Expression of Mcm2, geminin and Ki67 in normal oral mucosa, oral epithelial dysplasias and their corresponding squamous-cell carcinomas

Proteins necessary for the normal regulation of the cell cycle include minichromosome maintenance protein 2 (Mcm2) and geminin. These are overexpressed in several premalignant and malignant tumours. The Mcm2/Ki67 ratio can be used to estimate the population of cells that are in early G1 (licensed to proliferate), and the geminin/Ki67 ratio can determine the relative length of G1. A high ratio indicates a short G1 and a high rate of cell proliferation. Mcm2 and geminin have been scarcely explored in oral epithelial dysplasia (OED) and oral squamous-cell carcinoma (OSCC). The purpose of this study was to identify the expression pattern of Mcm2, Ki67 and geminin in normal oral mucosa (NOM), OED and their subsequent OSCC, to determine if expression could help predict the prognosis of OED. Paraffin sections of 41 OED cases that progressed to carcinoma, 40 OED without malignant progression, 38 OSCC and 15 NOM were immunostained with antibodies against Mcm2, geminin and Ki67. Labelling indices (LIs) increased progressively from NOM, OED and OSCC (Mcm2, Po0.001; geminin, Po0.001 and Ki67, Po0.001). In all the OED cases (n ¼ 81) the levels of expression of Mcm2 (LI, 73.6), geminin (LI, 24.4) and Ki67 (LI, 44.5) were elevated indicating a constant cellcycle re-entry. When the OED groups were compared, Mcm2 protein expression was higher in the OED with malignant progression (P ¼ 0.04), likewise there was a significant increase in the Mcm2/Ki67 and geminin/Ki67 ratios (P ¼ 0.04 and 0.02 respectively). Mcm2 and geminin proteins seem to be novel biomarkers of growth and may be useful prognostic tools for OED

VLPs and particle strategies for cancer vaccines

n/

Tumores do mediastino em crianças Mediastinal tumors in children

INTRODUÇÃO: Os tumores mediastinais na criança compreendem um grupo heterogêneo de lesões com origem embrionária distinta. Podem apresentar-se como cistos benignos ou lesões malignas. OBJETIVO: Descrever os procedimentos diagnósticos, tratamento e evolução de uma série de crianças e adolescentes com tumores do mediastino. MÉTODO: Análise retrospectiva de vinte crianças com tumores de mediastino, no período de julho de 1996 a julho de 2002 no Hospital de Clínicas de Porto Alegre. Todos os pacientes foram submetidos a algum procedimento cirúrgico, seja diagnóstico, terapêutico ou ambos. RESULTADOS: Doze meninos e oito meninas foram estudados. A idade média no momento do diagnóstico foi de seis anos e oito meses, variando entre três meses e 16 anos. Quatorze tumores (70%) ocorreram no mediastino anterior, sendo os mais comuns os linfomas de Hodgkin e não-Hodgkin; seis tumores (30%) ocorreram no mediastino posterior, sendo o neuroblastoma o mais freqüente. Nos tumores anteriores, a abordagem cirúrgica mais comum foi a toracotomia anterior de Chamberlain; nos posteriores, a toracotomia póstero-lateral. No período de seguimento ocorreram seis óbitos, todos sem nenhuma relação com o procedimento cirúrgico. CONCLUSÃO: Os tumores mediastinais em crianças são responsáveis por morbimortalidade. No mediastino anterior foram mais comuns os linfomas; no posterior, os tumores de origem neural. A cirurgia é um passo importante no diagnóstico e tratamento dessas lesões<br>BACKGROUND: Mediastinal tumors in children comprise a heterogeneous group of lesions that have a range of embryonic origins. They may present as benign cysts, as well as malignant lesions. OBJECTIVE: To describe the diagnostic procedures, the treatments and outcomes of a group of children and adolescents with mediastinal tumors. METHOD: A retrospective analysis of twenty children and adolescents with mediastinal tumors who were treated at the Hospital de Clínicas de Porto Alegre from July, 1996 to July, 2002. All patients were submitted to some kind of surgical procedure: diagnostic, therapeutic, or both. RESULTS: Twelve boys and eight girls were studied. Mean age at diagnosis was 6 years and 8 months (ranging from 3 months to 16 years). Fourteen tumors (70%) were located at the anterior, and six (30%) at the posterior mediastinum. Hodgkin and non-Hodgkin lymphomas were the most common tumors found in anterior mediastinum, whereas neuroblastoma was the most common among posterior malignancies. The most used surgical procedure for anterior tumors was Chamberlain anterior thoracotomy; posterolateral thoracotomy was usually performed for posterior tumors. Six patients died during the follow-up period but none of the deaths was considered related to the surgical procedure. CONCLUSION: Mediastinal tumors in children and adolescents represent an important cause of morbidity/mortality. The most common tumors at the anterior mediastinum were lymphomas, whereas at the posterior mediastinum the most common were neurogenic tumors. Surgery is an important step for the diagnosis and treatment of such lesion

Multimodal decoding of human liver regeneration.

Acknowledgements: This work was supported by a Wellcome Trust Senior Research Fellowship in Clinical Science (ref. 219542/Z/19/Z) to N.C.H., a Chan Zuckerberg Initiative Seed Network Grant to N.C.H., and a Tenovus Scotland grant (E20-03) to K.P.M., S. J. Wallace and N.C.H. J.R.P. was supported by a Medical Research Council Precision Medicine PhD studentship. C.A.K. was a cross-disciplinary post-doctoral fellow (XDF) supported by funding from the University of Edinburgh and Medical Research Council (MC_UU_00009/2). T.G.B. was funded by the Wellcome Trust (ref. WT107492Z). S.M. was funded by Cancer Research UK core funding to the CRUK Beatson Institute (refs. A17196 and A31287). J.B.G.M. was supported by a CRUK programme grant (A23390). F.F., J.B.G.M. and L.M.C. were supported by CRUK core funding to the Beatson Institute (A31287) and CRUK core funding to L.M.C. (A23983; DRCRPG-Nov22/100007). D.J.M. was supported by a Medical Research Council Senior Clinical Fellowship (MR/P008887/1). P.R. was supported by a Medical Research Council Clinician Scientist Fellowship (MR/N008340/1) and Medical Research Council Senior Clinical Fellowship (MR/W015919/1). M.M.S. was supported by a Peter Samuel Fellowship. We thank the patients who donated liver tissue for this study; J. Davidson, J. Black, C. Ibbotson and A. Baird of the Scottish Liver Transplant Unit and the research nurses of the Wellcome Trust Clinical Research Facility for assistance with consenting patients for this study; the liver transplant coordinators and surgeons of the Scottish Liver Transplant Unit and the surgeons and staff of the Hepatobiliary Surgical Unit, Royal Infirmary of Edinburgh for assistance in procuring human liver samples; the US ALFSG network for assistance in procuring human liver samples; core facilities and services at the Beatson Institute, in particular the Biological Research Unit & the Beatson Advanced Imaging Resource (BAIR); G. Jacquemet for advice on Cellpose segmentation for IVM analysis; R. Insall and L. Machesky for helpful scientific discussions; W. Mungall for technical support; C. Nicol for help with manuscript illustrations; N. Pham for technical assistance with Incucyte; and C. Winchester and R. Li for critical reading of the manuscript. We acknowledge the contribution to this study made by the University of Birmingham’s Human Biomaterials Resource Centre, which has been supported through Birmingham Science City–Experimental Medicine Network of Excellence project. This research was funded in whole, or in part, by the Wellcome Trust (Wellcome Trust Senior Research Fellowship in Clinical Science to N.C.H.; ref. 219542/Z/19/Z). This publication is part of the Human Cell Atlas (www.humancellatlas.org/publications).The liver has a unique ability to regenerate1,2; however, in the setting of acute liver failure (ALF), this regenerative capacity is often overwhelmed, leaving emergency liver transplantation as the only curative option3-5. Here, to advance understanding of human liver regeneration, we use paired single-nucleus RNA sequencing combined with spatial profiling of healthy and ALF explant human livers to generate a single-cell, pan-lineage atlas of human liver regeneration. We uncover a novel ANXA2+ migratory hepatocyte subpopulation, which emerges during human liver regeneration, and a corollary subpopulation in a mouse model of acetaminophen (APAP)-induced liver regeneration. Interrogation of necrotic wound closure and hepatocyte proliferation across multiple timepoints following APAP-induced liver injury in mice demonstrates that wound closure precedes hepatocyte proliferation. Four-dimensional intravital imaging of APAP-induced mouse liver injury identifies motile hepatocytes at the edge of the necrotic area, enabling collective migration of the hepatocyte sheet to effect wound closure. Depletion of hepatocyte ANXA2 reduces hepatocyte growth factor-induced human and mouse hepatocyte migration in vitro, and abrogates necrotic wound closure following APAP-induced mouse liver injury. Together, our work dissects unanticipated aspects of liver regeneration, demonstrating an uncoupling of wound closure and hepatocyte proliferation and uncovering a novel migratory hepatocyte subpopulation that mediates wound closure following liver injury. Therapies designed to promote rapid reconstitution of normal hepatic microarchitecture and reparation of the gut-liver barrier may advance new areas of therapeutic discovery in regenerative medicine