The influence of supportive therapy with a six-component myophlebotropic preparation on the reduction of symptoms in patients with symptoms of hemorrhoidal disease.

<b>Introduction:</b> Hemorrhoidal disease is the most common disease treated in proctology ambulatories. Conservative treatment is the basic form of treatment for this disease. One of the elements of treatment may be preparations with myoand phlebotropic effects.<b>Aim:</b> To assess the effect of a multi-ingredient myophlebotropic dietary supplement used as an adjunct on the rate and effectiveness of symptom relief in patients with stage II and III hemorrhoidal disease.<b>Material and method:</b> Patients with stage II and III hemorrhoidal disease with clinical symptoms such as pain, burning, itching and bleeding were qualified for the study. The patients were divided into two groups. The control group (Group I) of 29 patients receiving standard local treatment plus placebo and the study group (Group II) of 32 patients receiving the same local treatment and a six-component myophlebotropic product. Symptoms were analyzed at the time of inclusion in the study (day 0), after 4 and 10 days of therapy. The severity of hemorrhoidal disease and the feeling of relief were assessed on the day of inclusion (W0) and after 30 days of therapy.<b>Results:</b> There were no statistical differences between the groups in terms of disease advancement, age, gender, and duration of symptoms. Compared to the moment of inclusion in the study (W0), after 4 days (W1), after 10 days (W2) of taking the multi- -component product, there was a statistically significant improvement in the VAS scale: spontaneous pain and pain during defecation. In the qualitative assessment (yes/no), there were statistically significantly fewer cases of burning in the anus and itching. The treatment did not affect the rate of spontaneous bleeding, which was low at the beginning of the study, but significantly reduced the rate of bleeding during defecation. After 30 days of observation, it was found that the improvement in the severity of hemorrhoidal disease symptoms was significantly higher in the group using the tested preparation. Relief after a month of the study (one-question method) was noted in the group of patients receiving the tested product.<b>Conclusions:</b> The tested six-component myophlebotropic product proved to be effective in reducing the severity of symptoms such as spontaneous pain, pain during defecation, burning/burning in the anus and bleeding during defecation. Statistical significance was demonstrated in the symptom's relief and reduction in the severity of hemorrhoidal disease.

Happiness Maximization Is a WEIRD Way of Living.

Psychological science tends to treat subjective well-being and happiness synonymously. We start from the assumption that subjective well-being is more than being happy to ask the fundamental question: What is the ideal level of happiness? From a cross-cultural perspective, we propose that the idealization of attaining maximum levels of happiness may be especially characteristic of Western, educated, industrial, rich, and democratic (WEIRD) societies but less so for others. Searching for an explanation for why "happiness maximization" might have emerged in these societies, we turn to studies linking cultures to their eco-environmental habitat. We discuss the premise that WEIRD cultures emerged in an exceptionally benign ecological habitat (i.e., faced relatively light existential pressures compared with other regions). We review the influence of the Gulf Stream on the Northwestern European climate as a source of these comparatively benign geographical conditions. We propose that the ecological conditions in which WEIRD societies emerged afforded them a basis to endorse happiness as a value and to idealize attaining its maximum level. To provide a nomological network for happiness maximization, we also studied some of its potential side effects, namely alcohol and drug consumption and abuse and the prevalence of mania. To evaluate our hypothesis, we reanalyze data from two large-scale studies on ideal levels of personal life satisfaction-the most common operationalization of happiness in psychology-involving respondents from 61 countries. We conclude that societies whose members seek to maximize happiness tend to be characterized as WEIRD, and generalizing this across societies can prove problematic if adopted at the ideological and policy level.

Enhancing the Drug-Like Profile of a Potent Peptide PACE4 Inhibitor by the Formation of a Host-Guest Inclusion Complex with ß-Cyclodextrin.

The enzyme PACE4 has been validated as a promising therapeutic target to expand the range of prostate cancer (PCa) treatments. In recent years, we have developed a potent peptidomimetic inhibitor, namely, compound C23 (Ac-(DLeu)LLLRVK-4-amidinobenzylamide). Like many peptides, C23 suffers from an unfavorable drug-like profile which, despite our efforts, has not yet benefited from the usual SAR studies. Hence, we turned our attention toward a novel formulation strategy, i.e., the use of cyclodextrins (CDs). CDs can benefit compounds through the formation of "host-guest" complexes, shielding the guest from degradation and enhancing biological survival. In this study, a series of ßCD-C23 complexes have been generated and their properties evaluated, including potency toward the enzyme in vitro, a cell-based proliferation assay, and stability in plasma. As a result, a new ßCD-formulated lead compound has been identified, which, in addition to being more soluble and more potent, also showed an improved stability profile.

Cleavage of the V-ATPase associated prorenin receptor is mediated by PACE4 and is essential for growth of prostate cancer cells.

Phosphatase and tensin homolog (PTEN) mutation is common in prostate cancer during progression to metastatic and castration resistant forms. We previously reported that loss of PTEN function in prostate cancer leads to increased expression and secretion of the Prorenin Receptor (PRR) and its soluble processed form, the soluble Prorenin Receptor (sPRR). PRR is an essential factor required for proper assembly and activity of the vacuolar-ATPase (V-ATPase). The V-ATPase is a rotary proton pump required for the acidification of intracellular vesicles including endosomes and lysosomes. Acidic vesicles are involved in a wide range of cancer related pathways such as receptor mediated endocytosis, autophagy, and cell signalling. Full-length PRR is cleaved at a conserved consensus motif (R-X-X-R↓) by a member of the proprotein convertase family to generate sPRR, and a smaller C-terminal fragment, designated M8.9. It is unclear which convertase processes PRR in prostate cancer cells and how processing affects V-ATPase activity. In the current study we show that PRR is predominantly cleaved by PACE4, a proprotein convertase that has been previously implicated in prostate cancer. We further demonstrate that PTEN controls PRR processing in mouse tissue and controls PACE4 expression in prostate cancer cells. Furthermore, we demonstrate that PACE4 cleavage of PRR is needed for efficient V-ATPase activity and prostate cancer cell growth. Overall, our data highlight the importance of PACE4-mediated PRR processing in normal physiology and prostate cancer tumorigenesis.

Multicultural Identity Integration versus Compartmentalization as Predictors of Subjective Well-Being for Third Culture Kids: The Mediational Role of Self-Concept Consistency and Self-Efficacy.

Globalization has resulted in an exponential increase in the number of Third Culture Kids (TCKs), defined as being raised in a culture other than that of their parents (or the passport country) and meaningfully interacting with different cultures. Inconsistencies regarding the effect of multicultural and transient experiences on well-being exist in the psychological literature. We aimed to reveal associations between multicultural identity configurations (integration, categorization, compartmentalization) and well-being with the mediating role of self-concept consistency and self-efficacy. Participants (n = 399, M = 21.2 years) were students at an international university in the United Arab Emirates. We used the Multicultural Identity Integration Scale, the Berne Questionnaire of Subjective Well-Being, the General Self-Efficacy Scale, and the Self-Consistency Subscale from the Self-Construal Scale. The findings suggest that not merely exposure to diversity but also internal integration versus identity compartmentalization moderate the well-being of TCKs. We explained such mechanisms via partial mediation of self-consistency and self-efficacy. Our study contributed to a better understanding of the TCKs' identity paradigm and pointed to multicultural identity integration as vital to TCKs' well-being via its effect on self-consistency and self-efficacy. Conversely, identity compartmentalization decreased well-being via a reduction in the sense of self-consistency.

New Ecological Paradigm and third culture kids: Multicultural identity configurations, global mindset and values as predictors of environmental worldviews.

Ecological degradation threatens human survival, increasing the need to understand factors related to pro-environmental attitudes and worldviews. In a globalising world, new paradigms arise as central to social sciences, including the New Ecological Paradigm (NEP) and the multicultural identities of individuals raised between the cultures, third culture kids (TCKs). NEP is an ecocentric perspective that stresses the interdependence between nature and humans, opposite to anthropocentrism. TCKs' exposure to cultural diversity during developmental years might support global issues engagement and ecocentric worldviews. The present study focused on non-Western TCKs (N = 399; mean age 21 years), aiming to explore whether multicultural identity configurations (integration, categorisation, compartmentalisation), values dimensions (self-transcendence, openness and conservation) and global mindset predicted ecocentric and anthropocentric worldviews. The results demonstrated that TCKs were ecocentrically inclined. The path model revealed that ecocentrism could be directly positively predicted by integrated multicultural identity, self-transcendence and a global mindset. Anthropocentrism was predicted by multicultural identity categorisation and conservation values. Also, values of self-transcendence and openness buffered the impact of compartmentalisation and categorisation on ecocentrism and anthropocentrism. This study set innovative directions in multiculturism and environmentalism discourse through understanding a multicultural identity's relationships with pro-environmental attitudes.

Efficacy of PACE4 pharmacotherapy in JHU-LNCaP-SM preclinical model of androgen independent prostate cancer.

Prostate cancer (PCa) is a complex disease progressing from in situ to invasive or metastatic tumors while also being capable of modulating its androgen dependence. Understanding how novel therapies are working across the different stages of the disease is critical for their proper positioning in the spectrum of PCa treatments. The targeting of proprotein convertase PACE4 (Paired basic Amino Acid-Cleaving Enzyme 4) has been proposed as a novel approach to treat PCa. Animal studies performed on LNCaP xenografts, an androgen-dependent model, already yielded positive results. In this study, we tested PACE4 inhibition on JHU-LNCaP-SM, a newly described androgen-independent model, in cell-based and xenograft assays. Like LNCaP, JHU-LNCaP-SM cells express PACE4 and its oncogenic isoform PACE4-altCT. Using isoform-specific siRNAs, downregulation of PACE4-altCT resulted in JHU-LNCaP-SM growth inhibition. Furthermore, JHU-LNCaP-SM responded to the PACE4 pharmacological inhibitor known as C23 in cell-based assays as well as in athymic nude mice xenografts. These data support the efficacy of PACE4 inhibitors against androgen independent PCa thereby demonstrating that PACE4 is a key target in PCa. The JHU-LNCaP-SM cell line represents a model featuring important aspects of androgen-independent PCa, but it also represents a very convenient model as opposed to LNCaP cells for in vivo studies, as it allows rapid screening due to its high implantation rate and growth characteristics as xenografts.

Relationships between Spirituality, Religious Fundamentalism and Environmentalism: The Mediating Role of Right-Wing Authoritarianism.

According to past research, religious attitudes can strongly influence individuals' beliefs and behaviors. The purpose of this study was to assess the relationships between spirituality (the Scale of Spirituality; dimensions include religious spirituality, expanding consciousness, searching for meaning, sensitivity to art, doing good, and sensitivity to inner beauty), religious fundamentalism (the Religious Fundamentalism Scale), support for right-wing authoritarianism (the Right-Wing Authoritarianism Scale), climate concerns (the Environmental Concern Scale), and pro-environmental behavior (the Pro-Environmental Behavior Scale). The cross-sectional study involved 512 Poles aged 18-63 (M = 34.63, SD = 5.96; Mdn = 33), including 51% females. Multiple regression analysis revealed that two dimensions of spirituality (sensitivity to art and doing good) and religious fundamentalism are significant and opposite predictors of climate concern and pro-environmental behavior. Spirituality appeared to foster increased climate concern and caring behavior, while religious fundamentalism negatively predicted the same variables. Mediation analysis revealed that the relationship between religion and environmentalism could be explained in part by differences in support for right-wing authoritarianism (authoritarianism itself was negatively related to environmental outcomes). In addition, analysis of variance revealed that believers (70% of participants in the study were Catholic) showed significantly lower scores regarding climate concerns and pro-environmental behavior than non-believers, yet the inclusion of support for right-wing authoritarianism as a covariate in the equation reduced intergroup differences to statistical insignificance. The data obtained suggest that religious attitudes and socio-political views may play important roles in solving environmental problems.

Synthesis of the precursors of iminosugars with 7-membered ring.

d-Glucose was converted into the orthogonally protected open-chain derivative having different blocks at both terminal positions: C1 and C6. Selective deprotection of the C1-position opened a route to intermediate with the D-gluco-configuration, while deprotection at the C6-position gave the L-gulo isomer. In both derivatives, the oxime functionality was installed at the proper terminal position, which produced the corresponding precursors of a family of 7-membered ring iminosugars. One of these oximes was converted into the direct precursor: 6,1-bromonitrile.

The Path to Therapeutic Furin Inhibitors: From Yeast Pheromones to SARS-CoV-2.

The spurious acquisition and optimization of a furin cleavage site in the SARS-CoV-2 spike protein is associated with increased viral transmission and disease, and has generated intense interest in the development and application of therapeutic furin inhibitors to thwart the COVID-19 pandemic. This review summarizes the seminal studies that informed current efforts to inhibit furin. These include the convergent efforts of endocrinologists, virologists, and yeast geneticists that, together, culminated in the discovery of furin. We describe the pioneering biochemical studies which led to the first furin inhibitors that were able to block the disease pathways which are broadly critical for pathogen virulence, tumor invasiveness, and atherosclerosis. We then summarize how these studies subsequently informed current strategies leading to the development of small-molecule furin inhibitors as potential therapies to combat SARS-CoV-2 and other diseases that rely on furin for their pathogenicity and progression.

Activated interleukin-7 receptor signaling drives B-cell acute lymphoblastic leukemia in mice.

Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a high-risk subtype of B-ALL often associated with genetic variants that alter cytokine receptor signaling, including mutations in the interleukin-7 receptor (IL7R). To investigate whether IL7R variants are leukemia-initiating, we built mouse models expressing activated Il7r (aIL7R). B-cell intrinsic aIL7R mice developed spontaneous B-ALL, demonstrating sufficiency of Il7r activating mutations in leukemogenesis. Concomitant introduction of a knock-out allele in the associated adapter protein Lnk (encoded by Sh2b3) or a dominant-negative variant of the transcription factor Ikaros (Ikzf1) increased disease penetrance. The resulting murine leukemias displayed monoclonality and recurrent somatic Kras mutations and efficiently engrafted into immunocompetent mice. Phosphoproteomic analyses of aIL7R leukemic cells revealed constitutive Stat5 signaling and B cell receptor (BCR)-like signaling despite the absence of surface pre-BCR. Finally, in vitro treatment of aIL7R leukemic B-cells with Jak, mTOR, or Syk inhibitors blocked growth, confirming that each pathway is active in this mouse model of IL7R-driven B-ALL.

Design and Structure-Activity Relationship of a Potent Furin Inhibitor Derived from Influenza Hemagglutinin.

Furin plays an important role in various pathological states, especially in bacterial and viral infections. A detailed understanding of the structural requirements for inhibitors targeting this enzyme is crucial to develop new therapeutic strategies in infectious diseases, including an urgent unmet need for SARS-CoV-2 infection. Previously, we have identified a potent furin inhibitor, peptide Ac-RARRRKKRT-NH 2 (CF1), based on the highly pathogenic avian influenza hemagglutinin. The goal of this study was to determine how its N-terminal part (the P8-P5 positions) affects its activity profile. To do so, the positional-scanning libraries of individual peptides modified at the selected positions with natural amino acids were generated. Subsequently, the best substitutions were combined together and/or replaced by unnatural residues to expand our investigations. The results reveal that the affinity of CF1 can be improved (2-2.5-fold) by substituting its P5 position with the small hydrophobic residues (Ile or Val) or a basic Lys.

The link between ego-resiliency, social support, SARS-CoV-2 anxiety and trauma effects. Polish adaptation of the Coronavirus Anxiety Scale.

Reports to date have shown that the SARS-CoV-2 pandemic may have a negative impact on individuals' mental health. The purpose of this study was to assess the relation between ego-resiliency, social support, coronavirus anxiety and trauma effects. The study employed the Polish adaptation of the Coronavirus Anxiety Scale (CAS). It involved 515 individuals aged 18-78. The Polish version of CAS revealed satisfactory internal consistency (α = 0.86). Structural equation modeling indicated that ego-resiliency (the Ego-Resiliency Scale) and social support (the Multidimensional Scale of Perceived Social Support) were correlated and negatively predicted the severity of the novel coronavirus anxiety (CAS). Moreover, the level of anxiety showed positive correlation with negative trauma effects (the short form of the Changes in Outlook Questionnaire). The scores indicate the need for practitioners to focus on interventions which elevate ego-resiliency and perceived social support to improve mental health during the SARS-CoV-2 pandemic.

Synthesis of Highly Oxygenated Bicyclic Carbasugars. Remarkable Difference in the Reactivity of the d-gluco and d-xylo- Derived Trienes.

2,3,4-Tri-O-benzyl-D-xylopyranose was used as a starting material in the preparation of the corresponding triene, which underwent smooth cyclization to a polyhydroxylated hydrindane, as a single diastereoisomer. The analogous triene prepared from D-glucose did not undergo any cyclization even under high pressure.

Synthesis of sulfur containing macrocycles with sucrose scaffold.

The first synthesis of sucrose-based macrocycles containing two sulfur atoms in the ring was presented. The synthesis was initiated from known 6,6'-dideoxy-6,6'-di-chloro-1',2,3,3',4,4'-hexa-O-benzyl-sucrose in which both terminal positions (C6 and C6') were elongated by the -S-CH2-CH2-OH unit. The resulting diol was converted into dichloride and reacted further with a series of diamines which afforded the corresponding macrocyclic derivatives in high yields.

Prognostic Factors for Immune Thrombocytopenic Purpura Remission after Laparoscopic Splenectomy: A Cohort Study.

BACKGROUND AND OBJECTIVES: Laparoscopic splenectomy (LS) has become the gold standard for patients with immune thrombocytopenic purpura (ITP). The total remission rate after splenectomy is 70%-90%, of which 66% is long-term. Despite this high response rate, some patients do not benefit from surgery. It is therefore important to try to identify risk factors for an unsatisfactory clinical response. The aim of this study was to assess long-term outcomes of LS for ITP and identify factors associated with increased disease remission rates. MATERIALS AND METHODS: We retrospectively studied consecutive patients with ITP undergoing LS in a tertiary referral surgical center prospectively recorded in a database. Inclusion criteria were: Elective, laparoscopic splenectomy for diagnosed ITP, and complete follow-up. The cohort was divided into two groups-Group 1 (G1) patients with ITP remission after splenectomy and Group 2 (G2) patients without remission. There were 113 G1 patients and 52 G2 patients. Median follow-up was 9.5 (IQR: 5-15) years. RESULTS: In univariate analysis, patient's age, body mass index (BMI), preoperative platelet count, the need for platelet transfusions, and presence of hemorrhagic diathesis were shown to be statistically significant factors. Next, we built a multivariate logistic regression model using factors significant in univariate analysis. Age <41 years (odds ratio (OR) 4.49; 95% CI: 1.66-12.09), BMI <24.3 kg/m2 (OR: 4.67; 95% CI: 1.44-15.16), and preoperative platelet count ≥97 × 103/mm3 (OR: 3.50; 95% CI: 1.30-9.47) were shown to be independent prognostic factors for ITP remission after LS. CONCLUSION: The independent prognostic factors for ITP remission after LS revealed in our study are: age <41 years, BMI <24.3 kg/m2, and preoperative platelet count ≥97 × 103/mm3. Duration of the ITP and the time of treatment are not related to remission after LS.

Enhanced anti-tumor activity of the Multi-Leu peptide PACE4 inhibitor transformed into an albumin-bound tumor-targeting prodrug.

The proprotein convertase PACE4 has been validated as a potential target to develop new therapeutic interventions in prostate cancer (PCa). So far, the most effective compound blocking the activity of this enzyme has been designed based on the structure of a small peptide Ac-LLLLRVKR-NH2 known as the Multi-Leu (ML) peptide. Optimization of this scaffold led to the synthesis of compound C23 (Ac-[DLeu]LLLRVK-amidinobenzylamide) with a potent in vivo inhibitory effect on the tumor growth. However, further developments of PACE4 inhibitors may require additional improvements to counter their rapid renal clearance and to increase their tumor targeting efficiency. Herein, we explored the transformation of the ML-peptide into an albumin-binding prodrug containing a tumor specific release mechanism based on the prostate-specific antigen. Our data confirms that intravenous treatment using the ML-peptide alone has little effect on tumor growth, whereas by using the ML-prodrug in LNCaP xenograft-bearing mice it was significantly reduced. Additionally, excellent in vivo stability and tumor-targeting efficiency was demonstrated using a radiolabelled version of this compound. Taken together, these results provide a solid foundation for further development of targeted PACE4 inhibition in PCa.

Polish Honor and Norwegian Dignity: Life Satisfaction, Acculturation, and Self-Worth / El Honor Polaco, La Dignidad Noruega: Satisfacción de Vida, Aculturación y Autoestima

Abstract Locus of self-worth shifts from internal in cultures of dignity to external in cultures of honor. It remains yet unknown whether it can be modified, for example, under an influence of important life events, as migration to a culture of a distinct logic. Our study aimed to analyse relationships between the locus of self-worth and the acculturation strategies on life satisfaction. We collected data from 60 heterosexual Polish couples living in Poland, 120 Polish migrant couples in Norway, and 60 Norwegian couples living in Norway. Groups differed from each other in life satisfaction and in locus of self-worth, with Norwegians valuating the self the most internally and Poles in Poland the most externally. Our results on locus of self-worth show that Polish culture fits in the classification of culture of honor, while Norwegians represent culture of dignity. Moreover, a series of hierarchical linear regressions demonstrated that both locus of self-worth and acculturation strategy are significant predictors of participants' life satisfaction, with a moderating role of migrants' attachment to Polish culture and adaptation to Norwegian society.

Resumen En las culturas de dignidad, que ocurren principalmente en los estados del norte de los Estados Unidos, Canadá y el noroeste de Europa, la autoestima es inalienable y se valora internamente. Esto significa que la autoestima se basa en los logros, las decisiones y los valores del individuo (Aslani et al., 2016). En las culturas de dignidad, nadie puede privar a los individuos de su valor, ya que su ubicación está en lo más profundo de la persona. Por el contrario, en culturas de honor, el valor de una persona se basa en cualidades internas y externas. El honor puede ser quitado, si una persona rompe las reglas de conducta social. El locus de la autoestima cambia de lo interno en las culturas de dignidad, a lo externo en las culturas de honor. Aún no es claro si se puede modificar, por ejemplo, bajo la influencia de eventos importantes de la vida, como la migración a una cultura de una lógica distinta. Este estudio tuvo como objetivo analizar las relaciones entre el locus de autoestima y las estrategias de aculturación sobre la satisfacción con la vida. Se levantaron datos de 60 parejas heterosexuales polacas que viven en Polonia, 120 parejas polacas de inmigrantes en Noruega y 60 parejas noruegas que viven en Noruega. Los grupos diferían entre sí en la satisfacción con la vida y en el locus de la autoestima, los noruegos valoraban el yo más internamente y los polacos en Polonia más externamente. Los resultados en el locus de la autoestima muestran que la cultura polaca encaja en la clasificación de la cultura del honor, mientras que los noruegos representan la cultura de la dignidad. Además, una serie de regresiones lineales jerárquicas mostraron que tanto el locus de la autoestima como la estrategia de aculturación son predictores significativos de la satisfacción con la vida, con un papel moderador del apego de los migrantes a la cultura polaca y la adaptación a la sociedad noruega.

Improving the Selectivity of PACE4 Inhibitors through Modifications of the P1 Residue.

Paired basic amino acid cleaving enzyme 4 (PACE4), a serine endoprotease of the proprotein convertases family, has been recognized as a promising target for prostate cancer. We previously reported a selective and potent peptide-based inhibitor for PACE4, named the multi-Leu peptide (Ac-LLLLRVKR-NH2 sequence), which was then modified into a more potent and stable compound named C23 with the following structure: Ac-dLeu-LLLRVK-Amba (Amba: 4-amidinobenzylamide). Despite improvements in both in vitro and in vivo profiles of C23, its selectivity for PACE4 over furin was significantly reduced. We examined other Arg-mimetics instead of Amba to regain the lost selectivity. Our results indicated that the replacement of Amba with 5-(aminomethyl)picolinimidamide increased affinity for PACE4 and restored selectivity. Our results also provide a better insight on how structural differences between S1 pockets of PACE4 and furin could be employed in the rational design of selective inhibitors.

Increasing C-Terminal Hydrophobicity Improves the Cell Permeability and Antiproliferative Activity of PACE4 Inhibitors against Prostate Cancer Cell Lines.

The serine protease, PACE4, is a proprotein convertase that plays a substantial role in malignancy of prostate cancer. Our initial selective PACE4 inhibitor (Ac-LLLLRVKR-NH2) has evolved to the current lead compound C23 (Ac-dLeu-LLLRVK-Amba), which is active both in vitro and in vivo. By screening natural residues, except Cys, in C-terminal P1' position, it was established that increasing hydrophobicity was improving cell permeability, which was directly translated into PCa cells antiproliferative activity. This cell antiproliferation enhancement seems independent from effect of P1' residue on PACE4 affinity. Replacement of P1-Amba of C23 by Acpa (( S)-2-amino-3-(4-carbamimidoylphenyl)propanoic acid) followed by addition of tryptamine in P1' resulted in compound 32 exhibiting superior PCa cells antiproliferative activity over the reference compound C23 (3-fold). This study sheds light on key factors that improve cell penetrating property and antiproliferative activity of PACE4 inhibitors.