We hypothesise that regression may have an impact on the effectiveness of adjuvant IFN therapy, based on its role in the host immune response. Our purpose is to investigate regression and ulceration as prognostic factors in case of interferon-alpha (IFN)-treated melanoma patients. We followed 357 IFN-treated melanoma patients retrospectively, investigating progression-free survival (PFS) and overall survival (OS) depending on the presence of ulceration and regression. A Kaplan–Meier analysis was performed, and we used a Cox regression analysis to relate risk factors. The survival function of the Cox regression was used to measure the effect of regression and ulceration on PFS and OS depending on the Breslow thickness (T1–T4) of the primary tumour. Regression was significantly positively related to PFS ( P = 0.0018, HR = 0.352) and OS ( P = 0.0112, HR = 0.380), while ulceration showed a negative effect (PFS: P = 0.0001, HR = 2.629; OS: P = 0.0001, HR = 2.388). They influence survival independently. The most favourable outcome was measured in the regressed/non-ulcerated group, whereas the worse was in the non-regressed/ulcerated one. Of risk factors, Breslow thickness is the most significant predictor. The efficacy of regression is regardless of Breslow thickness, though the more favourable the impact of regression was in the thicker primary lesions. Our results indicate that regression is associated with a more favourable outcome for IFN-treated melanoma patients, whereas ulceration shows an inverse relation. Further studies are needed to analyse the survival benefit of regression in relation to innovative immune checkpoint inhibitors.

Abstract Classic diffusely infiltrating lobular carcinoma has imaging features divergent from the breast cancers originating from the terminal ductal lobular units and from the major lactiferous ducts. Although the term “invasive lobular carcinoma” implies a site of origin within the breast lobular epithelium, we were unable to find evidence supporting this assumption. Exceptional excess of fibrous connective tissue and the unique cell architecture combined with the aberrant features at breast imaging suggest that this breast malignancy has not originated from cells lining the breast ducts and lobules. The only remaining relevant component of the fibroglandular tissue is the mesenchyme. The cells freshly isolated and cultured from diffusely infiltrating lobular carcinoma cases contained epithelial–mesenchymal hybrid cells with both epithelial and mesenchymal properties. The radiologic and histopathologic features of the tumours and expression of the mesenchymal stem cell positive markers CD73, CD90, and CD105 all suggest development in the direction of mesenchymal transition. These hybrid cells have tumour-initiating potential and have been shown to have poor prognosis and resistance to therapy targeted for malignancies of breast epithelial origin. Our work emphasizes the need for new approaches to the diagnosis and therapy of this highly fatal breast cancer subtype. Citation Format: Andras Voros, Laszlo Tabar, Renata Bozo, Orsolya Olah, Katalin Ormandi, Zoltan Vereb, Istvan Nemeth, Peter B. Dean, Olga Puchkova, Ming-Fang Yen, Li-Sheng Chen. Does Diffusely Infiltrating Lobular Carcinoma of the Breast Arise from Epithelial-Mesenchymal Hybrid Cells? [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-28-09.

Importance The COVID-19 pandemic resulted in delayed access to medical care. Restrictions to health care specialists, staff shortages, and fear of SARS-CoV-2 infection led to interruptions in routine care, such as early melanoma detection; however, premature mortality and economic burden associated with this postponement have not been studied yet. Objective To determine the premature mortality and economic costs associated with suspended melanoma screenings during COVID-19 pandemic lockdowns by estimating the total burden of delayed melanoma diagnoses for Europe. Design, Setting, and Participants This multicenter economic evaluation used population-based data from patients aged at least 18 years with invasive primary cutaneous melanomas stages I to IV according to the American Joint Committee on Cancer (AJCC) seventh and eighth editions, including melanomas of unknown primary (T0). Data were collected from January 2017 to December 2021 in Switzerland and from January 2019 to December 2021 in Hungary. Data were used to develop an estimation of melanoma upstaging rates in AJCC stages, which was verified with peripandemic data. Years of life lost (YLL) were calculated and were, together with cost data, used for financial estimations. The total financial burden was assessed through direct and indirect treatment costs. Models were building using data from 50 072 patients aged 18 years and older with invasive primary cutaneous melanomas stages I to IV according to the AJCC seventh and eighth edition, including melanomas of unknown primary (T0) from 2 European tertiary centers. Data from European cancer registries included patient-based direct and indirect cost data, country-level economic indicators, melanoma incidence, and population rates per country. Data were analyzed from July 2021 to September 2022. ExposureCOVID-19 lockdown-related delay of melanoma detection and consecutive public health and economic burden. As lockdown restrictions varied by country, lockdown scenario was defined as elimination of routine medical examinations and severely restricted access to follow-up examinations for at least 4 weeks. Main Outcomes and Measures Primary outcomes were the total burden of a delay in melanoma diagnosis during COVID-19 lockdown periods, measured using the direct (in US$) and indirect (calculated as YLL plus years lost due to disability [YLD] and disability-adjusted life-years [DALYs]) costs for Europe. Secondary outcomes included estimation of upstaging rate, estimated YLD, YLL, and DALY for each European country, absolute direct and indirect treatment costs per European country, proportion of the relative direct and indirect treatment costs for the countries, and European health expenditure. Results There were an estimated 111 464 (range, 52 454-295 051) YLL due to pandemic-associated delay in melanoma diagnosis in Europe, and estimated total additional costs were $7.65 (range, $3.60 to $20.25) billion. Indirect treatment costs were the main cost driver, accounting for 94.5% of total costs. Estimates for YLD in Europe resulted in 15 360 years for the 17% upstaging model, ranging from 7228 years (8% upstaging model) to 40 660 years (45% upstaging model). Together, YLL and YLD constitute the overall disease burden, ranging from 59 682 DALYs (8% upstaging model) to 335 711 DALYs (45% upstaging model), with 126 824 DALYs for the real-world 17% scenario. Conclusions and Relevance This economic analysis emphasizes the importance of continuing secondary skin cancer prevention measures during pandemics. Beyond the personal outcomes of a delayed melanoma diagnosis, the additional economic and public health consequences are underscored, emphasizing the need to include indirect economic costs in future decision-making processes. These estimates on DALYs and the associated financial losses complement previous studies highlighting the cost-effectiveness of screening for melanoma.

Microphthalmia-associated transcription factor (MITF) is a master regulator of melanocyte function, development and plays a significant role in melanoma pathogenesis. MITF genomic amplification promotes melanoma development, and it can facilitate resistance to multiple therapies. Here, we show that MITF regulates a global antioxidant program that increases survival of melanoma cell lines by protecting the cells from reactive oxygen species (ROS)-induced damage. In addition, this redox program is correlated with MITF expression in human melanoma cell lines and patient-derived melanoma samples. Using a zebrafish melanoma model, we show that MITF decreases ROS-mediated DNA damage in vivo. Some of the MITF target genes involved, such as IDH1 and NNT, are regulated through direct MITF binding to canonical enhancer box (E-BOX) sequences proximal to their promoters. Utilizing functional experiments, we demonstrate the role of MITF and its target genes in reducing cytosolic and mitochondrial ROS. Collectively, our data identify MITF as a significant driver of the cellular antioxidant state.

Classic diffusely infiltrating lobular carcinoma has imaging features divergent from the breast cancers originating from the terminal ductal lobular units and from the major lactiferous ducts. Although the term "invasive lobular carcinoma" implies a site of origin within the breast lobular epithelium, we were unable to find evidence supporting this assumption. Exceptional excess of fibrous connective tissue and the unique cell architecture combined with the aberrant features at breast imaging suggest that this breast malignancy has not originated from cells lining the breast ducts and lobules. The only remaining relevant component of the fibroglandular tissue is the mesenchyme. The cells freshly isolated and cultured from diffusely infiltrating lobular carcinoma cases contained epithelial-mesenchymal hybrid cells with both epithelial and mesenchymal properties. The radiologic and histopathologic features of the tumours and expression of the mesenchymal stem cell positive markers CD73, CD90, and CD105 all suggest development in the direction of mesenchymal transition. These hybrid cells have tumour-initiating potential and have been shown to have poor prognosis and resistance to therapy targeted for malignancies of breast epithelial origin. Our work emphasizes the need for new approaches to the diagnosis and therapy of this highly fatal breast cancer subtype.

The incidence of cutaneous melanoma continues to rise despite the increased use of sunscreens within the last several decades. Some research even suggests that the use of sunscreen is associated with increased rates of melanoma. Given the aggressive, and often deadly, nature of cutaneous melanoma, the aim of this communication is to better elucidate the relationship between sunscreen use and melanoma development and if there are other preventative measures to be aware of. A search was performed to identify the studies that have investigated melanoma development in individuals who used sunscreen and those who did not. Study limitations and possible confounding variables were identified, which guided a subsequent search to determine what data were available to support that these limitations and confounding variables may explain the perplexing association between sunscreen use and melanoma development. Five hypotheses were generated, which were related to increased awareness and reporting, the relationship between sunscreen use and the duration of sun exposure, the importance of broad-spectrum protection, and the effect of sunscreen on reactive oxygen species formation. The main conclusion is that more recent studies that control for confounding variables are required to determine the true effect of adequate broad-spectrum sunscreen use today on the development of melanoma.

Based on large international multicentre trials sentinel lymph node biopsy was found clinically relevant in intermediate thickness melanomas, furthermore sentinel lymph node positivity proved to be the single most important factor in overall survival. However, there is an ongoing debate in the literature regarding the need of sentinel lymph node biopsy in thin (<1mm) and thick (>4mm) melanomas. We aimed to analyse the clinicopathologic predictors of SNB positivity and the possible advantages of the procedure.

Merkel cell carcinoma is a rare neuroendocrine skin tumor with an aggressive behavior. The clonal integration of the Merkel cell polyomavirus and the UV light can be highlighted in its pathogenesis. Risk factors for its development are advanced age, chronic UV exposure, caucasian skin type, male gender, and immunosuppression. The disease is prone to rapid progression and the prognosis is unfavorable. In its treatment, surgical removal of the primary tumor and biopsy of the sentinel lymph node, as well as adjuvant radiation therapy, are of particular importance. Among the systemic treatments, immune checkpoint inhibitors are recommended as the first line. The authors discuss the latest European guideline for the diagnosis and the treatment.

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.

Emerging data suggest that the majority of patients who die from melanoma experience recurrence of disease that is early-stage (Stage I or II) at the time of diagnosis. Therefore, we aim to understand the clinical (demographics, medical history, surgical margins) and histopathologic (synoptic features) characteristics that influence early-stage melanoma recurrence utilizing a multi-institutional database comprising of 1,244 patients with 1,342 early-stage primary cutaneous melanomas from 2000-2020. A multivariable Cox proportional hazards model with clustering adjustment was used to analyze the risk for melanoma recurrence. Harrell C's concordance index was used to assess the goodness of fit. 331 (24.7%) of melanomas recurred within the study period. Among the recurrent melanomas, 52% of patients progressed to develop metastatic disease and 39.9% were deceased at end of follow-up. In univariate modeling for risk of melanoma recurrence, Breslow depth, AJCC stage, and tumor mitotic rate had the highest Harrell's C (0.8, 0.77, and 0.77 respectively) and were at significantly higher risk of melanoma recurrence. Multivariate modeling demonstrated that individuals who are older at diagnosis (HR 1.02, p<0.001), in the second quartile of income range of $77,484-$99,677 (HR 1.36, p=0.046), Clark's level above 4, melanoma stage above 2A, with the presence of tumor-infiltrating lymphocytes (HR 1.51, p=0.02), and presence of mitoses (HR 2.09, p=0.001) were at higher risk of melanoma recurrence. The risk factors identified above, particularly mitotic rate, can guide clinicians in risk stratifying patients with early-stage melanoma for increased surveillance to detect recurrence.

Emerging data suggests that the majority of melanoma mortality occurs in patients with recurrence of disease that was initially early-stage (Stage I or II). Thus, there is a need for prognostic tools to identify patients at high risk of recurrence. This study examines the capability of weakly-supervised Convolutional Neural Networks (CNNs) for detecting prognostic signals of early-stage melanoma recurrence using whole-slide histopathology images (WSIs). We collected 224 WSIs from 58 patients with recurrence and 203 WSIs from 58 patients without recurrence and a minimum of 5-year follow-up. Each gigapixel WSI was processed into 512 x 512 pixel patches. We annotated regions of tumor for 50 patients and performed a two-step analysis. First, a model was trained to classify melanoma and non-melanoma patches. Second, a model was trained to differentiate between patches at high- and low-risk of recurrence. We compared performance of two CNN architectures, VGG16 and ResNet50, using 5-fold cross-validation. The median study follow-up for non-recurrent tumors was 6.5 years. Both architectures successfully identified melanoma patches: VGG16 (ACC 94.5%, AUC 98.9%) and ResNet50 (ACC 95%, AUC 99%). For recurrence prediction, VGG16 achieved slightly better patient-level performance (ACC 85.3%, AUC 93.5%) compared to ResNet50 (ACC 85.3%, AUC 91.3%). We demonstrate that a state-of-the-art CNN pipeline can accurately detect prognostic signals for early-stage melanoma recurrence using only WSIs. Our patch-based approach achieved these results without requiring detailed region of interest annotation. This approach can be used to automatically identify tumor areas with high-risk features, enabling subsequent molecular analyses of these regions to understand specific mechanisms for recurrence.

Recent animal studies, as well as quantitative sodium MRI observations on humans demonstrated that remarkable amounts of sodium can be stored in the skin. It is also known that excess sodium in the tissues leads to inflammation in various organs, but its role in dermal pathophysiology has not been elucidated. Therefore, our aim was to study the effect of dietary salt loading on inflammatory process and related extracellular matrix (ECM) remodeling in the skin. To investigate the effect of high salt consumption on inflammation and ECM production in the skin mice were kept on normal (NSD) or high salt (HSD) diet and then dermatitis was induced with imiquimod (IMQ) treatment. The effect of high salt concentration on dermal fibroblasts (DF) and peripheral blood mononuclear cells (PBMC) was also investigated in vitro. The HSD resulted in increased sodium content in the skin of mice. Inflammatory cytokine Il17 expression was elevated in the skin of HSD mice. Expression of anti-inflammatory Il10 and Il13 decreased in the skin of HSD or HSD IMQ mice. The fibroblast marker Acta2 and ECM component Fn and Col1a1 decreased in HSD IMQ mice. Expression of ECM remodeling related Pdgfb and activation phosphorylated (p)-SMAD2/3 was lower in HSD IMQ mice. In PBMCs, production of IL10, IL13 and PDGFB was reduced due to high salt loading. In cultured DFs high salt concentration resulted in decreased cell motility and ECM production, as well. Our results demonstrate that high dietary salt intake is associated with increased dermal pro-inflammatory status. Interestingly, although inflammation induces the synthesis of ECM in most organs, the expression of ECM decreased in the inflamed skin of mice on high salt diet. Our data suggest that salt intake may alter the process of skin remodeling.

In plants, biomass and nutrient allocation often generate trade-offs between the different biochemical pathways conflicting the utilization of the common source among growth, reproduction and chemical defence. However, in dioecious plant species, these trade-off patterns could appear as a more contrasted problem between males and females due to the dissimilar reproduction investment. Generally, the growth ratio is higher in males than females, while females have a stronger defence than males. To understand the possible role of the sex-specific dissimilarities within the growth-defence conflict framework, we investigated the possible causes of the high variance of the essential oil yield in a dioecious evergreen species, Juniperus communis. Specifically, we tested the correlations between the essential oil yield with other individual-specific traits (e.g. sex, age), the presence of the growth-defence trade-off, and the differential growth and survival patterns between males and females through an extensive field survey with sample collection in three natural populations (Kiskunság National Park, Hungary). The individual-specific essential oil yield was also measured and served as a proxy to describe the degree of chemical defence. We found that the essential oil yield showed strong and consistent sex-specific patterns decreasing with age in adults. Contrary to the predictions, the males showed a consistently higher yield than the females. We also observed a growth-defence trade-off in males but not in females. Consistently with the growth-defence conflict hypothesis, the populations' sex ratio was male-biased, and this pattern was more evident with ageing modifying the demographic structure due to the sexually dissimilar lifespan. Our juniper study revealed a contrasting and unique essential oil accumulation driven by the complex allocation trade-off mechanisms within individuals, which could be a flexible and adaptive defence response against the increasing biotic and abiotic environmental stresses exacerbated under global climate change.

Journal of the European Academy of Dermatology and VenereologyVolume 34, Issue 9 p. e523-e524 Letter To The Editor Anti-interleukin-6 receptor therapy-induced cutaneous symptoms resembling purpura fulminans in a patient with seropositive rheumatoid arthritis G.R. Nagy, Corresponding Author G.R. Nagy n.geza@outlook.com orcid.org/0000-0002-3876-0422 Department of Dermatology and Allergology, University of Szeged, Szeged, Hungary Correspondence: G.R. Nagy. E-mail: n.geza@outlook.comSearch for more papers by this authorE. Varga, E. Varga Department of Dermatology and Allergology, University of Szeged, Szeged, HungarySearch for more papers by this authorL. Kovács, L. Kovács Department of Rheumatology and Immunology, University of Szeged, Szeged, HungarySearch for more papers by this authorI. Németh, I. Németh Department of Dermatology and Allergology, University of Szeged, Szeged, HungarySearch for more papers by this authorE. Varga, E. Varga Department of Dermatology and Allergology, University of Szeged, Szeged, HungarySearch for more papers by this authorL. Kemény, L. Kemény Department of Dermatology and Allergology, University of Szeged, Szeged, HungarySearch for more papers by this authorZ. Bata-Csörgő, Z. Bata-Csörgő Department of Dermatology and Allergology, University of Szeged, Szeged, HungarySearch for more papers by this author G.R. Nagy, Corresponding Author G.R. Nagy n.geza@outlook.com orcid.org/0000-0002-3876-0422 Department of Dermatology and Allergology, University of Szeged, Szeged, Hungary Correspondence: G.R. Nagy. E-mail: n.geza@outlook.comSearch for more papers by this authorE. Varga, E. Varga Department of Dermatology and Allergology, University of Szeged, Szeged, HungarySearch for more papers by this authorL. Kovács, L. Kovács Department of Rheumatology and Immunology, University of Szeged, Szeged, HungarySearch for more papers by this authorI. Németh, I. Németh Department of Dermatology and Allergology, University of Szeged, Szeged, HungarySearch for more papers by this authorE. Varga, E. Varga Department of Dermatology and Allergology, University of Szeged, Szeged, HungarySearch for more papers by this authorL. Kemény, L. Kemény Department of Dermatology and Allergology, University of Szeged, Szeged, HungarySearch for more papers by this authorZ. Bata-Csörgő, Z. Bata-Csörgő Department of Dermatology and Allergology, University of Szeged, Szeged, HungarySearch for more papers by this author First published: 10 April 2020 https://doi.org/10.1111/jdv.16442Citations: 2Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article.Citing Literature Volume34, Issue9September 2020Pages e523-e524 RelatedInformation

Recently, it has been described that programmed cell death protein 1 (PD-1) overexpressing melanoma cells are highly aggressive. However, until now it has not been defined which factors lead to the generation of PD-1 overexpressing subpopulations. Here, we present that melanoma-derived exosomes, conveying oncogenic molecular reprogramming, induce the formation of a melanoma-like, PD-1 overexpressing cell population (mMSCPD-1+) from naïve mesenchymal stem cells (MSCs). Exosomes and mMSCPD-1+ cells induce tumor progression and expression of oncogenic factors in vivo. Finally, we revealed a characteristic, tumorigenic signaling network combining the upregulated molecules (e.g., PD-1, MET, RAF1, BCL2, MTOR) and their upstream exosomal regulating proteins and miRNAs. Our study highlights the complexity of exosomal communication during tumor progression and contributes to the detailed understanding of metastatic processes.

Despite diagnostic refinements, pancreatic resection (PR) is eventually performed in some patients with asymptomatic serous cystadenoma (A-SCA). The aim of this study was to define incidence and reasons of PR in A-SCA.A retrospective analysis of a prospectively maintained database was performed for all the patients referred for pancreatic cystic lesions (PCL) between January 2005 and March 2016.Overall, there were 1488 patients with PCL, including 1271 (85.4%) with incidental PCL (I-PCL). During the study period referral of I-PCL increased 8.5-fold. Surgery was immediately advised in 94 I-PCL (7.3%) and became necessary later on in 11 additional patients (0.9%), because of the development of symptoms. Overall, PR was performed in 105/1271 patients presenting with I-PCL (8.2%), including 27 with A-SCA (2.1%). All patients with A-SCA underwent ultrasonography and contrast-enhanced computed tomography. Magnetic resonance imaging was performed in 21 patients (77.8%), 18 F-FDG positron emission tomography in 8 (29.6%), endoscopic ultrasonography (EUS) in 2 (7.4%), and EUS-guided fine needle aspiration (EUS-FNA) in 1 (3.7%). These studies demonstrated a combination of atypical features such as solid tumor (3; 11.1%), oligo-/macrocystic tumor (24; 88.8%), mural nodules (14; 51.8%), enhancing cyst walls (17; 62.9%), dilation of the main pancreatic duct (3; 11.1%), and upstream pancreatic atrophy (1; 3.7%). Additionally, 14/27 patients (51.8%) were females with oligo-/macrocystic tumors located in the body-tail of the pancreas.Management of patients with A-SCA entails a small risk of PR especially when these tumors demonstrate atypical radiologic features associated with confounding anatomic and demographic characteristics.

Purpose: The role of cystic fibrosis transmembrane conductance regulator (CFTR) in lacrimal gland (LG) function has only recently received some attention, mainly from our group. In the present study, we investigated the potential changes of LG pathology, tear secretion, ocular surface integrity, and fluid secretion in isolated LG ducts from CFTR knockout (KO) mice. Methods: Tear production and ocular surface integrity were investigated in anesthetized wild-type (WT) and KO mice using cotton threads and fluorescein staining, respectively. Immunofluorescence was used to localize CFTR protein in the LGs. Ductal fluid secretions evoked by forskolin (10 μM); cell-permeable cAMP analogue (8-bromo cAMP, 100 μM); or carbachol (100 μM) were measured in isolated LG ducts using video-microscopy. Intracellular Ca2+ homeostasis underlying carbachol stimulation was investigated with microfluorometry. Results: Significant decrease in tear secretion and impaired ocular surface integrity were observed in KO mice. Immunofluorescence demonstrated the predominant presence of CFTR protein in the apical membranes of the duct cells from WT mice. Continuous fluid secretion was evoked by forskolin and 8-bromo cAMP in LG ducts from WT mice, while no secretory response was observed in ducts from KO mice. Carbachol caused similar secretory responses in ducts from WT and KO animals without significant differences in cytosolic Ca2+ signaling. Conclusions: Our results suggest the important role of CFTR in LG ductal secretion and in the maintenance of ocular surface integrity, suggesting that CFTR may be a promising target of novel therapeutic approaches in the treatment of dry eye.

D-type cyclins are important regulatory proteins of the G1/S phase of the cell cycle however, their specific functions are only partially understood. We show that silencing of individual D-type cyclins has no effect on the proliferation and morphology of Immortalized non-tumorigenic human epidermal (HaCaT) cells, while double and triple D cyclin silencing results in the failure of the cytokinesis leading to the appearance of large multinucleated cells. Both CDC20 and Ki67 mRNA is downregulated in these cells. Ki67 mRNA silenced cells show similar multinucleated cellular phenotype as double or triple D cyclin silenced cells without affecting D cyclin expression, suggesting that Ki67 is necessary for normal G2/M transition. Our data have revealed that cyclin D1 may have a leading role in G1/S phase regulation and suggest an incomplete functional overlap among D cyclins. Our results indicate that beside their well-known functions during the G0-G1/S phase, D-type cyclins play a pivotal role in the regulation of mitosis via influencing Ki67 expression in a downstream manner probably through E2F1 activation in HaCaT cells.