Kratom safety and toxicology in the public health context: research needs to better inform regulation.

Although kratom use has been part of life for centuries in Southeast Asia, the availability and use of kratom in the United States (US) increased substantially since the early 2000s when there was little information on kratom pharmacology, use patterns, and effects, all critical to guiding regulation and policy. Here we provide a synthesis of research with several hundred English-language papers published in the past 5 years drawing from basic research, epidemiological and surveillance data, and recent clinical research. This review of available literature aims to provide an integrated update regarding our current understanding of kratom's benefits, risks, pharmacology, and epidemiology, which may inform United States-based kratom regulation. Recent surveillance indicates there are likely several million past-year kratom consumers, though estimates vary widely. Even without precise prevalence data, kratom use is no longer a niche, with millions of United States adults using it for myriad reasons. Despite its botanical origins in the coffee tree family and its polypharmacy, kratom is popularly characterized as an opioid with presumed opioid-system-based risks for addiction or overdose. Neuropharmacology, toxicology, and epidemiology studies show that kratom is more accurately characterized as a substance with diverse and complex pharmacology. Taken together the work reviewed here provides a foundation for future scientific studies, as well as a guide for ongoing efforts to regulate kratom. This work also informs much-needed federal oversight, including by the United States Food and Drug Administration. We conclude with recommendations for kratom regulation and research priorities needed to address current policy and knowledge gaps around this increasingly used botanical product.

Progesterone receptor mediates ovulatory transcription through RUNX transcription factor interactions and chromatin remodelling.

Progesterone receptor (PGR) plays diverse roles in reproductive tissues and thus coordinates mammalian fertility. In the ovary, rapid acute induction of PGR is the key determinant of ovulation through transcriptional control of a unique set of genes that culminates in follicle rupture. However, the molecular mechanisms for this specialized PGR function in ovulation is poorly understood. We have assembled a detailed genomic profile of PGR action through combined ATAC-seq, RNA-seq and ChIP-seq analysis in wildtype and isoform-specific PGR null mice. We demonstrate that stimulating ovulation rapidly reprograms chromatin accessibility in two-thirds of sites, correlating with altered gene expression. An ovary-specific PGR action involving interaction with RUNX transcription factors was observed with 70% of PGR-bound regions also bound by RUNX1. These transcriptional complexes direct PGR binding to proximal promoter regions. Additionally, direct PGR binding to the canonical NR3C motif enable chromatin accessibility. Together these PGR actions mediate induction of essential ovulatory genes. Our findings highlight a novel PGR transcriptional mechanism specific to ovulation, providing new targets for infertility treatments or new contraceptives that block ovulation.

A randomised controlled trial of a digital intervention (Renewed) to support symptom management, wellbeing and quality of life in cancer survivors.

BACKGROUND: Many cancer survivors following primary treatment have prolonged poor quality of life. AIM: To determine the effectiveness of a bespoke digital intervention to support cancer survivors. DESIGN: Pragmatic parallel open randomised trial. SETTING: UK general practices. METHODS: People having finished primary treatment (<= 10 years previously) for colo-rectal, breast or prostate cancers, with European-Organization-for-Research-and-Treatment-of-Cancer QLQ-C30 score <85, were randomised by online software to: 1)detailed 'generic' digital NHS support ('LiveWell';n=906), 2) a bespoke complex digital intervention ('Renewed';n=903) addressing symptom management, physical activity, diet, weight loss, distress, or 3) 'Renewed-with-support' (n=903): 'Renewed' with additional brief email and telephone support. RESULTS: Mixed linear regression provided estimates of the differences between each intervention group and generic advice: at 6 months (primary time point: n's respectively 806;749;705) all groups improved, with no significant between-group differences for EORTC QLQ-C30, but global health improved more in both intervention groups. By 12 months there were: small improvements in EORTC QLQ-C30 for Renewed-with-support (versus generic advice: 1.42, 95% CIs 0.33-2.51); both groups improved global health (12 months: renewed: 3.06, 1.39-4.74; renewed-with-support: 2.78, 1.08-4.48), dyspnoea, constipation, and enablement, and lower NHS costs (generic advice £265: in comparison respectively £141 (153-128) and £77 (90-65) lower); and for Renewed-with-support improvement in several other symptom subscales. No harms were identified. CONCLUSION: Cancer survivors quality of life improved with detailed generic online support. Robustly developed bespoke digital support provides limited additional short term benefit, but additional longer term improvement in global health enablement and symptom management, with substantially lower NHS costs.

For Better or Worse: Self-reported Changes in Kratom and Other Substance Use as a Result of the COVID-19 Pandemic.

Background: Kratom is taken to self-treat pain and symptoms of psychiatric disorders, including substance-use disorders (SUDs) and opioid withdrawal. Before COVID-19, kratom use was increasing in the US, however, there are few published data on whether that trend continued during the COVID-19 pandemic, which could have affected kratom use in multiple ways. Aim: To examine COVID-19-related changes in kratom use and how these changes were experienced, relative to changes in other commonly used substances. Methods: Using Amazon Mechanical Turk, 2615 evaluable surveys were completed between September 2020 and March 2021. Responses from past-month and past-year kratom-using adults (N = 174) indicating changes for the better or worse were examined using generalized linear mixed effects models, and relevant open-text responses (n = 85) were thematically coded. Results: For kratom 33% (n = 58) reported a Covid-related increase and 24% (n = 42) reported a Covid-related decrease. Controlling for changes in amount used, alcohol (OR = 5.02), tobacco (OR = 4.72), and nonmedical opioid use (OR = 3.42) were all more likely to have changed for the worse, compared with kratom use. Relative to decreases in kratom use, decreases in alcohol (OR = 3.21) and tobacco (OR = 6.18) use were more likely to be changes for the better. Cannabis use was the only substance to display a probability lower than 50% of being a decrease for the better, and of the increases, cannabis use displayed the highest probability of being for the better. Conclusions: Increases in kratom and cannabis use were less likely than alcohol and tobacco to be reported as changes for the worse, and decreases in kratom and cannabis use were more likely than alcohol and tobacco to be reported as changes for the better. These findings indicate that people differently conceptualize their relationships with kratom and cannabis, compared to their relationships with alcohol and tobacco.

Intraovarian, Isoform-Specific Transcriptional Roles of Progesterone Receptor in Ovulation.

Progesterone receptor (PGR) activity is obligatory for mammalian ovulation; however, there is no established direct functional pathway explaining how progesterone receptor completely and specifically regulates oocyte release. This study examined the overarching cell- and isoform-specific effects of the PGR within each cellular compartment of the ovary, using mice null for the PGR (PRKO), as well as isoform-specific null mice. The PGR was expressed in ovarian granulosa and stromal cells and although PRKO ovaries showed no visible histological changes in preovulatory ovarian morphology, follicle rupture did not occur. Reciprocal ovarian transplant experiments established the necessity of ovarian PGR expression for ovulation. Cumulus-oocyte complexes of PRKO mice exhibited normal morphology but showed some altered gene expression. The examination of mitochondrial activity showed subtle differences in PRKO oocytes but no differences in granulosa cell respiration, glycolysis or ß-oxidation. Concurrently, RNA-seq identified novel functional pathways through which the PGR may regulate ovulation. PGR-A was the predominant transcriptionally active isoform in granulosa cells and 154 key PGR-dependent genes were identified, including a secondary network of transcription factors. In addition, the PGR regulated unique gene networks in the ovarian stroma. Collectively, we establish the effector pathways activated by the PGR across the ovarian cell types and conclude that PGR coordinates gene expression in the cumulus, granulosa and stromal cells at ovulation. Identifying these networks linking the PGR to ovulation provides novel targets for fertility therapeutics and nonhormonal contraceptive development.

A qualitative analysis of loss-related memories after cancer loss: a comparison of bereaved people with and without prolonged grief disorder.

Objective: The study aimed to explore the content and features of loss-related memories in a sample of individuals bereaved by cancer with and without a probable diagnosis of prolonged grief disorder/persistent complex bereavement disorder (PGD/PCBD). Methods: Semi-structured interviews with 28 bereaved adults (PGD/PCBD = 12, NoPGD/PCBD = 16) were analysed using thematic analysis. Results: Three superordinate themes were identified: (1) intrusive imagery, (2) qualities of memory, and (3) triggers. Results showed that individuals suffering from probable PGD/PCBD reported a predominance of negative and upsetting memories, happy memories triggering pain and more negative intrusive imagery than those without PGD/PCBD. Conclusions: Bereavement by cancer can result in troubling intrusive memories that overshadow positive memories. Sufferers of PGD/PCBD are more likely to experience loss-related memories as negative and upsetting. Clinical approaches that utilise memory processing may be of particular relevance in this group.

Objetivo: El estudio tuvo como objetivo explorar el contenido y las características de los recuerdos relacionados con la pérdida en una muestra de personas viviendo un duelo por cáncer con y sin un diagnóstico probable de trastorno de duelo prolongado/trastorno de duelo complejo persistente (PGD/PCBD).Métodos: Se analizaron entrevistas semiestructuradas con 28 adultos dolientes (PGD/PCBD = 12, NoPGD/PCBD = 16) mediante análisis temático.Resultados: Se identificaron tres temas supraordinados: (1) imágenes intrusivas, (2) cualidades de la memoria y (3) gatillantes. Los resultados mostraron que las personas que padecen un probable PGD/PCBD informaron un predominio de recuerdos negativos y molestos, recuerdos felices que desencadenan dolour y más imágenes intrusivas negativas que aquellos sin PGD/PCBD.Conclusiones: El duelo por cáncer puede provocar recuerdos intrusivos problemáticos que eclipsan los recuerdos positivos. Las víctimas de PGD/PCBD tienen más probabilidades de experimentar los recuerdos relacionados con la pérdida como negativos y molestos. Los enfoques clínicos que utilizan el procesamiento de memoria pueden ser de particular relevancia en este grupo.

Late boosting of the RV144 regimen with AIDSVAX B/E and ALVAC-HIV in HIV-uninfected Thai volunteers: a double-blind, randomised controlled trial.

BACKGROUND: The RV144 phase 3 vaccine trial in Thailand demonstrated that ALVAC-HIV (vCP1521) and AIDSVAX B/E administration over 6 months resulted in a 31% efficacy in preventing HIV acquisition. In this trial, we assessed the immunological effect of an additional vaccine boost to the RV144 regimen at varying intervals between the priming vaccine series and the boost. METHODS: RV306 is a double-blind, placebo-controlled, randomised clinical trial done at three clinical sites in Thailand. Eligible volunteers were HIV-uninfected individuals aged 20-40 years who were at low risk for HIV infection and in good health. A randomisation schedule was centrally generated with fixed sized strata for Research Institute for Health Sciences Chiang Mai and combined Bangkok clinics. Participants were randomly assigned to one of five groups and then further randomly assigned to either vaccine or placebo. All participants received the primary RV144 vaccine series at months 0, 1, 3, and 6. Group 1 received no additional boost, group 2 received additional AIDSVAX B/E and ALVAC-HIV (vCP1521) or placebo at month 12, group 3 received AIDSVAX B/E alone or placebo at month 12, group 4a received AIDSVAX B/E and ALVAC-HIV or placebo at month 15, and group 4b received AIDSVAX B/E and ALVAC-HIV or placebo at month 18. Primary outcomes were safety and tolerability of these vaccination regimens and cellular and humoral immune responses compared between the RV144 series alone and regimens with late boosts at different timepoints. Safety and tolerability outcomes were assessed by evaluating local and systemic reactogenicity and adverse events in all participants. This trial is registered at ClinicalTrials.gov (NCT01931358); clinical follow-up is now complete. FINDINGS: Between Oct 28, 2013, and April 29, 2014, 367 participants were enrolled, of whom 27 were assigned active vaccination in group 1, 102 in group 2, 101 in group 3, 52 in group 4a, 51 in group 4b, and 34 combined placebo across all the groups. No vaccine-related serious adverse events were recorded. Occurrence and severity of local and systemic reactogenicity were similar across active groups. Groups with late boosts (groups 2, 3, 4a, and 4b) had increased peak plasma IgG-binding antibody levels against gp70 V1V2 relative to group 1 vaccine recipients with no late boost (gp70 V1V2 92TH023 adjusted p<0·02 for each; gp70 V1V2 CaseA2 adjusted p<0·0001 for each). Boosting at month 12 (groups 2 and 3) did not increase gp120 responses compared with the peak responses after the RV144 priming regimen at month 6; however, boosting at month 15 (group 4a) improved responses to gp120 A244gD- D11 (p=0·0003), and boosting at month 18 (group 4b) improved responses to both gp120 A244gD- D11 (p<0·0001) and gp120 MNgD- D11 (p=0·0016). Plasma IgG responses were significantly lower among vaccine recipients boosted at month 12 (pooled groups 2 + 3) than at month 15 (group 4a; adjusted p<0·0001 for each, except for gp70 V1V2 CaseA2, p=0·0142) and at month 18 (group 4b; all adjusted p<0·001). Boosting at month 18 versus month 15 resulted in a significantly higher plasma IgG response to gp120 antigens (all adjusted p<0·01) but not gp70 V1V2 antigens. CD4 functionality and polyfunctionality scores after stimulation with HIV-1 Env peptides (92TH023) increased with delayed boosting. Groups with late boosts had increased functionality and polyfunctionality scores relative to vaccine recipients with no late boost (all adjusted p<0·05, except for the polyfunctionality score in group 1 vs group 4b, p<0·01). INTERPRETATION: Taken together, these results suggest that additional boosting of the RV144 regimen with longer intervals between the primary vaccination series and late boost improved immune responses and might improve the efficacy of preventing HIV acquisition. FUNDING: US National Institute of Allergy and Infectious Diseases and US Department of the Army.

Self-reported Health Diagnoses and Demographic Correlates With Kratom Use: Results From an Online Survey.

OBJECTIVES: To determine whether diagnosed pre-existing health conditions correlate with Kratom demographics and use patterns. METHODS: A cross-sectional, anonymous US national online survey was conducted among 8049 Kratom users in October, 2016 to obtain demographic, health, and Kratom use pattern information. RESULTS: People who use Kratom to mitigate illicit drug dependence self-reported less pain and better overall health than individuals who used Kratom for acute/chronic pain. Self-reported improvements in pre-existing mental health symptoms (attention deficit and hyperactivity disorder/attention deficit disorder, anxiety, bipolar disorder, post-traumatic stress disorder, and depression) attributed to Kratom use were greater than those related to somatic symptoms (back pain, rheumatoid arthritis, acute pain, chronic pain, fibromyalgia). Demographic variables, including female sex, older age, employment status, and insurance coverage correlated with increased likelihood of Kratom use. CONCLUSIONS: Kratom use may serve as a self-treatment strategy for a diverse population of patients with pre-existing health diagnoses. Healthcare providers need to be engaging with patients to address safety concerns and potential limitations of its use in clinical practice for specific health conditions.

Developing a digital intervention for cancer survivors: an evidence-, theory- and person-based approach.

This paper illustrates a rigorous approach to developing digital interventions using an evidence-, theory- and person-based approach. Intervention planning included a rapid scoping review that identified cancer survivors' needs, including barriers and facilitators to intervention success. Review evidence (N = 49 papers) informed the intervention's Guiding Principles, theory-based behavioural analysis and logic model. The intervention was optimised based on feedback on a prototype intervention through interviews (N = 96) with cancer survivors and focus groups with NHS staff and cancer charity workers (N = 31). Interviews with cancer survivors highlighted barriers to engagement, such as concerns about physical activity worsening fatigue. Focus groups highlighted concerns about support appointment length and how to support distressed participants. Feedback informed intervention modifications, to maximise acceptability, feasibility and likelihood of behaviour change. Our systematic method for understanding user views enabled us to anticipate and address important barriers to engagement. This methodology may be useful to others developing digital interventions.

Effectiveness of a Cancer Bereavement Therapeutic Group.

This study examined the effectiveness of a novel cancer bereavement group. Twenty-seven participants attended a sixsession cancer bereavement therapeutic group. Data were collected at baseline, intervention completion, and three-month follow-up. Grief intensity and symptoms of posttraumatic stress disorder (PTSD), depression, and anxiety were reduced postintervention, and self-compassion increased. At follow-up, improvement remained for grief, PTSD, and depression. A small quasi-experimental waiting-list comparison group showed no change on any measure between baseline and waiting-list end. This study provides preliminary evidence that a brief therapeutic group is an effective intervention for cancer bereavement.

Prevalence and Correlates of Electronic Cigarette Use Among a Clinical Sample of Polysubstance Users in Kentucky: Long Live the Cigarette?

BACKGROUND: E-cigarette use has increased in the US, yet, in some regions rates of cigarette use remain high. PURPOSE: To describe the prevalence and features of lifetime and past-year e-cigarette use among a clinical sample of polysubstance users in Kentucky, and to determine significant associations of past-year e-cigarette use. RESULTS: Of the final sample (N = 497), 83.5% reported having ever used e-cigarettes and 97.2% reported having ever used cigarettes. These rates surpass those found among Kentucky's general population. Compared to those who did not report e-cigarette use, e-cigarette users were more likely to be younger ( x¯ = 33.4 vs. 43.6, p<.001) and White (88.2.1% vs. 62.5%, p = .001). E-cigarette users showed higher rates for lifetime incarceration (91.1% vs. 72.8%, p = .001) and past-year arrest (75.0% vs. 47.5%, p = .001). This group also presented with more severe substance use history and lower mean age for illicit drug use initiation ( x¯ = 13.8 vs. 16.4, p = .001). Approximately 65% of the sample reported past-year e-cigarette use and 96.6% reported past-year cigarette use. Logistic regression indicated that being younger (AOR = .973, p = .030), White (AOR = 1.92, .046), having a past-year arrest (AOR = 1.73, p = .047) and having used cigarettes (AOR = 8.93, p = .001) or kratom (AOR = 3.04, p = .025) within the past year were significantly associated with past-year e-cigarette use. CONCLUSIONS: E-cigarette use was related to more severe drug-using patterns. Rates of dual tobacco use among this sample are high, particularly among younger individuals. In ecological contexts where cigarette use remains normative, it is likely that dual use will persist for nicotine-dependent, polysubstance-using individuals.

Synthetic cannabinoid use among a sample of individuals enrolled in community-based recovery programs: Are synthetic cannabinoids actually preferred to other drugs?

Background: Over the past decade, availability and use of novel psychoactive substances such as synthetic cannabinoid receptor agonists (SCRA) have proliferated globally. However, the prevalence of SCRAs use remains uncertain, as does the degree to which individuals reporting SCRA use prefer SCRA to other drugs. Methods: In April 2017, a total of 500 anonymous surveys were completed by clients enrolled in a residential drug recovery program. Chi-square and t tests were used to examine significant differences between those who had ever used SCRA and those who had not. Logistic regression analysis was conducted in order to determine which other substances used within the past 12 months were significantly associated with past-12-month SCRA use. Results: About 69% (68.4%) of clients reported lifetime SCRA use. Those reporting SCRA use were predominantly younger ( x¯ = 32.5 vs. 40.7, P < .001), single (60.3% vs. 48.1%, P = .011), and white (87.1% vs. 77.7%, P = .008) and were more likely to have experienced past-12-month homelessness (6.5% vs. 3.2%, P = .004). This group had higher rates of probation/parole involvement (79.2% vs. 61.8%, P < .001) and incarceration (91.8% vs. 79.6%, P < .001). Individuals reporting SCRA use also showed extensive substance use histories and favored heroin, opioids, and amphetamines compared with SCRA. Only 5.2% of the SCRA-using group stated that SCRA was a preferred substance, and only 11.8% reported that they would try SCRA again. E-cigarettes (adjusted odds ratio [AOR] = 1.88), traditional cannabis (AOR = 3.87), amphetamines (AOR = 2.20), and synthetic cathinones (AOR = 3.51) were significantly associated with past-12-month SCRA use. Motivations for use included circumnavigating drug screens and peer influence. Approximately half of those who tried SCRA reported adverse effects associated with use. Conclusions: Prevalence of SCRA use among individuals with a history of substance misuse and criminal justice system involvement is high; however, SCRA are not indicated as a preferred drug.

A Recombinant Vesicular Stomatitis Virus Ebola Vaccine.

BACKGROUND: The worst Ebola virus disease (EVD) outbreak in history has resulted in more than 28,000 cases and 11,000 deaths. We present the final results of two phase 1 trials of an attenuated, replication-competent, recombinant vesicular stomatitis virus (rVSV)-based vaccine candidate designed to prevent EVD. METHODS: We conducted two phase 1, placebo-controlled, double-blind, dose-escalation trials of an rVSV-based vaccine candidate expressing the glycoprotein of a Zaire strain of Ebola virus (ZEBOV). A total of 39 adults at each site (78 participants in all) were consecutively enrolled into groups of 13. At each site, volunteers received one of three doses of the rVSV-ZEBOV vaccine (3 million plaque-forming units [PFU], 20 million PFU, or 100 million PFU) or placebo. Volunteers at one of the sites received a second dose at day 28. Safety and immunogenicity were assessed. RESULTS: The most common adverse events were injection-site pain, fatigue, myalgia, and headache. Transient rVSV viremia was noted in all the vaccine recipients after dose 1. The rates of adverse events and viremia were lower after the second dose than after the first dose. By day 28, all the vaccine recipients had seroconversion as assessed by an enzyme-linked immunosorbent assay (ELISA) against the glycoprotein of the ZEBOV-Kikwit strain. At day 28, geometric mean titers of antibodies against ZEBOV glycoprotein were higher in the groups that received 20 million PFU or 100 million PFU than in the group that received 3 million PFU, as assessed by ELISA and by pseudovirion neutralization assay. A second dose at 28 days after dose 1 significantly increased antibody titers at day 56, but the effect was diminished at 6 months. CONCLUSIONS: This Ebola vaccine candidate elicited anti-Ebola antibody responses. After vaccination, rVSV viremia occurred frequently but was transient. These results support further evaluation of the vaccine dose of 20 million PFU for preexposure prophylaxis and suggest that a second dose may boost antibody responses. (Funded by the National Institutes of Health and others; rVSV∆G-ZEBOV-GP ClinicalTrials.gov numbers, NCT02269423 and NCT02280408 .).

Fragment-Based Discovery of Potent and Selective DDR1/2 Inhibitors.

The DDR1 and DDR2 receptor tyrosine kinases are activated by extracellular collagen and have been implicated in a number of human diseases including cancer. We performed a fragment-based screen against DDR1 and identified fragments that bound either at the hinge or in the back pocket associated with the DFG-out conformation of the kinase. Modeling based on crystal structures of potent kinase inhibitors facilitated the "back-to-front" design of potent DDR1/2 inhibitors that incorporated one of the DFG-out fragments. Further optimization led to low nanomolar, orally bioavailable inhibitors that were selective for DDR1 and DDR2. The inhibitors were shown to potently inhibit DDR2 activity in cells but in contrast to unselective inhibitors such as dasatinib, they did not inhibit proliferation of mutant DDR2 lung SCC cell lines.

Antimalarial activity of 9a-N substituted 15-membered azalides with improved in vitro and in vivo activity over azithromycin.

Novel classes of antimalarial drugs are needed due to emerging drug resistance. Azithromycin, the first macrolide investigated for malaria treatment and prophylaxis, failed as a single agent and thus novel analogues were envisaged as the next generation with improved activity. We synthesized 42 new 9a-N substituted 15-membered azalides with amide and amine functionalities via simple and inexpensive chemical procedures using easily available building blocks. These compounds exhibited marked advances over azithromycin in vitro in terms of potency against Plasmodium falciparum (over 100-fold) and high selectivity for the parasite and were characterized by moderate oral bioavailability in vivo. Two amines and one amide derivative showed improved in vivo potency in comparison to azithromycin when tested in a mouse efficacy model. Results obtained for compound 6u, including improved in vitro potency, good pharmacokinetic parameters, and in vivo efficacy higher than azithromycin and comparable to chloroquine, warrant its further development for malaria treatment and prophylaxis.

Minimal social network effects evident in cancer screening behavior.

BACKGROUND: Social networks may influence screening behaviors. We assessed whether screening for breast, prostate, or colorectal cancer is influenced by the actual screening behaviors of siblings, friends, spouses, and coworkers. METHODS: We conducted an observational study using Framingham Heart Study data to assess screening for eligible individuals during the late 1990s. We used logistic regression to determine whether the probability of screening for breast, prostate, or colorectal cancer was influenced by the proportion of siblings, friends, and coworkers who had the same screening, as well as spouse's screening for colorectal cancer, adjusting for other factors that might influence screening rates. RESULTS: Among 1660 women aged 41-70 years, 71.7% reported mammography in the previous year; among 1217 men aged 51-70 years, 43.3% reported prostate-specific antigen testing in the previous year; and among 1426 men and women aged 51-80 years, 46.9% reported stool blood testing and/or sigmoidoscopy in the previous year. An increasing proportion of sisters who had mammography in the previous year was associated with mammography screening in the ego (odds ratio [OR], 1.034; 95% confidence interval [CI], 1.000-1.065 for each 10% increase). A spouse with recent screening was associated with more colorectal cancer screening (OR, 1.65; 95% CI, 1.39-1.98 vs unmarried). Otherwise, screening behaviors of siblings, friends, and coworkers were not associated with screening in the ego. CONCLUSIONS: Aside from a slight increase in breast cancer screening among women whose sisters were screened and colorectal cancer screening if spouses were screened, the screening behavior of siblings, friends, or coworkers did not influence cancer screening behaviors.

Chemical stability of the peroxide bond enables diversified synthesis of potent tetraoxane antimalarials.

Of 17 prepared 1,2,4,5-tetraoxacyclohexanes stable to reductive and acidic conditions, 3 of them were more active than artemisinin against CQ and MFQ resistant strain TM91C235 and all compounds were more active in vitro against W2 than against D6 strain. In vivo, amines 10 and 11a cured all mice at higher doses with MCD < or = 37.5 (mg/kg)/day. Triol 13 was exceptionally active against melanoma (LOX IMVI) and ovarian cancer (IGROV1), both with LC 50 = 60 nM.

Synthesis and structure-activity relationship studies on tryprostatin A, an inhibitor of breast cancer resistance protein.

Tryprostatin A is an inhibitor of breast cancer resistance protein, consequently a series of structure-activity studies on the cell cycle inhibitory effects of tryprostatin A analogues as potential antitumor antimitotic agents have been carried out. These analogues were assayed for their growth inhibition properties and their ability to perturb the cell cycle in tsFT210 cells. SAR studies resulted in the identification of the essential structural features required for cytotoxic activity. The absolute configuration L-Tyr-L-pro in the diketopiperazine ring along with the presence of the 6-methoxy substituent on the indole moiety of 1 was shown to be essential for dual inhibition of topoisomerase II and tubulin polymerization. Biological evaluation also indicated the presence of the 2-isoprenyl moiety on the indole scaffold of 1 was essential for potent inhibition of cell proliferation. Substitution of the indole N(a)-H in 1 with various alkyl or aryl groups, incorporation of various L-amino acids into the diketopiperazine ring in place of L-proline, and substitution of the 6-methoxy group in 1 with other functionality provided active analogues. The nature of the substituents present on the indole N(a)-H or the indole C-2 position influenced the mechanism of action of these analogues. Analogues 68 (IC(50)=10 microM) and 67 (IC(50)=19 microM) were 7-fold and 3.5-fold more potent, respectively, than 1 (IC(50)=68 microM) in the inhibition of the growth of tsFT210 cells. Diastereomer-2 of tryprostatin B 8 was a potent inhibitor of the growth of three human carcinoma cell lines: H520 (IC(50)=11.9 microM), MCF-7 (IC(50)=17.0 microM) and PC-3 (IC(50)=11.1 microM) and was equipotent with etoposide, a clinically used anticancer agent. Isothiocyanate analogue 71 and 6-azido analogue 72 were as potent as 1 in the tsFT210 cell proliferation and may be useful tools in labeling BCRP.

Deoxycholic acid-derived tetraoxane antimalarials and antiproliferatives(1).

The synthesis of deoxycholic acid (DCA)- and cholic acid (CA)-derived mixed tetraoxanes revealed that N-(2-dimethylamino)ethyl derivatives are potent antimalarials in vitro and in vivo. The tetraoxanes presented in this paper are dual inhibitors: besides curing mice in vivo without observed toxic effects, they kill cancer cell lines at very low concentrations. For example, DCA and CA derivatives 16 and 25 cured 3/5 (160 mg/kg/day) and 2/5 (40 mg/kg/day, MTD >960 mg/kg), respectively, and they were extremely active against melanoma LOX IMVI cancer, LC50 = 22 nM and 69 nM, respectively.

Tetraoxane antimalarials and their reaction with Fe(II).

Mixed tetraoxanes 5a and 13 synthesized from cholic acid and 4-oxocyclohexanecarboxylic acid were as active as artemisinin against chloroquine-susceptible, chloroquine-resistant, and multidrug-resistant Plasmodium falciparum strains (IC50, IC90). Most active 13 is metabolically stable in in vitro metabolism studies. In vivo studies on tetraoxanes with a C(4' ') methyl group afforded compound 15, which cured 4/5 mice at 600 and 200 mg.kg-1.day-1, and 2/5 mice at 50 mg.kg-1.day-1, showing no toxic effects. Tetraoxane 19 was an extremely active antiproliferative with LC50 of 17 nM and maximum tolerated dose of 400 mg/kg. In Fe(II)-induced scission of tetraoxane antimalarials only RO* radicals were detected by EPR experiments. This finding and the indication of Fe(IV)=O species led us to propose that RO* radicals are probably capable of inducing the parasite's death. Our results suggest that C radicals are possibly not the only lethal species derived from peroxide prodrug antimalarials, as currently believed.