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Based on 26 cases and 52 controls and using a log-linear dose-response model treating estimated individual thyroid radiation dose as a continuous variable pulse pressure response to exercise generic moduretic 50 mg without prescription, the trend of increasing risk with increasing dose was statistically significant (one-sided p = blood pressure gauge cheap 50 mg moduretic otc. The third is a population-based blood pressure chart with age and weight generic moduretic 50mg with mastercard, casecontrol study of thyroid cancer carried out in contaminated regions of Belarus and the Russian Federation (Cardis and others hypertension treatment in pregnancy order moduretic 50 mg with amex, 2005) blood pressure chart age 50 discount 50mg moduretic overnight delivery. The study included 276 cases and 1300 matched controls aged less than 15 years at the time of the accident blood pressure medication make you tired quality 50 mg moduretic. A clear linear doseresponse relationship was observed up to about 1 Gy, followed by a marked flattening. Collectively, data from these studies suggest that exposure to radiation from Chernobyl is associated with an increased risk of thyroid cancer and that the relationship is dose dependent. These findings are consistent with descriptive reports from contaminated areas of Ukraine and Belarus, and the quantitative estimate of thyroid cancer risk is generally consistent with estimates from other radiation-exposed populations. A number of the studies have also focused on the potentially modifying influence of a number of host and environmental factors. Results from studies of atomic bomb survivors and persons exposed to external irradiation have shown that exposure at the youngest ages is associated with the greatest risk of thyroid cancer. The available data on exposure from the Chernobyl accident are largely in agreement with this observation. One study of thyroid cancer diagnosed in adolescents and adults in the Bryansk region of Russia reported a small excess of thyroid cancer among adults (Ivanov and others 2003), but the excess was not correlated Copyright National Academy of Sciences. Leukemia the evidence from epidemiologic studies regarding the risk of leukemia in populations exposed to radiation from Chernobyl comes from studies of recovery operation workers, some of whom were exposed at a high or moderate dose levels and dose rates (depending on when and where they worked), and the general population who have been subject to low-dose-rate exposure (primarily from 137Cs) for a number of years and will continue to be exposed in the future. Resident populations were exposed at all ages, but studies of residents are primarily of persons exposed as children and/or in utero. Several studies have investigated the risk of leukemia in children exposed to Chernobyl fallout in utero. The initial study compared rates for temporal cohorts born during "exposed" and "unexposed" periods in Greece and found a 2. In a study in Belarus (Ivanov and others 1998), where levels of contamination are higher by a factor of 10 or more, the results were similar to the Greek study but the trend was weaker. A more recent small study published by Noshchenko and colleagues (2001) compared leukemia incidence during 1986 to 1996 among children born in 1986 and thus exposed in utero in Zhitomir, a contaminated region, to children born in Poltava, a relatively uncontaminated region. Focusing on the risk of leukemia by age of diagnosis in 6-month intervals in relation to estimated doses from the Chernobyl fallout received in utero, preliminary results suggest a small increase in risk in infant leukemia and leukemia diagnosed between 24 and 29 months. Thus, at present the available evidence from ecologic studies does not convincingly indicate an increased risk of leukemia among persons exposed in utero to radiation from Chernobyl. However, the statistical power of these studies is low for detecting moderate-sized associations, and the exposure measures are crude. There are no data from analytic epidemiologic studies in which individual dose estimates are available. Consequently, there is neither strong evidence for or against an association between in utero exposure to Chernobyl fallout and an increased risk of leukemia. Several ecologic studies also have investigated the association between radiation exposure of children from Chernobyl and the occurrence of leukemia. Additional reports have focused on changes in childhood leukemia rates before and after the accident in individual European countries and elsewhere. Overall, there was little evidence for an increase in rates of childhood leukemia in Ukraine, Belarus, Russia, Finland, Sweden, Greece, or a number of other countries from Central, Eastern and Southern Europe after the Chernobyl accident. Furthermore, there was no association between the extent of contamination and the increase in risk in these countries. There has been only one analytic (case-control) study of childhood leukemia reported (Noshchenko and others 2002) based on cases identified among residents of the Rivno and Zhytomir Oblasts in Ukraine. Cases were under age 20 at the time of the accident and were diagnosed between 1987 and 1997. Data were collected on 272 cases; however the analysis was based on only 98 cases that were independently verified and interviewed. Similarly, Prisyazhniuk and colleagues (1995) investigated the incidence of leukemia and lymphoma in the three most contaminated regions of Ukraine. There was a steady increase in leukemia and lymphoma rates for both men and women between 1980 and 1993, but there was no evidence of a more pronounced increase after the accident. Thus, on balance, there is no convincing evidence that the incidence of leukemia has increased in adult residents of the exposed populations that have been studied in Russia and Ukraine. However, few studies of the general adult population have been conducted to date, and they have employed ecologic designs that are relatively insensitive. Solid Tumors Other Than Thyroid Cancer There has been relatively little study of the incidence of or mortality from solid cancers other than thyroid cancer in populations exposed to radiation from the Chernobyl accident. Two studies have investigated solid cancer incidence in liquidation workers (Prisyazhnik and others 1996; Ivanov and others 2004a, 2004b) and are considered in Chapter 8. No descriptive or analytical epidemiologic studies of breast cancer risk in populations exposed to radiation from Chernobyl have been published in the peer-reviewed literature. However, one monograph report has cited elevated breast cancer incidence rates based on members of Ukrainian registries (Prysyazhnyuk and others 2002). These registry-derived estimates must be interpreted with considerable caution because they were not subject to diagnostic confirmation and may be influenced by differences in screening intensity. Similarly, although no descriptive or analytical epidemiologic studies of bladder or kidney cancer risk in relation to Chernobyl radiation have been published in the peer-reviewed literature, there has been a series of papers investigating aspects of possible radiation carcinogenesis in these organs. Romanenko and colleagues (2003) have continued to monitor the incidence of urinary bladder cancer in Ukraine, reporting that it increased from 26. In a study of 204 the same oblasts, excluding the raion of residence of the case, and matched according to age at the time of the accident, sex, and type of settlement. The study found a statistically significant increased risk of acute leukemia among males with cumulative doses greater than 10 mSv diagnosed from 1993 to 1997. These results should be interpreted cautiously, however, because they are based only on approximately one-third of the cases and a lesser proportion of controls, and it is not clear whether cases and controls were selected for dose estimation in an unbiased manner. On balance, the existing evidence does not support the conclusion that rates of childhood leukemia have increased as a result of radiation exposures from the Chernobyl accident. However, ecologic studies are not particularly sensitive to detecting relatively small changes in the incidence of a disease as uncommon as childhood leukemia over time or by different geographic areas. The single analytical study is insufficient to draw convincing conclusions regarding leukemia risk after Chernobyl exposure of children. A few studies have investigated adult resident populations living in highly contaminated areas. The incidence rates in the six most contaminated districts (more than 37 kBq m2 of 137Cs deposition density) did not exceed the rates in the rest of the region or in Bryansk city, where the highest rates were observed. Similarly, Ivanov and colleagues (1997a, 1997b) found no evidence of an increase in leukemia rates in the most contaminated areas of the Kaluga district of the Russian Federation after the Chernobyl accident. In Ukraine, Bebeshko and colleagues (1997) examined incidence rates for leukemia and lymphoma in the most highly contaminated areas of the Zhytomir and Kiev districts before and after the Chernobyl accident. Romanenko and colleagues (2000) have also reported that renal carcinoma incidence has increased from 4. In summary, there is now little doubt that an excess of thyroid cancer has occurred in areas highly contaminated by radiation from the Chernobyl accident. Analytical studies further indicate that exposure to radiation from Chernobyl is associated with an increased risk of thyroid cancer and that the relationship is dose dependent. Quantitative estimates of risk from these studies are consistent with estimates from other radiation-exposed populations. There is evidence that young age at exposure and iodine deficiency may be important modifiers of the risk of radiation-induced thyroid cancer. There is no convincing evidence that the incidence of leukemia has increased in children or adult residents of the exposed populations; however, few studies of leukemia have been conducted to date and most have employed ecologic designs that are relatively insensitive. A number of different cancer outcomes were studied, based on incidence, mortality, and prevalence data. These studies did not find higher disease rates in geographic areas with high background levels of radiation exposure compared to areas with lower background levels. However, these studies were ecologic in design and utilized population-based measures of exposure rather than individual estimates of radiation dose. Thus, they cannot provide any quantitative estimates of disease risk associated with the exposure levels found in the areas studied. These studies followed the findings first published by Gardner and colleagues (Gardner and others 1990a, 1990b) suggesting that an excess incidence of leukemia in children in West Cumbria may be due to parental preconception exposure to ionizing radiation during employment at the nearby Sellafield nuclear fuel processing plant. All three studies were conducted in relation to exposures received by parents working at the Sellafield nuclear facility in Great Britain. One study (Parker and others 1993) is a radioecologic study, examining the distribution of possible doses received by fathers employed at Sellafield of children born in Cumbria from 1950 to 1989; it does not address disease outcome. Although there is some evidence of an increased risk associated with measures of individual dose in the other two studies, the findings are based on very small numbers of cases and the results across studies are not consistent. A larger number of case-control studies have been conducted to investigate the possible relationship between radiation exposure of adults and subsequent cancer in their offspring. Six of the seven studies included in the table are investigations that are related to findings first published by Gardner and colleagues (1990b). The six studies summarized here include investigations in England and Wales, Scotland, and Canada. The seventh study by Sever and colleagues (1988) is a study of congenital malformations. All but the study by Sorahan and Roberts (1993) used employment records and recorded doses to estimate individual preconception radiation dose. The study by Sorahan and Roberts (1993) used job histories to estimate paternal exposure to ionizing radiation and the potential for exposure to radionuclides in the 6 months prior to the conception of 14,869 children dying of cancer. There was no evidence of an association between external ionizing radiation and cancer risk. In summary, none of the studies provides quantitative information from doseresponse analyses or quantitative estimates of the risk of disease associated with exposure, and results across studies are inconsistent. Table 9-5C describes cohort studies published regarding the risk of cancer and adverse reproductive outcomes in children of adults exposed to radiation. Two are studies by Gardner and colleagues (1987) that are not based on individual estimates of radiation dose but rather on proximity to the Sellafield nuclear plant at different ages (at birth and while attending school). Person-years at risk were accrued from date of birth for 39,557 children of male workers and 8883 children of female workers until age 25, cancer diagnosis, or death. A total of 111 cases of malignant cancer were found, but there was no evidence of increased risk relative to the general population. Rate ratios for all cancers (adjusted for calendar Copyright National Academy of Sciences. Observed and expected stillbirth rates by distance (in circles of 5, 10, 15, 20, and 25 km) and direction. No significant increase in stillbirths with distance within any of six directional sectors Parker and others (1999) Mortality 248,097 live and 3715 stillbirths to mothers resident in Cumbria, U. An earlier study of stillbirth rates around Sellafield (Dummer and others 1998) found no increase in stillbirths in the resident population within 25 km of the facility. The Nuclear Industry Family Study in the United Kingdom has also investigated possible links between occupational radiation exposures and reproductive health (Maconochie and others 1999). Information on reproductive health and health of children was obtained through a mailed questionnaire and linked with data from the employers on occupational exposure to ionizing radiation. The database consists of 53,672 pregnancies, 39,557 reported by men and 8,883 by women. Results of the analysis of fetal deaths and congenital malformations were reported by Doyle and colleagues (2000). The risk of neither fetal death nor major congenital malformation was related to paternal preconception radiation dose. In summary, there have been a number of studies of children of adults exposed to radiation. Ecologic studies are based on very small numbers, and none provide quantitative information from dose-response analyses or quantitative estimates of the risk of disease associated with exposure. There is little conclusive evidence from epidemiologic studies of a link between parental preconception exposure to radiation and childhood leukemia or other cancers. Few studies have been conducted to evaluate other possible indices of the occurrence of transmissible genetic damage from preconception radiation exposures, such as spontaneous abortions, congenital malformations, neonatal mortality, stillbirths, and the sex ratio of offspring. Some but not all studies have found a significant positive association between total cumulative dose, as well as dose during the 90 d prior to conception, and the risk of stillbirth. The risk of neither fetal death nor major congenital malformation has been related to paternal preconception radiation dose. It should be noted that these results were based on very few cases (four and three, respectively). None of the three studies provide quantitative estimates of risk based on doseresponse analyses, and the results across studies are not consistent. Thus, there is little evidence from epidemiologic studies of a link between parental preconception exposure to ionizing radiation and childhood leukemia or other cancers.
Results N-glycan analysis of IgG M-protein was differentially expressed across the patient groups from prehypertension to hypertension additional evidence order 50mg moduretic with amex. The formation of these larger sialylated glycans is likely the result of less steric hindrance allowing better access by glycosyltransferases during oligosaccharide biosynthesis blood pressure going up and down purchase moduretic 50 mg otc. Conclusions Glycan analysis of the enriched IgG M-protein from sera of patients across myeloma spectrum were successfully characterised showing differential glycosylation between patient groups with alteration in the levels of fucosylation and sialylation heart attack high bride in a brothel generic moduretic 50 mg with visa. Specific biantennary sialylated glycans displayed potential as markers for disease progression and therapeutic targets heart attack nausea order 50mg moduretic visa. We recently developed novel superparamagnetic iron oxide nanoparticles which selectively accumulate in extramedullary plasmacytoma and to kill their progenitors by heat generated with magnetic resonance (Theranostics arrhythmia research summit buy cheap moduretic 50 mg line, 2013) blood pressure 200110 cheap moduretic 50 mg visa. Therefore, superparamagnetic iron oxide nanoparticles potentially achieve what is called 'theranostics', a combination of tumor imaging and targeting treatment for extramedullary tumors. We are currently developing new versions of smart nanoparticles which generate heat in response to an alternating current magnetic field and that sequentially release an anticancer drug, such as doxorubicin (Theranostics, 2014). Keywords: epigenetic histone modifications Transcription factor Tracks: Multiple Myeloma Novel Drug Targets interactions, also contribute to drug-resistance and immune suppression. Similar expression profiles of methylatin and demethylation genes we obtained from samples of multiple myeloma patients. This is promising as it is comparable to the therapeutic plasma drug level clinically. We plan to eventually expand this study by using patient samples with the eventual aim for translation into clinical application. Results 1) Bioinformatic analysis of publicaly available gene expression profiling database show that Rpn10 expression inversely correlate with overall patient survival (n=175; p = 0. Rpn13 is associated with 19S regulatory lid of proteasome and play a key role in recognizing ubiquitylated proteins and directing their degradation via downstream 20S proteasome. The combination rapidly (<24h) decreased the expression of downstream -catenin targets c-myc, pan-myc, cyclinD1 and cyclinD2 as shown by immunoblotting. Similarly, glycolytic activity was also inhibited by the combination reducing both basal glycolysis and glycolytic capacity (from 48. Disease burden was reduced in the combination arm compared to single drug and vehicle arms as early as day 14 after inoculation (p=0. When investigating the role of adenosine in the immune 17th International Myeloma Workshop, September 12-15, 2019 213 Abstracts response patients, we found increased concentration of adenosine in bone marrow plasma from myeloma patients compared with healthy controls. This suggests that the adenosine pathway is involved in immune suppression in multiple myeloma and that this pathway is a potential novel therapeutic target. In the hematological cancer multiple myeloma, we sought to identify analogous synthetic lethality mechanisms that could be leveraged upon established cancer treatments. Cell proliferation, induction of apoptosis, tumor growth and animal survival were assessed. The combination was dramatically effective in targeting myeloma primary patient cells and cell lines reducing cell proliferation and inducing apoptosis. The combination therapy significantly reduced tumor burden and prolonged survival in animal models. In vivo experiments showed that the tumor burden of mice was significantly more severe compared with the mice of control group. A single centre experience of rapid daratumumab infusion (90 minutes) is reported (Barr, Leukemia 2018). In our practice, moving from the observation of a low rate of adverse reactions even in patients with advanced disease, since February 2019 we adopted an analogue infusion protocol. Herein we report the results of the singlecenter safety study of the rapid daratumumab infusion. The only inclusion criterion was the previous delivery of six doses of daratumumab, according to standard practice. Median number of daratumumab infusions prior starting protocol was 12 (range 6-24). These were mainly conjunctivitis, rhinorrhoea, cough, wheezing or hypertension treated with hydrocortisone 500 mg and promptly reverted. Twenty-two percent of patients suffered from cardiovascular disease (hypertension, arrhythmia or valvulopathy) and one patient presented cardiac amyloidosis at diagnosis. All patients maintained accelerated infusion regimen for subsequent administrations. Reconstitution of the immune system might play a crucial role in long-term disease control. In a prospective scientific program, prospective immune monitoring is performed in order to correlate response outcomes with distinct immune signatures. Analysis was performed at baseline (bs), during induction, prior consolidation and prior maintenance (pm). To address this, we evaluated the practice patterns among patients who developed focal progression while on dara-based regimens at our center. Methods We identified all pts who were treated with dara within the period November 1, 2015, to July 4, 2018. Pts had received a median 3 prior lines of therapy (range 111), the median time to initiation of dara from diagnosis was 66 months (1998 days;1085-2799). The median time to development of the first dara escape lesion was 6 months (196 days; 37-504). Development of focal 17th International Myeloma Workshop, September 12-15, 2019 221 Abstracts should be explored in the appropriate clinical scenario. Also, these pts may reflect an ideal population to investigate other synergistic immunomodulatory approaches. FcRn-mediated recycling of Dara and endogenous IgG was approximated using Michaelis-Menten kinetics; target-mediated elimination of Dara. In model simulations comparing the kinetics of Dara and endogenous IgG, the clearance of the drug was greater during the initial treatment cycles due to FcRn saturation; but approached normal rates as the endogenous IgG load fell towards normal levels and receptors become less saturated. These results suggest that competition for recycling receptors could impact circulating Dara concentrations; consequently, we compared the kinetics of Dara for high (approx. Pre- and post-infusion plasma Dara concentrations were lower for the highIgG loads during the initial treatment cycles, consistent with faster IgG clearance rates; subsequently these differences reduced as the endogenous IgG load approached normal levels and clearance rates normalised. Maximum trough Dara concentrations (maximal quantity of drug before an infusion) was observed immediately prior to the ninth Dara infusion in both models (1. We assessed whether the increased drug clearance caused by high IgG loads could be compensated with a more intensive dosing regimen consisting of eleven Dara infusions every five days. In simulations Dara kinetics show a similar profile for high- and low-IgG loads, despite the former having an increased drug clearance rate. Our model shows theoretical potential for personalised dosing to improve drug exposure. Chappell1 Institutions: 1 School of Engineering, University of Warwick, Coventry, Warwickshire, 2The Binding Site Group Ltd, Birmingham, West Midlands, 3The Binding Site Group Ltd, Birmingham, United Kingdom Abstract: Introduction. The pharmacokinetics of Dara demonstrate large differences in linear clearance between IgG patients and those with other M-protein isotypes. This could be explained by competition between Dara and endogenous IgG for binding neonatal Fc receptors (FcRn), effectively impacting IgG catabolic rates and half-life. The ability to determine a unique molecular mass for any myeloma paraprotein offers an innovative addition for the identification and quantification of monoclonal immunoglobulins. Alternative laboratory methods that overcome the limitations of traditional approaches are necessary. Mass spectrometry is a highly sensitive technique that has shown potential for the identification of individual M-Igs based on their unique mass-tocharge (m/z) protein characteristics. Eligible patients have received only 1 prior line of therapy which included 2 consecutive cycles of lenalidomide therapy. Patients must have an Eastern Cooperative Oncology Group performance status 2, left ventricular ejection fraction 40%, and no uncontrolled hypertension. Our studies showed that compared to Ig control-treated mice, anti-Grem1treated mice showed a 54. Dara was approved in relapse cases and It is becoming approved as first line treatment for eligible and not eligible patients. An exploratory endpoint is to analyze the immunologic profile changing during the treatment phases and the influence of Dara use in It. During maintenance phase Dara 16mg/Kg will be used monthly until progression or limiting toxicity. Resistance eventually occurs in the majority of patients, but the mechanisms of acquired resistance are not well delineated. It is necessary to evaluate the results of these treatments in daily clinical practice in order to elucidate the real impact of the incorporation of new treatments to the therapeutic arsenal already available and to know as 17th International Myeloma Workshop, September 12-15, 2019 228 Abstracts objectively as possible the benefit they bring to the patients. The results of effectiveness and tolerability of the patients included in the two groups will be described. Group A: starts treatment between 01/10/17 and 03/31/18 with a combination of 2 drugs. Group B: starts treatment between 04/01/18 and 09/30/18 with daratumumab in combination with lenalidomide or bortezomib and dexamethasone. Table 2 presents the data obtained from the first line of treatment of available patients (84). The final data cut for this intermediate analysis will take place on July 19, 2019. Updated data on effectiveness and tolerability will be presented during the Congress. Splitting of the first dose in two days has already reduced length of the first infusion (4 hours each). Nothing was reported however on prolonged safety overtime and most of all efficacy. The infusion rate was calculated to deliver 20% of the dose over 30 min (200 mL/hr), and then the rate was increased to deliver the remain-ing 80% over 60 min (450 mL/hr). Preexisting chronic obstructive pulmonary disease or asthma were absent in previous patient history. All 5 patients that had a reaction during first split dose did not have other reactions. A phase 2 trial has demonstrated the safety of reducing daratumumab infusion time from 4. We explored the utilization and cost impacts of a rapid infusion rate for daratumumab in a communitybased, quasi-academic setting. All costs estimated were for infusion initiation and continuation during a 12-month period. The model assumed once patients switched to rapid infusion rate on cycle 1, day 15 they remained on rapid infusion rates. Total costs estimated for the standard rate was $137,200 and $122,200 for the rapid rate (p-value: < 0. Drug and administration costs were similar between the standard and rapid cohorts ($112,300 vs. Costs associated with staffing and patient productivity were greatest in the standard cohort (staff: $21,600 vs. Authors: Issam Hamadeh1, Emily Reese1, Meghan Schneider1, Andre Williams1, Justin Arnall1, Ekaterina Kachur1, Allison Martin1, Manisha Bhutani1, Shebli Atrash1, 17th International Myeloma Workshop, September 12-15, 2019 231 Abstracts while drug costs are similar between rapid and standard cohorts, utilizing a rapid infusion rate could save patients lost productivity and allow infusion staff to increase efficiency. In conclusion, this novel assay helps in accurate assessment of tumor response to isatuximab treatment. Moreover, this methodology may be adapted to new therapeutic antibodies to characterize a potential interference and distinguish endogenous M-protein from these antibodies. This was managed by interruption/ dose reduction of B and a prolonged increased frequency of dexamethasone eye drops (median 4xday (range 1 hourly-3xday)) and artificial tears under ophthalmology guidance. All patients maintained their response despite treatment interruptions of up to 98 days. All patients were hypogammaglobulinaemic at baseline which worsened during treatment. Dose interruptions, reductions and escalation of topical therapies under ophthalmology supervision appeared effective in improving symptoms thereby allowing further dosing. Blurring of vision and thrombocytopenia were the most significant toxicities requiring dose reduction. Methods: this is a case series of 5 consecutively treated patients with B at the recommended dose of 3. Results: Patients had a median age of 57 years (5166), median time from diagnosis of 3. All patients with known cytogenetic results were adverse risk (n=4, 1 patient = del(17p)). Results: A total of 25 patients received the outlined regimen and were included in the analysis. Methods: An observational, single-center, non-randomized, retrospective chart review of patients receiving treatment with a modified DaraVd was conducted between December 1, 2015 to July 1, 2018. Results: We reviewed 44 patients who received Dara (21 male, 23 female) with a median of age of 70 years, for a two years and a half period. One patient underwent autologous followed by haploidentical stem cell transplantation after Dara. In 2 patients a positive direct antiglobulin test was detected after starting Dara treatment. However, its utility in routine laboratory practice for plasma cell gating is still not established. It can be effectively used as a gating marker in addition to traditional markers for plasma cell quantitation, especially after daratumumab-therapy.
Some new alleles are the result of point mutations heart attack arena purchase 50 mg moduretic with amex, but many arise from the combination of sequences from different alleles either by genetic recombination or by gene conversion blood pressure is lowest in generic moduretic 50 mg, a process in which one sequence is replaced heart attack early symptoms buy moduretic 50mg online, in part pulse pressure 83 buy moduretic 50 mg overnight delivery, by another from a different gene hypertension 4 mg generic 50 mg moduretic with visa. Point mutations can be classified as replacement substitutions pulse pressure of 78 discount 50 mg moduretic free shipping, which change an amino acid, or silent substitutions, which simply change the codon but leave the amino acid the same. Sequences can be transferred from one gene to a similar but different gene by a process known as gene conversion. This can occur as a consequence of the misalignment of the two paired homologous chromosomes when there are many copies of similar genes arrayed in tandem somewhat like buttoning in the wrong buttonhole. In this way several nucleotide changes can be inserted all at once into a gene and can cause several simultaneous amino acid changes between the new gene sequence and the original gene. These are derived either from internalized mycobacteria or from the uptake of lipoarabinomannans by the mannose receptor that is expressed by many phagocytic cells (see Section 2-15). A mutant cell in which association of class I heavy and light chains is induced by viral peptides Cold Spring Harbor Symp. Proteolysis and class I major histocompatibility complex antigen presentation Immunol. Tapasin is required for efficient peptide binding to transporter associated with antigen processing J. Involvement of immune response (Ir) gene control of lymphocyte interaction controlled by the gene. Restriction of in vivoT-cell mediated cytotoxicity in lymphocytic choriomeningitis within a syngeneic or semiallogeneic system Nature 1974. Elimination of T-cell-receptor betachain diversity in transgenic mice restricts antigen-specific but not alloreactive responses Immunology 1997. Interplays between mouse mammary tumor virus and the cellular and humoral immune response Immunol. Crystal structure of a T cell receptor chain complexed with a superantigen Nature 1996. Superantigens: mechanisms by which they may induce, exacerbate and control autoimmune diseases Int. Threedimensional structure of the complex between a T cell receptor beta chain and the superantigen staphylococcal enterotoxin B Immunity 1998. Mate selection and the evolution of highly polymorphic self/nonself recognition genes Science 2000. Molecular analysis of the association of B53 and resistance to severe malaria Nature 1992. Conserved lipid and peptide presentation functions of nonclassical class I molecules Immunol. Signaling Through Immune System Receptors Introduction to Chapter 6 General principles of transmembrane signaling Antigen receptor structure and signaling pathways Other signaling pathways that contribute to lymphocyte behavior Summary to Chapter 6 References to Chapter 6 Introduction to Chapter 6 Cells communicate with their environment through a variety of cell-surface receptors that recognize and bind molecules present in the extracellular environment. The main function of T and B lymphocytes is to respond to antigen and so, in their case, the receptors for antigen are the most important and the best-studied. Because of the diversity of antigen receptors in the normal lymphocyte population, most of our information on intracellular signaling in lymphocytes comes from tumor-derived lymphoid cell lines that are activated when their antigen receptors are stimulated by anti-receptor antibodies. However, more information is increasingly being derived from studies on normal cells from transgenic animals that express a single type of antigen receptor on their B or T cells. We will use this information to infer the signaling pathways generated when a mature naive lymphocyte binds its specific antigen and is activated to undergo clonal expansion followed by differentiation to a functional effector cell. We will, however, also consider how signaling via the antigen receptor and other lymphocyte receptors can lead to other responses such as inactivation or cell death, depending on the stage of development of the cell and the nature of the ligand. The antigen receptors of B and T lymphocytes are present at the cell surface as multiprotein complexes. These are composed of clonally variable antigen-binding chains associated with invariant accessory chains that have signaling function. The B- and T-cell antigen receptors are formed from different proteins and have different recognition properties, which have been described in Chapters 3 and 4. After these receptors bind their ligand, however, the intracellular signaling pathways leading from the receptor are remarkably similar in B and T cells. We will start this chapter by discussing some general principles of cell signaling and will introduce some of the common mechanisms used in intracellular signaling pathways, with particular reference to the antigen receptor signaling pathways. In the second part of the chapter we will outline the signaling pathways from the antigen receptors to the nucleus, and consider how these can be supplemented or inhibited by signals simultaneously received from other receptors. Other signals act through different receptors at different times to influence the development, survival, and responses of lymphocytes and other immune system cells, and these will be considered in the third and final part of the chapter. The challenge that faces all cells that respond to external stimuli is how the recognition of a stimulus, usually by receptors on the outer surface of the cell, is able to effect changes within the cell. Extracellular signals are transmitted across the plasma membrane by receptor proteins, which are instrumental in converting extracellular ligand binding into an intracellular biochemical event. Conversion of a signal from one form into another is known as signal transduction, and in this part of the chapter we consider several different mechanisms of signal transduction in cell signaling. Cell-surface receptors activate intracellular signaling pathways and so convert an extracellular signal into an intracellular one that then transmits the signal onward. The signal is converted into different biochemical forms, distributed to different sites in the cell, and sustained and amplified as it proceeds toward its various destinations. One result of intracellular signaling may be changes in the cytoskeleton and secretory apparatus. This is seen in the activation of effector T cells, which direct the release of secretory vesicles to the site where the antigen receptor is bound to antigen on the target cell. The final destination of intracellular signaling is usually the nucleus, where the activation of trans- cription factors turns on new gene expression and cell division may be induced. All cell-surface receptors that have a signaling function are either transmembrane proteins themselves, or form parts of protein complexes that link the exterior and interior of the cell. In some types of receptor, this conformational change opens an ion channel into the cell and the resulting change in the concentration of important ions within the cell acts as the intracellular signal, which is then converted into an intracellular response. In other receptors, the conformational change affects the cytoplasmic portion of the receptor, enabling it to associate with and activate intracellular signaling proteins and enzymes. The antigen receptors on lymphocytes transmit a signal when they bind a ligand that causes them to cluster together on the cell surface. The requirement for receptor clustering was first shown experimentally in somewhat artificial systems by using antibodies against the extracellular portion of the receptor to mimic antigen binding. Antibodies specific for the B-cell receptor or the T-cell receptor activate signaling by inducing clustering of the receptor complexes. This is a very convenient system for the analysis of early events after activation, as all the cells in a sample will be stimulated at the same time, making the course of the response easier to follow. Antigen receptor clustering occurs when the receptors are cross-linked to each other. The importance of cross-linking was shown by comparing the response to stimulation with antibody F(ab)2 fragments, which have two binding sites, and with Fab fragments, which have only one. On lymphocytes treated with Fab fragments the antigen receptors do not cluster and the cells make no response, whereas on lymphocytes treated with F(ab)2 fragments the receptors become dimerized and the cells respond, although they may respond only weakly. The response is strongest when the F(ab)2 cross-linked dimers are further clustered using anti-immunoglobulin sera directed against the F(ab)2 fragments. The extensive cross-linking of the antigen receptors that then occurs delivers a very strong signal to the cell. The Y-shaped immunoglobulin molecule can be dissected by partial digestion with proteases. Pepsin cleaves immunoglobulin to yield one F(ab)2 fragment and many small pieces of the Fc fragment, the largest of which is called the pFc fragment (lower panels). F(ab)2 is written with a prime because it contains a few more amino acids than Fab, including the cysteines that form the disulfide bonds. As shown in the left panel, Fab fragments of an anti-immunoglobulin can bind to the receptors but cannot cross-link them; they also fail to activate B cells. F(ab)2 fragments of the same anti-immuno-globulin, which have two binding sites, can bridge two receptors (center panel), and thus signal, albeit weakly, to the B cell. The most effective activation occurs when receptors are extensively cross-linked by first adding the F(ab)2 frag-ments and then rabbit antibody molecules that bind and cross-link the bound F(ab)2 fragments (right panel). The use of antibodies generally to stimulate receptors is described in Appendix I, Section A-19. How antigen receptors are clustered in vivo when B and T cells encounter their specific antigens is not yet completely understood. As we will see in Chapter 8, the T-cell receptors become involved in an organized cluster with other cell-surface signaling molecules, but the details of this clustering remain poorly understood. B-cell receptors can be cross-linked by pathogens such as intact bacteria and viruses that have repetitive epitopes on their surfaces. Complex molecules that contain regularly repeated identical epitopes will have the same effect. However, it is still uncertain how B-cell receptors can be clustered by soluble monomeric antigens, such as most of the experimental antigens that immunologists use to study immune responses. An inability, or limited ability, of soluble monomeric antigens to induce receptor clustering may explain why the activation of naive B cells in response to these antigens depends on receiving activating signals from antigen-specific T cells. As we will see in Chapter 9, the binding of soluble monomeric antigen by the B-cell receptor triggers receptor-mediated endocytosis, but is not sufficient by itself to stimulate cell division and differentiation. Understanding how the binding of antigen leads to receptor clustering and signaling in lymphocytes is complicated by the diversity of antigen receptors and their ligands. In addition, as we will see in Section 6-8, co-receptors for antigen-linked molecules may also cluster with the receptor and contribute to the initiation of intracellular signaling. How ligand binding leads to receptor clustering and generates a signal is more clearly understood for some other simpler receptors, as we will see in the next section. Clustering of antigen receptors leads to activation of intracellular signal molecules. Most of the receptors discussed in this chapter initiate intracellular signaling by the activation of protein tyrosine kinases, enzymes that affect the activity of other proteins by adding a phosphate group to certain tyrosine residues. The receptors for some growth factors provide the simplest example of this type of receptor. These enzyme domains are normally inactive, but when brought together by receptor clustering they are able to activate each other by transphosphorylation. Once activated, these tyrosine kinases can phosphorylate and activate other cytoplasmic signaling molecules. Ligand binding to the growth factor receptor Kit induces receptor dimerization and transphosphorylation of its cytoplasmic tyrosine kinase domains. Transactivation of protein kinases by transphosphorylation is an important step in signaling from many cell-surface kinases. As we will see later, they do not themselves have intrinsic tyrosine kinase activity. Instead, the cytoplasmic portions of some of the receptor components bind to intracellular protein tyrosine kinases, which are therefore known as receptor-associated tyrosine kinases. When the receptors cluster, these enzymes are brought together and act on each other and on the receptor cytoplasmic tails to initiate the signaling process as in the example above. The Src-family kinases are common components of signaling pathways concerned with the control of cell division and differentiation in vertebrates and other animals. The prototypic family member Src was initially discovered as the oncogene v-src which is responsible for the ability of the Rous sarcoma virus to produce tumors in chickens. This viral gene was subsequently shown to be a modified form of a normal cellular gene called c-src that the virus had picked up from its host cell at some time in the past. Several other common components of signaling pathways that regulate cell growth and division were also first discovered through their oncogenic action when mutated or removed from their normal controls. The receptor-associated Src-family kinases play a key role in transducing signals across the lymphocyte membrane; their activation informs the cell interior that the receptor has encountered its antigen. When a cell is signaled by the binding of ligand to a kinase-coupled receptor, kinase activation initiates a cascade of intracellular signaling that transfers the signal to other molecules and eventually carries it to the nucleus. Phosphorylation of receptor cytoplasmic tails by tyrosine kinases concentrates intracellular signaling molecules around the receptors. Phosphorylation of enzymes and other proteins by protein kinases is a common general mechanism by which cells regulate their biochemical activity, and has many advantages as a control mechanism. It is rapid, not requiring new protein synthesis or protein degradation to change the biochemical activity of a cell. It can also be easily reversed by the action of protein phosphatases, which remove the phosphate group. Many enzymes become active when phosphorylated and inactive when dephosphorylated, or vice versa; the activity of many of the protein kinases involved in signaling is regulated in this way. Another and equally important outcome of protein phosphorylation is the creation of a binding site for other proteins. In this case, phosphorylation is used as a tag, allowing the recruitment of other proteins that bind to the phosphorylated site. For example, many kinases involved in signaling are associated with the inner surface of the cell membrane and can act only in-efficiently upon their target proteins when these are free in the cytosol. Receptor activation and the phosphorylation of membrane-associated proteins can, however, create binding sites for these target proteins. Cytosolic proteins that bind to phosphorylated sites at the membrane are thus concentrated near to the kinase and can in their turn be phosphorylated and activated. This is an example of allosteric activation, as binding the phosphotyrosine leads to an alteration in their molecular conformation. Receptor-associated protein kinases are localized at the inner surface of the cell membrane and cannot activate their cytosolic targets efficiently unless these are brought to the membrane. However, another membrane-associated protein functions as an adaptor, being phosphorylated by the active kinase to create a binding site for the cytosolic target, bringing the target molecules to the membrane. These proteins can then be phosphorylated, and thus activated, by the membraneassociated kinase. Proteins can be phosphorylated on three classes of amino acid on tyrosine, on serine or threonine, or on histidine.
Syndromes
Individual organ doses were estimated based on detailed radiotherapy records and simulation of pelvic irradiation treatments on phantoms blood pressure medication guide moduretic 50 mg discount. In addition blood pressure position purchase 50 mg moduretic visa, significant increases were observed for deaths from colon and uterine cancer heart attack from stress moduretic 50 mg without prescription, cancers of the female genital organs pulse pressure pda buy 50mg moduretic with amex, and leukemia blood pressure medication edema moduretic 50 mg fast delivery. Inskip and colleagues (1990a) studied the risk of leukemia in relation to radiation dose among 4483 of these women arrhythmia originating in the upper chambers of the heart order 50 mg moduretic. Individual doses to various sections of the red bone marrow were calculated from detailed radiotherapy records. An elevated risk of circulatory disease mortality was observed among those who received ra- Copyright National Academy of Sciences. The risk of leukemia, lymphoma, and multiple myeloma was studied in an expanded cohort of 12,955 women treated for benign gynecological disorders at one of 17 hospitals in Massachusetts, Connecticut, Rhode Island, or New York State between 1925 and 1965 (Inskip and others 1993). Of these women, 9770 were treated with radiation (either intracavitary 226Ra or external beam X-rays), while the rest were treated by other methods. The risk of lymphomas, multiple myeloma, and nonacute lymphocytic leukemia was similar between irradiated and nonirradiated women. A cohort of 2067 women who received radiotherapy for metropathia hemorrhagica (uterine bleeding disorders) in Scotland between 1940 and 1960 was followed until the end of 1990 (Darby and others 1994). Absorbed doses to the active bone marrow and to 20 solid organs or anatomical sites were estimated from treatment records. A deficit of breast cancer mortality was also observed in this cohort, due mainly to a large deficit in women who had received doses to the ovary of 5 Gy or more. A Swedish cohort study included 2007 women treated for metropathia hemorrhagica between 1912 and 1977. The population was followed up for cancer mortality and incidence from 1958 to 1982, with a mean follow-up period of 28 years (Ryberg and others 1990). A decreased risk for breast cancer was also observed in this cohort, except for women treated at the age of 50 or more. No increase in mortality rates was found for leukemia or sites directly exposed to radiation, such as the ovary or brain, based on a very small number of deaths (two leukemia, three ovary, and one brain cancer death). Radiation doses to various organs were calculated for a sample of patients, and average estimated doses from all treatment courses occurring within 5 years of the initial treatment courses were attributed to all patients. There was no increased risk in breast cancer in Copyright National Academy of Sciences. No excess of leukemia or thyroid cancer was observed among patients treated with 131I. In a follow-up to this study, Hoffman (1984) studied cancer risk up to 1979 in the subgroup of 3696 women who had been treated at the Mayo Clinic, one of the original participating centers. Among these, 1005 had received 131I therapy alone and 2141 had been treated with surgery alone. A total of 527 cancer cases were identified in these two study groups; 175 were excluded because they occurred within a year of treatment. There was no increased cancer risk among those treated with 131I and no indication of a relation with 131I activity delivered. Nonsignificant increased risks were seen for cancers in the two most exposed organs (thyroid and salivary glands, based on three and two cases, respectively). Goldman and colleagues (1988) reported on an extended follow-up of 1762 women, included in the Cooperative Thyrotoxicosis Therapy Follow-up Study, who were treated at the Massachusetts General Hospital between 1946 and 1964. Ron and colleagues (1998a) reported on mortality to the end of 1990 in the Cooperative Thyrotoxicosis Therapy Follow-up Study. The mean length of follow-up was 21 years, and 51% of the subjects had died during the study period. A nonsignificant increase in mortality from thyroid cancer was seen with increasing 131I administered activity-when deaths occurring in the first 5 years after treatment were excluded, there was no evidence of a relationship with total activity; it is therefore likely that the underlying thyroid disease played a role in the observed cancer increase. Cancer incidence was also studied in 4557 patients who received 131I therapy for hyperthyroidism in Sweden between 1950 and 1975 at Radiumhemmet, Sweden (Holm 1984). The risk of leukemia mortality in this cohort was studied further by Weiss and colleagues (1995), using a casesubcohort approach. A Swedish cohort of 20,024 patients who received X-ray therapy between 1950 and 1964 for painful benign conditions of the locomotor system (including arthrosis and spondylosis) was followed for cancer incidence and mortality until the end of 1988 (Damber and others 1995). Average conversion factors between surface dose and mean absorbed dose in the red bone marrow were estimated by treatment site (for six sites), based on the treatment records of random samples of 30 subjects drawn from the cohort (Damber and others 1995). The conversion factors were applied to the entire cohort and used for stratification of subjects in different levels of exposure. Thyroid Diseases Iodine-131 is currently the treatment of choice for hyperthyroidism, largely because no serious side effects are known. Several studies of patients treated with 131I for hyperthyroidism have been carried out in the United States, Sweden, and the United Kingdom. The occurrence of leukemia and of thyroid neoplasms (both benign and malignant) was studied among 36,050 patients treated for hyperthyroidism between 1946 and 1968 and included in the Cooperative Thyrotoxicosis Therapy Follow-up Study (Saenger and others 1968; Dobyns and others 1974). Approximately 20,000 subjects had been treated Copyright National Academy of Sciences. Cancer diagnoses in these patients were identified from the Swedish Cancer Registry for 1958 to 1976. There was no increased risk of cancer as a whole or of leukemia in this population. The risk of cancer was studied in 10,552 patients (including the 4557 in the previous study) treated for hyperthyroidism with 131I in seven hospitals in Sweden between 1950 and 1975 (Holm and others 1991). The mean follow-up time of subjects who survived more than a year after treatment was 15 years, with a maximum of 28 years. Significant increases were seen for cancers of the lung and kidney and, among 10-year survivors, for cancers of the stomach, kidney, and brain. A population-based study of cancer incidence in a cohort of 7417 patients treated with 131I in the West Midlands region of the United Kingdom between 1950 and 1991 was carried out (Franklyn and others 1999). The subjects were followed up for cancer incidence and mortality from 1971 to 1991. Studies of patients treated for ankylosing spondylitis, benign breast disease, benign gynecological disease, and peptic ulcer have provided valuable information for the quantification of radiation risk estimates for cancers of the lung, breast, and stomach and for leukemia. These estimates are reviewed in detail, and compared with risk estimates derived from other medical exposure studies, in section "Evaluation of Risk for Specific Cancer Sites. Radiotherapy for Benign Disease Among Children Tinea Capitis Between 1948 and 1960 nearly 20,000 children, primarily immigrants to Israel or children of immigrants from North Africa and the Middle East, were treated with radiation for tinea capitis (ringworm of the scalp) in Israel (Ron and others 1988b). This treatment modality was used in other countries as well, and a study also was carried out in New York (Shore and others 1984). In Israel, mortality in a cohort of 10,834 irradiated children, 10,834 matched comparison subjects, and 5392 sibling controls was studied by Ron and colleagues (1989). Crude dose estimates were derived from treatment information (dosage, area), age of the child, and the use of filtration. Radiotherapy in childhood was associated with an increased risk of mortality from tumors of the head and neck (particularly brain and thyroid tumors) and leukemia. The dose reconstruction method used was improved compared to the above paper, relying heavily on dosimetric studies and measurements in a simulated phantom model of a 6-year-old child. Doses used in the treatment of benign conditions were generally not as high as those used to treat malignant disease, so that cell-killing effects do not predominate, survival after treat- Copyright National Academy of Sciences. Delivered doses ranged from 3 to 6 Gy depending on the portion of the scalp, with lower doses to the skin of the face and neck (0. In the irradiated group, 41 subjects had a diagnosis of basal carcinoma of the scalp or face, compared to 3 in the control group. The minimum latent period was long (about 20 years); skin cancers were more pronounced on the face, where the potential for exposure to ultraviolet is higher, and were restricted to Caucasians although one-quarter of the study population was African American. A more recent study (Sadetski and others 2005) conducted a survival analysis using Poisson regression to estimate the excess relative and absolute risks for brain tumors. Modan and colleagues (1989) reported on an additional 5-year follow-up (until 1986) of the Israeli tinea capitis cohort. Ron and colleagues (1989) reported on the risk of thyroid cancer following irradiation in childhood for tinea capitis, based on an extended follow-up (until 1986). To adjust the dose for possible head movement during treatment, individual dose estimates were multiplied by a factor of 1. Overall, 98 thyroid tumors were identified among the exposed and 57 among the two control populations. A clear dose-response association with both cancer and benign tumors was demonstrated. In New York, about 2200 children who received X-ray treatment for tinea capitis during the 1940s and 1950s and a comparable group of 1400 treated without X-rays were fol- Enlarged Thymus Gland Patients in Rochester, New York who received X-ray treatment between 1926 and 1957 in infancy (before 6 months of age) for an enlarged thymus gland and their nonirradiated siblings have been followed up periodically through the use of a mail questionnaire (Shore and others 1985, 1993a, 1993b; Hildreth and others 1985). Information on X-ray treatment factors was extracted from medical records and supplemented by interviews with the treating physicians. These, along with anatomic measurements for infants, allowed estimation of doses to various nearby organs. The thyroid doses were estimated by irradiating a radiological phantom of an infant. The irradiated group had a statistically significant increase of both benign and malignant thyroid tumors (Shore and others 1985) and extrathyroid tumors (Hildreth and others 1985), particularly benign tumors of the bone, nervous system, salivary glands, skin, and breast (women only) and malignant tumors of the skin and breast. In the most recent paper on thyroid cancer, which reports on follow-up to 1986, the cohort included 2657 exposed subjects and 4833 unexposed siblings with at least 5 years of follow-up (Shore and others 1993a). There were 37 pathologically confirmed thyroid cancers among the irradiated group and 5 among the sibling controls. The risk ratio decreased over time, but was still highly elevated 45 years after exposure. Analyses of interactions suggested that all Jewish subjects and women with older ages at menarche Copyright National Academy of Sciences. The risk of benign thyroid adenomas was also studied in more detail (Shore and others 1993b). There were 86 pathologically confirmed thyroid adenomas among the irradiated group and 11 in the sibling controls. Adenoma rates were elevated even at lower doses, with a significant increase in the lowest-dose group (<0. Analyses of the risk of breast cancer in relation to radiation dose were also carried out in this population. Hildreth and colleagues (1989) reported on the follow-up to 1985 of 1200 women who received X-ray treatment and their 2469 nonirradiated sisters. Twenty-two breast cancer cases were diagnosed in the irradiated group and twelve in the control group. Radiotherapy was given with -particles, X- and/or -rays, and usually, with some type of 226Ra applicator. Individual organ doses were calculated using treatment information and, for 226Ra needles and tubes, phantom simulations. Seventeen thyroid cancers were registered in this cohort during the follow-up period. A significant excess thyroid cancer incidence was seen in this cohort, starting 19 years after treatment and persisting at least 40 years after irradiation. Lundell and Holm (1995) also studied the risk of other solid tumors in this cohort. Lundell and colleagues (1996) reported more specifically on the risk of breast cancer among women from this cohort. In an analysis of leukemia mortality in the same cohort, 20 deaths from leukemia were observed (11 in childhood and 9 among adults). There was no association between radiation dose and leukemia (childhood or adult) in this cohort. No correction was made for different body sizes according to the age of the child at the time of treatment. Karlsson and others (1997) studied the risk of intracranial tumors in this cohort further in a cohort and a case-control study. In the case-control study, the dose at the exact tumor site was calculated by considering the exact distance between the treatment location, according to the record, and the site of the tumor. For the controls, the dose was calculated at the location of the tumor in the corresponding case. An excess was found for many histopathological subgroups but was significant only for gliomas and meningiomas. There was an excess of brain tumors in all dose categories, but no clear doseresponse relationship. When analyses were restricted to subjects treated before the age of 7 months, both a linear and a Copyright National Academy of Sciences. The cohort included 4296 patients, of whom 3843 had estimated dose to the thyroid and 2634 could be followed up.
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