Paragangliomas and pheochromocytomas (PPGLs) are chromaffin tumors associated with severe catecholamine-induced morbidities. Surgical removal is often curative. However, complete resection may not be ...an option for patients with succinate dehydrogenase subunit A-D (
) mutations.
mutations are associated with a high risk for multiple recurrent, and metastatic PPGLs. Treatment options in these cases are limited and prognosis is dismal once metastases are present. Identification of new therapeutic targets and candidate drugs is thus urgently needed. Previously, we showed elevated expression of succinate receptor 1 (
) in
PPGLs and
head and neck paragangliomas. Its ligand succinate has been reported to accumulate due to
mutations. We thus hypothesize that autocrine stimulation of SUCNR1 plays a role in the pathogenesis of
mutation-derived PPGLs. We confirmed elevated SUCNR1 expression in
PPGLs and after
knockout in progenitor cells derived from a human pheochromocytoma (hPheo1). Succinate significantly increased viability of
-transfected PC12 and ERK pathway signaling compared to control cells. Candidate
inhibitors successfully reversed proliferative effects of succinate. Our data reveal an unrecognized oncometabolic function of succinate in
PPGLs, providing a growth advantage
.
It is the purpose of this presentation to review the unique structure and function of bone marrow anchored hematopoiesis in their significance for its response mechanisms to an exposure to ionizing ...radiation. The ultimate objective of bone marrow hematopoiesis is to maintain in the peripheral blood a constant level of the different blood cell types (erythrocytes, granulocytes, platelets, lymphocytes, etc.). All of them have their particular turnover kinetics (such as granulocytes 120 x 10(9)/d, erythrocytes 200 x 10(9)/d or thrombocytes 150 x 10(9)/d), are semi-autonomous in their steady state regulatory mechanisms and dependent on a life-long supply of mature cells from a stem cell pool with unlimited replicative and pluripotent differentiative potential. The present knowledge of hematopoietic cellular renewal is the result of years of basic experimental and clinical studies using radionuclides in various metabolic forms including (59)Fe, (32)P (DF (32)P), (51)Cr, (131)I, (60)Co, (3)H ((3)HTdR) and (14)C ((14)CTdR). To understand the physiology but in particular the radiation-pathophysiology, it is essential to recognize in detail the infrastructure of the bone marrow as a distinct unit. Indispensable for a life-long cell production is the capsule of the marrow - the bone cortex -, the arterial supply of blood connected to the sinusoidal microvascular architecture with its sinusoids contorti and recti as well as the central (cell collecting) sinusoids. It is further of importance to recognize the significance of nerval regulation of blood flow, characterized by myelinated and unmyelinated nerve fibers. The type of unique lining cells of the sinusoids is the prerequisite for the cell traffic between the hemopoietic parenchyma and the blood. This in turn cannot be achieved without an alternative opening and closing of the sinusoidal segments which - in turn - requires a rigid long capsule to assure an - in toto - constant volume of each bone marrow unit. If a bone marrow unit is exposed to ionizing radiation, a perturbance of the balance between cellular growth pressure and blood flow dynamics can be observed, resulting in a special type of bone marrow hemorrhage and an "excess cell loss" that may result in an non-thrombopenic exhaustion of the stem cell pool. Of great importance is the question as to the mechanisms that allow the bone marrow hemopoiesis to act as one cell renewal system although the bone marrow units are distributed throughout more than 100 bone marrow areas or units in the skeleton. The observation that "the bone marrow" acts and reacts as "one organ" is due to the regulatory mechanisms: the humeral factors (such as erythropoietins, granulopoietins, thrombopoietins etc.), the nerval factors (central nervous regulation) and cellular factors (continuous migration of stem cells through the blood to assure a sufficient stem cell pool size in each bone marrow "sub-unit"). It should be recalled that the bone marrow functions as a physiological chimera and becomes established by the hematogeneic seeding of stem cells to a mesenchymal matrix during embryogenesis. The repopulation of the bone marrow after partial body irradiation, after strongly inhomogeneous radiation exposure or after total body exposure with stem cell transplantation can well be considered as a repetition of the embryogenesis of bone marrow hemopoiesis with the key element of stem cells migrating via the blood to stromal sites of the marrow prepared to accept stem cells to home and start their replication and differentiation if the micro-environmental quality permits. In summary, the radiation biology of bone marrow hemopoiesis requires a thorough understanding of the physiology and pathophysiology of structure, function and regulation not only of the process of cellular renewal but also of the intricate infrastructure.
Swallowing dysfunction in cancer patients Raber-Durlacher, Judith E.; Brennan, Mike T.; Verdonck-de Leeuw, Irma M. ...
Supportive care in cancer,
03/2012, Letnik:
20, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Purpose
Dysphagia (swallowing dysfunction) is a debilitating, depressing, and potentially life-threatening complication in cancer patients that is likely underreported. The present paper is aimed to ...review relevant dysphagia literature between 1990 and 2010 with a focus on assessment tools, prevalence, complications, and impact on quality of life in patients with a variety of different cancers, particularly in those treated with curative chemoradiation for head and neck cancer.
Methods
The literature search was limited to the English language and included both MEDLINE/PubMed and EMBASE. The search focused on papers reporting dysphagia as a side effect of cancer and cancer therapy. We identified relevant literature through the primary literature search and by articles identified in references.
Results
A wide range of assessment tools for dysphagia was identified. Dysphagia is related to a number of factors such as direct impact of the tumor, cancer resection, chemotherapy, and radiotherapy and to newer therapies such as epidermal growth factor receptor inhibitors. Concomitant oral complications such as xerostomia may exacerbate subjective dysphagia. Most literature focuses on head and neck cancer, but dysphagia is also common in other types of cancer.
Conclusions
Swallowing impairment is a clinically relevant acute and long-term complication in patients with a wide variety of cancers. More prospective studies on the course of dysphagia and impact on quality of life from baseline to long-term follow-up after various treatment modalities, including targeted therapies, are needed.
A concerted action, termed METREPOL, was accepted by the Commission of the European Communities and was started in December 1997. Its purpose was to develop a new approach to the medical management ...of radiation accident victims with respect to diagnostic procedures and therapeutic options, based on recognition and evaluation of health impairments after acute radiation exposure. The result of this interdisciplinary project is a manual entitled "Medical management of radiation accidents: manual on the acute radiation syndrome". The manual compiles recommendations for assessing the state and outcome of a radiation accident victim in the shortest possible time. Furthermore, it provides guiding support for the medical management of patients accidentally exposed to ionising radiation, based on a new strategic approach for the diagnosis of the acute radiation syndrome: the response category concept. This commentary outlines the background for the development of such a manual and the realisation of the response category concept.
Gottlöber, P., Steinert, M., Weiss, M., Bebeshko, V., Belyi, D., Nadejina, N., Stefani, F. H., Wagemaker, G., Fliedner, T. M. and Peter, R. U. The Outcome of Local Radiation Injuries: 14 Years of ...Follow-up after the Chernobyl Accident. The Chernobyl nuclear power plant accident on April 26, 1986 was the largest in the history of the peaceful use of nuclear energy. Of the 237 individuals initially suspected to have been significantly exposed to radiation during or in the immediate aftermath of the accident, the diagnosis of acute radiation sickness (ARS) could be confirmed in 134 cases on the basis of clinical symptoms. Of these, 54 patients suffered from cutaneous radiation syndrome (CRS) to varying degrees. Among the 28 patients who died from the immediate consequences of accidental radiation exposure, acute hemopoietic syndrome due to bone marrow failure was the primary cause of death only in a minority. In 16 of these 28 deaths, the primary cause was attributed to CRS. This report describes the characteristic cutaneous sequelae as well as associated clinical symptoms and diseases of 15 survivors of the Chernobyl accident with severe localized exposure who were systematically followed up by our groups between 1991 and 2000. All patients presented with CRS of varying severity, showing xerosis, cutaneous telangiectasias and subungual splinter hemorrhages, hemangiomas and lymphangiomas, epidermal atrophy, disseminated keratoses, extensive dermal and subcutaneous fibrosis with partial ulcerations, and pigmentary changes including radiation lentigo. Surprisingly, no cutaneous malignancies have been detected so far in those areas that received large radiation exposures and that developed keratoses; however, two patients first presented in 1999 with basal cell carcinomas on the nape of the neck and the right lower eyelid, areas that received lower exposures. During the follow-up period, two patients were lost due to death from myelodysplastic syndrome in 1995 and acute myelogenous leukemia in 1998, respectively. Other radiation-induced diseases such as dry eye syndrome (3/15), radiation cataract (5/15), xerostomia (4/15) and increased FSH levels (7/15) indicating impaired fertility were also documented. This study, which analyzes 14 years in the clinical course of a cohort of patients with a unique exposure pattern, corroborates the requirement for long-term, if not life-long, follow-up not only in atomic bomb survivors, but also after predominantly local radiation exposure.
It has been the purpose of this keynote address to review available evidence for the notion that the stem and progenitor cells circulating in the peripheral blood play a decisive role in the ...homeostasis of blood cell formation distributed throughout dozens of bone marrow units in the skeleton. Furthermore, if this notion is correct, one could speculate that the quantity and quality of stem and progenitor cells in the blood should reflect the functional state of the hematopoietic stem cell system throughout the skeletal bone marrow and provide a new tool for the evaluation of alteration in blood cell production. On this basis, the following questions are considered: A) What do we know about the quality and quantity of blood stem cells in steady-state conditions? B) In what way do blood stem cells respond to perturbations of the "steady-state" of blood cell formation? C) Which role do blood stem cells play during hemopoietic development assuming that the establishment of bone marrow hemopoiesis requires the "seeding" of blood stem cells into an appropriate cellular environment? D) What is the role of blood stem cells in hemopoietic regeneration after partial body irradiation with a small volume of marrow (and hence stem cells) protected? and E) What are the mechanisms and/or kinetics of hemopoietic recovery if stem cells introduced into the circulation were collected from exogenous (autologous or allogeneic) sources? In this review presentation, experimental work of our group and of other members of the scientific community is summarized. It becomes obvious that blood stem and progenitor cells play a key role in hematopoietic homeostasis. Furthermore, their physiology and pathophysiology deserve rigorous experimental studies in order to develop a novel tool in the diagnosis and prognosis of neoplastic and non-neoplastic disorders of blood cell formation.
Gamma-glutamyl transferase (GGT), alanine transaminase (ALT), and aspartate transaminase (AST) are widely used as markers of hepatobiliary disorders in occupational health surveillance. Little is ...known, however, about the prevalence and occupational and non-occupational determinants of elevated levels of these enzymes in specific occupational groups or about the prognostic value of elevated levels with respect to long-term outcomes such as all-cause mortality and vocational disability.
A cohort study was conducted among 8,043 male construction workers aged 25-64 years who had undergone occupational health examinations in 6 centers in southern Germany from 1986 to 1988 and had been followed until 1994. The prevalence of elevated levels of GGT, ALT, and AST, depending on the sociodemographic and medical characteristics determined at the baseline examination and the risk of vocational disability and all-cause mortality in relation to elevated liver enzyme activity at baseline were assessed. Covariates considered in multivariate analysis included age, nationality, occupation, body mass index (BMI), smoking, and alcohol consumption.
The baseline prevalence of elevated activity levels of GGT (>28 U/1 at 25 degrees C), ALT (>22 U/1), and AST (>18 U/1) was 32%, 22%, and 12%, respectively. Factors most strongly related to elevated serum activity levels for all three enzymes were self-reported alcohol consumption, diabetes, and hypertension. BMI was strongly associated with elevations in GGT and ALT but not in AST. Elevated levels of AST and GGT were strongly related to early retirement and all-cause mortality. Men with AST levels exceeding 18 U/1 had a 2-fold risk of early retirement and a 3 times higher risk of all-cause mortality as compared with men with lower AST levels. No significant association was observed between ALT and either of the long-term outcomes.
Our findings suggest that screening for elevated GGT and AST levels, which are a common finding among construction workers, may be a powerful tool for the identification of individuals at increased risk of early retirement and preterm mortality and may be helpful in targeting of prevention efforts.
On the occasion of the first international workshop on systems radiation biology we review the role of cell renewal systems in maintaining the integrity of the mammalian organism after irradiation. ...First, 11 radiation emergencies characterized by chronic or protracted exposure of the human beings to ionizing irradiation were “revisited”. The data provide evidence to suggest that at a daily exposure of about 10–100 mSv, humans are capable of coping with the excess cell loss for weeks or even many months without hematopoietic organ failure. Below 10 mSv/day, the organisms show some cellular or subcellular indicators of response. At dose rates above 100 mSv/day, a progressive shortening of the life span of the irradiated organism is observed. To elucidate the mechanisms relevant to tolerance or failure, the Megakaryocyte–thrombocyte cell renewal system was investigated. A biomathematical model of this system was developed to simulate the development of thrombocyte concentration as a function of time after onset of chronic radiation exposure. The hematological data were taken from experimental chronic irradiation studies with dogs at the Argonne National Laboratory, USA. The results of thrombocyte response patterns are compatible with the notion of an “excess cell loss” (compared to the steady-state) in all proliferative cell compartments, including the stem cell pool. The “excess cell loss” is a function of the daily irradiation dose rate. Once the stem cell pool is approaching an exhaustion level, a “turbulence region” is reached. Then it takes a very little additional stress for the system to fail. We conclude that in mammalian radiation biology (including radiation medicine), it is important to understand the physiology and pathophysiology of cell renewal systems in order to allow predicting the development of radiation induced lesions.
After accidental radiation exposure, one of the most significant health impairments is the partial or complete failure of the blood forming systems. Depending on the degree of damage, a suitable ...therapy must be prepared in time. This requires the assessment of the degree of damage of the blood-forming system and, in particular, of the stem-cell pool. A new approach for assessing the degree of hematopoietic impairment based on dynamic reactions of blood counts immediately following radiation exposure is presented. Cell kinetic mathematical models of blood cell turnover, neural networks, and expert-assessed clinical data records of historical radiation accidents are combined to provide a method for automatic classification of patients and to assign them to clinically related categories of severity. Using this computer-assisted approach, it is possible to distinguish those patients that are likely to restore their blood-cell formation autochthonously from those that need stem-cell transplantation.
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