Publications

Natural products (NPs) are compounds that are derived from natural sources such as plants, animals, and micro-organisms. Therapeutics has benefited from numerous drug classes derived from natural product sources. The Biopharmaceutics Drug Disposition Classification System (BDDCS) was proposed to serve as a basis for predicting the importance of transporters and enzymes in determining drug bioavailability and disposition. It categorizes drugs into one of four biopharmaceutical classes according to their water solubility and extent of metabolism. The present paper reviews 109 drugs from natural product sources: 29% belong to class 1 (high solubility, extensive metabolism), 22% to class 2 (low solubility, extensive metabolism), 40% to class 3 (high solubility, poor metabolism), and 9% to class 4 (low solubility, poor metabolism). Herein we evaluated the characteristics of NPs in terms of BDDCS class for all 109 drugs as wells as for subsets of NPs drugs derived from plant sources as antibiotics. In the 109 NPs drugs, we compiled 32 drugs from plants, 50% (16) of total in class 1, 22% (7) in class 2 and 28% (9) in class 3, none found in class 4; Meantime, the antibiotics were found 5 (16%) in class 2, 22 (71%) in class 3, and 4 (13%) in class 4; no drug was found in class 1. Based on this classification, we anticipate BDDCS to serve as a useful adjunct in evaluating the potential characteristics of new natural products.

PURPOSE

The management of advanced or recurrent prostate cancer is limited in part by the lack of effective imaging agents. Metabolic changes in prostate cancer have previously been exploited for imaging, culminating in the recent US FDA approval of [C]choline for the detection of subclinical recurrent disease after definitive local therapy. Despite this milestone, production of [C]choline requires an on-site cyclotron, limiting the scope of medical centers at which this scan can be offered. In this pilot study, we tested whether prostate cancer could be imaged with positron emission tomography (PET) using [Ga]citrate, a radiotracer that targets iron metabolism but is produced without a cyclotron.

PROCEDURES

Eight patients with castrate-resistant prostate cancer were enrolled in this single-center feasibility study. All patients had evidence of metastatic disease by standard of care imaging [X-ray computed tomography (CT), bone scan, or magnetic resonance imaging (MRI)] prior to PET with [Ga]citrate. Patients were intravenously injected with increasing doses of [Ga]citrate (136.9 to a maximum of 259 MBq). Uptake time was steadily increased from 1 h to approximately 3.5 h for the final 4 patients, and all patients were imaged with a PET/MRI. Qualitative and semi-quantitative (maximum standardized uptake value (SUV)) assessment of the metastatic lesions was performed and compared to the standard of care imaging.

RESULTS

At 1- and 2-h imaging times post injection, there were no detectable lesions with [Ga]citrate PET. At 3- to 4-h uptake time, there were a total of 71 [Ga]citrate-positive lesions (67 osseous, 1 liver, and 3 lymph node). Of these, 65 lesions were visible on the standard of care imaging (CT and/or bone scan). One PET-avid osseous vertebral body metastasis was not apparent on either CT or bone scan. Twenty-five lesions were not PET-avid but seen on CT and bone scan (17 bone, 6 lymph node, 1 pleural, and 1 liver). The average of the maximum SUVs for bone or soft tissue metastases for patients treated at higher doses and uptake time was statistically higher than the corresponding parameter in normal liver, muscle, and bone. Visually obvious blood pool activity was observed even 3-4 h post injection, suggesting that further optimization of the [Ga]citrate imaging protocol is required to maximize signal-to-background ratios.

CONCLUSIONS

Our preliminary results support that PET with [Ga]citrate may be a novel tool for imaging prostate cancer. Future studies are needed to determine the optimal imaging protocol, the clinical significance of [Ga]citrate uptake, and its role in therapeutic decisions.

Germ-cell tumours (GCTs) are derived from germ cells and occur most frequently in the testes. GCTs are histologically heterogeneous and distinctly curable with chemotherapy. Gains of chromosome arm 12p and aneuploidy are nearly universal in GCTs, but specific somatic genomic features driving tumour initiation, chemosensitivity and progression are incompletely characterized. Here, using clinical whole-exome and transcriptome sequencing of precursor, primary (testicular and mediastinal) and chemoresistant metastatic human GCTs, we show that the primary somatic feature of GCTs is highly recurrent chromosome arm level amplifications and reciprocal deletions (reciprocal loss of heterozygosity), variations that are significantly enriched in GCTs compared to 19 other cancer types. These tumours also acquire KRAS mutations during the development from precursor to primary disease, and primary testicular GCTs (TGCTs) are uniformly wild type for TP53. In addition, by functional measurement of apoptotic signalling (BH3 profiling) of fresh tumour and adjacent tissue, we find that primary TGCTs have high mitochondrial priming that facilitates chemotherapy-induced apoptosis. Finally, by phylogenetic analysis of serial TGCTs that emerge with chemotherapy resistance, we show how TGCTs gain additional reciprocal loss of heterozygosity and that this is associated with loss of pluripotency markers (NANOG and POU5F1) in chemoresistant teratomas or transformed carcinomas. Our results demonstrate the distinct genomic features underlying the origins of this disease and associated with the chemosensitivity phenotype, as well as the rare progression to chemoresistance. These results identify the convergence of cancer genomics, mitochondrial priming and GCT evolution, and may provide insights into chemosensitivity and resistance in other cancers.

RATIONALE

Despite abundant state-level policy activity in the U.S. related to immigration, no research has examined the mental health impact of the overall policy climate for Latinos, taking into account both inclusionary and exclusionary legislation.

OBJECTIVE

To examine associations between the state-level policy climate related to immigration and mental health outcomes among Latinos.

METHODS

We created a multi-sectoral policy climate index that included 14 policies in four domains (immigration, race/ethnicity, language, and agricultural worker protections). We then examined the relation of this policy climate index to two mental health outcomes (days of poor mental health and psychological distress) among Latinos from 31 states in the 2012 Behavioral Risk Factor Surveillance System (BRFSS), a population-based health survey of non-institutionalized individuals aged 18 years or older.

RESULTS

Individuals in states with a more exclusionary immigration policy climate had higher rates of poor mental health days than participants in states with a less exclusionary policy climate (RR: 1.05, 95% CI: 1.00, 1.10). The association between state policies and the rate of poor mental health days was significantly higher among Latinos versus non-Latinos (RR for interaction term: 1.03, 95% CI: 1.01, 1.06). Furthermore, Latinos in states with a more exclusionary policy climate had 1.14 (95% CI: 1.04, 1.25) times the rate of poor mental health days than Latinos in states with a less exclusionary policy climate. Results were robust to individual- and state-level confounders. Sensitivity analyses indicated that results were specific to immigration policies, and not indicators of state political climate or of residential segregation. No relationship was observed between the immigration policy index and psychological distress.

CONCLUSION

These results suggest that restrictive immigration policies may be detrimental to the mental health of Latinos in the United States.

Metformin is used as a first-line therapy for type 2 diabetes (T2D) and prescribed for numerous other diseases. However, its mechanism of action in the liver has yet to be characterized in a systematic manner. To comprehensively identify genes and regulatory elements associated with metformin treatment, we carried out RNA-seq and ChIP-seq (H3K27ac, H3K27me3) on primary human hepatocytes from the same donor treated with vehicle control, metformin or metformin and compound C, an AMP-activated protein kinase (AMPK) inhibitor (allowing to identify AMPK-independent pathways). We identified thousands of metformin responsive AMPK-dependent and AMPK-independent differentially expressed genes and regulatory elements. We functionally validated several elements for metformin-induced promoter and enhancer activity. These include an enhancer in an ataxia telangiectasia mutated (ATM) intron that has SNPs in linkage disequilibrium with a metformin treatment response GWAS lead SNP (rs11212617) that showed increased enhancer activity for the associated haplotype. Expression quantitative trait locus (eQTL) liver analysis and CRISPR activation suggest that this enhancer could be regulating ATM, which has a known role in AMPK activation, and potentially also EXPH5 and DDX10, its neighboring genes. Using ChIP-seq and siRNA knockdown, we further show that activating transcription factor 3 (ATF3), our top metformin upregulated AMPK-dependent gene, could have an important role in gluconeogenesis repression. Our findings provide a genome-wide representation of metformin hepatic response, highlight important sequences that could be associated with interindividual variability in glycemic response to metformin and identify novel T2D treatment candidates.

OBJECTIVE

To investigate safety of hormonal contraception with regard to thromboembolic events in women with type 1 or 2 diabetes.

RESEARCH DESIGN AND METHODS

We used data from 2002-2011 in Clinformatics Data Mart to identify women in the U.S., 14-44 years of age, with an ICD-9-CM code for diabetes and a prescription for a diabetic medication or device. We examined contraceptive claims and compared time to thromboembolism (venous thrombosis, stroke, or myocardial infarction) among women with diabetes dispensed hormonal contraception using a modification of Cox regression to control for age, smoking, obesity, hypertension, hyperlipidemia, diabetic complications, and history of cancer; we excluded data for 3 months after women gave birth.

RESULTS

We identified 146,080 women with diabetes who experienced 3,012 thromboembolic events. Only 28% of reproductive-aged women with diabetes had any claims for hormonal contraception, with the majority receiving estrogen-containing oral contraceptives. Rates of thromboembolism were highest among women who used the contraceptive patch (16 per 1,000 woman-years) and lowest among women who used intrauterine (3.4 per 1,000 woman-years) and subdermal (0 per 163 woman-years) contraceptives. Compared with use of intrauterine contraception, progestin-only injectable contraception was associated with increased risk of thromboembolism (12.5 per 1,000 woman-years; adjusted hazard ratio 4.69 [95% CI 2.51-8.77]).

CONCLUSIONS

The absolute risk of thromboembolism among women with type 1 or 2 diabetes using hormonal contraception is low. Highly effective, intrauterine and subdermal contraceptives are excellent options for women with diabetes who hope to avoid the teratogenic effects of hyperglycemia by carefully planning their pregnancies.