A genome-scale CRISPR screen reveals PRMT1 as a critical regulator of androgen receptor signaling in prostate cancer.

Androgen receptor (AR) signaling is the central driver of prostate cancer across disease states. While androgen deprivation therapy (ADT) is effective in the initial treatment of prostate cancer, resistance to ADT or to next-generation androgen pathway inhibitors invariably arises, most commonly through the re-activation of the AR axis. Thus, orthogonal approaches to inhibit AR signaling in advanced prostate cancer are essential. Here, via genome-scale CRISPR-Cas9 screening, we identify protein arginine methyltransferase 1 (PRMT1) as a critical mediator of AR expression and signaling. PRMT1 regulates the recruitment of AR to genomic target sites and the inhibition of PRMT1 impairs AR binding at lineage-specific enhancers, leading to decreased expression of key oncogenes, including AR itself. In addition, AR-driven prostate cancer cells are uniquely susceptible to combined AR and PRMT1 inhibition. Our findings implicate PRMT1 as a key regulator of AR output and provide a preclinical framework for co-targeting of AR and PRMT1 in advanced prostate cancer.

Design and Synthesis of New 1,3,5-Trisubstituted Triazines for the Treatment of Cancer and Inflammation.

Low-molecular-weight synthetic molecules 1 with the general 2-(fluorophenylamino)-4,6-disubstituted 1,3,5-triazine structure and showing anti-inflammatory and anticancer activities were explored. Structure-activity relationship studies demonstrated the importance of the aminopentyl chain, the 3- or 4-fluorophenylaniline component, and the presence of at least one substituent, such as a tyramine moiety, attached directly to the triazine ring as essential for good activity. These compounds, represented by leads 4-{2-[4-(5-Aminopentylamino)-6-(3-fluorophenylamino)-1,3,5-triazin-2-ylamino]ethyl}phenol (6) and 4-{2-[4-(5-Aminopentylamino)-6-(4-fluorophenylamino)-1,3,5-triazin-2-ylamino]ethyl}phenol (10), displayed moderate and significant in vitro and in vivo dual activities, respectively, and address the molecular link between inflammation and cancer. Compound 10 demonstrated significant antitumor efficacy upon administration by the oral and intravenous routes in several animal models. This class of triazine compounds is new, safe, and nontoxic and offers a novel approach to the treatment of inflammation and cancer.

A Newly Discovered Antifibrotic Pathway Regulated by Two Fatty Acid Receptors: GPR40 and GPR84.

Numerous clinical conditions can lead to organ fibrosis and functional failure. There is a great need for therapies that could effectively target pathophysiological pathways involved in fibrosis. GPR40 and GPR84 are G protein-coupled receptors with free fatty acid ligands and are associated with metabolic and inflammatory disorders. Although GPR40 and GPR84 are involved in diverse physiological processes, no evidence has demonstrated the relevance of GPR40 and GPR84 in fibrosis pathways. Using PBI-4050 (3-pentylbenzeneacetic acid sodium salt), a synthetic analog of a medium-chain fatty acid that displays agonist and antagonist ligand affinity toward GPR40 and GPR84, respectively, we uncovered an antifibrotic pathway involving these receptors. In experiments using Gpr40- and Gpr84-knockout mice in models of kidney fibrosis (unilateral ureteral obstruction, long-term post-acute ischemic injury, and adenine-induced chronic kidney disease), we found that GPR40 is protective and GPR84 is deleterious in these diseases. Moreover, through binding to GPR40 and GPR84, PBI-4050 significantly attenuated fibrosis in many injury contexts, as evidenced by the antifibrotic activity observed in kidney, liver, heart, lung, pancreas, and skin fibrosis models. Therefore, GPR40 and GPR84 may represent promising molecular targets in fibrosis pathways. We conclude that PBI-4050 is a first-in-class compound that may be effective for managing inflammatory and fibrosis-related diseases.

Potential years of life lost at ages 25 to 74 among Métis and non-Status Indians, 1991 to 2001.

BACKGROUND: Aboriginal peoples experience a disproportionate burden of disease, compared with other Canadians. However, relatively little information is available about mortality among Métis and non-Status Indians. METHODS: This study calculates potential years of life lost before age 75 (PYLL) for people aged 25 to 74 by all-cause and cause-specific mortality, and examines the effect of socio-economic factors on premature mortality. Age-specific and age-standardized PYLL rates were calculated for 11,600 Métis, 5,400 non-Status Indians, and 2,475,700 non-Aboriginal adults based on the number of person-years at risk up to age 75. RESULTS: Métis and non-Status Indian adults had about twice the risk of dying before age 75, compared with non-Aboriginal adults. While the largest percentage of PYLL was due to non-communicable diseases such as cardiovascular disease and cancer, relative and absolute inequalities were greatest for injuries. Socioeconomic indicators such as income, education and employment explained a large share of the disparities in premature mortality. INTERPRETATION: The results highlight the losses of potential years of life due to chronic diseases, as well as the possible importance of injury prevention programs for Métis and non-Status Indians.

Birth outcomes in the Inuit-inhabited areas of Canada.

BACKGROUND: Information on health disparities between Aboriginal and non-Aboriginal populations is essential for developing public health programs aimed at reducing such disparities. The lack of data on disparities in birth outcomes between Inuit and non-Inuit populations in Canada prompted us to compare birth outcomes in Inuit-inhabited areas with those in the rest of the country and in other rural and northern areas of Canada. METHODS: We conducted a cohort study of all births in Canada during 1990-2000 using linked vital data. We identified 13,642 births to residents of Inuit-inhabited areas and 4,054,489 births to residents of all other areas. The primary outcome measures were preterm birth, stillbirth and infant death. RESULTS: Compared with the rest of Canada, Inuit-inhabited areas had substantially higher rates of preterm birth (risk ratio [RR] 1.45, 95% confidence interval [CI] 1.38-1.52), stillbirth (RR 1.68, 95% CI 1.38-2.04) and infant death (RR 3.61, 95% CI 3.17-4.12). The risk ratios and absolute differences in risk for these outcomes changed little over time. Excess mortality was observed for all major causes of infant death, including congenital anomalies (RR 1.64), immaturity-related conditions (RR 2.96), asphyxia (RR 2.43), sudden infant death syndrome (RR 7.15), infection (RR 8.32) and external causes (RR 7.30). Maternal characteristics accounted for only a small part of the risk disparities. Substantial risk ratios for preterm birth, stillbirth and infant death remained when the comparisons were restricted to other rural or northern areas of Canada. INTERPRETATION: The Inuit-inhabited areas had much higher rates of preterm birth, stillbirth and infant death compared with the rest of Canada and with other rural and northern areas. There is an urgent need for more effective interventions to improve maternal and infant health in Inuit-inhabited areas.

2,4,6-trisubstituted triazines as protein a mimetics for the treatment of autoimmune diseases.

A first-in-class series of low molecular weight trisubstituted triazines were synthesized and evaluated for their ability to mimic protein A binding to human IgG antibody. The structure-activity relationship (SAR) demonstrates that the 1,3-phenylenediamine component was essential for robust activity. Twenty-two compounds, represented by lead molecule 34, displayed significant activity compared to protein A. These compounds may prove useful for the treatment of autoimmune disease.

Synthesis and antimicrobial activity of 2-fluorophenyl-4,6-disubstituted [1,3,5]triazines.

A series of 2-fluorophenyl-4,6-disubstituted [1,3,5]triazines (1) and (2) were synthesized and evaluated for their antimicrobial activity against three representative gram-positive bacteria and two fungi. The structure-activity relationship (SAR) demonstrates that the 3- or 4-fluorophenyl component attached directly to the triazine ring was essential for activity. Of these compounds, 14, 15, and 25 demonstrated significant activity against all selected organisms compared to control. These compounds were generally nontoxic and may prove useful as antimicrobial agents.

Mortality of Métis and registered Indian adults in Canada: an 11-year follow-up study.

BACKGROUND: Little information has been published about the mortality of the Métis people of Canada. This study describes mortality patterns among Métis and Registered Indian adults, compared with the non-Aboriginal population. DATA SOURCE AND METHODS: The 1991 to 2001 Canadian census mortality followup study tracked mortality among a 15% sample of respondents aged 25 or older, including 11,800 Métis, 56,700 Registered Indians and 2,624,300 non-Aboriginal adults, all of whom were enumerated by the 1991 census long-form questionnaire. Age-specific and age-standardized mortality rates and period life tables based on the number of person-years at risk were calculated across the various groups. Métis were defined by ethnic origin (ancestry). RESULTS: Compared with non-Aboriginal members of the cohort, life expectancy at age 25 was 3.3 and 5.5 years shorter for Métis men and women, respectively, and 4.4 and 6.3 years shorter for Registered Indians. For both Aboriginal groups, mortality rate ratios were highest at younger ages. Mortality rate differences among Métis men were particularly elevated for external causes and circulatory, respiratory and digestive system diseases; among Métis women, for circulatory system diseases, cancers, and digestive and respiratory system diseases. Generally, rate differences for Registered Indian men and women were further elevated. CONCLUSIONS: Métis adults had higher mortality rates compared with non-Aboriginal members of the cohort, but lower rates than did Registered Indians.

2,6,9-Trisubstituted purine derivatives as protein A mimetics for the treatment of autoimmune diseases.

A series of 9-substituted and 2,9-disubstituted 6-(3-aminophenylamino) purines were synthesized and evaluated for their ability to mimic protein A binding to human IgG antibody. The structure-activity relationship (SAR) demonstrates that the 6-(3-aminoanilinyl) purine component was essential for activity. Purine 14 demonstrated significant activity, compared to protein A. These compounds may prove useful for the treatment of autoimmune diseases.

Enhancement of Th1 type cytokine production and primary T cell activation by PBI-1393.

In previous reports, we have shown that PBI-1393 (formerly BCH-1393), N,N-Dimethylaminopurine pentoxycarbonyl D-arginine, stimulates cytotoxic T-lymphocyte (CTL) responses both in vitro and in vivo in normal immune status and immunosuppressed mice. Additionally, PBI-1393 was tested for anticancer activity in syngeneic mouse experimental tumor models and it displayed significant inhibition of tumor outgrowths when given in combination with sub-therapeutic doses of cytotoxic drugs (cyclophosphamide, 5-fluorouracil, doxorubicin and cis-platinum). However, the mechanism of action of PBI-1393 was still unknown. Here, we report that PBI-1393 enhances IL-2 and IFN-gamma production in human activated T cells by 51% and 46% respectively. PBI-1393 increases also IL-2 and IFN-gamma mRNA expression as shown by RT-PCR. The physiological relevance of IL-2 and IFN-gamma gene modulation by PBI-1393 is illustrated by the advantageous increase of T cell proliferation (39+/-0.3% above control) and human CTL response against prostate (PC-3) cancer cells (42+/-0.03%). The enhancement of human T cell proliferation and CTL activation by PBI-1393 demonstrates that this compound potentiates the immune response and in this regard, it could be used as an alternative approach to IL-2 and/or IFN-gamma therapy against cancer.