastases; however, systemic therapy, small molecules and antibody drug conjugates can be successfully used. In this review, we summarize the systemic treatment landscape of brain metastases from breast cancer to shed light on the most favorable strategies. Breast cancer is the most frequently diagnosed neoplasm all over the world and the second leading cause of cancer death in women. Breast cancer prognosis has significantly improved in the last years due to the advent of novel therapeutic options, both in the early and in advanced stages. However, the spread of the disease to the brain, accounting for 15–30% of the metastatic diagnoses, is challenging, and its poor prognosis represents an unmet medical need, leading to deterioration of quality of life and causing morbidity and mortality. Generally, triple-negative and HER2-positive breast cancer subtypes more frequently spread to the brain or in the leptomeningeal space. Consequently, according to international guidelines, several systemic treatments can be offered as a first option in some subsets of patients. However, a multidisciplinary approach is recommended to offer the most appropriate strategy to patients. Antibody–drug conjugates such as trastuzumab deruxtecan or sacituzumab govitecan along with small molecules have led to important achievements in the treatment of brain metastases from HER2-positive and triple-negative breast cancer. In this narrative review, we will focus on the molecular features leading to the development of brain metastases and explore the risk and the prognostic factors involved in the development of brain metastases. Finally, we will review the major achievements in the treatment landscape of brain metastases from breast cancer and novel medical approaches. [ABSTRACT FROM AUTHOR]

Ketone bodies, or ketones, are an alternative energy source and have several nonmetabolic signaling actions, such as inhibiting inflammation. Because of this, exogenous ketone supplementation has been used to help treat various diseases. β-hydroxybutyrate (βHB) is the major ketone body that has reduced neurological injury and brain edema in animal models of ischemic stroke and traumatic brain injury. However, the therapeutic potential of βHB in intracerebral hemorrhage (ICH) has not yet been determined. Here we investigated the effects of exogenous βHB treatment following ICH on inflammation, edema, injury size, and functional outcomes. To do this, we administered 250 mg/kg of βHB (subcutaneously every 12 hours) starting 2 hours after collagenase-induced ICH in rats over 3 experiments. First, we observed that βHB-treated rats had significant reductions in transcript expression of pro-inflammatory markers Il1b (p = 0.0210), Tnfa (p = 0.0108), and Mcp1 (p = 0.0473) 3 days post-ICH. Second, βHB significantly improved neurological deficits measured by the neurological deficit scale on day 3 (p = 0.0416) in another cohort of rats, despite no treatment effect on edema (p = 0.2110). To test whether the effects of acute βHB treatment (for 7 days post-ICH) were chronically sustained, the third experiment used serial behavioural testing which confirmed that βHB significantly improved neurological deficit scores (p = 0.0459) 3 days post-ICH. These effects were not sustained at 7, 14, and 28 days post-ICH (all p≥0.1546). Similarly, βHB treatment did not yield differences in forelimb use asymmetry (all p>0.45) or brain lesion volume (p = 0.3381), the primary endpoint of this study. Thus, our studies show that an acute βHB treatment post-ICH can provide some early signs of functional benefit without evidence of lasting effects or neuroprotection. However, it remains to be tested whether other βHB dosing regimens may favorably affect these and other neurological, behavioral, and biochemical parameters, particularly given the early signals of reduced striatal inflammation. [ABSTRACT FROM AUTHOR]

In post-mortem (PM) investigations, forensic toxicologists attempt to identify legal or illegal substances present before death and determine how they contributed to the cause of death. A critical challenge is ensuring that PM sample concentrations accurately reflect those at the time of death, as postmortem redistribution (PMR) can alter these levels due to anatomical and physiological changes. The PMR phenomenon is called a 'toxicological nightmare'. PMR significantly affects post-mortem drug concentrations, particularly for lipophilic drugs and those with a high volume of distribution. The emergence of new psychoactive substances (NPSs) has led to a growing recognition of their role as a significant public health concern, frequently associated with fatalities related to polydrug use. These substances are renowned for their ability to induce intoxication at low doses, which has led to the continuous updating of toxicological and forensic methods to improve detection and adopt new analytical standards. The comprehensive detection of NPS metabolites, some of which are still undiscovered, presents an additional analytical challenge, as do their metabolic pathways. This complicates their identification in fatal cases using standard analytical methods, potentially leading to an underestimation of their actual prevalence in toxicological results. Furthermore, the interpretation of analytical results is hindered by the absence of data on PM blood levels and the specific contributions of NPS to causes of death, exacerbated by the lack of knowledge of whether the PMR phenomenon influences them. This paper presents a comprehensive review of the literature on post-mortem cases involving various NPS, categorized according to classifications by the United Nations Office on Drugs and Crime (UNODC) and the European Union Drugs Agency (EUDA). These categories include cathinones, phenylethylamines, arylalkylamines, phencyclidine-type substances, phenmetrazines, piperazines, phenidates, aminoindanes, LSD-like NPSs, tryptamines, fentanyl analogs, designer benzodiazepines, synthetic cannabinoids, and nitazenes. This review covers not only postmortem blood levels but also the stability of the substances studied, the methods of analysis, and attempts to shed some light on the PMR phenomenon. This review used various key terms, such as PMR, NPS, and the names of previously categorized substances and drug analyses across multiple peer-reviewed journals and databases, including Scopus, Google Schoolar, Springer, PubMed, and Wiley Online Library. In addition, references from retrieved articles were examined to identify additional relevant research. Interpreting post-mortem toxicological results is complex and lacks definitive guidelines, requiring a nuanced understanding of its challenges and potential pitfalls. As a result, post-mortem toxicology is often regarded as an art. The primary aim of this review is to provide forensic toxicologists with a comprehensive framework to assist in the evaluation and interpretation of NPS analysis. This guide is intended to complement the existing knowledge and practices applied in forensic laboratories within the toxicological analysis of post-mortem cases. [ABSTRACT FROM AUTHOR]

The central nervous system (CNS) relies on precise regulation of potassium ion (K+) concentrations to maintain physiology. This regulation involves complex cellular and molecular mechanisms that work in concert to regulate both intracellular and extracellular K+ levels. Inflammation, a key physiological response, encompasses a series of cell-specific events leading to inflammasome activation. Perturbations in K+-sensitive processes can result in either chronic or uncontrolled inflammation, highlighting the intricate relationship between K+ homeostasis and inflammatory signalling. This review explores molecular targets that influence K+ homeostasis and have been implicated in inflammatory cascades, offering potential therapeutic avenues for managing inflammation. We examine both cell-specific and common molecular targets across different cell types, providing a comprehensive overview of the interplay between K+ regulation and inflammation in the CNS. By elucidating these mechanisms, we identify leads for drug discovery programmes aimed at modulating inflammatory responses. Additionally, we highlight potential consequences of targeting individual molecular entities for therapeutic purposes, emphasizing the need for a nuanced approach in developing anti-inflammatory strategies. This review considers current knowledge on K+-sensitive inflammatory processes within the CNS, offering critical insights into the molecular underpinnings of inflammation and potential therapeutic interventions. Our findings underscore the importance of considering K+ homeostasis in the development of targeted therapies for inflammatory conditions within the CNS. [ABSTRACT FROM AUTHOR]

Adrenocorticotropic hormone-producing pheochromocytomas/paragangliomas are rare neuroendocrine tumors that co-secrete excess catecholamines and adrenocorticotropic hormone, resulting in Cushing syndrome (CS). This review aims to summarize important patient characteristics, investigations, and outcomes in all cases reported in the English literature. A literature search was conducted to identify all English-language case reports and case series describing adrenocorticotropic hormone-producing pheoc hromo cytom as/pa ragan gliom as. Relevant characteristics were systematically recorded. Cases that did not provide definitive evidence of an adrenocorticotropin (ACTH)-producing pheochromocytoma/paraganglioma were excluded. Our search strategy identified 93 published cases that met the inclusion criteria. We additionally reported one patient for a total of 94 cases. Details related to patient characteristics, laboratory data, and outcomes were commonly underreported. The median age was 47 years, and females accounted for 72% of cases. A cushingoid appearance was reported in 82% of patients, and hypertension in 86%. Infections were reported in 23% of patients. Urinary metanephrines were elevated at least three-fold above normal in 74% of cases. ACTH levels were high in 88% of patients and inappropriately normal in 12%. The median 24-hour urinary cortisol was 21-fold the upper limit of normal. Adrenalectomy was performed in nearly all patients, with 88% achieving a cure for both catecholamine and glucocorticoid excess. A total of 11 patients died. Metastases were uncommon (6%). Adrenocorticotropic hormone-producing pheochromocytomas/paragangliomas are associated with considerable morbidity and mortality. It should be considered in the diagnostic workup of all patients with ectopic CS. Surgical cure is achieved in most patients, and infections are the leading cause of peri-operative mortality. [ABSTRACT FROM AUTHOR]

Background/Objectives: Chemerin, which is a multifunctional cytokine and adipokine, has been implicated in inflammatory and metabolic processes and might play a role in upper gastrointestinal (GI) malignancies, particularly gastric and esophageal cancer. The aim of this review is to explore the role of chemerin in the pathophysiology of upper GI cancers, as well as its potential as a biomarker for early detection and as a therapeutic target. Methods: A comprehensive review of recent studies about chemerin's biochemical properties and interaction with its receptors, as well as its effects on inflammatory responses, immune regulation, and metabolic processes, was conducted. The clinical implications of chemerin for gastric and esophageal cancer were analyzed, whereas the potential therapeutic strategies targeting chemerin were discussed. Results: Elevated chemerin levels are associated with poor prognosis in gastric cancer and promote invasiveness and metastasis in esophageal cancer. Chemerin receptor antagonists show promising results in inhibiting cancer cell migration, invasion, and progression. Conclusions: Chemerin could represent a valuable prognostic biomarker and therapeutic target for upper GI cancers. Future observational studies should validate its clinical applications and investigate the efficacy of chemerin inhibitors as potential therapeutic targets. [ABSTRACT FROM AUTHOR]

Sphingosine-1-phosphate (S1P) is a sphingolipid metabolic product produced via the phosphorylation of sphingosine by sphingosine kinases (SPHKs), serving as a powerful modulator of various cellular processes through its interaction with S1P receptors (S1PRs). Currently, this incompletely understood mechanism in pancreatic diseases including pancreatitis and pancreatic cancer, largely limits therapeutic options for these disorders. Recent evidence indicates that S1P significantly contributes to pancreatic diseases by modulating inflammation, promoting pyroptosis in pancreatic acinar cells, regulating the activation of pancreatic stellate cells, and affecting organelle functions in pancreatic cancer cells. Nevertheless, no review has encapsulated these advancements. Thus, this review compiles information about the involvement of S1P signaling in exocrine pancreatic disorders, including acute pancreatitis, chronic pancreatitis, and pancreatic cancer, as well as prospective treatment strategies to target S1P signaling for these conditions. The insights presented here possess the potential to offer valuable guidance for the implementation of therapies targeting S1P signaling in various pancreatic diseases. [ABSTRACT FROM AUTHOR]

Chemerin is an adipokine with chemotactic activity to a subset of leukocytes. Chemerin binds to 3 G protein-coupled receptors, including chemokine-like receptor 1 (CMKLR1), G protein-coupled receptor 1 (GPR1), and C-C chemokine receptor-like 2 (CCRL2). Here, we report that GPR1 is capable of Gi signaling when stimulated with full-length chemerin or its C-terminal nonapeptide (C9, YFPGQFAFS). We present high-resolution cryo-EM structures of Gi-coupled GPR1 bound to full-length chemerin and to the C9 peptide, respectively. C9 insertion into the transmembrane (TM) binding pocket is both necessary and sufficient for GPR1 signaling, whereas the full-length chemerin uses its bulky N-terminal core for interaction with a β-strand located at the N-terminus of GPR1. This interaction involves multiple β-strands of full-length chemerin, forming a β-sheet that serves as a "lid" for the TM binding pocket and is energetically expensive to remove as indicated by molecular dynamics simulations with free energy landscape analysis. Combining results from functional assays, our structural model explains why C9 is an activating peptide at GPR1 and how the full-length chemerin uses a "two-site" model for enhanced interaction with GPR1. GPR1 is a chemerin receptor, but whether Gi signaling is elicited upon binding to the chemerin adipokine remains unclear. This study reports a cryo-EM structural analysis of the GPR1-Gi complex bound to chemerin, confirming Gi signaling and a 'two-site' activation mechanism. [ABSTRACT FROM AUTHOR]

Background: Crohn's disease (CD) is a chronic intestinal inflammatory disorder, the etiology of which remains unknown, and is characterized by symptoms such as chronic abdominal pain, diarrhea, obstruction, and perianal lesions. Histopathology is widely regarded as the preferred method for diagnosing CD, although the histological diagnosis may lack specificity. The identification of granulomas is commonly believed to be the most reliable diagnostic indicator for CD, surpassing all other clinical features in significance. Nevertheless, research indicates that the detection rate of granulomas in CD exhibits considerable variability. Furthermore, granulomas can manifest in various specific infections including tuberculosis and Yersinia, as well as in a range of diseases characterized by macrophage reactions such as sarcoidosis and drug-induced enteritis. Granulomas associated with CD typically do not exhibit necrosis. However, the formation of caseous granulomas may occur as a result of secondary infections related to anti-CD drug treatment or perforation of the intestinal wall. Case presentation: In this study, we present a case of a 28-year-old female patient diagnosed with CD exhibiting histologic granulomas, including both caseating and non-caseating forms, which demonstrated a positive response to medical treatment. Conclusion: In clinical practice, various forms of granulomas may indicate diverse underlying diseases, yet lack specificity. It is suggested that the presence of caseous granulomas should not be considered as a definitive exclusion criterion for the diagnosis when clinical, endoscopic, imaging and other histopathological features are consistent with CD. This study is the first report of caseous granulomas in CD without concomitant tuberculosis infection. [ABSTRACT FROM AUTHOR]

Background and Objectives: Squamous cell carcinoma (SQCC) represents a significant proportion of human malignancies affecting various anatomical sites, including the lung. Understanding the prognostic factors is crucial for establishing effective risk stratification in these patients, as multiple critical aspects significantly impact overall survival. Materials and Methods: A retrospective study was conducted on 99 patients with operable lung SQCC treated at a tertiary center. The exclusion criteria included patients under 18, those with in situ or metastatic SQCC, and those who received neoadjuvant therapy. The surgical specimens were re-analyzed, and data were collected on multiple variables, including pTNM staging, tumor characteristics, and overall survival (OS). The Kaplan–Meier survival analysis and Cox regression models were used to identify significant prognostic factors. Results: The Kaplan–Meier analysis showed a median survival of 36 months with a 65.65% mortality rate. Significant factors influencing survival included keratinization, histological grading, tumor size and stage, pleural invasion, tumor cell arrangement, tumor budding, spread through air space (STAS), and mitotic index. A multiple Cox regression highlighted the nonkeratinizing tumors, advanced pT stages, single-cell invasion, and high mitotic index as key predictors of poorer outcomes. The nonkeratinizing tumors showed higher mortality and shorter median survival rates compared to keratinizing tumors. The tumor staging, cell arrangement, and tumor budding significantly impacted the survival curves. Conclusions: The study underscores the importance of detailed histopathological evaluations in lung SQCC. The nonkeratinizing tumors, advanced pT stage, single-cell invasion, and high mitotic index were associated with higher hazard rates, emphasizing the need for a comprehensive grading system incorporating these factors to improve prognostic accuracy and guide treatment strategies. [ABSTRACT FROM AUTHOR]

Background: Chronic migraine is a severe and common neurological disorder, yet its precise physiological mechanisms remain unclear. The IGF1/IGF1r signaling pathway plays a crucial role in pain modulation. Studies have shown that IGF1, by binding to its receptor IGF1r, activates a series of downstream signaling cascades involved in neuronal survival, proliferation, autophagy and functional regulation. The activation of these pathways can influence nociceptive transmission. Furthermore, alterations in IGF1/IGF1r signaling are closely associated with the development of various chronic pain conditions. Therefore, understanding the specific mechanisms by which this pathway contributes to pain is of significant importance for the development of novel pain treatment strategies. In this study, we investigated the role of IGF1/IGF1r and its potential mechanisms in a mouse model of chronic migraine. Methods: Chronic migraine was induced in mice by repeated intraperitoneal injections of nitroglycerin. Mechanical and thermal hypersensitivity responses were assessed using Von Frey filaments and radiant heat, respectively. To determine the role of IGF1/IGF1r in chronic migraine (CM), we examined the effects of the IGF1 receptor antagonist ppp (Picropodophyllin) on pain behaviors and the expression of calcitonin gene-related peptide (CGRP) and c-Fos. Result: In the nitroglycerin-induced chronic migraine model in mice, neuronal secretion of IGF1 is elevated within the trigeminal nucleus caudalis (TNC). Increased phosphorylation of the IGF1 receptor occurs, predominantly co-localizing with neurons. Treatment with ppp alleviated basal mechanical hypersensitivity and acute mechanical allodynia. Furthermore, ppp ameliorated autophagic dysfunction and reduced the expression of CGRP and c-Fos. Conclusion: Our findings demonstrate that in the chronic migraine (CM) model in mice, there is a significant increase in IGF1 expression in the TNC region. This upregulation of IGF1 leads to enhanced phosphorylation of IGF1 receptors on neurons. Targeting and inhibiting this signaling pathway may offer potential preventive strategies for mitigating the progression of chronic migraine. [ABSTRACT FROM AUTHOR]

Objective: Major depressive disorder (MDD) stands as one of the serious psychiatric conditions that detrimentally affect patients' quality of life and leads to a significant part of disability worldwide. Due to the limited understanding of the basic molecular mechanisms of depression and antidepressant medications, a clear understanding of the onset and development of MDD is unavailable. This study aims to figure out the pivotal genes and pathways implicated in the MDD development and identify medications that can potentially improve MDD treatment based on their relation with the key genes. Method: Symbols of human coding genes were retrieved from the HUGO Gene Nomenclature Committee database. These symbols were then queried for MDD-related associations using a Python script in PubMed. Subsequently, genes with two or more related articles to MDD were selected. A union of our search data and MDD-related genes in the DisGeNET database was found. The gene interaction network was generated and analyzed utilizing the STRING and Cytoscape, respectively. Finally, a drug-gene network was constructed and medications that can affect multiple genes were selected. Results: The union of our search data and DisGeNET data contained 1734 genes. Based on network analysis, TNF, IL1B, IL6, STAT1, and STAT3 were identified as the key genes in the MDD pathogenesis. Eleven drugs that affect more than one gene were detected through a drug-gene network. These medications include Acitretin, Adalimumab, Alteplase, Cisplatin, Digoxin, Etanercept, Infliximab, Insulin, Omeprazole, Pentoxifylline, and Rabeprazole. Conclusion: In summary, our findings identified five genes as key genes in MDD development, as well as medications related to key genes. This study provides a new vision of the pathogenesis and treatment of MDD. However, further experimental and clinical studies are necessary. [ABSTRACT FROM AUTHOR]