108 research outputs found
Recommended from our members
Pathogenic variants in the AFG3L2 proteolytic domain cause SCA28 through haploinsufficiency and proteostatic stress-driven OMA1 activation
Background: Spinocerebellar ataxia type 28 (SCA28) is a dominantly inherited neurodegenerative disease caused by pathogenic variants in AFG3L2. The AFG3L2 protein is a subunit of mitochondrial m-AAA complexes involved in protein quality control. Objective of this study was to determine the molecular mechanisms of SCA28, which has eluded characterisation to date. Methods: We derived SCA28 patient fibroblasts carrying different pathogenic variants in the AFG3L2 proteolytic domain (missense: the newly identified p.F664S and p.M666T, p.G671R, p.Y689H and a truncating frameshift p.L556fs) and analysed multiple aspects of mitochondrial physiology. As reference of residual m-AAA activity, we included SPAX5 patient fibroblasts with homozygous p.Y616C pathogenic variant, AFG3L2 +/\ue2 ' HEK293 T cells by CRISPR/Cas9-genome editing and Afg3l2 \ue2 '/\ue2 ' murine fibroblasts. Results: We found that SCA28 cells carrying missense changes have normal levels of assembled m-AAA complexes, while the cells with a truncating pathogenic variant had only half of this amount. We disclosed inefficient mitochondrial fusion in SCA28 cells caused by increased OPA1 processing operated by hyperactivated OMA1. Notably, we found altered mitochondrial proteostasis to be the trigger of OMA1 activation in SCA28 cells, with pharmacological attenuation of mitochondrial protein synthesis resulting in stabilised levels of OMA1 and OPA1 long forms, which rescued mitochondrial fusion efficiency. Secondary to altered mitochondrial morphology, mitochondrial calcium uptake resulted decreased in SCA28 cells. Conclusion: Our data identify the earliest events in SCA28 pathogenesis and open new perspectives for therapy. By identifying similar mitochondrial phenotypes between SCA28 cells and AFG3L2 +/- cells, our results support haploinsufficiency as the mechanism for the studied pathogenic variants
Consistency and accuracy of diagnostic cancer codes generated by automated registration: comparison with manual registration
BACKGROUND: Automated procedures are increasingly used in cancer registration, and it is important that the data produced are systematically checked for consistency and accuracy. We evaluated an automated procedure for cancer registration adopted by the Lombardy Cancer Registry in 1997, comparing automatically-generated diagnostic codes with those produced manually over one year (1997). METHODS: The automatically generated cancer cases were produced by Open Registry algorithms. For manual registration, trained staff consulted clinical records, pathology reports and death certificates. The social security code, present and checked in both databases in all cases, was used to match the files in the automatic and manual databases. The cancer cases generated by the two methods were compared by manual revision. RESULTS: The automated procedure generated 5027 cases: 2959 (59%) were accepted automatically and 2068 (41%) were flagged for manual checking. Among the cases accepted automatically, discrepancies in data items (surname, first name, sex and date of birth) constituted 8.5% of cases, and discrepancies in the first three digits of the ICD-9 code constituted 1.6%. Among flagged cases, cancers of female genital tract, hematopoietic system, metastatic and ill-defined sites, and oropharynx predominated. The usual reasons were use of specific vs. generic codes, presence of multiple primaries, and use of extranodal vs. nodal codes for lymphomas. The percentage of automatically accepted cases ranged from 83% for breast and thyroid cancers to 13% for metastatic and ill-defined cancer sites. CONCLUSION: Since 59% of cases were accepted automatically and contained relatively few, mostly trivial discrepancies, the automatic procedure is efficient for routine case generation effectively cutting the workload required for routine case checking by this amount. Among cases not accepted automatically, discrepancies were mainly due to variations in coding practice
Pediatric Intensive Care Unit admission criteria for haemato-oncological patients: a basis for clinical guidelines implementation
Recent advances in supportive care and progress in the development and use of chemotherapy have considerably improved the prognosis of many children with malignancy, thus the need for intensive care admission and management is increasing, reaching about 40% of patients throughout the disease course. Cancer remains a major death cause in children, though outcomes have considerably improved over the past decades. Prediction of outcome for children with cancer in Pediatric Intensive Care Unit (PICU) obviously requires clinical guidelines, and these are not well defined, as well as admission criteria. Major determinants of negative outcomes remain severe sepsis/septic shock association and respiratory failure, deserving specific approach in children with cancer, particularly those receiving a bone marrow transplantation. A nationwide consensus should be achieved among pediatric intensivists and oncologists regarding the threshold clinical conditions requiring Intensive Care Unit (ICU) admission as well as specific critical care protocols. As demonstrated for the critically ill non-oncologic child, it appears unreasonable that pediatric patients with malignancy can be admitted to an adult Intensive Care Unit ICU. On a national basis a pool of refecence institutions should be identified and early referral to an oncologic PICU is warranted
Calcium Signals Driven by Single Channel Noise
Usually, the occurrence of random cell behavior is appointed to small copy numbers of molecules involved in the stochastic process. Recently, we demonstrated for a variety of cell types that intracellular Ca2+ oscillations are sequences of random spikes despite the involvement of many molecules in spike generation. This randomness arises from the stochastic state transitions of individual Ca2+ release channels and does not average out due to the existence of steep concentration gradients. The system is hierarchical due to the structural levels channel - channel cluster - cell and a corresponding strength of coupling. Concentration gradients introduce microdomains which couple channels of a cluster strongly. But they couple clusters only weakly; too weak to establish deterministic behavior on cell level. Here, we present a multi-scale modelling concept for stochastic hierarchical systems. It simulates active molecules individually as Markov chains and their coupling by deterministic diffusion. Thus, we are able to follow the consequences of random single molecule state changes up to the signal on cell level. To demonstrate the potential of the method, we simulate a variety of experiments. Comparisons of simulated and experimental data of spontaneous oscillations in astrocytes emphasize the role of spatial concentration gradients in Ca2+ signalling. Analysis of extensive simulations indicates that frequency encoding described by the relation between average and standard deviation of interspike intervals is surprisingly robust. This robustness is a property of the random spiking mechanism and not a result of control
G protein-coupled receptor-mediated calcium signaling in astrocytes
Astrocytes express a large variety of G~protein-coupled receptors (GPCRs)
which mediate the transduction of extracellular signals into intracellular
calcium responses. This transduction is provided by a complex network of
biochemical reactions which mobilizes a wealth of possible calcium-mobilizing
second messenger molecules. Inositol 1,4,5-trisphosphate is probably the best
known of these molecules whose enzymes for its production and degradation are
nonetheless calcium-dependent. We present a biophysical modeling approach based
on the assumption of Michaelis-Menten enzyme kinetics, to effectively describe
GPCR-mediated astrocytic calcium signals. Our model is then used to study
different mechanisms at play in stimulus encoding by shape and frequency of
calcium oscillations in astrocytes.Comment: 35 pages, 6 figures, 1 table, 3 appendices (book chapter
Glutamate regulation of calcium and IP3 oscillating and pulsating dynamics in astrocytes
Recent years have witnessed an increasing interest in neuron-glia
communication. This interest stems from the realization that glia participates
in cognitive functions and information processing and is involved in many brain
disorders and neurodegenerative diseases. An important process in neuron-glia
communications is astrocyte encoding of synaptic information transfer: the
modulation of intracellular calcium dynamics in astrocytes in response to
synaptic activity. Here, we derive and investigate a concise mathematical model
for glutamate-induced astrocytic intracellular Ca2+ dynamics that captures the
essential biochemical features of the regulatory pathway of inositol
1,4,5-trisphosphate (IP3). Starting from the well-known two-state Li-Rinzel
model for calcium-induced-calcium release, we incorporate the regulation of the
IP3 production and phosphorylation. Doing so we extended it to a three-state
model (referred as the G-ChI model), that could account for Ca2+ oscillations
triggered by endogenous IP3 metabolism as well as by IP3 production by external
glutamate signals. Compared to previous similar models, our three-state models
include a more realistic description of the IP3 production and degradation
pathways, lumping together their essential nonlinearities within a concise
formulation. Using bifurcation analysis and time simulations, we demonstrate
the existence of new putative dynamical features. The cross-couplings between
IP3 and Ca2+ pathways endows the system with self-consistent oscillator
properties and favor mixed frequency-amplitude encoding modes over pure
amplitude modulation ones. These and additional results of our model are in
general agreement with available experimental data and may have important
implications on the role of astrocytes in the synaptic transfer of information.Comment: 42 pages, 16 figures, 1 table. Figure filenames mirror figure order
in the paper. Ending "S" in figure filenames stands for "Supplementary
Figure". This article was selected by the Faculty of 1000 Biology: "Genevieve
Dupont: Faculty of 1000 Biology, 4 Sep 2009" at
http://www.f1000biology.com/article/id/1163674/evaluatio
Nonlinear gap junctions enable long-distance propagation of pulsating calcium waves in astrocyte networks
A new paradigm has recently emerged in brain science whereby communications
between glial cells and neuron-glia interactions should be considered together
with neurons and their networks to understand higher brain functions. In
particular, astrocytes, the main type of glial cells in the cortex, have been
shown to communicate with neurons and with each other. They are thought to form
a gap-junction-coupled syncytium supporting cell-cell communication via
propagating Ca2+ waves. An identified mode of propagation is based on
cytoplasm-to-cytoplasm transport of inositol trisphosphate (IP3) through gap
junctions that locally trigger Ca2+ pulses via IP3-dependent Ca2+-induced Ca2+
release. It is, however, currently unknown whether this intracellular route is
able to support the propagation of long-distance regenerative Ca2+ waves or is
restricted to short-distance signaling. Furthermore, the influence of the
intracellular signaling dynamics on intercellular propagation remains to be
understood. In this work, we propose a model of the gap-junctional route for
intercellular Ca2+ wave propagation in astrocytes showing that: (1)
long-distance regenerative signaling requires nonlinear coupling in the gap
junctions, and (2) even with nonlinear gap junctions, long-distance
regenerative signaling is favored when the internal Ca2+ dynamics implements
frequency modulation-encoding oscillations with pulsating dynamics, while
amplitude modulation-encoding dynamics tends to restrict the propagation range.
As a result, spatially heterogeneous molecular properties and/or weak couplings
are shown to give rise to rich spatiotemporal dynamics that support complex
propagation behaviors. These results shed new light on the mechanisms
implicated in the propagation of Ca2+ waves across astrocytes and precise the
conditions under which glial cells may participate in information processing in
the brain.Comment: Article: 30 pages, 7 figures. Supplementary Material: 11 pages, 6
figure
Cumulative Prognostic Score Predicting Mortality in Patients Older Than 80 Years Admitted to the ICU.
OBJECTIVES: To develop a scoring system model that predicts mortality within 30 days of admission of patients older than 80 years admitted to intensive care units (ICUs). DESIGN: Prospective cohort study. SETTING: A total of 306 ICUs from 24 European countries. PARTICIPANTS: Older adults admitted to European ICUs (N = 3730; median age = 84 years [interquartile range = 81-87 y]; 51.8% male). MEASUREMENTS: Overall, 24 variables available during ICU admission were included as potential predictive variables. Multivariable logistic regression was used to identify independent predictors of 30-day mortality. Model sensitivity, specificity, and accuracy were evaluated with receiver operating characteristic curves. RESULTS: The 30-day-mortality was 1562 (41.9%). In multivariable analysis, these variables were selected as independent predictors of mortality: age, sex, ICU admission diagnosis, Clinical Frailty Scale, Sequential Organ Failure Score, invasive mechanical ventilation, and renal replacement therapy. The discrimination, accuracy, and calibration of the model were good: the area under the curve for a score of 10 or higher was .80, and the Brier score was .18. At a cut point of 10 or higher (75% of all patients), the model predicts 30-day mortality in 91.1% of all patients who die. CONCLUSION: A predictive model of cumulative events predicts 30-day mortality in patients older than 80 years admitted to ICUs. Future studies should include other potential predictor variables including functional status, presence of advance care plans, and assessment of each patient's decision-making capacity
ITALIAN CANCER FIGURES - REPORT 2015: The burden of rare cancers in Italy = I TUMORI IN ITALIA - RAPPORTO 2015: I tumori rari in Italia
OBJECTIVES:
This collaborative study, based on data collected by the network of Italian Cancer Registries (AIRTUM), describes the burden of rare cancers in Italy. Estimated number of new rare cancer cases yearly diagnosed (incidence), proportion of patients alive after diagnosis (survival), and estimated number of people still alive after a new cancer diagnosis (prevalence) are provided for about 200 different cancer entities.
MATERIALS AND METHODS:
Data herein presented were provided by AIRTUM population- based cancer registries (CRs), covering nowadays 52% of the Italian population. This monograph uses the AIRTUM database (January 2015), which includes all malignant cancer cases diagnosed between 1976 and 2010. All cases are coded according to the International Classification of Diseases for Oncology (ICD-O-3). Data underwent standard quality checks (described in the AIRTUM data management protocol) and were checked against rare-cancer specific quality indicators proposed and published by RARECARE and HAEMACARE (www.rarecarenet.eu; www.haemacare.eu). The definition and list of rare cancers proposed by the RARECAREnet "Information Network on Rare Cancers" project were adopted: rare cancers are entities (defined as a combination of topographical and morphological codes of the ICD-O-3) having an incidence rate of less than 6 per 100,000 per year in the European population. This monograph presents 198 rare cancers grouped in 14 major groups. Crude incidence rates were estimated as the number of all new cancers occurring in 2000-2010 divided by the overall population at risk, for males and females (also for gender-specific tumours).The proportion of rare cancers out of the total cancers (rare and common) by site was also calculated. Incidence rates by sex and age are reported. The expected number of new cases in 2015 in Italy was estimated assuming the incidence in Italy to be the same as in the AIRTUM area. One- and 5-year relative survival estimates of cases aged 0-99 years diagnosed between 2000 and 2008 in the AIRTUM database, and followed up to 31 December 2009, were calculated using complete cohort survival analysis. To estimate the observed prevalence in Italy, incidence and follow-up data from 11 CRs for the period 1992-2006 were used, with a prevalence index date of 1 January 2007. Observed prevalence in the general population was disentangled by time prior to the reference date (≤2 years, 2-5 years, ≤15 years). To calculate the complete prevalence proportion at 1 January 2007 in Italy, the 15-year observed prevalence was corrected by the completeness index, in order to account for those cancer survivors diagnosed before the cancer registry activity started. The completeness index by cancer and age was obtained by means of statistical regression models, using incidence and survival data available in the European RARECAREnet data.
RESULTS:
In total, 339,403 tumours were included in the incidence analysis. The annual incidence rate (IR) of all 198 rare cancers in the period 2000-2010 was 147 per 100,000 per year, corresponding to about 89,000 new diagnoses in Italy each year, accounting for 25% of all cancer. Five cancers, rare at European level, were not rare in Italy because their IR was higher than 6 per 100,000; these tumours were: diffuse large B-cell lymphoma and squamous cell carcinoma of larynx (whose IRs in Italy were 7 per 100,000), multiple myeloma (IR: 8 per 100,000), hepatocellular carcinoma (IR: 9 per 100,000) and carcinoma of thyroid gland (IR: 14 per 100,000). Among the remaining 193 rare cancers, more than two thirds (No. 139) had an annual IR <0.5 per 100,000, accounting for about 7,100 new cancers cases; for 25 cancer types, the IR ranged between 0.5 and 1 per 100,000, accounting for about 10,000 new diagnoses; while for 29 cancer types the IR was between 1 and 6 per 100,000, accounting for about 41,000 new cancer cases. Among all rare cancers diagnosed in Italy, 7% were rare haematological diseases (IR: 41 per 100,000), 18% were solid rare cancers. Among the latter, the rare epithelial tumours of the digestive system were the most common (23%, IR: 26 per 100,000), followed by epithelial tumours of head and neck (17%, IR: 19) and rare cancers of the female genital system (17%, IR: 17), endocrine tumours (13% including thyroid carcinomas and less than 1% with an IR of 0.4 excluding thyroid carcinomas), sarcomas (8%, IR: 9 per 100,000), central nervous system tumours and rare epithelial tumours of the thoracic cavity (5%with an IR equal to 6 and 5 per 100,000, respectively). The remaining (rare male genital tumours, IR: 4 per 100,000; tumours of eye, IR: 0.7 per 100,000; neuroendocrine tumours, IR: 4 per 100,000; embryonal tumours, IR: 0.4 per 100,000; rare skin tumours and malignant melanoma of mucosae, IR: 0.8 per 100,000) each constituted <4% of all solid rare cancers. Patients with rare cancers were on average younger than those with common cancers. Essentially, all childhood cancers were rare, while after age 40 years, the common cancers (breast, prostate, colon, rectum, and lung) became increasingly more frequent. For 254,821 rare cancers diagnosed in 2000-2008, 5-year RS was on average 55%, lower than the corresponding figures for patients with common cancers (68%). RS was lower for rare cancers than for common cancers at 1 year and continued to diverge up to 3 years, while the gap remained constant from 3 to 5 years after diagnosis. For rare and common cancers, survival decreased with increasing age. Five-year RS was similar and high for both rare and common cancers up to 54 years; it decreased with age, especially after 54 years, with the elderly (75+ years) having a 37% and 20% lower survival than those aged 55-64 years for rare and common cancers, respectively. We estimated that about 900,000 people were alive in Italy with a previous diagnosis of a rare cancer in 2010 (prevalence). The highest prevalence was observed for rare haematological diseases (278 per 100,000) and rare tumours of the female genital system (265 per 100,000). Very low prevalence (<10 prt 100,000) was observed for rare epithelial skin cancers, for rare epithelial tumours of the digestive system and rare epithelial tumours of the thoracic cavity.
COMMENTS:
One in four cancers cases diagnosed in Italy is a rare cancer, in agreement with estimates of 24% calculated in Europe overall. In Italy, the group of all rare cancers combined, include 5 cancer types with an IR>6 per 100,000 in Italy, in particular thyroid cancer (IR: 14 per 100,000).The exclusion of thyroid carcinoma from rare cancers reduces the proportion of them in Italy in 2010 to 22%. Differences in incidence across population can be due to the different distribution of risk factors (whether environmental, lifestyle, occupational, or genetic), heterogeneous diagnostic intensity activity, as well as different diagnostic capacity; moreover heterogeneity in accuracy of registration may determine some minor differences in the account of rare cancers. Rare cancers had worse prognosis than common cancers at 1, 3, and 5 years from diagnosis. Differences between rare and common cancers were small 1 year after diagnosis, but survival for rare cancers declined more markedly thereafter, consistent with the idea that treatments for rare cancers are less effective than those for common cancers. However, differences in stage at diagnosis could not be excluded, as 1- and 3-year RS for rare cancers was lower than the corresponding figures for common cancers. Moreover, rare cancers include many cancer entities with a bad prognosis (5-year RS <50%): cancer of head and neck, oesophagus, small intestine, ovary, brain, biliary tract, liver, pleura, multiple myeloma, acute myeloid and lymphatic leukaemia; in contrast, most common cancer cases are breast, prostate, and colorectal cancers, which have a good prognosis. The high prevalence observed for rare haematological diseases and rare tumours of the female genital system is due to their high incidence (the majority of haematological diseases are rare and gynaecological cancers added up to fairly high incidence rates) and relatively good prognosis. The low prevalence of rare epithelial tumours of the digestive system was due to the low survival rates of the majority of tumours included in this group (oesophagus, stomach, small intestine, pancreas, and liver), regardless of the high incidence rate of rare epithelial cancers of these sites. This AIRTUM study confirms that rare cancers are a major public health problem in Italy and provides quantitative estimations, for the first time in Italy, to a problem long known to exist. This monograph provides detailed epidemiologic indicators for almost 200 rare cancers, the majority of which (72%) are very rare (IR<0.5 per 100,000). These data are of major interest for different stakeholders. Health care planners can find useful information herein to properly plan and think of how to reorganise health care services. Researchers now have numbers to design clinical trials considering alternative study designs and statistical approaches. Population-based cancer registries with good quality data are the best source of information to describe the rare cancer burden in a population
- …