Soft ferroelectret ultrasound receiver for targeted peripheral neuromodulation.

Bioelectronic medicine is a rapidly growing field where targeted electrical signals can act as an adjunct or alternative to drugs to treat neurological disorders and diseases via stimulating the peripheral nervous system on demand. However, current existing strategies are limited by external battery requirements, and the injury and inflammation caused by the mechanical mismatch between rigid electrodes and soft nerves. Here we report a wireless, leadless, and battery-free ferroelectret implant, termed NeuroRing, that wraps around the target peripheral nerve and demonstrates high mechanical conformability to dynamic motion nerve tissue. As-fabricated NeuroRing can act as an ultrasound receiver that converts ultrasound vibrations into electrostimulation pulses, thus stimulating the targeted peripheral nerve on demand. This capability is demonstrated by the precise modulation of the sacral splanchnic nerve to treat colitis, providing a framework for future bioelectronic medicines that offer an alternative to non-specific pharmacological approaches.

Increasing prevalence of human papillomavirus-positive oropharyngeal cancers among older adults.

BACKGROUND: The incidence of oropharyngeal squamous cell carcinoma (OPSCC) is increasing among older adults. It is unknown whether these trends can be explained by human papillomavirus (HPV) and whether HPV-related tumors remain associated with an improved prognosis among older patients. METHODS: In a retrospective study of OPSCCs diagnosed from 1995 to 2013 at 2 National Comprehensive Cancer Network-designated cancer centers, p16 immunohistochemistry and in situ hybridization (ISH) for HPV-16, high-risk DNA, and/or E6/E7 RNA were performed. The median age at diagnosis was compared by p16 and ISH tumor status. Trends in age were analyzed with nonparametric trends. Survival was analyzed with the Kaplan-Meier method and Cox proportional hazards models. RESULTS: Among 239 patients, 144 (60%) were p16-positive. During 1998-2013, the median age increased among p16-positive patients (Ptrend = .01) but not among p16-negative patients (Ptrend = .71). The median age of p16-positive patients increased from 53 years (interquartile range [IQR] in 1995-2000, 45-65 years) to 58 years (IQR for 2001-2013, 53-64 years). Among patients ≥ 65 years old, the proportion of OPSCCs that were p16-positive increased from 41% during 1995-2000 to 75% during 2007-2013 (Ptrend = .04). Among all age groups, including older patients, a p16-positive tumor status conferred improved overall survival in comparison with a p16-negative status. CONCLUSIONS: The median age at diagnosis for HPV-related OPSCC is increasing as the proportion of OPSCCs caused by HPV rises among older adults. The favorable survival conferred by an HPV-positive tumor status persists in older adults. Cancer 2018;124:2993-9. © 2018 American Cancer Society.

Assessment of the rates and characteristics of the short-term supply of medication (Tider) from an integrated healthcare delivery system in the United States.

OBJECTIVES: The purpose of this study was to describe the rate of medication short-term supply dispensings (tider), patient and medication characteristics associated with a tider, and costs for tider dispensings in an integrated healthcare delivery system in Colorado, United States. METHODS: This was a retrospective study conducted in an integrated healthcare delivery system's outpatient clinics. All patients who had a prescription dispensed for a study medication at any of the system's 28 outpatient pharmacies during the first quarter of 2016 were included. A tider was identified as a 3-day supply of a prescription medication that was dispensed at no charge to a patient. The quarterly tider rate and the per member per month (PMPM) cost of tiders were estimated. Patient and medication characteristics associated with a tider were assessed. RESULTS: A total of 444,225 study medications were dispensed for 135,907 patients during the study period. There were 3,430 (0.77%, 95%CI 0.75%:0.80%) medications dispensed as a tider. The PMPM cost of tider medications and their dispensing fees was USD 0.03. There were 1,092 (0.8%) and 134,815 (99.2%) patients who did and did not, respectively, have at least one tider dispensed during the study period. Patient characteristics strongly associated with having had a tider dispensed included being older, male, and a Medicare beneficiary. Cardiovascular and neuromuscular medications had the highest rates of tider dispensing. CONCLUSIONS: The rate of tider dispensing was relatively low; however, approximately one out of 125 patients had at least one tider. Patients who had a tider were more likely to be older, female, a Medicare beneficiary, and having had a previous tider dispensing and a higher burden of chronic disease. The tider medication was more likely to be a cardiovascular or neuromuscular medication class and more likely to be dispensed on a weekend. The total cost of dispensing a tider appears reasonable since the benefits of providing patients with needed medications likely outweigh the cost. Future studies should be performed to assess the impact of tider dispensing on health outcomes.

Assessment of the rates and characteristics of the short-term supply of medication (Tider) from an integrated healthcare delivery system in the United States

Objectives: The purpose of this study was to describe the rate of medication short-term supply dispensings (tider), patient and medication characteristics associated with a tider, and costs for tider dispensings in an integrated healthcare delivery system in Colorado, United States. Methods: This was a retrospective study conducted in an integrated healthcare delivery system’s outpatient clinics. All patients who had a prescription dispensed for a study medication at any of the system’s 28 outpatient pharmacies during the first quarter of 2016 were included. A tider was identified as a 3-day supply of a prescription medication that was dispensed at no charge to a patient. The quarterly tider rate and the per member per month (PMPM) cost of tiders were estimated. Patient and medication characteristics associated with a tider were assessed. Results: A total of 444,225 study medications were dispensed for 135,907 patients during the study period. There were 3,430 (0.77%, 95%CI 0.75%:0.80%) medications dispensed as a tider. The PMPM cost of tider medications and their dispensing fees was USD 0.03. There were 1,092 (0.8%) and 134,815 (99.2%) patients who did and did not, respectively, have at least one tider dispensed during the study period. Patient characteristics strongly associated with having had a tider dispensed included being older, male, and a Medicare beneficiary. Cardiovascular and neuromuscular medications had the highest rates of tider dispensing. Conclusions: The rate of tider dispensing was relatively low; however, approximately one out of 125 patients had at least one tider. Patients who had a tider were more likely to be older, female, a Medicare beneficiary, and having had a previous tider dispensing and a higher burden of chronic disease. The tider medication was more likely to be a cardiovascular or neuromuscular medication class and more likely to be dispensed on a weekend. The total cost of dispensing a tider appears reasonable since the benefits of providing patients with needed medications likely outweigh the cost. Future studies should be performed to assess the impact of tider dispensing on health outcomes (AU)

No disponible

The advantages and drawbacks of routine magnetic resonance imaging for long-term post-treatment locoregional surveillance of oral cavity squamous cell carcinoma.

PURPOSE: Assess the clinical utility and accuracy of routine surveillance head and neck magnetic resonance imaging (HN-MRI) for the detection of locoregional recurrence in patients with a history of oral cavity squamous cell carcinoma (OCSCC) without concurrent suspicious symptoms or signs 6 months or more after treatment. MATERIALS AND METHODS: For OCSCC patients who underwent routine (defined as: without concurrent suspicious symptoms or signs) surveillance HN-MRI at 6 months or more after treatment completion, we retrospectively determined the detection rate of locoregional disease and false positive rate. RESULTS: Out of an original cohort of 533 OCSCC patients, 46 patients, who were disease-free 6 months after treatment, had undergone 108 routine HN-MRIs from 6 to 48 months after surgery without the presence of concurrent suspicious symptoms or signs and had 6 months of subsequent follow up. 1 out of 46 (2.2%) had a true positive regional recurrence. 10 out of 46 (21.7%) patients experienced a false positive locoregional finding. CONCLUSIONS: Routine HN-MRI for locoregional surveillance of OCSCC, when used in patients without concurrent suspicious symptoms or exam findings over 6 months since treatment, may be unnecessary and costly given the very low rate of recurrence and high false positive rate. Our study supports the National Comprehensive Cancer Network guideline of limiting imaging after 6 months of primary treatment completion to patients with suspicious clinical findings. Nonetheless, managing physicians should continue to be empowered to use surveillance imaging based on risk profiles and unique circumstances for each patient.

The economic impact of improving phosphate binder therapy adherence and attainment of guideline phosphorus goals in hemodialysis patients: a Medicare cost-offset model.

INTRODUCTION: Hyperphosphatemia (serum phosphorus >5.5 mg/dL) in hemodialysis patients is a key factor in mineral and bone disorders and is associated with increased hospitalization and mortality risks. Treatment with oral phosphate binders offers limited benefit in achieving target serum phosphorus concentrations due to high daily pill burden (7-10 pills/day) and associated poor medication adherence. The economic value of improving phosphate binder adherence and increasing percent time in range (PTR) for target phosphorus concentrations has not been previously assessed in dialysis patients. The current retrospective analysis was conducted to summarize health care cost savings to United States (US) payers associated with improved phosphate binder adherence and increased PTR for target phosphorus concentrations in adult end-stage renal disease (ESRD) patients receiving hemodialysis therapy. METHODS: Phosphate binder adherence and PTR were derived from hemodialysis patients who were treated at a large dialysis organization between January 2007 and December 2011. Cost model inputs were derived from US Renal Data System data between July 2007 and December 2009. A cost-offset model was constructed to estimate monthly and annual incremental health care costs (total Medicare; inpatient, outpatient, and Medicare Part B) associated with different levels of phosphate binder adherence and PTR. Model inputs included number of ESRD patients, population adherence to phosphate binders, PTR associated with adherence to phosphate binders, and per-patient per-month cost associated with PTR. A base case model estimated monthly and annual costs of phosphate binder therapy in the population using estimated model inputs. The estimated adherence rate was used to determine number of patients in compliant and noncompliant groups. Monthly costs were calculated as the sum of per-patient per-month cost times the number of patients in adherent and nonadherent groups. Annual costs were monthly costs times 12 and assumed the same level of adherence, PTR, and per-patient per-month costs over time. To study the impact of improving phosphate binder adherence and PTR on cost outcomes, we hypothetically and simultaneously increased both base phosphate binders adherence and PTR for adherent patients (adherence/PTR: 10/20%, 20/40%, 30/60%). Monthly and annual costs were derived for each scenario and compared against the results of the base case model. One-way sensitivity analysis was performed to test model robustness. RESULTS: The base case model estimated total Medicare and inpatient costs of $5,152,342 and $1,435,644, respectively (N = 1,000). When base case model costs were compared to results of each extended model scenario, overall Medicare cost savings (range 0.3-1.9%) and inpatient cost savings (range 1.2-5.7%) were observed. The one-way sensitivity analysis indicated that results were sensitive to PTR for adherent and nonadherent patients and the factor used to increase adherence rate and PTR associated with adherence in the hypothetical scenarios. However, cost savings in overall Medicare costs and inpatient costs were still noted. CONCLUSION: Increasing phosphate binder adherence and improving phosphorus control were associated with increased cost savings in total Medicare costs and inpatient costs.

Serum phosphorus levels and pill burden are inversely associated with adherence in patients on hemodialysis.

BACKGROUND: Phosphate binders (PBs) account for about one half of the daily pill burden for US hemodialysis (HD) patients, which may reduce adherence. Adherence can be estimated by the medication possession ratio (MPR), which is defined as the proportion of time a patient had sufficient medication to have taken it as prescribed. Gaps of time between prescription fills lower the patient's MPR. We assessed the association of PB pill burden and adherence (MPR) with phosphorus goal attainment. METHODS: Using pharmacy management program data, HD patients on PB monotherapy were tracked from first PB fill during 1 January 2007-30 June 2011 for 1 year, or until PB change or censoring. Data were assessed with generalized linear models. RESULTS: We analyzed 8616 patients. Higher pill burden was associated with lower adherence. Lower adherence tended to be associated with higher mean phosphorus levels and lower percentage of patients with serum phosphorus ≤5.5 mg/dL (P < 0.001). The association between adherence and these clinical outcomes was most pronounced in the lowest and highest pill burden strata (<3, >3-6, >12-15, >15). CONCLUSIONS: Adherence, as measured by the MPR, was negatively related to higher pill burden and phosphorus levels and positively related to patients in the phosphorus target range. Within pill burden strata, phosphorus increased and patients in the target range generally decreased with decreasing adherence, suggesting that patients prescribed fewer PB pills are less likely to have treatment gaps, and may be more likely to achieve phosphorus targets.

Genipin-cross-linked poly(L-lysine)-based hydrogels: synthesis, characterization, and drug encapsulation.

Genipin-cross-linked hydrogels composed of biodegradable and pH-sensitive cationic poly(L-lysine) (PLL), poly(L-lysine)-block-poly(L-alanine) (PLL-b-PLAla), and poly(L-lysine)-block-polyglycine (PLL-b-PGly) polypeptides were synthesized, characterized, and used as carriers for drug delivery. These polypeptide hydrogels can respond to pH-stimulus and their gelling and mechanical properties, degradation rate, and drug release behavior can be tuned by varying polypeptide composition and cross-linking degree. Comparing with natural polymers, the synthetic polypeptides with well-defined chain length and composition can warrant the preparation of the hydrogels with tunable properties to meet the criteria for specific biomedical applications. These hydrogels composed of natural building blocks exhibited good cell compatibility and enzyme degradability and can support cell attachment/proliferation. The evaluation of these hydrogels for in vitro drug release revealed that the controlled release profile was a biphasic pattern with a mild burst release and a moderate release rate thereafter, suggesting the drug molecules were encapsulated inside the gel matrix. With the versatility of polymer chemistry and conjugation of functional moieties, it is expected these hydrogels can be useful for biomedical applications such as polymer therapeutics and tissue engineering.

Transcriptional profiling of Chinese medicinal formula Si-Wu-Tang on breast cancer cells reveals phytoestrogenic activity.

BACKGROUND: Si-Wu-Tang (SWT), comprising the combination of four herbs, Paeoniae, Angelicae, Chuanxiong and Rehmanniae, is one of the most popular traditional oriental medicines for women's diseases. In our previous study, the microarray gene expression profiles of SWT on breast cancer cell line MCF-7 were found similar to the effect of ß-estradiol (E2) on MCF-7 cells in the Connectivity Map database. METHODS: Further data analysis was conducted to find the main similarities and differences between the effects of SWT and E2 on MCF-7 gene expression. The cell proliferation assay on MCF-7 (ER-positive) and MDA-MB-231 (ER-negative) cells were used to examine such estrogenic activity. The estrogenic potency of SWT was further confirmed by estrogen-responsive element (ERE) luciferase reporter assay in MCF-7 cells. RESULTS: Many estrogen regulated genes strongly up-regulated by E2 were similarly up-regulated by SWT, e.g., GREB1, PGR and EGR3. Of interest with regard to safety of SWT, the oncogenes MYBL1 and RET were strongly induced by E2 but not by SWT. Quantitative RT-PCR analysis revealed a highly concordant expression change in selected genes with data obtained by microarrays. Further supporting SWT's estrogenic activity, in MCF-7 but not in MDA-MB-231 cells, SWT stimulated cell growth at lower concentrations (< 3.0 mg/ml), while at high concentrations, it inhibits the growth of both cell lines. The growth inhibitory potency of SWT was significantly higher in MDA-MB-231 than in MCF-7 cells. The SWT-induced cell growth of MCF-7 could be blocked by addition of the estrogen receptor antagonist tamoxifen. In addition, SWT was able to activate the ERE activity at lower concentrations. The herbal components Angelicae, Chuanxiong and Rehmanniae at lower concentrations (< 3.0 mg/ml) also showed growth-inducing and ERE-activating activity in MCF-7 cells. CONCLUSIONS: These results revealed a new mechanism to support the clinical use of SWT for estrogen related diseases and possibly for cancer prevention. This study also demonstrated the feasibility of using microarray transcriptional profiling to discover phytoestrogenic components that are present in natural products.

Identification, optimisation and in vivo evaluation of oxadiazole DGAT-1 inhibitors for the treatment of obesity and diabetes.

A novel series of DGAT-1 inhibitors was discovered from an oxadiazole amide high throughput screening (HTS) hit. Optimisation of potency and ligand lipophilicity efficiency (LLE) resulted in a carboxylic acid containing clinical candidate 53 (AZD3988), which demonstrated excellent DGAT-1 potency (0.6 nM), good pharmacokinetics and pre-clinical in vivo efficacy that could be rationalised through a PK/PD relationship.

The role of antioxidants in photoprotection: a critical review.

Free radicals have long been studied as a contributor to aging and disease processes. Endogenous production of radicals from cellular metabolism and exogenous sources from ultraviolet radiation and pollution can damage the skin on the cellular and tissue levels. Although the body possesses an elegant defense system to prevent radical damage, this innate system can be overwhelmed and lead to a state of oxidative stress or immunosuppression, and can even trigger carcinogenesis. Topical supplementation of antioxidants can provide additional protection to neutralize reactive oxygen species from both endogenous and exogenous sources. This review will discuss our current understanding of the mechanisms of free radical damage and evaluate the potential benefit of topical antioxidants in sunscreens and skin care products.

Discovery of molecular mechanisms of traditional Chinese medicinal formula Si-Wu-Tang using gene expression microarray and connectivity map.

To pursue a systematic approach to discovery of mechanisms of action of traditional Chinese medicine (TCM), we used microarrays, bioinformatics and the "Connectivity Map" (CMAP) to examine TCM-induced changes in gene expression. We demonstrated that this approach can be used to elucidate new molecular targets using a model TCM herbal formula Si-Wu-Tang (SWT) which is widely used for women's health. The human breast cancer MCF-7 cells treated with 0.1 µM estradiol or 2.56 mg/ml of SWT showed dramatic gene expression changes, while no significant change was detected for ferulic acid, a known bioactive compound of SWT. Pathway analysis using differentially expressed genes related to the treatment effect identified that expression of genes in the nuclear factor erythroid 2-related factor 2 (Nrf2) cytoprotective pathway was most significantly affected by SWT, but not by estradiol or ferulic acid. The Nrf2-regulated genes HMOX1, GCLC, GCLM, SLC7A11 and NQO1 were upregulated by SWT in a dose-dependent manner, which was validated by real-time RT-PCR. Consistently, treatment with SWT and its four herbal ingredients resulted in an increased antioxidant response element (ARE)-luciferase reporter activity in MCF-7 and HEK293 cells. Furthermore, the gene expression profile of differentially expressed genes related to SWT treatment was used to compare with those of 1,309 compounds in the CMAP database. The CMAP profiles of estradiol-treated MCF-7 cells showed an excellent match with SWT treatment, consistent with SWT's widely claimed use for women's diseases and indicating a phytoestrogenic effect. The CMAP profiles of chemopreventive agents withaferin A and resveratrol also showed high similarity to the profiles of SWT. This study identified SWT as an Nrf2 activator and phytoestrogen, suggesting its use as a nontoxic chemopreventive agent, and demonstrated the feasibility of combining microarray gene expression profiling with CMAP mining to discover mechanisms of actions and to identify new health benefits of TCMs.

Estimated equivalency of vitamin D production from natural sun exposure versus oral vitamin D supplementation across seasons at two US latitudes.

BACKGROUND: The relationship between oral vitamin D supplementation and cutaneous photosynthesis is not well understood. OBJECTIVE: We sought to provide estimates of the equivalency of vitamin D production from natural sun exposure versus oral supplementation. METHODS: Using the FastRT simulation tool, we determined sun exposure times needed to achieve serum vitamin D(3) concentrations equivalent to 400 or 1000 IU vitamin D for individuals of various Fitzpatrick skin types living in Miami, FL, and Boston, MA, during the months of January, April, July, and October. RESULTS: Peak ultraviolet B irradiation for vitamin D synthesis occurs around 12 pm Eastern Standard Time (EST). In Boston, MA, from April to October at 12 pm EST an individual with type III skin, with 25.5% of the body surface area exposed, would need to spend 3 to 8 minutes in the sun to synthesize 400 IU of vitamin D. It is difficult to synthesize vitamin D during the winter in Boston, MA. For all study months in Miami, FL, an individual with type III skin would need to spend 3 to 6 minutes at 12 pm EST to synthesize 400 IU. Vitamin D synthesis occurs faster in individuals with lighter Fitzpatrick skin types. The duration to attain 1000 IU of vitamin D is longer in all scenarios. LIMITATIONS: Results of the computer model are only approximations. In addition, calculations were made based on the assumption that (1/4) of 1 minimal erythema dose directed at (1/4) body surface area is equal to 1000 IU of oral vitamin D. CONCLUSIONS: Although it may be tempting to recommend intentional sun exposure based on our findings, it is difficult, if not impossible to titrate one's exposure. There are well-known detrimental side effects of ultraviolet irradiation. Therefore, oral supplementation remains the safest way for increasing vitamin D status.

Molecular basis of traditional Chinese medicine in cancer chemoprevention.

Cancer is the second leading cause of death, for which current therapeutic approaches are still very limited. Chemoprevention is an important approach to decreasing cancer morbidity and mortality by the use of non-toxic natural or synthetic substances to reverse the processes of initiation and subsequent progression of cancer. A substantial amount of evidence from human, animal and cell line studies has shown that many herbal products used for traditional Chinese medicine (TCM) can exert chemopreventive effects. The underlying theory for TCM to treat or prevent cancer is to bring the patient back to a healthy state by modifying multiple cancer-causing events. Since carcinogenesis involves multiple abnormal genes/pathways, using TCM in cancer chemoprevention may be superior to the agents targeting a single molecular target alone. However, before TCM can be accepted universally as complementary and alternative medicine for cancer treatment and prevention, it is crucial to understand the molecular basis for their effects. This review highlights several known molecular mechanisms of selected TCM in chemoprevention. Many TCM products or single active components have been reported to inhibit a variety of processes in cancer cell growth, invasion and metastasis by modulating a wide range of molecular targets, including cyclooxygenase-2 (COX-2), nuclear factor-Kappa B (NF-kappaB) and nuclear factor erythroid 2 -related factor 2 (Nrf2)-mediated antioxidant signaling pathways. The TCM and their active components with potent chemopreventive effects can be considered as promising lead agents for the design of more effective and less toxic agents for cancer chemoprevention.

Inhibition of intestinal tumorigenesis in Apc(min/+) mice by green tea polyphenols (polyphenon E) and individual catechins.

In this work, we compared the cancer preventive activities of Polyphenon E (PPE), a standardized green tea polyphenol preparation given in diet versus drinking fluid as well as the activities of PPE versus individual catechins. We treated Apc(Min/+) mice for 9 wk with 0.08% (-)-epigallocatechin-3-gallate (EGCG), 0.08% (-)-epicatechin-3-gallate, or 0.12% PPE in drinking fluid or diet. Only 0.12% dietary PPE and 0.08% EGCG in drinking fluid significantly decreased tumor multiplicity (70% and 51%, respectively). Compared to PPE in drinking fluid, dietary PPE delivered twofold more EGCG to the small intestine. Immunohistochemistry showed that adenomas in groups treated with PPE and EGCG had decreased cell proliferation, Beta -catenin nuclear expression, and phospho-Akt levels; higher cleaved caspase-3 levels, and partially restored retinoid X receptor alpha expression. The results suggest that these molecular events contribute to the cancer prevention activity of EGCG and PPE. Furthermore, diet appears to be a better route of administration for PPE than drinking fluid.

Wheat bran oil and its fractions inhibit human colon cancer cell growth and intestinal tumorigenesis in Apc(min/+) mice.

This study was designed to investigate the cancer preventive activities of wheat bran (WB) oil. We studied the colon cancer preventive effects of WB oil and its subfractions in the Apc(min/+) mouse model, a recognized mouse model for human colorectal cancer, and used human colon cancer cell lines (HCT-116 and HT-29) to identify possible active fractions in WB oil. Our results showed that the oil fraction of WB was more active than the water fraction against the growth of human colon cancer cell lines and that 2% WB oil significantly inhibited the overall tumorigenesis by 35.7% (p < 0.0001) in the Apc(min/+) mouse model. The WB oil was further fractioned into nonpolar lipids and phytochemicals and the phytochemical fraction was fractionated into phytosterols and phytosterol ferulates, 5-alk(en)ylresorcinols, and unidentified constituents by normal phase silica gel column chromatography. Results on cell culture showed that the phytochemical fraction had a higher inhibitory effect on HCT-116 human colon cancer cells than that of WB oil, whereas the nonpolar lipid fraction had less growth inhibitory effectiveness. However, neither fractions showed a stronger inhibition than WB oil in the Apc(min/+) mouse model. The current results demonstrate, for the first time, the intestinal cancer preventive activity of WB oil. The active ingredients, however, remain to be identified.

Gene expression profile in human prostate LNCaP cancer cells by (--) epigallocatechin-3-gallate.

Green tea is an effective chemopreventive agent in animal tumor bioassays and some human cancers. Much of its cancer preventive effects appear to be mediated by its major polyphenolic constituent (-) epigallocatechin-3-gallate (EGCG). In order to better understand the molecular regulation underlying the anti-proliferative activity of EGCG in prostate cancer, we have utilized cDNA microarray to elucidate how EGCG alters program of gene expression in prostate carcinoma LNCaP cells. Fluorophore-labeled cDNA probes synthesized from the untreated LNCaP cells or the cells treated for 12 h with EGCG (12 microM), a physiologically achievable dose, were competitively hybridized to the microarray that contained a total of 250 kinases and phosphatases genes. Such high-throughput screening has identified a number of EGCG-responsive gene candidates. Of these, we found that EGCG induced a subset of genes that functionally could exhibit inhibitory effects on cell growth. The genes repressed by EGCG mostly belonged to the G-protein signaling network. Interestingly, the protein kinase C-alpha (PKC-alpha) form, whose inhibition of expression has been shown to inhibit cell growth in some cancer cells, was selectively repressed by EGCG while the expression of six other PKC isoforms (beta, delta, epsilon, micro, eta and zeta) was unaffected. These EGCG-responsive genes may provide key insights from which to understand mechanisms of action of other polyphenolic compounds in prostate cancer chemoprevention.