Hasil untuk "Pathology"

Jihui Han, June‐Hyun Jeong, Dongjoon Lee et al.

ABSTRACT Alzheimer's disease (AD) is marked by progressive cognitive decline driven largely by tau pathology, yet disease‐modifying therapies targeting tau remain limited. In this study, we re‐evaluated abemaciclib, a clinically approved CDK4/6 inhibitor for breast cancer and uncovered its previously unrecognized therapeutic potential in AD via CDK4/6‐independent mechanisms. Using the APPNL−F/MAPT double knock‐in mouse model (dKI) and AD patient‐derived brain organoids, we found that abemaciclib robustly ameliorates cognitive deficits and reduces neurodegeneration without altering amyloid burden or glial activation. Mechanistically, abemaciclib selectively inhibited key tau kinases, particularly Ca2⁺/calmodulin‐dependent protein kinase II (CaMKII) and glycogen synthase kinase 3β (GSK3β), independent of CDK4/6 inhibition, as confirmed by lentiviral knockdown experiments. Furthermore, abemaciclib enhanced autophagic flux and lysosomal activity, promoting clearance of pathological tau proteins. This dual modulation—suppression of tau phosphorylation and facilitation of degradation—highlights abemaciclib as a promising repurposed therapeutic for AD. Our findings establish a novel pharmacological profile for abemaciclib beyond its canonical role in cell cycle control, offering immediate translational potential for tau‐targeted AD therapy.

Tina Howischer, Lukas Gattermeyer-Kell, Stephanie Hirschbichler et al.

Background/Objectives: Anti-IgLON5 disease is a neurological disorder characterized by the presence of autoantibodies directed against the neuronal cell adhesion protein IgLON5. Pathophysiology involves both autoimmune inflammation and neurodegenerative processes. The most common causes of death are sudden death, central hypoventilation, dysphagia, and aspiration. However, the high rate of largely unclear sudden deaths calls for further research in this area. Methods: We performed a systematic search of the literature on causes of death in anti-IgLON5 disease following the PRISMA guidelines. In addition, we present a new case that was followed up in our clinic until death. Results: Of 258 publications with anti-IgLON5 disease, 21 publications comprising 61 cases that reported the causes of death were included in the analysis. The most common cause of death was death due to complications at 36.1%, followed by sudden death, accounting for 32.8% of the cases. Other causes include respiratory, cardiac, and unknown causes. The patient presented here as a case report was also diagnosed with cardiac amyloidosis and died from a cardiac cause of sudden death. Conclusions: Sudden death in anti-IgLON5 disease is one of the most common causes of death in the literature. A progressive neurodegenerative process in the brain stem causing central hypoventilation is generally assumed as a major causative factor. The case reported here had concomitant cardiac amyloidosis, which may raise the question as to whether unrecognized cardiac causes, which are not routinely screened for in this population, might represent another cause of sudden death, which would have important therapeutic implications.

Sibel SENSU, Nusret ERDOGAN

Objective: This review which aims to examine the recent and current status of pathology education in medical schools, and covers the publications related to undergraduate pathology education published between 2010 January and June 2023. Material and method: A search was performed through PubMed, Google Scholar, Semantic Scholar, and Ulakbim search engines for the Science Citation Index, Science Citation Index Expanded, Emerging Sources Citation Index, Directory of Open Access Journals, Scopus, PubMed as well as TR Dizin indexed articles. The findings are categorized into two periods as 2010 January - 2020 April (pre-COVID-19 pandemic) and May 2020 - 2023 June. A total of 24 reviews/editorials/letters to the editor and 63 research articles in the pre-pandemic period and 11 reviews/ editorials/ letters to the editor and 35 research articles between 2020 May and 2023 June are included in the analysis. Results: Currently, medical education generally depends on core education programs with defined learning objectives and outcomes. Moreover, problem-based, case-based, and team-based interactive learning are being used along with traditional didactic courses. Additionally, digital/ web-based/remote education methods have gained prominence after the COVID-19 pandemic. The virtual or augmented reality and 3D drawing applications are offered as a solution for the autopsy and macroscopy courses. A scarce number of publications are found on measuring and evaluating the effectiveness of learning. Conclusion: Artificial intelligence in pathology education is a topic that looks likely to become important in the near future. National and international comprehensive standardization is a necessity. A joint effort and collective intelligence are needed to achieve the desired goals in undergraduate pathology education.

Petra Ilenič, Ajda Herman, Erik Langerholc et al.

Background: As compared to endocrine responsive breast cancer bone is less frequent site of distant recurrence in triple-negative breast cancer (TNBC). A biomarker which predicts bone recurrence would allow a more personalized treatment approach with adjuvant bisphosphonates in TNBC. Here we hypothesised that tumour expression of androgen receptor (AR) is associated with bone recurrence in TNBC. Materials and methods: Patients with operable TNBC who were treated at the Institute of Oncology Ljubljana between 2005 and 2015 and developed distant recurrence were included into our study. Nuclear expression of AR in the tissue of primary tumours was determined immunohistochemically by using the Androgen Receptor (SP107) Rabbit Monoclonal Antibody. We applied a logistic regression model to test the association between expression of AR and development of bone metastases. The model was adjusted for selected known prognostic factors and possible confounders in TNBC, including the level of the stromal tumour-infiltrating lymphocytes (sTILs). Results: At recurrence 45 (45 %) out of 100 patients presented with bone metastases. Additionally, seven (7 %) developed bone metastases metachronously. AR was expressed in primary tumours of 35 (35 %) women and 19 (54.3 %) developed bone recurrence. In 25 (25 %) patients sTILs were absent. Neither the proportion of AR positive cancer cells (OR = 1.00; 95 % CI 0.96–1.03; p = 1.00) nor the intensity of AR positive reaction (OR = 0.71; 95 % CI 0.02–21.4; p = 1.00) were significantly associated with bone recurrence. However, women with at least mild level of the sTILs were at significantly lower risk for bone recurrence as compared to those without any sTILs (OR = 0.01; 95 % CI < 0.01–0.08; p = 0.01). Conclusions: Expression of AR is not significantly associated with the development of bone metastases in TNBC. However, patients with absent sTILs in their primary tumours are highly susceptible for recurrence in the bone and might particularly benefit from adjuvant bisphosphonates.

Chi-Ying Lee, Zih-Yin Lai, Yung-Jen Chuang

Background: During the COVID-19 pandemic, the viral illness caused by SARS-CoV-2 spread through respiratory droplets, resulting in a global pandemic with a range of symptoms from mild to severe. Pathological inflammation posed a critical issue, yet the genetic mechanisms behind the excessive activation of inflammatory responses remained unclear. To uncover the genetic and regulatory basis of the pathogenesis, we first explored possible genetic mechanisms from phenome-wide association studies (PWAS) with different severity levels of COVID-19. PWAS is a genetic research approach that identifies pleiotropic risk variants that contribute to elucidating potential physiological mechanisms from different traits. Methods: We used the PWAS approach to link the multiple clinical symptoms to the variants. We discovered a common variant, rs2109069, in dipeptidyl peptidase 9 (DPP9), which relates to the elevated odds ratio of developing severe illness from COVID-19. Interestingly, the proxy of rs2109069 has been identified as the susceptible locus of interstitial lung disease (ILD) and idiopathic pulmonary fibrosis (IPF). We thus examined the DPP9 expression patterns in selected organs, including the lungs, blood vessels, and skin. Results: In silico analysis revealed conserved driver activation between COVID-19-induced inflammation and the association with ILD and IPF. Multi-omics analysis further verified the association of DPP9 with abnormal inflammatory responses in COVID-19. Lastly, gene homology analysis inferred a potential regulatory role of DPP9 in inhibiting inflammasome activation, which suggests that DPP9 deficiency may exacerbate inflammation observed in some COVID-19 patients. Conclusions: Our in silico findings reveal that severe COVID-19 inflammatory responses and inflammatory lung diseases share the same genetic risk loci, helping to elucidate the underlying physiological mechanisms of severe COVID-19 inflammation. Additionally, the individual differences in immune sensitivity may contribute to the varying multi-organ inflammatory effects among patients. The rs2109069 of DPP9 could be a genetic marker to predict the risk of specific COVID-19 symptoms and severity.

Bo Li, Lili Duan, Xiali Li et al.

ObjectivesTumor-induced osteomalacia (TIO) is a rare acquired paraneoplastic disorder characterized by hypophosphatemia resulting from tumor-secreted fibroblast growth factor-23 (FGF23). Surgical resection of the culprit TIO is the first choice of treatment. However, TIO is difficult to detect with conventional diagnostic tools due to its small size and variable location in the body. Somatostatin receptor scintigraphy (SSR) has recently emerged as a functional molecular imaging choice for TIO detection and localization. This research was undertaken to evaluate the efficacy of 99mTc-labeled hydrazinonicotinyl-Tyr3-octreotide (99mTc-HYNIC-TOC) SPECT/CT in detecting TIO.Methods99mTc-HYNIC-TOC SPECT/CT and the available clinical data of 25 patients with suspected TIO were analyzed retrospectively. The 99mTc-HYNIC-TOC SPECT/CT findings were compared with the post-surgical pathology diagnosis and clinical follow-up results.ResultsUsing 99mTc-HYNIC-TOC SPECT/CT, suspicious tumors were found in 18 of the 25 patients, and 15 of them underwent surgical resection. The post-operative pathology confirmed a TIO in those 13 patients whose symptoms and biochemical anomalies gradually resolved after the surgery. The remaining five patients were finally considered false positives. Moreover, the 99mTc-HYNIC-TOC SPECT/CT results were negative in seven patients, with six patients being true negative (4 patients were diagnosed with acquired Fanconi syndrome and 2 patients responded well to conservative therapy) and one being false negative. Therefore, the sensitivity and specificity values of 99mTc-HYNIC-TOC SPECT/CT in the evaluation of TIO were 92.9% (13/14) and 54.5% (6/11), respectively. The overall accuracy of 99mTc-HYNIC-TOC SPECT/CT for detecting TIO was 76.0% (19/25).ConclusionsThe 99mTc-HYNIC-TOC SPECT/CT is an accurate imaging modality for locating culprit tumors in TIO.

Aurelian Anghelescu, Gelu Onose, Cristina Popescu et al.

Accumulating data suggest that chronic neuroinflammation-mediated neurodegeneration is a significant contributing factor for progressive neuronal and glial cell death in age-related neurodegenerative pathology. Furthermore, it could be encountered as long-term consequences in some viral infections, including post-COVID-19 Parkinsonism-related chronic sequelae. The current systematic review is focused on a recent question aroused during the pandemic’s successive waves: are there post-SARS-CoV-2 immune-mediated reactions responsible for promoting neurodegeneration? Does the host’s dysregulated immune counter-offensive contribute to the pathogenesis of neurodegenerative diseases, emerging as Parkinson’s disease, in a complex interrelation between genetic and epigenetic risk factors? A synthetic and systematic literature review was accomplished based on the ”Preferred Reporting Items for Systematic Principles Reviews and Meta-Analyses” (PRISMA) methodology, including registration on the specific online platform: International prospective register of systematic reviews—PROSPERO, no. 312183. Initially, 1894 articles were detected. After fulfilling the five steps of the selection methodology, 104 papers were selected for this synthetic review. Documentation was enhanced with a supplementary 47 bibliographic resources identified in the literature within a non-standardized search connected to the subject. As a final step of the PRISMA method, we have fulfilled a Population-Intervention-Comparison-Outcome-Time (PICOT)/Population-Intervention-Comparison-Outcome-Study type (PICOS)—based metanalysis of clinical trials identified as connected to our search, targeting the outcomes of rehabilitative kinesitherapeutic interventions compared to clinical approaches lacking such kind of treatment. Accordingly, we identified 10 clinical trials related to our article. The multi/interdisciplinary conventional therapy of Parkinson’s disease and non-conventional multitarget approach to an integrative treatment was briefly analyzed. This article synthesizes the current findings on the pathogenic interference between the dysregulated complex mechanisms involved in aging, neuroinflammation, and neurodegeneration, focusing on Parkinson’s disease and the acute and chronic repercussions of COVID-19. Time will tell whether COVID-19 neuroinflammatory events could trigger long-term neurodegenerative effects and contribute to the worsening and/or explosion of new cases of PD. The extent of the interrelated neuropathogenic phenomenon remains obscure, so further clinical observations and prospective longitudinal cohort studies are needed.

Enaam Ali ElSayed Al Mowafy, Salma AbdelGhany Shawkat

Abstract Backgrounds and aim Neutrophil extracellular traps (NETs) have been shown to play an important role in inflammatory and thrombotic processes. Investigating the presence of NETs in liver cirrhosis to detect any contribution to occurrence of complications may help predict or prevent those complications. Methods Among 78 cirrhotic patients, the serum NETs level was measured using ELISA and compared to different etiologies of liver cirrhosis (Viral, HCC, Bilharzial, NASH, cardiac cirrhosis and undetermined etiology) as well as markers of inflammation and complications in those patients. Results We found that NETs are substantially found in LCF and have a significant relation to malignant portal vein thrombosis but not other studied complications or etiology of liver cirrhosis. Conclusion NETs however found in liver cirrhosis patients may not play as a significant role in occurrence of complications as thought. So, NETs cannot be reliably used as a biomarker or predictor for occurrence of thrombosis in liver cirrhosis patients. Lay summary Liver cirrhosis patients have many factors at play that lead to development of thrombosis. NETS may play a role with the development of malignant thrombosis in those patients. Further evaluation for their level and action should be studied before considering NETs as a key player in development of complications.

Raquel Rodrigues da Silva Barbosa, Cristiane Souza da Silva, Arthur Alves Pereira Sousa

Este artigo é um relato de experiência da implementação de um projeto denominado “ECOS: consciência, cor e saúde”, realizado em uma Unidade Básica de Saúde da região oeste do Distrito Federal, que teve como objetivo dialogar com profissionais de saúde e qualificar as ações junto à população negra que acessa o SUS. Inicialmente é feito um debate sobre as implicações da violência para a saúde e a correlação entre racismo e violência. Em seguida, discute-se sobre a importância da abordagem dessa temática na Atenção Básica. São resgatados dados sobre as iniquidades em saúde provocadas em decorrência do racismo e a importância de abordar essa temática no processo de formação de profissionais de saúde, ressaltando a centralidade da Política Nacional de Saúde Integral da População Negra. Por fim, relata-se a experiência obtida com o projeto, compreendendo que ele esteve inserido em um importante processo de rompimento de ciclos de violência racial.

Muhammad Adeel Akhtar, Joanne Edwards, Rebecca Tate et al.

Central acetabular defects are rare, and have been described using various terminologies (notches, fossae, pits). They are generally regarded as normal variants and often overlooked. This case series reviews five cases (age range 9-14 years) where presentation included hip pain and no alternative pathology was found. The defects tend to be bilateral but not symmetrical, and often just the side with the largest defect is symptomatic. The aetiology is unknown but there was no recollection of prior trauma. The literature suggests they are developmental in nature. The cases series highlights that these anatomical variants should not be entirely disregarded when imaging is reviewed.

Raíza Dias Freitas, Raíza Dias Freitas, Rosane Borges Dias et al.

Oral Squamous Cell Carcinoma (OSCC) presents an important challenge for the health systems worldwide. Thus, unraveling the biological mechanisms involved in OSCC pathogenesis is essential to the discovery of new drugs with anticancer potential. The Hedgehog (HH) pathway has shown promising results as a therapeutic target both in vitro and in vivo. This study aimed to investigate the effects of vismodegib and itraconazole on the expression of Hedgehog (HH) genes (PTCH1, SMO, and GLI1), cell cycle and cell death in OSCC cells. Alamar Blue assay was used to assess the cytotoxicity of vismodegib and itraconazole in a panel of oral cancer cell lines, including CAL27. The expression of HH signaling components after treatment with vismodegib and itraconazole, at concentrations of 25 or 50 μg/ml was evaluated by qPCR. Cell cycle and apoptosis were evaluated by flow cytometry after 72 h treatment with 50 μg/ml of vismodegib or itraconazole. HH signaling was activated in OSCC cell lines CAL27, SCC4, SCC9, and HSC3. Vismodegib and itraconazole significantly reduced CAL27 cell viability after 48 h of treatment. Gene expression of PTCH1, SMO, and GLI1 decreased in response to 24 h of treatment with vismodegib or itraconazole. Furthermore, CAL27 cells exhibited alterations in morphology, cell size, and cellular granularity. An increase in the DNA fragmentation was observed after treatment and both inhibitors induced apoptosis after 72 h. In conclusion, SMO inhibitors vismodegib and itraconazole demonstrably reduced the expression of HH genes in CAL27 OSCC cell line. In addition, treatment with vismodegib and itraconazole reduced cellular viability and altered the morphology of CAL27 cells, and also induced apoptosis.

Ana-Rosa Ballester, Luis González-Candelas

<i>Penicillium digitatum</i> is the main fungal postharvest pathogen of citrus fruit under Mediterranean climate conditions. The role of ethylene in the <i>P. digitatum</i>–citrus fruit interaction is unclear and controversial. We analyzed the involvement of the 2-oxoglutarate-dependent ethylene-forming enzyme (EFE)-encoding gene (<i>efeA</i>) of <i>P. digitatum</i> on the pathogenicity of the fungus. The expression of <i>P. digitatum</i><i>efeA</i> parallels ethylene production during growth on PDA medium, with maximum levels reached during sporulation. We generated Δ<i>efeA</i> knockout mutants in <i>P. digitatum</i> strain Pd1. These mutants showed no significant defect on mycelial growth or sporulation compared to the parental strain. However, the knockout mutants did not produce ethylene in vitro. Citrus pathogenicity assays showed no differences in virulence between the parental and Δ<i>efeA</i> knockout mutant strains, despite a lack of ethylene production by the knockout mutant throughout the infection process. This result suggests that ethylene plays no role in <i>P. digitatum</i> pathogenicity. Our results clearly show that EFE-mediated ethylene synthesis is the major ethylene synthesis pathway in the citrus postharvest pathogen <i>P. digitatum</i> during both in vitro growth on PDA medium and the infection process, and that this hormone is not necessary for establishing <i>P. digitatum</i> infection in citrus fruit. However, our results also indicate that ethylene produced by <i>P. digitatum</i> during sporulation on the fruit surface may influence the development of secondary fungal infections.

Emmanuel Byamukama, Shaukat Ali, Jonathan Kleinjan et al.

Winter wheat is susceptible to several fungal pathogens throughout the growing season and foliar fungicide application is one of the strategies used in the management of fungal diseases in winter wheat. However, for fungicides to be profitable, weather conditions conducive to fungal disease development should be present. To determine if winter wheat yield response to fungicide application at the flowering growth stage (Feekes 10.5.1) was related to the growing season precipitation, grain yield from fungicide treated plots was compared to non-treated plots for 19 to 30 hard red winter wheat cultivars planted at 8 site years from 2011 through 2015. At all locations, Prothioconazole + Tebuconazole or Tebuconazole alone was applied at flowering timing for the fungicide treated plots. Grain yield response (difference between treated and non-treated) ranged from 66-696 kg/ha across years and locations. Grain yield response had a positive and significant linear relationship with cumulative rainfall in May through June for the mid and top grain yield ranked cultivars (R2=54%, 78%, respectively) indicating that a higher amount of accumulated rainfall in this period increased chances of getting a higher yield response from fungicide application. Cultivars treated with a fungicide had slightly higher protein content (up to 0.5%) compared to non-treated. These results indicate that application of fungicides when there is sufficient moisture in May and June may increase chances of profitability from fungicide application.

P. Scheuer, P. Scheuer, Roger L. Williams et al.

Gorlin Rj, Goldman Hm, W. Hurt

Henriette Loss, Jörg R. Aschenbach, Karsten Tedin et al.

The gut epithelium constitutes an interface between the intestinal contents and the underlying gut-associated lymphoid tissue (GALT) including dendritic cells (DC). Interactions of intestinal epithelial cells (IEC) and resident DC are characterized by bidirectional crosstalk mediated by various factors, such as transforming growth factor-β (TGF-β) and thymic stromal lymphopoietin (TSLP). In the present study, we aimed (1) to model the interplay of both cell types in a porcine in vitro coculture consisting of IEC (cell line IPEC-J2) and monocyte-derived DC (MoDC) and (2) to assess whether immune responses to bacteria are altered because of the interplay between IPEC-J2 cells and MoDC. With regard to the latter, we focused on the inflammasome pathway. Here, we propose caspase-13 as a promising candidate for the noncanonical inflammasome activation in pigs. We conducted challenge experiments with enterotoxigenic Escherichia coli (ETEC) and probiotic Enterococcus faecium (E. faecium) NCIMB 10415. As potential mediators of IEC/DC interactions, TGF-β and TSLP were selected for analyses. Cocultured MoDC showed attenuated ETEC-induced inflammasome-related and proinflammatory interleukin (IL)-8 reactions compared with MoDC monocultures. Caspase-13 was more strongly expressed in IPEC-J2 cells cocultured with MoDC and upon ETEC incubation. We found that IPEC-J2 cells and MoDC were capable of releasing TSLP. The latter cells secreted greater amounts of TSLP when cocultured with IPEC-J2 cells. TGF-β was not modulated under the present experimental conditions in either cell types. We conclude that, in the presence of IPEC-J2 cells, porcine MoDC exhibited a more tolerogenic phenotype, which might be partially regulated by autocrine TSLP production. Noncanonical inflammasome signaling appeared to be modulated in IPEC-J2 cells. Our results indicate that the reciprocal interplay of the intestinal epithelium and GALT is essential for promoting balanced immune responses.

A. Blaustein

Anders Lindholm Sørensen, Klaus Kallenbach, Hans Carl Hasselbalch

We report a 57-year old man with polycythemia vera, who had a remarkable hematological and molecular response during treatment with simvastatin and alendronate. The patient was treated with this combination for 56 months, and during this period the patient has been in complete hematological remission. The JAK2-V617F allele burden has dropped from 64% to sustained values below 20%, and follow-up bone marrow biopsies have revealed no change in PV features, without any regular cytoreductive treatment.

Education in Pathology

J. L. Gordon