Alternative splicing could be responsible for generating up to three times as many proteins as the ~19 150 mg wellbutrin sr mastercard depression symptoms postpartum,000 genes encoded by the human genome. Gene Expression Analysis on Biopsy Samples Patient outcomes are frequently known for people whose biopsy samples have been archived and gene expression analysis of these samples could provide a wealth of additional information. Analyzing these samples could help scientists determine why patients did or did not respond to the treatments they were given and provide greater understanding of which genes are involved in disease mechanisms. Fortunately, hospitals have collected millions of clinical tissue samples over the past few decades because they are required to store tumor samples from surgical proce- dures in case need arises for further testing. However, the standard procedure for preserving these samples involves immersing the tissue in formalin and embedding it in parafﬁn wax. These proﬁles may be used for diagnostic, prognos- tic and therapeutic evaluations and also provide a method for the evaluation of the safety and efﬁcacy of various therapeutics. Gene expression ﬁngerprints are useful tools for monitoring exercise and training loads and thereby help to avoid training- associated health risks. Although some pathological states such as hypoxia may have direct impact on white blood cells that is manifested by speciﬁc expression proﬁles, seemingly unrelated events affecting various organs can markedly alter white blood cell gene expression in a predictable, characteristic way that provides a novel approach to diagnosis of diseases such as those involving the nervous system. One short oligonucleotide sequence from a deﬁned location within a transcript (“tag”) allows accurate quantitation 2. Tag size (10–14 bp) is optimal for high throughput while maintaining accurate gene identiﬁcation and quantitation. The combined power of serial and parallel processing increases data throughput by orders of magnitude when compared to conventional expressed sequence analysis. Important uses of this test include the study of differences in gene expression between cancer cells and their normal counterparts and identiﬁcation of genes that may serve as useful diagnostic and prognostic markers. Analysis of gene expression dif- ferences in treatment responders versus non-responders could delineate differences between various patient populations and provide insight into the mechanism of action of different treatments. Gene expression patterns can also be useful in identi- fying new targets for therapeutic agents. Monitoring In Vivo Gene Expression by Molecular Imaging Molecular imaging is an emerging ﬁeld of study that deals with imaging of disease on a cellular and molecular level. In contradis- tinction to “classical” diagnostic imaging, it sets forth to probe the molecular abnor- malities that are the basis of disease rather than to image the end effects of these molecular alterations. Several current in vitro assays for protein and gene expression have been trans- lated into the radiologic sciences. The merging ﬁelds of molecular biology, molecular medicine, and imaging modalities may provide the means to screen active drugs in vivo, image molecular processes, and diagnose disease at a presymptomatic stage. The positrons that are emitted from the isotopes then interact locally with negatively charged electrons and emit what is called annihilat- ing radiation. It is the Universal Free E-Book Store 82 2 Molecular Diagnostics in Personalized Medicine timing and position of the detection that indicates the position of the molecule in time and space. Images can then be constructed tomographically, and regional time activities can be derived. The kinetic data produced provide information about the biological activity of the molecule. Molecular imaging provides in vivo information in contrast to the in vitro diagnostics. Moreover, it provides a direct method for the study of the effect of a drug in the human body. Molecular imaging plays a key role in the discovery and treatment process for neurological diseases such as Alzheimer’s and cancer. Combination of Diagnostics and Therapeutics The term “theranostic” is used to denote linking of a diagnostic to therapeutic. The second half of the word “nostic” is supposed to represent diagnostic but sounds more like “gnostic”, a word introduced into English from Latin and meaning “having knowledge of”. If one has to use a single word to describe a test linked to therapy, one can use “pharmacodiagnostic”, which is more appropriate and easier to understand. Use of Molecular Diagnostics for Stratiﬁcation in Clinical Trials One of the problems in clinical trials is that response to a drug may vary consider- ably among patients.
Further tests trusted 150 mg wellbutrin sr anxiety 100 symptoms, including the peripheral smear for malaria or babesiosis, should be guided by the patient’s history. Furthermore, Howell–Jolly bodies or other evidence of hyposplenism should be sought, especially in an individual with a history of an illness predisposing to hyposplenism. However, the literature does support that an aggressive approach improves survival (48). Despite the absence of any controlled studies, self- administration of an antibiotic at first sign of suspicious illness in the asplenic or hyposplenic person is advised, this should be specially instituted if delivery of medical care is not immediately available. In an outpatient setting, a patient suspected to have postsplenectomy sepsis should receive an appropriate broad-spectrum antimicrobial such as ceftriaxone parenterally prior to hospital transfer, whether or not blood cultures are obtained. Local resistance patterns should be taken into account when selecting an initial presumptive regimen, with consideration of antibiotic, such as ceftriaxone and cefotaxime, which are active against penicillin-resistant pneumococci, as well as beta-lactamase producers such as H. Some penicillin-resistant pneumococcal isolates are also resistant or only intermediately susceptible to cephalosporins. If such resistance is suspected, the use of vancomycin combined with gram-negative antibiotic coverage for organisms such as meningococcus must be considered. High-level penicillin-resistant pneumococci will definitely require vancomycin with or without rifampin. Other choices include an anti-pneumococcal quinolone, such as levofloxacin, amoxicillin/clavulanic acid, trimethoprim/sulfamethoxazole, or a newer macrolide (clarithromycin, azithromycin). The decision to broaden the gram- negative coverage to other gram negatives including P. In patients with known or suspected central nervous system infections, vancomycin with or without rifampin plus a third-generation cephalosporin is the most optimal initial therapy. Intravenous immunoglobulin is another intervention that has been shown to decrease mortality in asplenic animals (49,50). Granulocyte-macrophage colony– stimulating factor has increased macrophage bactericidal activity in eusplenic and asplenic mice. Babesiosis in the asplenic host is best treated with a combination of clindamycin and quinine. Exchange transfusions to lower high levels of parasitemia also have been used (52,53). Other therapeutic modalities, such as vasopressors, may be warranted in selected cases. Prevention Preventive strategies fall into three major categories: education, immunoprophylaxis, and chemoprophylaxis (33,54). Most patients with asplenia (11% to 50%) remain unaware of their increased risk of serious infection or the appropriate health precautions that should be undertaken (55,56). Asplenic patients should be encouraged to wear a Medi-Alert bracelet or necklace and carry a wallet explaining their lack of spleen and other medical details (33). Patients should be explained regarding the potential seriousness of postsplenectomy sepsis and rapid time course of progression. Patients should be instructed to notify their physician in the event of any acute febrile illness and proceed to nearest emergency department. They should inform any new health care provider, including their dentist, of their asplenic or hyposplenic status. Patients should also be educated regarding travel-related infections such as malaria and babesiosis. Malaria chemoprophylaxis relevant to the local pattern of infestation should be prescribed and preventive measures implemented to reduce mosquito bites (33,54). They should also be educated regarding prompt treatment of even minor dog or other animal bites. Asplenia or hyposplenism itself is not a contradiction for routine immunization including live vaccines. Vaccination significantly reduces the risk of bacteremia of any cause beyond the postoperative period, and vaccinated patients carry a lower risk of infection than non-vaccinated ones (57). Pneumococcal Vaccine Efficacy of pneumococcal polysaccharide vaccine in preventing postsplenectomy infections has not been determined. Most virulent pneumococcal serotypes tend to be the least immunogenic, and the efficacy of vaccine is poorest in younger patients who would be at the highest risk (58,59). Studies indicate that 30% to 60% postsplenectomy patients never receive the pneumococcal vaccine (55,56). Pneumococcal vaccination should be performed at least two weeks before an elective splenectomy (60).
The clinical development of contrast agents is typically faster than for thera- peutics buy wellbutrin sr 150 mg line depression relief, and clinical trials of this approach could be feasible within 12–18 months. The potential of the approach is enhanced by the fact that the targeted microbubbles are “read” using ultrasound technology, which is widely available in most physi- cians’ ofﬁces and is minimally invasive, safe and cost-effective. The personalized medicine made feasible by this approach has the potential to increase the efﬁcacy of cancer regimens, reduce side effects from ineffective treatments and improve the overall cost effectiveness of cancer therapy. Administered as prodrugs, dFdC and ara-C are transported across cell membranes and are converted to cytotoxic derivatives through consecutive phosphorylation Universal Free E-Book Store Determination of Response to Therapy 231 steps catalyzed by endogenous nucleoside kinases. As of September 2008, Cernostics Pathology was creating a complete digital imaging pathology platform by integrating the best available components, while building advanced informatics tools to manage, mine and classify patient tissue samples. The ﬁrst diagnostic/thera- peutic test being developed by Cernostics is a breast cancer test as part of collabora- tion with the Mayo Clinic. Universal Free E-Book Store 232 10 Personalized Therapy of Cancer Molecular Diagnostics Combined with Cancer Therapeutics Basics of combination of diagnostics with therapeutics are discussed in Chap. Cancer is a good example of such a combination, which would be useful for person- alized management of cancer. Approximately 800 oncology drugs, many of which target speciﬁc mutations, are currently in development, resulting in a growing need for new companion diagnostics. Examples of technologies that can be used to com- bine diagnosis and therapeutics for cancer are listed below and will be discussed further under personalized management of various cancers. Aptamers are beginning to emerge as a class of molecules that rival antibodies in both therapeutic and diagnostic applications. Aptamers are different from antibodies, yet they mimic properties of antibodies in a variety of diagnostic formats. High afﬁnity aptamers are being developed as targeted therapeutics for the diag- nosis, imaging, staging and treatment of cancer. This method offers, apart from an immediate application in the diagnosis, imaging and treatment of breast and other epithelial cancers, a generic application for the treatment of neoplastic disorders and a potential for future development. Combinatorial libraries have been used for the selection of aptamers that bind to well-characterized and established cancer bio- markers selectively and with high afﬁnity. As part of their design, the aptamers are conjugated to ligands, molecules bearing binding sites for metal ions, to impart the therapeutic and diagnostic properties. In particular, stable chelation of technetium, rhenium and yttrium radioisotopes result in novel radiopharmaceutical agents for imaging and selective cell kill as part of cancer diagnosis, imaging and therapy. The use of europium or terbium confers ﬂuorescent properties to the aptamer complex, for use in diagnostic assays. These molecules offer signiﬁcant advantages over existing antibody and peptide based recognition procedures in that they possess higher binding afﬁnities to the Universal Free E-Book Store Molecular Diagnostics Combined with Cancer Therapeutics 233 target leading to longer retention times and the ability to deliver a higher payload of the metal ion precisely to the target with a lower overall dose of the agent. The size of these molecules leads to reduced immunogenicity and increased tumor penetra- tion, further enhancing their efﬁcacy while minimizing potential side effects. Combining Diagnosis and Therapy of Metastatic Cancer Biomarkers of metastases of various cancers have been investigated. Mena protein potentiates and modulates cellular migration and is found in the developing embryo where it plays an important role in the developing nervous sys- tem among other functions. It facilitates and organizes formation, extension and navigation of growing nerve ﬁbers through tissue to link with other neurons, form- ing the proper circuits needed for a functional nervous system. However, in meta- static cancer cells, high levels of the Mena protein accumulate and inﬂuence a number of intracellular signaling programs. Mena facilitates a process whereby tumor cells send out a well-organized protuberance that invades surrounding tissue and pulls the remainder of the cell behind it. Mena modulates the strength and direc- tion of this invasive process and steers the migrating cancer cell in the direction of blood vessels through its ability to modulate the metastatic cell’s response to chemi- cal signals that attract it to blood vessels. Mena is present in cancer cells in several isoforms that are similar but slightly different in structure. Despite similarity in structure, protein isoforms differ considerably in their inﬂuence on cells.
T h e detection sensitivity is drastically increased by the use of the 3 - D mode discount wellbutrin sr 150 mg overnight delivery mood disorder icd 10. For example, the true coincidence sensitivity is increased by a factor of about two by the removal of the slice septa and by an additional factor of 2. T h e sensitivity is, however, no longer uniform along the axial direction and is highest at the centre of the axial F O V and decreases toward the end of the axial F O V. A problem is the increase of the singles count rate of detectors for a given dose of activity; and the highest activity allowable in an object is limited by the increase of r a n d o m coincidence events to unallowable level. It is of interest, however, to note that the r a n d o m coincidence rate is lower in the 3 - D m o d e than in the 2 - D m o d e for the s a m e total coincidence rate. This is due to the high detection efficiency for true coincidence in the 3 - D mode. T h e major benefits of the 3 - D m o d e will therefore be in the low activity range. Typically, the scatter fraction increases from 1 0 - 1 5 % to about 3 0 - 4 0 % depending upo n the energy threshold level. For attenuation correction, traditional transmission coincidence measurement using a rotating rod source is not adequate in the 3 - D m o d e , and a technique using a single photon transmission measurement has been developed using a rotating point source. T h e point source m a y be a positron emitter, such as 68G e - 68Ga, or a long life g a m m a ray source, such as 137C s . M o s t of the current 3 - D P E T scanners have retractable slice septa, as s h o w n in Fig. A n Nal(Tl) based P E T scanner ( G E Q E S T , developed b y U G M Medical Systems) is the first septa-less 3 - D P E T scanner . T h e detector system consists of six rectangular g a m m a cameras arranged hex- agonally. T h e advantage of the Nal(Tl) detector is its high energy resolution and, accordingly, better rejection capability for scatter events. A brain P E T scanner using a single annular NaI(Tl) crystal has also been developed . Dedicated animal P E T scanners With the progress of P E T technology, there is an increasing need for P E T scanners dedicated to animal studies. T h e size of the F O V and the spatial resolution depend on the species of animals to be studied. T h e mechanical or geometric specifi cations should match the habits of the animals. For example, dogs are usually posi tioned on their side, rabbits are positioned on their stomach and m o n k e y s prefer a sitting position o n a chair with a suitable headrest. A n animal P E T scanner ( H a m a m a t s u m o d e l S H R - 2 0 0 0 ) is designed for the imaging of animals of m e d i u m size u p to m o n k e y s . T h e detector is a single ring consisting of 15 block detectors and the inner diameter is 35 cm. E a c h block detector consists of a 3 inch square P S - P M T 3 and a B G O block segmented in a 4 x 8 array. E a c h block detector contains a 25 x 54 x 30 m m block of B G O seg mented into a 6 x 8 array of crystal elements (3. A n example is H a m m e r s m i t h ’s R A T P E T , which consists of 16 B G O detector blocks, each with a 23 x 50 x 30 m m B G O segmented into a 7 x 8 array arranged to give a tomograph with a ring diameter of 115 m m and an axial F O V of 50 m m. S U M M A R Y T h e current status of instrumentation for S P E C T and P E T has been reviewed. In both modes, m u c h effort has been m a d e to increase detection sensitivity by 3 - D data acquisition by the use of cone b e a m or m o r e sophisticated 3 - D collimation in S P E C T , or by 3 - D data acquisition in P E T. Howev e r , the fully 3 - D image recon struction and data correction for the attenuation and scatter of photons in the 3 - D m o d e are still in the development stage. Further w o r k is needed o n quantitation issues to reach the goal of septa-less 3 - D P E T. In order to avoid the problems inherent in data reconstruction and back projection in the field of image tomography, a technique for segmentation of the raw projection data set has been developed with the aim of providing quantitative parameters.