By R. Khabir. Liberty University. 2018.
Synthetic associations at genome-wide signals could therefore account for a proportion of the missing herita- bility of complex diseases such as cancer discount aurogra 100mg with visa. Such ﬁndings are useful for understand- ing some of the biological underpinnings of prostate cancer risk purchase 100 mg aurogra amex, but there is possibility of ﬁnding other situations involving synthetic associations between com- mon and rare variants inﬂuencing speciﬁc traits or conditions discount aurogra 100mg. Now oncologists can customize “targeted” cancer treatments for each patient based on the molecular make-up of their tumors 100mg aurogra fast delivery. These “smart drugs” selectively stop the growth of tumor cells with the molecular abnormality. Therefore, the experimental drug could potentially help about 60,000 prostate cancer patients a year, if the laboratory results are conﬁrmed in clinical trials, which are ongoing. Prostate Px (Aureon Laboratories), integrates histology, molecular biology and clinical information and applies bioinformatics to stratify patients as high or low risk for disease recurrence post-prostatectomy. Results are provided as the Prostate Px score (0–100), which reports the likelihood of recurrence of the prostate cancer. In a prospective study, integration of clinicopathological variables with imaging and biomarker data (systems pathology) resulted in a highly accurate tool for predicting clinical failure within 5 years after prostatectomy (Donovan et al. The data support a role for androgen receptor signaling in clinical progression and duration of response to androgen deprivation therapy. The anticancer agent docetaxel and thalidomide shows signiﬁcant inter- individual variation in their pharmacokinetic and toxicity proﬁles as well as wide pharmacological variations. Genetic poly- morphisms were analyzed for associations with clinical response and toxicity. MenaCalc™ Prostate (MetaStat Inc) is a diagnostic for prostate cancer to help in informed decision about whether to undergo radical surgery and risk its dreaded side effects. Effects of Lifestyle Changes Shown by Gene Expression Studies Epidemiological and prospective studies indicate that comprehensive lifestyle changes may modify the progression of prostate cancer. A pilot study was con- ducted to examine changes in prostate gene expression in a unique population of men with low-risk prostate cancer who declined immediate surgery, hormonal ther- apy, or radiation and participated in an intensive nutrition and lifestyle intervention while undergoing careful surveillance for tumor progression (Ornish et al. Consistent with previous studies, signiﬁcant improvements in weight, abdominal obesity, blood pressure, and lipid proﬁle were observed. Two-class paired analysis of global gene expression using signiﬁcance analysis of microarrays detected 48 up-regulated and 453 down-regulated tran- scripts after the intervention. Pathway analysis identiﬁed signiﬁcant modulation of biological processes that have critical roles in tumorigenesis, including protein metabolism and modiﬁcation, intracellular protein trafﬁc, and protein phosphoryla- tion. Intensive nutrition and lifestyle changes may modulate gene expression in the prostate. Understanding the prostate molecular response to comprehensive lifestyle changes may strengthen efforts to develop effective prevention and treatment. The study not only provides insights into potential drug targets, but also suggests that lifestyle changes could produce beneﬁts akin to therapeutic interventions. Use of the test in practice is likely to have an impact on the management in a signiﬁ- cant portion of tested patients, particularly by shifting the trend towards more con- servative management. This could reduce overtreatment of patients with less aggressive disease, decreasing patient morbidity and costs for payers and the health- care system. Nevertheless the outcome can be optimized by individualization, of the extent of surgery, the dosage of 131I therapy and the use of levothyroxine therapy (Luster et al. Newer imaging techniques and targeted molecular therapies such as multi- targeted kinase inhibitors provide new options for the personalized care of patients with advanced disease for whom no effective therapies were available previously. Individualized therapies could reduce adverse effects, including the sometimes debilitating hypothyroidism that used to be required before initiation of 131I treat- ment, and major salivary gland damage, a common and unpleasant side effect of 131 I therapy. However, in spite of ongoing research, personalized thera- pies remain in their infancy. Future of Cancer Therapy There are now unprecedented opportunities for the development of improved drugs for cancer treatment. Most of the genes in the majority of common human cancers are expected to be deﬁned over the next 5 years. This will provide the opportunity to develop a range of drugs targeted to the precise molecular abnormalities that Universal Free E-Book Store Future of Cancer Therapy 365 drive various human cancers and will open up the possibility of personalized thera- pies targeted to the molecular pathology and genomics of individual patients and their malignancies.
Presence of bone-and-visceral/local metastases in addition to these was associated with shorter overall survival aurogra 100 mg free shipping. Pharmacogenetics of Breast Cancer Polymorphisms in tamoxifen metabolizing genes affect the plasma concentration of tamoxifen metabolites discount aurogra 100 mg with visa. Proteomics-Based Personalized Management of Breast Cancer Nipple aspirate protein samples were taken from invasive ductal breast carcinoma and also had an apparently normal contralateral breast buy aurogra 100mg on-line. Among the differential expression pat- terns of ductal ﬂuid proteins discount aurogra 100 mg without a prescription, some evidence of known and possibly new biomarkers and drug targets for breast cancer has been observed. The patient-to-patient vari- ability of these differences may reﬂect variables in the disease structure and may prove to be of clinical diagnostic and therapeutic signiﬁcance to individual patients. For example, the presence or absence of known biomarkers detected in the differ- ences in the ﬂuids can be used to determine the aggressiveness of the cancer (e. However, this approach requires clinical trials for comparison with the gold stan- dards such as mammograms, ultrasound, biopsy, nipple lavage and aspirate cytol- ogy, and serum biomarkers. The presence of known drug targets detected in the differences in the ﬂuids may also be used in the future to indicate what drugs to use. Universal Free E-Book Store 302 10 Personalized Therapy of Cancer Despite recent advances in breast cancer therapy, women with similar types of breast cancers may respond very differently to standard treatments. The emerging ﬁeld of clinical proteomics has the potential to revolutionize breast cancer therapy. The ultimate goal of clinical proteomics is to characterize information ﬂow through protein cascades for individual patients. After the protein networks have been elu- cidated, drug therapies may be specially designed for each patient. Ultimately, proteomics will become an integral component of tracking and managing personalized breast cancer therapy. Predicting Response to Chemotherapy in Breast Cancer Breast cancer patients have beneﬁted from the use of targeted therapies directed at speciﬁc molecular alterations. This specialized microscope frequently requires that the analysis is done at a reference lab. Breast cancer treatment sensitivity was predicted using combination of signatures for (1) sensitivity to endocrine therapy, (2) chemoresistance, and (3) che- mosensitivity, with independent validation and comparison with other reported genomic predictors of chemotherapy response. Prediction of Response to Paclitaxel Breast cancers show variable sensitivity to paclitaxel. Tubulin polymerization assay has been used to show that low tau expres- sion renders microtubules more vulnerable to paclitaxel and makes breast cancer cells hypersensitive to this drug. Low tau expression, therefore, may be used as a biomarker to select patients for paclitaxel therapy. This is a way to predict when anti-estrogen drug therapies are inappropriate for patients with hormone-dependent breast cancer so that physicians can immedi- ately begin treating the patient with alternative drugs that are more likely to suc- ceed. However, comprehensive clinical research is needed before this new method for predicting the success of anti-estrogen drugs is applied in daily patient care. The p53 family member p63 controls a pathway for p73-dependent cisplatin sensitivity speciﬁc to these “triple- negative” tumors. About 83 % of patients are cured of breast cancer, but 17 % are resistant to current treatments. Decreased Breast Density as a Biomarker of Response to Tamoxifen Increased breast density on mammography is the leading risk factor for breast cancer, apart from age. Those with reduced breast density after 12 to 18 months of treatment had a 52 % reduced risk of breast cancer. By contrast, those women who did not have a decrease in breast density had only an 8 % risk reduction. Breast cancer experts also typically identify a ﬁfth breast cancer type known as normal-like. The 50-gene set also recognizes the normal-like type, but instead of being a ﬁfth type of breast cancer, the normal-like classiﬁcation is an Universal Free E-Book Store 306 10 Personalized Therapy of Cancer indicator that a sample contains insufﬁcient tumor cells to make a molecular diagnosis and that a new sample needs to be taken.
These agents are often combined with corticosteroids such as dexamethasone (Decadron) and methylprednisolone (Solu-Medrol) to produce an enhanced antiemetic effect that is possibly due to corticosteroid inhibition of prostaglandin synthesis trusted 100 mg aurogra. Dronabinol (Marinol) is an oral preparation of D-9-tetrahydrocannabinol discount 100mg aurogra mastercard, the active canna- binoid in marijuana aurogra 100mg without prescription. Adverse effects include sedation aurogra 100mg generic, tachycardia, hypotension, and behavioral alterations simi- lar to those associated with the use of marijuana (see V X F). Diazepam is useful as atreatm entofvertigo, and it controls symptoms in Meniere disease in 60%–70% of patients. Prolonged use of some anorexigenics may lead to physical or psychologic dependence. Amphetamine, methamphetamine, dextroamphetamine, and phentermine (Adipex) act cen- trally and elevate the synaptic concentration of catecholamines and dopamine, producing a reduction in food-seeking behavior. Orlistat is a reversible lipase inhibitor used for the management of obesity and is also available over the counter. This agent is contraindicated in patients with cholestasis and malabsorption syndromes. Dronabinol (D-9-tetrahydrocannabinol) (Marinol) stimulates appetite, among its other activities. Megestrol (Megace) is a progestational agent that has a side effect increased appetite. This agent is also used as a second- or third-line therapy for breast cancer patients who have progressed on tamoxifen (see Chapter 12). Antacids are weak bases that are taken orally and that partially neutralize gastric acid, reduce pepsin activity, and stimulate prostaglandin production. Sodium bicarbonate (Alka Seltzer) (1) Sodium bicarbonate is absorbed systemically and should not be used for long-term treatment. The increase in gastric pH produced by antacids decreases the absorption of acidic drugs and increases the absorption of basic drugs. The H2-receptor antagonists, cimetidine (Tagamet), ranitidine (Zantac), famotidine (Pepcid), and nizatidine (Axid) act as competitive inhibitors of the his- tamine H2-receptor on the parietal cell. This results in a marked decrease in histamine- stimulated gastric acid secretion. Although other agents such as gastrin and acetylcholine may induce acid secretion, histamine is the predominant final mediator that stimulates parietal acid secretion. These drugs are rapidly absorbed, and effects are observed within a few minutes to hours. Therapeutic uses (1) Histamine H2-receptor antagonists are used to treat peptic ulcer disease to promote the healing of gastric and duodenal ulcers. However, when they are used as sole agents, recurrence is observed in 90% of patients. As lipophilic weak bases, these prodrugs concentrate in the acidic compartments of parietal cells where they are rapidly converted to an active thiophilic sulfonamide cation. Desired effects may take 3–4 days since not all proton pumps are inhibited with the first dose of these medications. Proton pump inhibitors are more effective for this indication than histamine H2-receptor blockers. These agents are useful in patients with Zollinger-Ellison syndrome, for reflux esophagitis, and for ulcers refractory to H2-receptor antagonists. The most common cause of peptic and duodenal ulcers is infection by the anaerobic bacteria H. The most effective treatment is ‘‘triple therapy,’’ which consists of two antibiotics (usually clari- thromycin and amoxicillin) and a proton pump inhibitor, and it may include colloidal bismuth (Pepto Bismol) (Table 8-1). In refractory cases, antibacterial resistance or noncompliance should be assumed, and suscep- tibility testing should be undertaken.
The concept of personalized medicine is being accepted by the medical profession cheap aurogra 100 mg line, regulatory authorities aurogra 100mg low cost, health insurance organizations cheap 100 mg aurogra amex, and the biopharmaceutical industry buy cheap aurogra 100mg on line. Actually personalized medicine started before sequencing of the human genome was completed, but received a considerable impetus in its development from advances in genomic technologies. Some of these are stated brieﬂy as: • Sequencing is becoming cheap enough only recently to look for rare variants, and that many common variants do have roles in diseases. Although many more remain to be discovered, work can proceed to develop diagnostics and look for therapeutic possibilities of some diseases. That approach is now becoming feasible because the cost of sequencing is dropping and $1,000 genome is now feasible. They can pinpoint which genes bear the ﬁngerprints of recent natural selection, which in turn reveals the particular challenges to which the populations on different continents have had to adapt. The importance of this type of study is further echoed by the Human Epigenome Project. The rapid progress being made through meta-analyses suggests that many more common variants conferring a risk of disease will be identiﬁed in the next several years, leading to increasing stability of individual risk esti- mates. Once risk estimates are more stable, the usefulness of genetic screening will need to be considered for each disease, and recommendations about poten- tial interventions will need to be made for persons whose predicted risk exceeds some threshold. Appropriate guidelines are urgently needed to help physicians advise patients who are considering this form of genetic testing as to how to interpret, and when to act on, the results as they become more stable. We do not have to wait for 15–20 years to realize the potential of personalized medicine. Also to state that it will take that long for personalized medicine to become mainstream raises the question as to what is required to justify the use of the term “mainstream” in medicine. There are no deﬁnite criteria by which this term can be applied to personalized medicine. Not all the diseases will need personalized medicines or combination of diagnostics with therapeutics. Application of new technologies and medicines depends on the personal judgment and decision of the treating physician in each case. Personalized approaches will be available and are expected to be used where they are deemed appropriate. In conclusion, the progress in personalized medicine and related technologies justiﬁes a more optimistic view. The interest in per- sonalized medicine is worldwide although the implementation may be delayed due Universal Free E-Book Store 708 24 Future of Personalized Medicine to socio-economic factors in some developing Asian countries. Japan, with an advanced healthcare system and a prominent position of research activity in genomic medicine, has good prospects for introduction of personalized medicine. China, which is making considerable advances in new biotechnologies and applying them in genomics and sequencing, has the facilities for developing personalized medi- cine. A critical review of the Royal Society’s report on personalized medicine (editorial). The continuum of translation research in genomic medi- cine: how can we accelerate the appropriate integration of human genome discoveries into health care and disease prevention? Delivery of genomic medicine for common chronic adult diseases: a systematic review. Clinical translation of genotyping and haplotyping data: implementation of in vivo pharmacology experience leading drug prescription to pharmacotyping. Nanomedicine and personalized medicine toward the application of pharmacotyp- ing in clinical practice to improve drug-delivery outcomes. Requests to the Publisher for permission should be addressed to the Legal Department, Wiley Publishing, Inc. The publisher and the author make no representations or warranties with respect to the accuracy or completeness of the contents of this work and specifically disclaim all warranties, including without limitation warranties of fitness for a particular purpose.