325 research outputs found
Magnetic resonance tumor regression grade (MR-TRG) to assess pathological complete response following neoadjuvant radiochemotherapy in locally advanced rectal cancer
This study aims to evaluate the feasibility of a magnetic resonance (MR) automatic method for quantitative assessment of the percentage of fibrosis developed within locally advanced rectal cancers (LARC) after neoadjuvant radiochemotherapy (RCT). A total of 65 patients were enrolled in the study and MR studies were performed on 3.0 Tesla scanner; patients were followed-up for 30 months. The percentage of fibrosis was quantified on T2-weighted images, using automatic K-Means clustering algorithm. According to the percentage of fibrosis, an optimal cut-off point for separating patients into favorable and unfavorable pathologic response groups was identified by ROC analysis and tumor regression grade (MR-TRG) classes were determined and compared to histopathologic TRG. An optimal cut-off point of 81% of fibrosis was identified to differentiate between favorable and unfavorable pathologic response groups resulting in a sensitivity of 78.26% and a specificity of 97.62% for the identification of complete responders (CRs). Interobserver agreement was good (0.85). The agreement between P-TRG and MR-TRG was excellent (0.923). Significant differences in terms of overall survival (OS) and disease free survival (DFS) were found between favorable and unfavorable pathologic response groups. The automatic quantification of fibrosis determined by MR is feasible and reproducible
Critical role for prokineticin 2 in CNS autoimmunity
Objective: To investigate the potential role of prokineticin 2 (PK2), a bioactive peptide involved in multiple biological functions including immune modulation, in CNS autoimmune demyelinating disease.
Methods: We investigated the expression of PK2 in mice with experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis (MS), and in patients with relapsing-remitting MS. We evaluated the biological effects of PK2 on expression of EAE and on development of T-cell response against myelin by blocking PK2 in vivo with PK2 receptor antagonists. We treated with PK2 immune cells activated against myelin antigen to explore the immune-modulating effects of this peptide in vitro.
Results: Pk2 messenger RNA was upregulated in spinal cord and lymph node cells (LNCs) of mice with EAE. PK2 protein was expressed in EAE inflammatory infiltrates and was increased in sera during EAE. In patients with relapsing-remitting MS, transcripts for PK2 were significantly increased in peripheral blood mononuclear cells compared with healthy controls, and PK2 serum concentrations were significantly higher. A PK2 receptor antagonist prevented or attenuated established EAE in chronic and relapsing-remitting models, reduced CNS inflammation and demyelination, and decreased the production of interferon (IFN)-Îł and interleukin (IL)-17A cytokines in LNCs while increasing IL-10. PK2 in vitro increased IFN-Îł and IL-17A and reduced IL-10 in splenocytes activated against myelin antigen.
Conclusion: These data suggest that PK2 is a critical immune regulator in CNS autoimmune demyelination and may represent a new target for therapy
Mast cells counteract regulatory T-cell suppression through interleukin-6 and OX40/OX40L axis toward Th17-cell differentiation
The development of inflammatory diseases implies inactivation of regulatory T (Treg) cells through mechanisms that still are largely unknown. Here we showed that mast cells (MCs), an early source of inflammatory mediators, are able to counteract Treg inhibition over effector T cells. To gain insight into the molecules involved in their interplay, we set up an in vitro system in which all 3 cellular components were put in contact. Reversal of Treg suppression required T cell-derived interleukin-6 (IL-6) and the OX40/OX40L axis. In the presence of activated MCs, concomitant abundance of IL-6 and paucity of Th1/Th2 cytokines skewed Tregs and effector T cells into IL-17-producing T cells (Th17). In vivo analysis of lymph nodes hosting T-cell priming in experimental autoimmune encephalomyelitis revealed activated MCs, Tregs, and Th17 cells displaying tight spatial interactions, further supporting the occurrence of an MC-mediated inhibition of Treg suppression in the establishment of Th17-mediated inflammatory responses. © 2009 by The American Society of Hematology
Telemedicine for Delivery of Care in Frontotemporal Lobar Degeneration during COVID-19 Pandemic: Results from Southern Italy
Background: The COVID-19 pandemic is changing clinical practice in neurology, after the governments decided the introduction of social distancing and interruption of medical non-emergency services in many countries. Teleneurology is an effective tool for the remote evaluation of patients but its adoption for frontotemporal lobar dementia (FTD) is in a preliminary stage. Objective: We evaluated multidisciplinary assessment of patients with FTD using telehealth during the COVID-19 pandemic. Methods: All patients received a diagnosis of FTD during 2018-2019 according to international criteria. A structured questionnaire and Clinical Dementia Rating Scale (CDR)-FTD were used by the neurologist with patients and/or caregivers. Index symptoms of COVID-19 infection were searched. Results: Twenty-eight clinical interviews were completed with caregivers and four with both patients/caregivers. Most patients and caregivers were satisfied with the neurological interview and expressed their willingness to continue to be included in remote evaluation programs (90%). Fifty percent of patients experienced significant worsening of clinical picture and quality of life since the start of social distancing. The CDR-FTD scale revealed a significant worsening of behavior (p = 0.01) and language functions (p = 0.009), compared to the last in-person evaluation at the center. One patient presented index symptoms of COVID-19 infection and was confirmed to be positive for COVID-19 with pharyngeal swab. Conclusion: The study was conducted in Italy, one of the countries hit particularly hard by the COVID-19 pandemic, with interruption of all non-emergency medical services. Our study indicates that telemedicine is a valid tool to triage patients with FTD to increase practice outreach and efficiency
Pathogenic variants in EP300 and ANKRD11 in patients with phenotypes overlapping Cornelia de Lange syndrome
Cornelia de Lange syndrome (CdLS), Rubinstein–Taybi syndrome (RSTS), and KBG syndrome are three distinct developmental human disorders. Variants in seven genes belonging to the cohesin pathway, NIPBL, SMC1A, SMC3, HDAC8, RAD21, ANKRD11, and BRD4, were identified in about 80% of patients with CdLS, suggesting that additional causative genes remain to be discovered. Two genes, CREBBP and EP300, have been associated with RSTS, whereas KBG results from variants in ANKRD11. By exome sequencing, a genetic cause was elucidated in two patients with clinical diagnosis of CdLS but without variants in known CdLS genes. In particular, genetic variants in EP300 and ANKRD11 were identified in the two patients with CdLS. EP300 and ANKRD11 pathogenic variants caused the reduction of the respective proteins suggesting that their low levels contribute to CdLS-like phenotype. These findings highlight the clinical overlap between CdLS, RSTS, and KBG and support the notion that these rare disorders are linked to abnormal chromatin remodeling, which in turn affects the transcriptional machinery
Elevated expression of artemis in human fibroblast cells is associated with cellular radiosensitivity and increased apoptosis
Copyright @ 2012 Nature Publishing GroupThis article has been made available through the Brunel Open Access Publishing Fund.Background: The objective of this study was to determine the molecular mechanism(s) responsible for cellular radiosensitivity in two human fibroblast cell lines 84BR and 175BR derived from two cancer patients. Methods: Clonogenic assays were performed following exposure to increasing doses of gamma radiation to confirm radiosensitivity. Îł-H2AX foci assays were used to determine the efficiency of DNA double strand break (DSB) repair in cells. Quantitative-PCR (Q-PCR) established the expression levels of key DNA DSB repair proteins. Imaging flow cytometry using Annexin V-FITC was used to compare artemis expression and apoptosis in cells. Results: Clonogenic cellular hypersensitivity in the 84BR and 175BR cell lines was associated with a defect in DNA DSB repair measured by the Îł-H2AX foci assay. Q-PCR analysis and imaging flow cytometry revealed a two-fold overexpression of the artemis DNA repair gene which was associated with an increased level of apoptosis in the cells before and after radiation exposure. Over-expression of normal artemis protein in a normal immortalised fibroblast cell line NB1-Tert resulted in increased radiosensitivity and apoptosis. Conclusion: We conclude elevated expression of artemis is associated with higher levels of DNA DSB, radiosensitivity and elevated apoptosis in two radio-hypersensitive cell lines. These data reveal a potentially novel mechanism responsible for radiosensitivity and show that increased artemis expression in cells can result in either radiation resistance or enhanced sensitivity.This work was supported in part by The Vidal Sassoon Foundation USA. This article is made available through the Brunel Open Access Publishing Fund
Results of a survey on elderly head and neck cancer patients on behalf of the Italian association of radiotherapy and clinical oncology (Airo)
Objective. Over the years, evidence-based data and technical improvements have consolidated the central role of radiation therapy (RT) in head and neck cancer (HNC) treatment, even in the elderly. This survey aimed to describe the management of the elderly HNC patients among Italian Radiation Oncology Departments (RODs) and provide possible suggestions for improvement. Methods. An online survey based on 43 questions was sent to RODs via email. For each RODs, a radiation oncologist with expertise in HNC was invited to answer questions ad-dressing his/her demographic data, ROD multidisciplinary unit (MU) organisation and ROD management policy in elderly HNC patients. Results. In total, 68 RODs answered, representing centres located in 16 Italian regions. MU was considered the core of HNC patient management in almost all the entire country. However, in many RODs, there was minimal access to a routinely comprehensive geriatric assessment at diagnosis. Most treatments were reported by respondents as curative (89% on average) and the preferred treatment technique was intensity modulated radiation therapy (IMRT). A consider-able variation between RODs was found for RT target volumes. There was a relation between the specialist’s years of experience and type of concomitant systemic therapy prescribed. Conclusions. Substantial differences in elderly HNC management have been found, es-pecially concerning patient clinical evaluation and target volume delineation. This survey shows the necessity to design a prospective national trial to provide a uniform treatment strategy and define an effective patient-centred approach
Correlated fragile site expression allows the identification of candidate fragile genes involved in immunity and associated with carcinogenesis
Common fragile sites (cfs) are specific regions in the human genome that are
particularly prone to genomic instability under conditions of replicative
stress. Several investigations support the view that common fragile sites play
a role in carcinogenesis. We discuss a genome-wide approach based on graph
theory and Gene Ontology vocabulary for the functional characterization of
common fragile sites and for the identification of genes that contribute to
tumour cell biology. CFS were assembled in a network based on a simple measure
of correlation among common fragile site patterns of expression. By applying
robust measurements to capture in quantitative terms the non triviality of the
network, we identified several topological features clearly indicating
departure from the Erdos-Renyi random graph model. The most important outcome
was the presence of an unexpected large connected component far below the
percolation threshold. Most of the best characterized common fragile sites
belonged to this connected component. By filtering this connected component
with Gene Ontology, statistically significant shared functional features were
detected. Common fragile sites were found to be enriched for genes associated
to the immune response and to mechanisms involved in tumour progression such as
extracellular space remodeling and angiogenesis. Our results support the
hypothesis that fragile sites serve a function; we propose that fragility is
linked to a coordinated regulation of fragile genes expression.Comment: 18 pages, accepted for publication in BMC Bioinformatic
Primary squamous cell carcinoma of major salivary gland: “Sapienza Head and Neck Unit” clinical recommendations
Primary squamous cell carcinoma of salivary gland (SCG) is an extremely rare type of malignant salivary gland tumor, which in turn results in scarcity of data available regarding both its treatment and associated genetic alterations. A retrospective analysis of 12 patients with primary SCG was conducted, along with analysis of the association between treatment, clinical/pathological characteristics, and outcomes. Most patients (8) were staged IVa, with the majority of them (10) having G3 fast growing cancer. Local and systemic recurrence were reported in only three out of nine parotid cases (0 out of 2 submandibular SCGs). In two out of eight patients local relapse occurred after integrated treatment, while recurrence occurred in two out of three patients undergoing exclusive surgery. Five patients eventually died. Treatment of resectable disease must be aggressive and multimodal, with achievement of loco-regional control in order to reduce rate of recurrence and improve outcomes. Metastatic disease would require a therapeutic strategy tailored to the molecular profile in order to improve the currently disappointing results
Donor cell acute myeloid leukemia after hematopoietic stem cell transplantation for chronic granulomatous disease: a case report and literature review
The patient reported here underwent hematopoietic stem cell transplantation (HSCT) due to chronic granulomatous disease (CGD) caused by biallelic mutations of the NCF1 gene. Two years later, he developed AML, which was unexpected and was recognized via sex-mismatched chromosomes as deriving from the donor cells; the patient was male, and the donor was his sister. Donor cell leukemia (DCL) is very rare, and it had never been reported in patients with CGD after HSCT. In the subsequent ten years, the AML relapsed three times and the patient underwent chemotherapy and three further HSCTs; donors were the same sister from the first HSCT, an unrelated donor, and his mother. The patient died during the third relapse. The DCL was characterized since onset by an acquired translocation between chromosomes 9 and 11, with a molecular rearrangement between the MLL and MLLT3 genes-a quite frequent cause of AML. In all of the relapses, the malignant clone had XX sex chromosomes and this rearrangement, thus indicating that it was always the original clone derived from the transplanted sister's cells. It exhibited the ability to remain quiescent in the BM during repeated chemotherapy courses, remission periods and HSCT. The leukemic clone then acquired different additional anomalies during the ten years of follow-up, with cytogenetic results characterized both by anomalies frequent in AML and by different, non-recurrent changes. This type of cytogenetic course is uncommon in AML
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