Carcinogenic metal(loid)s in house dust compared to soil: Concentrations and gastric bioaccessibility.

As a sink and a source of chemicals, house dust represents a relevant medium to assess indoor exposure to metal(loid)s via incidental ingestion or inhalation. However, nationally representative indoor data are scarce. Results from the Canadian House Dust Study (CHDS, 2007-2010; n = 1025) provide nationally representative mean, median and 95th percentile concentrations for 38 elements in typical urban house dust, along with their gastric bioaccessibility. Total concentrations (median/95th percentile) of carcinogenic metal(loid)s in Canadian house dust (µg g-1) are as follows: As (9.0/40), Be (0.4/0.9), Cd (3.5/17), Co (5.6/19), Cr (99/214), Ni (62/322) and Pb (100/760). Total As and Pb concentrations in house dust exceed residential soil guidelines for the protection of human health in about one-third of Canadian homes. Percent bioaccessibilities (median) are: Cd (65%) > Pb (63%) > Be âˆ¼ Ni (36%) > Co (35%) > As (20%) > Cr (15%). Lead, Cd and Co concentrations are significantly greater in older houses (< 1976). Data from two pilot studies (n = 66 + 51) further demonstrate the distinct geochemistry of house dust compared to soils, notably enrichment of carcinogenic metal(loid)s and their increased bioaccessibility. These results provide essential baseline values to refine risk assessment and inform on health risk at contaminated sites.

Identification and quantification of trace metal(loid)s in water-extractable road dust nanoparticles using SP-ICP-MS.

Resuspension of road dust is a major source of airborne particulate matter (PM) in urban environments. Inhalation of ultrafine particles (UFP; < 0.1 µm) represents a health concern due to their ability to reach the alveoli and be translocated into the blood stream. It is therefore important to characterize chemical properties of UFPs associated with vehicle emissions. We investigated the capability of Single-Particle ICP-MS (SP-ICP-MS) to quantify key metal(loid)s in nanoparticles (NPs; < 0.1 µm) isolated from road dust collected in Toronto, Canada. Water extraction was performed to separate the <1-µm fraction from two different road dust samples (local road vs. arterial road) and a multi-element SP-ICP-MS analysis was then conducted on the samples' supernatants. Based on the particle number concentrations obtained for both supernatants, the metal(loid)-containing NPs could be grouped in the following categories: high (Cu and Zn, > 1.3 × 1011 particles/L), medium (V, Cr, Ba, Pb, Sb, Ce, La), low (As, Co, Ni, < 4.6 × 109 particles/L). The limit of detection for particle number concentration was below 5.5 × 106 particles/L for most elements, except for Cu, Co, Ni, Cr, and V (between 0.9 and 7.7 × 107 particles/L). The results demonstrate that road dust contains a wide range of readily mobilizable metal(loid)-bearing NPs and that NP numbers may vary as a function of road type. These findings have important implications for human health risk assessments in urban areas. Further research is needed, however, to comprehensively assess the NP content of road dust as influenced by various factors, including traffic volume and speed, fleet composition, and street sweeping frequency. The described method can quickly characterize multiple isotopes per sample in complex matrices, and offers the advantage of rapid sample scanning for the identification of NPs containing potentially toxic transition metal(loid)s at a low detection limit.

A drink equals how many cigarettes? Equating mortality risks from alcohol and tobacco use in Canada.

Objective: To quantify and communicate risk equivalencies for alcohol-and tobacco-attributable mortality by comparing per standard drinks consumed to per number of cigarettes smoked in Canada. Methods: Alcohol-and tobacco-attributable premature deaths (≤75 years of age) and years of life lost (YLL) were estimated using a lifetime risk modeling approach. Alcohol-attributable death statistics were obtained from the 2023 Canadian Guidance on Alcohol and Health data source. Tobacco-attributable death statistics were derived from the Mortality Population Risk Tool (MPoRT) model. Results: The risk of alcohol use on premature death and YLL increased non-linearly with the number of drinks consumed, while the risk for tobacco use on these two measures increased linearly with the number of cigarettes smoked. Males who consumed 5 drinks/day-a standard drink contains 13.45 grams of alcohol in Canada-had an equivalent risk as smoking 4.9 cigarettes/day (when modeling for premature death) and 5.1 cigarettes/day (when modeling for YLL). Females who consumed 5 drinks/day experienced an equivalent risk as smoking 4.2 cigarettes/day for premature deaths and YLL. At all levels of alcohol consumption females and males who consumed <5 drinks/day have less risks from consuming a standard drink than from smoking a cigarette. For males who consumed 5 drinks/day, the increased risks of death from per drink consumed and per cigarette smoked were equal. Conclusion: Risk equivalencies comparing alcohol use to tobacco use could help people who drink improve their knowledge and understanding of the mortality risks associated with increased number of drinks consumed per day.

Why do only some cohort studies find health benefits from low volume alcohol use? A systematic review and meta-analysis of study characteristics that may bias mortality risk estimates.

OBJECTIVE: Assumptions about alcohol's health benefits profoundly influence global disease burden estimates and drinking guidelines. Utilising theory and evidence, we identify and test study characteristics that may bias estimates of all-cause mortality risk associated with low volume drinking. METHOD: We identified 107 longitudinal studies by systematic review with 724 estimates of association between alcohol consumption and all-cause mortality for 4,838,825 participants with 425,564 recorded deaths. "Higher quality" studies had a mean cohort age of ≤55 years, followed-up beyond 55 years, and excluded former and occasional drinkers from abstainer reference groups. "Low volume" alcohol use was defined as between one drink per week (>1.30g ethanol/day) and two drinks per day (<25g ethanol/day). Mixed linear regression was used to model relative risks (RRs) of mortality for subgroups of higher versus lower quality studies. RESULTS: As predicted, studies with younger cohorts and separating former and occasional drinkers from abstainers estimated similar mortality risk for low volume drinkers (RR=0.98, 0.87-1.11) as abstainers. Studies not meeting these quality criteria estimated significantly lower risk for low volume drinkers (RR=0.84, 0.79-0.89). In exploratory analyses, studies controlling for smoking and/or socio-economic status had significantly reduced mortality risks for low volume drinkers. However, mean RR estimates for low volume drinkers in non-smoking cohorts were above 1.0 (RR=1.16, 0.91-1.41). CONCLUSIONS: Studies with lifetime selection biases may create misleading positive health associations. These biases pervade the field of alcohol epidemiology and can confuse communications about health risks. Future research should investigate whether smoking status mediates, moderates or confounds alcohol-mortality risk relationships.

Viable Clostridium botulinum spores not detected in the household dust of major Canadian cities.

Clostridium botulinum causes infant botulism by colonising the intestines and producing botulinum neurotoxin in situ. Previous reports have linked infant botulism cases to C. botulinum spores in household dust, yet the baseline incidence of C. botulinum spores in residential households is currently unknown. Vacuum cleaner dust from 963 households in 13 major Canadian cities was tested for C. botulinum using a novel real-time PCR assay directed against all known subtypes of the botulinum neurotoxin gene. None of the samples tested positive for C. botulinum. Analysis of a random subset of samples by MALDI Biotyper revealed that the most common anaerobic bacterial isolates were of the genus Clostridium and the most common species recovered overall was Clostridium perfringens. Dust that was spiked with C. botulinum spores of each toxin type successfully produced positive real-time PCR reactions. These control experiments indicate that this is a viable method for the detection of C. botulinum spores in household dust. We make several recommendations for future work that may help discover a common environmental source of C. botulinum spores that could lead to effective preventative measures for this rare but deadly childhood disease.

Pharmacological NF-κB inhibition decreases cisplatin chemoresistance in muscle-invasive bladder cancer and reduces cisplatin-induced toxicities.

Most patients with muscle-invasive bladder cancer (MIBC) are not cured with platinum chemotherapy. Up-regulation of nuclear factor kappa light-chain enhancer of activated B cells (NF-κB) is a major mechanism underlying chemoresistance, suggesting that its pharmacological inhibition may increase platinum efficacy. NF-κB signaling was investigated in two patient cohorts. The Cancer Genome Atlas (TCGA) was used to correlate NF-κB signaling and patient survival. The efficacy of cisplatin plus the NF-κB inhibitor dimethylaminoparthenolide (DMAPT) versus cisplatin or DMAPT alone was tested in vitro. Xenografted and immunocompetent MIBC mouse models were studied in vivo. Platinum-naive claudin-low MIBC showed constitutive NF-κB signaling and this was associated with reduced disease-specific survival in TCGA patients. Chemotherapy up-regulated NF-κB signaling and chemoresistance-associated genes, including SPHK1, PLAUR, and SERPINE1. In mice, DMAPT significantly improved the efficacy of cisplatin in both models. The combination preserved body weight, renal function, and morphology, reduced muscle fatigue and IL-6 serum levels, and did not aggravate immuno-hematological toxicity compared with cisplatin alone. These data provide a rationale for combining NF-κB inhibition with platinum-based chemotherapy and conducting a clinical trial in MIBC patients.

A systematic review of relative risks for the relationship between chronic alcohol use and the occurrence of disease.

Alcohol use is causally linked to the development of and mortality from numerous diseases. The aim of this study is to provide an update to a previous systematic review of meta-analyses that quantify the sex-specific dose-response risk relationships between chronic alcohol use and disease occurrence and/or mortality. An updated systematic search of multiple databases was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses criteria to identify meta-analyses published from January 1, 2017, to March 8, 2021, which quantified the risk relationships between chronic alcohol use and the risk of disease occurrence and/or mortality. This systematic review was not preregistered. The comparator was people who have never consumed at least one standard drink of alcohol. Measurements included relative risks, odds ratios, and hazard ratios of disease occurrence and/or mortality based on long-term alcohol intake measured in grams per day. The systematic search yielded 5953 articles, of which 14 were included in the narrative review. All diseases showed an increased risk of occurrence as alcohol use increased. At all doses examined, alcohol had a significant detrimental effect on tuberculosis, lower respiratory infections, oral cavity and pharyngeal cancers, esophageal cancer, colorectal cancer, liver cancer, laryngeal cancer, epilepsy, hypertension, liver cirrhosis, and pancreatitis (among men). For ischemic heart disease, ischemic stroke, and intracerebral hemorrhage, protective effects from low-dose chronic alcohol use among both men and women were observed. Low-dose alcohol consumption also had a protective effect for diabetes mellitus and pancreatitis among women (approximately to 50 g/day and 30 g/day, respectively). Alcohol use increases the risk of numerous infectious and noncommunicable diseases in a dose-response manner. Higher levels of alcohol use have a clear detrimental impact on health; however, at lower levels of use, alcohol can have both disease-specific protective and detrimental effects.

Relationships between House Characteristics and Exposures to Metal(loid)s and Synthetic Organic Contaminants Evaluated Using Settled Indoor Dust.

This study investigates associations between house characteristics and chemical contaminants in house dust, collected under the nationally representative Canadian House Dust Study (2007−2010). Vacuum samples (<80 µm fraction) were analysed for over 200 synthetic organic compounds and metal(loid)s. Spearman rank correlations between contaminant concentrations in dust and presence of children and pets, types of flooring, heating styles and other characteristics suggested a number of indoor sources, pointing to future research directions. Numerous synthetic organics were significantly associated with reported use of room deodorizers and with the presence of cats in the home. Hardwood flooring, which is a manufactured wood product, emerged as a source of metal(loid)s, phthalates, organophosphate flame retardants/plasticizers, and obsolete organochlorine pesticides such as ∑DDT (but not halogenated flame retardants). Many metal(loid)s were significantly correlated with flame-retardant compounds used in building materials and heating systems. Components of heating appliances and heat distribution systems appeared to contribute heat-resistant chemicals and alloys to settled dust. Carpets displayed a dual role as both a source and repository of dust-borne contaminants. Contaminant loadings (<80 µm fraction) were significantly elevated in heavily carpeted homes, particularly those located near industry. Depending on the chemical (and its source), the results show that increased dust mass loading may enrich or dilute chemical concentrations in dust. Research is needed to improve the characterisation of hidden indoor sources such as flame retardants used in building materials and heating systems, or undisclosed ingredients used in common household products, such as air fresheners and products used for companion animals.

Selection of metric for indoor-outdoor source apportionment of metals in PM2.5 : mg/kg versus ng/m3.

Trends in the elemental composition of fine particulate matter (PM2.5 ) collected from indoor, outdoor, and personal microenvironments were investigated using two metrics: ng/m3 and mg/kg. Pearson correlations that were positive using one metric commonly disappeared or flipped to become negative when the other metric was applied to the same dataset. For example, the correlation between Mo and S in the outdoor microenvironment was positive using ng/m3 (p < 0.05) but negative using mg/kg (p < 0.05). In general, elemental concentrations (mg/kg) within PM2.5 decreased significantly (p < 0.05) as PM2.5 concentrations (µg/m3 ) increased-a dilution effect that was observed in all microenvironments and seasons. An exception was S: in the outdoor microenvironment, the correlation between wt% S and PM2.5  flipped from negative in the winter (p < 0.01) to positive (p < 0.01) in the summer, whereas in the indoor microenvironment, this correlation was negative year-round (p < 0.05). Correlation analyses using mg/kg indicated that elemental associations may arise from Fe-Mn oxyhydroxide sorption processes that occur as particles age, with or without the presence of a common anthropogenic source. Application of mass-normalized concentration metrics (mg/kg or wt%), enabled by careful gravimetric analysis, revealed new evidence of the importance of indoor sources of elements in PM2.5 .

Characterizing the sources, concentrations and resuspension potential of metals and metalloids in the thoracic fraction of urban road dust.

Road dust is a sink and source of metals and metalloids of human health concern. To date, many studies have examined the composition of road dust but there remain critical knowledge gaps on the chemistry of thoracic fractions (< 10 µm) and their patterns of deposition and resuspension. The goal of this study is to characterize the elemental concentrations and sources of thoracic fractions of road dust and their resuspension potential for Toronto, Ontario, Canada. Bulk and thoracic road sweepings were acid digested (HF, HClO4, HNO3 and HCl) and the elemental concentrations measured using ICP-MS. Principal component analysis (PCA) was applied to infer source emissions. Annual elemental loadings to roads were estimated using data on total sweepings collected by the City of Toronto. The mass amounts of metals and metalloids (< 10 µm) available for resuspension were calculated assuming a contribution of 10% to total loadings for this fraction. The median trace element concentrations in city sweepings (n = 64) ranged from highest to lowest as follows: Mn > Zn > Ba > Cr > Cu > Pb > V > Ni > Sn > Mo > Co > As > Sb > Cd. Iron, Cr, Ni, Co, Mo and Cu levels were significantly associated with road class, with the highest concentrations measured for the expressway. Most elements, especially Sb and Zn, were enriched in thoracic sweepings. The PCA results demonstrate the importance of non-fossil fuel, traffic-related elemental emissions. Difficulties in identifying sources, given uncertainties regarding overlapping chemical profiles, are also highlighted. Significant elemental loadings to roads were estimated to occur, with the largest amounts identified for Fe, Al, Mn, Zn, Cr and Cu. Road dust resuspension is predicted to be the most important source of emissions for Fe, Al, Mn, Cr, V, Sn, Mo, Co and Sb.

Characterization of Airborne Particles Emitted During Application of Cosmetic Talc Products.

A pilot study was undertaken to characterize the concentration, duration and particle size distribution of the talc cloud that forms in the personal breathing zone (PBZ) during application of certain talc-containing cosmetics. Multiple direct-reading instruments were employed to simultaneously monitor PM4 concentrations (particulate matter with aerodynamic diameter < 4 µm; mg/m3) at different distances from each of three subjects while they applied talc products. Results indicated that the purpose and method of applying the talc product, combined with behavioral and physical differences amongst subjects, all strongly influenced airborne talc concentrations and the duration of the cloud. Air concentrations of talc in the PBZ averaged around 1.0 mg/m3, and the duration of exposure varied from less than one minute to more than ten minutes. The real-time monitors captured the occasional formation of secondary clouds, likely caused by resuspension of talc particles from skin or other surfaces. Measurements of aerosolized baby powder, face powder, and two adult body powders indicated that the median aerodynamic diameter of the talc cloud ranged from 1.7 to 2.0 µm. These direct-reading approaches were valuable for providing detailed characterization of short duration exposures to airborne talc particles, and will be useful to support future exposure assessments of talc and other powders in consumer products.

An assessment of the inhalation bioaccessibility of platinum group elements in road dust using a simulated lung fluid.

Metal enrichment of road dust is well characterized but available data on the bioaccessibility of metals in particle size fractions relevant to human respiratory health remain limited. The study goal was to investigate the bioaccessibility of platinum group elements (PGE), which are used as catalysts in automotive exhaust converters, in the inhalable fraction of road dust. Street sweepings were provided by the City of Toronto, Canada, collected as part of its Clean Roads to Clean Air program.The particle size relevance of road dust for inhalation exposures was confirmed using a laser diffraction particle size analyzer (mean Dx(50): 9.42 µm). Total PGE were determined in both bulk and inhalable fractions using nickel sulfide (NiS) fire-assay and instrumental neutron-activation analysis (INAA). PGE lung solubility was examined for the inhalable fraction using Gamble's extraction. Sample digests were co-precipitated with Te-Sn, to pre-concentrate and isolate PGE, prior to their measurement using inductively coupled plasma mass spectrometry (ICP-MS).Total PGE concentrations were enriched in the inhalable fraction of road sweepings. Geomean concentrations in the inhalable fraction were: palladium (Pd) (152 µg/kg), platinum (Pt) (55 µg/kg), rhodium (Rh) (21 µg/kg) and iridium (Ir) (0.23 µg/kg). Osmium (Os) concentrations were below the limit of detection (LOD). Bioaccessible PGEs (n = 16) using Gamble's solution were below LOD for Ir and ruthenium (Ru). For the remainder, the geomean % bioaccessibility was highest for platinum (16%), followed by rhodium (14%) and palladium (3.4%). This study provides evidence that PGE in road dust are bioaccessible in the human lung.

Cellular Constituents of the Prostate Stroma: Key Contributors to Prostate Cancer Progression and Therapy Resistance.

Reciprocal signaling between prostate stroma and its epithelium are fundamental to organ development and homeostasis. Similarly, interactions between tumor cells and stromal constituents are central to key aspects of carcinogenesis and malignancy growth involving tumor cell invasion, dissemination, and growth in distant sites. The prostate stroma is complex with several distinct resident cell types, infiltrating nonresident cell types and an amalgam of structural matrix factors, matricellular proteins, metabolites, growth factors, and cytokines. Of importance, the stroma is dynamic with changes in composition as a cause or consequence of intrinsic and extrinsic factors. In the context of epithelial neoplasia, the prostate stroma undergoes phenotypic changes with a loss of well-differentiated smooth muscle cell population and the expansion of cancer-associated fibroblast populations. This reactive stroma further coevolves with tumor progression. Recent studies show the role of tumor microenvironment components in therapy resistance and highlight the importance of a thorough knowledge of cross talk between tumor cells and microenvironment niches to develop new therapeutic strategies.

I Am Not in Your Shoes: Low Perspective Taking Mediating the Relation Among Attachment Insecurities and Physical Intimate Partner Violence in Chilean University Students.

Guided by the attachment theory, this study tested the degree to which perspective taking mediates the effects of romantic attachment on the use of physical intimate partner violence (IPV) toward the partner. Participants consisted of 608 Chilean university students involved in a romantic relationship, among whom 44.2% of women and 34.7% of men reported inflicting at least one act of violence toward their partner during the previous year. Results from a structural equation model showed that the association between avoidance of intimacy and physical IPV is mediated by perspective taking for both men and women. However, perspective taking mediated the link between attachment anxiety and physical IPV in women only. Our findings underline the importance of the individual's sense of attachment security in relation to their ability to empathize with their partners, as well as prevent the perpetration of physical IPV against them.

Positional Scanning Identifies the Molecular Determinants of a High Affinity Multi-Leucine Inhibitor for Furin and PACE4.

The proprotein convertase family of enzymes includes seven endoproteases with significant redundancy in their cleavage activity. We previously described the peptide Ac-LLLLRVK-Amba that displays potent inhibitory effects on both PACE4 and prostate cancer cell lines proliferation. Herein, the molecular determinants for PACE4 and furin inhibition were investigated by positional scanning using peptide libraries that substituted its leucine core with each natural amino acid. We determined that the incorporation of basic amino acids led to analogues with improved inhibitory potency toward both enzymes, whereas negatively charged residues significantly reduced it. All the remaining amino acids were in general well tolerated, with the exemption of the P6 position. However, not all of the potent PACE4 inhibitors displayed antiproliferative activity. The best analogues were obtained by the incorporation of the Ile residue at the P5 and P6 positions. These substitutions led to inhibitors with increased PACE4 selectivity and potent antiproliferative effects.

Comparison of Gastric versus Gastrointestinal PBET Extractions for Estimating Oral Bioaccessibility of Metals in House Dust.

Oral bioaccessibility estimates for six metals which are prevalent as contaminants in Canada (zinc, lead, cadmium, copper, nickel, and chromium) are investigated for house dust using the simple gastric phase versus the two-phase physiologically-based extraction technique (PBET). The purpose is to determine whether a complete gastrointestinal (GI) assay yields a more conservative (i.e., higher) estimate of metal bioaccessibility in house dust than the gastric phase alone (G-alone). The study samples include household vacuum dust collected from 33 homes in Montreal, Canada, plus four certified reference materials (NIST 2583, NIST 2584, NIST 2710 and NIST 2710a). Results indicate that percent bioaccessibilities obtained using G-alone are generally greater than or equivalent to those obtained using the complete GI simulation for the six studied metals in house dust. Median bioaccessibilities for G-alone/GI in household vacuum dust samples (n = 33) are 76.9%/19.5% for zinc, 50.4%/6.2% for lead, 70.0%/22.4% for cadmium, 33.9%/30.5% for copper and 28.5%/20.7% for nickel. Bioaccessible chromium is above the detection limit in only four out of 33 samples, for which G-alone results are not significantly different from GI results (p = 0.39). It is concluded that, for the six studied metals, a simple G-alone extraction provides a conservative and cost-effective approach for estimating oral bioaccessibility of metals in house dust.

The Mediating Effects of Emotion Regulation and Dyadic Coping on the Relationship Between Romantic Attachment and Non-suicidal Self-injury.

Insecure attachment is believed to play a fundamental role in non-suicidal self-injury (NSSI). In fact, the quality of parent-child attachment relationships has become an emerging topic attracting a growing number of theoretical and research contributions in the field of NSSI. However, despite these considerable advances in the scientific study of NSSI, progress pertaining to investigating the quality of romantic attachment relationship is lacking. In an effort to expand current knowledge, the present study aims to not only explore the relationships between romantic attachment and NSSI, but also to explore the mechanisms by which these two variables relate by examining the mediating role that emotion regulation and dyadic coping might play in this relationship. Participants consisted of 797 (81.9 % female) university students, all of whom were involved in a romantic relationship for at least 6 months and between the ages of 17 and 25. Results revealed that although difficulties in emotion regulation mediated the relationships between romantic attachment insecurity (i.e., attachment anxiety and avoidance) and NSSI, dyadic coping was not found to be a significant mediator. These results highlight the importance of attachment security and internal processes to manage stress in the prevention of NSSI.

Romantic Attachment and Physical Intimate Partner Violence Perpetration in a Chilean Sample: The Mediating Role of Emotion Regulation Difficulties.

Despite evidence that adult attachment insecurity has been linked to the perpetration of physical intimate violence, the mechanisms underlying this link need further exploration. The goal of this study was to evaluate the mediating role of emotion regulation difficulties in the association between romantic attachment and the use of physical intimate partner violence. To this end, 611 students recruited from Chilean universities completed the Experiences in Close Relationships questionnaire, the Difficulties in Emotion Regulation Scale, and the Revised Conflict Tactics Scales. Structural equation modeling (SEM) analyses revealed that emotion regulation difficulties mediated the relationship between dimensions of romantic attachment (anxiety over abandonment and avoidance of intimacy) and physical violence perpetration among both male and female participants. Implications for future research and clinical practice are presented herein.

Romantic Attachment and Physical Intimate Partner Violence Perpetration in a Chilean Sample: The Mediating Role of Emotion Regulation Difficulties.

Despite evidence that adult attachment insecurity has been linked to the perpetration of physical intimate violence, the mechanisms underlying this link need further exploration. The goal of this study was to evaluate the mediating role of emotion regulation difficulties in the association between romantic attachment and the use of physical intimate partner violence. To this end, 611 students recruited from Chilean universities completed the Experiences in Close Relationships questionnaire, the Difficulties in Emotion Regulation Scale, and the Revised Conflict Tactics Scales. Structural equation modeling (SEM) analyses revealed that emotion regulation difficulties mediated the relationship between dimensions of romantic attachment (anxiety over abandonment and avoidance of intimacy) and physical violence perpetration among both male and female participants. Implications for future research and clinical practice are presented herein.

Novel Insights into Structure-Activity Relationships of N-Terminally Modified PACE4 Inhibitors.

PACE4 plays important roles in prostate cancer cell proliferation. The inhibition of this enzyme has been shown to slow prostate cancer progression and is emerging as a promising therapeutic strategy. In previous work, we developed a highly potent and selective PACE4 inhibitor, the multi-Leu (ML) peptide, an octapeptide with the sequence Ac-LLLLRVKR-NH2 . Here, with the objective of developing a useful compound for in vivo administration, we investigate the effect of N-terminal modifications. The inhibitory activity, toxicity, stability, and cell penetration properties of the resulting analogues were studied and compared to the unmodified inhibitor. Our results show that the incorporation of a polyethylene glycol (PEG) moiety leads to a loss of antiproliferative activity, whereas the attachment of a lipid chain preserves or improves it. However, the lipidated peptides are significantly more toxic when compared with their unmodified counterparts. Therefore, the best results were achieved not by the N-terminal extension but by the protection of both ends with the d-Leu residue and 4-amidinobenzylamide, which yielded the most stable inhibitor, with an excellent activity and toxicity profile.