Hasil untuk "Cytology"

G. Palade

and (b) the vesicular character of its component elements, were already clearly noted in its first description. In subsequent papers, Porter and his collaborators described the preferential concentration of the vesicular elements of the reticulum in the endoplasm, and their scarcity or absence in the supposedly exoplasmic periphery of the cytoplasm (2, 3), a finding which eventually led to the selection of "endoplasmic reticulum" as a name for the system. The term was first cautiously tried in a caption in 1948 (3) and finally used in an article published by Porter and Kallman in 1952 (4). It appears that, at that time, our group was not yet engaged in large scale production of new cytological terms with a heavy Latin flavor, and was still proceeding with cautious restraint in matters of nomenclature. Besides the reticular disposition and the endoplasmic location implied in the name, Porter's studies established a number of other important features for the new cytoplasmic component, namely the usual continuity of the system throughout the endoplasm of normal cells, the remarkable polymorphism of its component elements, and the breaking down of the entire system in cytolysis into a collection of isolated vesicles.

K. Nanda, D. Mccrory, E. Myers et al.

G. Walker

T. Wright, J. Cox, L. Massad et al.

J. Cuzick, M. Arbyn, R. Sankaranarayanan et al.

T. Wright, L. Massad, C. Dunton et al.

Xiaofeng Yan, Yaqiong Zhang, Aizhen Yang et al.

Abstract Background The family of protein disulfide isomerases (PDIs) are thiol oxidoreductases located predominantly in the endoplasmic reticulum that catalyze thiol-disulfide exchange for normal protein folding. Recent studies have shown that this family enzymes such as PDI contribute to the meiosis of spermatocytes and male fertility. However, the role of PDIA6 in the PDI family in spermatogenesis has not been characterized using genetically modified animal models. Methods A premeiotic PDIA6 conditional knockout (Stra8-Cre/Pdia6 fl/fl ) mouse model was generated for showing an essential role for PDIA6 in male fertility. To investigate the mechanism underlying the role of PDIA6 in this process, we performed a series of experiments including fertility assessment, scanning and transmission electron microscopy, TUNEL assay, spermatocyte spreading, immunofluorescence staining, intracellular calcium concentration measurement, 3-(N-maleimide-propionyl) biocytin (MPB) labeling and protein quantitative mass spectrometry. Results Abnormal round-headed shape resembling partial globozoospermia was observed in Stra8-Cre/Pdia6 fl/fl mice. Ultrastructural analysis of PDIA6-deficient sperm demonstrated acrosome fragmentation and detachment from the nucleus, disrupted acroplaxome structure, disorganized flagellar axonemes, and cytoplasmic retention. PDIA6 deficiency also impaired the sperm acrosome reaction and calcium mobilization. Proteomic profiling revealed downregulation of acrosomal membrane and vesicle proteins, as well as calcium channel complexes in PDIA6-deficient testes. Moreover, PDIA6 deficiency down-regulated the synthesis of zona pellucida binding protein (ZPBP) in testes by impairing disulfide bond formation, and induced endoplasmic reticulum stress and apoptosis. Conclusions PDIA6 is essential for redox regulation of protein synthesis and spermatogenesis causing male fertility in mice.

Analytical Cellular Pathology

P. Shiny Latha, B. Sudha, C. Gugan

Background: Argyrophilic nucleolar organizer region (AgNOR) staining is a rapid and cost-effective marker of cellular proliferation, useful in differentiating benign from malignant breast lesions. This study evaluated the mean AgNOR count and the subjective AgNOR pattern assessment (SAPA) score in fine needle aspiration cytology (FNAC) samples of breast neoplasms. Materials and Methods: This prospective study included 100 women with palpable breast lumps who underwent FNAC at a tertiary care teaching hospital over 2 years. Smears were stained with hematoxylin and eosin (H and E) for cytology and silver stain for AgNOR analysis. Mean AgNOR count (mAgNOR) and SAPA score were evaluated in 100 neoplastic cells per case. Histopathology was available for 61 cases for correlation. Data were analyzed using SPSS 20.0; descriptive statistics and Chi-square tests were applied, with P < 0.05 considered statistically significant. Results: Among 100 breast lesions, FNAC classified 53% as benign, 36% as malignant, and 11% as premalignant, with fibroadenoma and ductal carcinoma being the most common benign and malignant lesions, respectively. Histopathological follow-up was available for 61 cases. Mean AgNOR counts rose progressively from benign (3.62 ± 0.91) to premalignant (4.92 ± 1.52) and malignant lesions (6.79 ± 2.11; P < 0.001), paralleling histopathology. SAPA scores similarly distinguished benign (6.92 ± 1.49), premalignant (10.27 ± 1.95), and malignant lesions (12.42 ± 2.43; P < 0.001). FNAC-histopathology concordance was high, with all malignant cases confirmed and 75% of premalignant cases upgraded to malignancy. Conclusion: These findings suggest that both AgNOR count and SAPA score are reliable indicators of proliferative activity and can effectively differentiate malignant from benign breast lesions in FNAC smears.

P. Castle, M. Stoler, Thomas C Wright et al.

L. R. Remonti, C. Kramer, C. Leitão et al.

Background: Thyroid nodules are a common finding in the general population, and their detection is increasing with the widespread use of ultrasound (US). Thyroid cancer is found in 5–15% of cases depending on sex, age, and exposure to other risk factors. Some US parameters have been associated with increased risk of malignancy. However, no characteristic seems sufficiently reliable in isolation to diagnose malignancy. The objective of this meta-analysis was to evaluate the diagnostic performance of US features for thyroid malignancy in patients with unselected thyroid nodules and nodules with indeterminate fine-needle aspiration (FNA) cytology. Methods: Electronic databases were reviewed for studies published prior to July 2012 that evaluated US features of thyroid nodules and reported postoperative histopathologic diagnosis. A manual search of references of review and key articles, and previous meta-analyses was also performed. A separate meta-analysis was performed including only nodules with indeterminate cytology. Analyzed features were solid structure, hypoechogenicity, irregular margins, absence of halo, microcalcifications, central vascularization, solitary nodule, heterogeneity, taller than wide shape, and absence of elasticity. Results: Fifty-two observational studies (12,786 nodules) were included. Nine studies included nodules with indeterminate cytology as a separate category, comprising 1851 nodules. In unselected nodules, all US features were significantly associated with malignancy with an odds ratio varying from 1.78 to 35.7, and microcalcifications, irregular margins, and a taller than wide shape had high specificities (Sp; 87.8%, 83.1%, 96.6%) and positive likelihood ratios (LHR; 3.26, 2.99, 8.07). Absence of elasticity was the single feature with the best diagnostic performance (sensitivity 87.9%, Sp 86.2%, and positive LHR 6.39). The presence of central vascularization was the most specific US feature in nodules with indeterminate cytology (Sp 96% and positive LHR 2.13). Conclusions: US features in isolation do not provide reliable information to select nodules that should have a FNA performed. A combination of US characteristics with higher likelihood ratios and consequently with higher post-test probabilities of malignancy—microcalcifications, or a taller than wide shape, or irregular margins, or absence of elasticity—will probably identify nodules with an increased risk for malignancy. Further studies are required to standardize elastography techniques and evaluate outcomes, especially in nodules with an indeterminate cytology.

K. Ng, A. Stenzl, Anand Sharma et al.

AIM This narrative review aims to describe established and emerging urinary biomarkers in the diagnosis and surveillance of non-muscle invasive bladder cancer. It provides a comprehensive account of classical, FDA-approved protein biomarkers and discusses their limitations. Further, we discuss the role that epigenetic, genetic, and exosomal markers can play to enhance sensitivity and specificity of the available tests. BACKGROUND The initial diagnosis and surveillance of bladder cancer involves a combination of cystoscopy, upper urinary tract imaging, and urine cytology. Despite high specificity, cytology is limited by low sensitivity. There are currently 6 urinary assays approved by the FDA to enhance diagnosis and surveillance of bladder cancer. While these have improved diagnosis and surveillance when combined with cytology, these tests are still not sufficiently sensitive and false positives often occur in benign conditions which result in inflammation of the urinary tract. Advancements in laboratory techniques have produced significant advancements in epigenetic and genetic markers, as well as extracellular vesicles, with DNA- and RNA-based markers dominating the research in this area in recent years. METHODS We identified relevant published data, using the PubMed/ Medline search engines as well as Google Scholar. We performed an online search using the terms "bladder cancer", "non-muscle invasive bladder cancer" in combination with "urine biomarkers" and limited articles in English published up to February 2020. This review consolidated on all available narrative and systematic reviews published in the 5 years in this field, while also reviewing the original data of each clinical trial or observational study which led to the development of the biomarkers. CONCLUSION The development of laboratory techniques and understanding urine-based biomarkers in BC has fuelled the use of noninvasive liquid-based biomarkers to complement urine cytology. Nonetheless, none are sufficiently effective when used in isolation, and cytology remains the gold standard in many practices. Future efforts will be focused on using these markers in combination as a predictive signature, and moving on to validating them for use in everyday clinical practice.

N. Bhatla, S. Singhal

Cytology-based cervical screening had unequivocal success in reducing the incidence and mortality of cervical cancer in the last century. The recognition of the role of human papillomavirus (HPV) as a necessary cause of cervical cancer led to the development of HPV testing. Gradually, there has been a shift from reflex HPV testing for mild cytological abnormalities, to co-testing with cytology and HPV, and lately to primary HPV screening, based on evidence from well-designed large randomized controlled trials and meta-analyses. Advantages of primary HPV screening include higher sensitivity to detect pre-neoplastic lesions, better re-assurance with a negative test, and safe prolongation of screening intervals. However, clinicians and policy makers must ensure the availability of clinically validated HPV assays and triage protocols of screen positive cases prior to implementation of primary HPV screening. This is likely to reduce potential harm from over-treatment as well as extra burden on the health care system.

L. Peirson, D. Fitzpatrick-Lewis, D. Ciliska et al.

BackgroundThe systematic review on which this paper is based provided evidence for the Canadian Task Force on Preventive Health Care to update their guideline regarding screening for cervical cancer. In this article we highlight three questions covered in the full review that pertain to the effectiveness of screening for reducing cervical cancer mortality and incidence as well as optimal timing and frequency of screening.MethodsWe searched MEDLINE, Embase and Cochrane Central from 1995 to 2012 for relevant randomized controlled trials and observational studies with comparison groups. Eligible studies included women aged 15 to 70 years who were screened using conventional cytology, liquid-based cytology or human papillomavirus DNA tests. Relevance screening, data extraction, risk of bias analyses and quality assessments were performed in duplicate. We conducted a meta-analysis using a random-effects model on the one body of evidence that could be pooled.ResultsFrom the 15,145 screened citations, 27 papers (24 studies) were included; five older studies located in a United States Preventive Services Task Force review were also included. A randomized controlled trial in India showed even a single lifetime screening test significantly decreased the risk of mortality from and incidence of advanced cervical cancer compared to no screening (mortality: risk ratio 0.65, 95% confidence interval 0.47, 0.90; incidence: relative risk 0.56, 95% confidence interval 0.42, 0.75). Cytology screening was shown to be beneficial in a cohort study that found testing significantly reduced the risk of being diagnosed with invasive cervical cancer compared to no screening (risk ratio 0.38; 95% confidence interval 0.23, 0.63). Pooled evidence from a dozen case–control studies also indicated a significant protective effect of cytology screening (odds ratio 0.35; 95% confidence interval 0.30, 0.41). This review found no conclusive evidence for establishing optimal ages to start and stop cervical screening, or to determine how often to screen; however the available data suggests substantial protective effects for screening women 30 years and older and for intervals of up to five years.ConclusionsThe available evidence supports the conclusion that cervical screening does offer protective benefits and is associated with a reduction in the incidence of invasive cervical cancer and cervical cancer mortality.

Götz Schmidt, Frederic Borchers, Sabrina Müller et al.

Mucociliary clearance, the ability of the respiratory tract to protect the integrity of the airways through the mechanical removal of potentially harmful substances, is of enormous importance during intensive care treatment. The present study aimed to evaluate the influence of clinically relevant inotropic agents on mucociliary clearance. The particle transport velocity (PTV) of isolated murine tracheae was measured as a surrogate for mucociliary clearance in the presence of dobutamine, epinephrine, and milrinone. Inhibitory substances were applied to elucidate the signal transduction cascades and the value and origin of calcium ions which provoke alterations in mucociliary clearance function. Dobutamine, epinephrine, and milrinone increased the PTV in a dose-dependent manner with half maximal effective concentrations of 75.7 nM, 87.0 nM, and 13.7 µM, respectively. After the depletion of intracellular calcium stores, no increase in PTV was observed after administering any of the three inotropic agents. While dobutamine and epinephrine activated β-adrenergic receptors, epinephrine used both the phospholipase C (PLC) and protein kinase A (PKA) pathway to promote the release of intracellular Ca²⁺. However, dobutamine primarily acted on the PKA pathway, having only a minor influence on the PLC pathway. The induced changes in PTV following milrinone administration required both the PKA and PLC pathway, although the PKA pathway was responsible for most of the induced changes. In conclusion, the common inotropic agents dobutamine, epinephrine, and milrinone increase murine PTV in a concentration-dependent manner and ultimately release Ca²⁺ from intracellular calcium stores, suggesting the function of changes in mucociliary clearance in the respiratory tract.

Alexandru Tîrziu, Florina Maria Bojin, Oana Isabella Gavriliuc et al.

Chimeric antigen receptor (CAR) cell therapies have revolutionized cancer immunotherapy by enabling targeted and potent antitumor immune responses. However, clinical challenges such as limited efficacy in solid tumors, severe toxicities including cytokine release syndrome (CRS), and manufacturing complexities restrict their broader use. Recently, CAR cell-derived exosomes (CAR-Exos) have emerged as promising cell-free therapeutic alternatives that retain the key antitumor functionalities of their parent cells while potentially overcoming the limitations of live cellular therapies. These nanoscale vesicles can deliver bioactive CAR molecules, cytotoxic proteins, and immunomodulatory cargo, enabling targeted tumor cell killing with reduced systemic toxicity and offering “off-the-shelf” applicability. This review comprehensively explores the biology, engineering, and therapeutic potential of CAR-Exos derived from T cells, natural killer (NK) cells, and other immune effectors. We discuss advances in isolation, characterization, and cargo profiling techniques, as well as preclinical and early clinical data supporting their application. Further, we address translational challenges including large-scale production, biodistribution, and immune evasion in tumor microenvironments. Combining cellular and exosomal CAR platforms holds promise to enhance efficacy and safety in cancer treatment, representing a frontier in targeted immunotherapy.

Saber Nahdi, Maria Arafah, Abdel Halim Harrath

Female infertility, affecting millions worldwide, involves complex molecular mechanisms such as chronic inflammation, impaired cellular death, and protein regulation. This study explores how the cytokine IL-6, the autophagy marker LC3, ubiquitination process, and three miRNAs, miR-146a-5p, miR-9-5p, and miR-9-3p, contribute to the control of ovarian function and female infertility. Two expression profile datasets (GSE199225 and GSE146856) were screened and downloaded from GEO. DEGs were screened using the GEO2R and ggVennDiagram tools. The three miRNAs were retrieved from datasets using the multiMiR tool, and IL6-targeted genes were retrieved from MSigDB. IL6 and miRNA interaction networks were constructed. Further, the cross-correlation of LC3 and ubiquitination with the DEGs associated miRNAs was demonstrated. Meanwhile, GO/KEGG pathway enrichment analyses and molecular network interaction analysis were performed. Lastly, immunohistochemistry and quantitative PCR (qPCR) were used to confirm the expression of IL6, LC3, and miRNA in ovarian endometrial tissues compared to control tissues. The results showed that IL-6 drives inflammation in conditions of PCOS and ovarian endometriosis, which then disrupts ovulation and embryo implantation. miR-146a-5p reduced inflammation by targeting the gene TRAF6, while miR-9-5p regulated protein degradation via SQSTM1. In agreement with the bioinformatic approach, experimental analysis revealed reduced IL6 protein expression in ovarian endometriosis tissues while the mRNA IL6 level was increased, suggesting the presence of post-transcriptional regulatory mechanisms that act to limit excessive inflammation, probably through miRNAs. Indeed, the levels of miR-146a-5, which plays a role in immune modulation and inflammatory signaling, were significantly upregulated. Interestingly, an alteration in autophagic markers revealed by elevated LC3 was also observed. Aligned with these experimental data, bioinformatic analysis showed that autophagy genes LC3 and ATG5 and ubiquitination processes were tightly linked to ovarian health, with disruptions accelerating follicle loss and oxidative damage. In conclusion, the results showed that IL-6, miRNAs, and autophagy processes work together to control inflammation and cellular repair in ovarian disorders. This study opens new avenues for targeted treatments to improve fertility outcomes by connecting molecular networks to clinical insights.

N. Schlecht, S. Kulaga, J. Robitaille et al.

Jane J. Kim, E. Burger, C. Regan et al.

Importance Evidence on the relative benefits and harms of primary high-risk human papillomavirus (hrHPV) testing is needed to inform guidelines. Objective To inform the US Preventive Services Task Force by modeling the benefits and harms of various cervical cancer screening strategies. Design, Setting, and Participants Microsimulation model of a hypothetical cohort of women initiating screening at age 21 years. Exposures Screening with cytology, hrHPV testing, and cytology and hrHPV cotesting, varying age to switch from cytology to hrHPV testing or cotesting (25, 27, 30 years), rescreening interval (3, 5 years), and triage options for hrHPV-positive results (16/18 genotype, cytology testing). Current guidelines-based screening strategies comprised cytology alone every 3 years starting at age 21 years, with or without a switch to cytology and hrHPV cotesting every 5 years from ages 30 to 65 years. Complete adherence for all 19 strategies was assumed. Main Outcomes and Measures Lifetime number of tests, colposcopies, disease detection, false-positive results, cancer cases and deaths, life-years, and efficiency ratios expressing the trade-off of harms (ie, colposcopies, tests) vs benefits (life-years gained, cancer cases averted). Efficient strategies were those that yielded more benefit and less harm than another strategy or a lower harm to benefit ratio than a strategy with less harms. Results Compared with no screening, all modeled cervical cancer screening strategies were estimated to result in substantial reductions in cancer cases and deaths and gains in life-years. The effectiveness of screening across the different strategies was estimated to be similar, with primary hrHPV-based and alternative cotesting strategies having slightly higher effectiveness and greater harms than current guidelines-based cytology testing. For example, cervical cancer deaths associated with the guidelines-based strategies ranged from 0.30 to 0.76 deaths per 1000 women, whereas new strategies involving primary hrHPV testing or cotesting were associated with fewer cervical cancer deaths, ranging from 0.23 to 0.29 deaths per 1000 women. In all analyses, primary hrHPV testing strategies occurring at 5-year intervals were efficient. For example, 5-year primary hrHPV testing (cytology triage) based on switching from cytology to hrHPV screening at ages 30 years, 27 years, and 25 years had ratios per life-year gained of 73, 143, and 195 colposcopies, respectively. In contrast, strategies involving 3-year hrHPV testing had much higher ratios, ranging from 2188 to 3822 colposcopies per life-year gained. In most analyses, strategies involving cotesting were not efficient. Conclusions and Relevance In this microsimulation modeling study, it was estimated that primary hrHPV screening may represent a reasonable balance of harms and benefits when performed every 5 years. Switching from cytology to hrHPV testing at age 30 years yielded the most efficient harm to benefit ratio when using colposcopy as a proxy for harms.

J. Cuzick, A. Szarewski, H. Cubie et al.