Janus kinase 2 inhibition by pacritinib as potential therapeutic target for liver fibrosis.

BACKGROUND AND AIMS: Janus kinase 2 (JAK2) signaling is increased in human and experimental liver fibrosis with portal hypertension. JAK2 inhibitors, such as pacritinib, are already in advanced clinical development for other indications and might also be effective in liver fibrosis. Here, we investigated the antifibrotic role of the JAK2 inhibitor pacritinib on activated hepatic stellate cells (HSCs) in vitro and in two animal models of liver fibrosis in vivo . APPROACH AND RESULTS: Transcriptome analyses of JAK2 in human livers and other targets of pacritinib have been shown to correlate with profibrotic factors. Although transcription of JAK2 correlated significantly with type I collagen expression and other profibrotic genes, no correlation was observed for interleukin-1 receptor-associated kinase and colony-stimulating factor 1 receptor. Pacritinib decreased gene expression of fibrosis markers in mouse primary and human-derived HSCs in vitro . Moreover, pacritinib decreased the proliferation, contraction, and migration of HSCs. C 57 BL/6J mice received ethanol in drinking water (16%) or Western diet in combination with carbon tetrachloride intoxication for 7 weeks to induce alcoholic or nonalcoholic fatty liver disease. Pacritinib significantly reduced liver fibrosis assessed by gene expression and Sirius red staining, as well as HSC activation assessed by alpha-smooth muscle actin immunostaining in fibrotic mice. Furthermore, pacritinib decreased the gene expression of hepatic steatosis markers in experimental alcoholic liver disease. Additionally, pacritinib protected against liver injury as assessed by aminotransferase levels. CONCLUSIONS: This study demonstrates that the JAK2 inhibitor pacritinib may be promising for the treatment of alcoholic and nonalcoholic liver fibrosis and may be therefore relevant for human pathology.

When cancer cannot be cured: A qualitative study on relationship changes in couples facing advanced melanoma.

OBJECTIVE: The aim of this qualitative study was to gain a deeper understanding about couples' relationship changes over time (the first six months) after one partner is diagnosed with an incurable advanced melanoma (stage III or IV). METHOD: In semistructured interviews, eight patients and their partners were asked separately about potential changes in their relationship since diagnosis. The same questions were asked again six months later, but focusing on relationship changes over the preceding six months. Some 32 audiotaped interviews were analyzed applying qualitative content analysis. RESULTS: At baseline (t1), relationship changes were mostly reported in terms of caring, closeness/distance regulation, and communication patterns. While changes in caregiving and distance/closeness regulation remained main issues at six months follow-up (t2), greater appreciation of the relationship and limitations in terms of planning spare time also emerged as major issues. Unexpectedly, 50% of patients and partners reported actively hiding their negative emotions and sorrows from their counterparts to spare them worry. Furthermore, qualitative content analysis revealed relationship changes even in those patients and partners who primarily reported no changes over the course of the disease. SIGNIFICANCE OF RESULTS: Our findings revealed a differentiated and complex picture about relationship changes over time, which also might aid in the development of support programs for couples dealing with advanced cancer, focusing on the aspects of caring, closeness/distance regulation, and communication patterns.

The non-selective Rho-kinase inhibitors Y-27632 and Y-33075 decrease contraction but increase migration in murine and human hepatic stellate cells.

BACKGROUND: The Rho-kinase ROCK II plays a major role in the activation of hepatic stellate cells (HSC), which are the key profibrotic and contractile cells contributing to the development of chronic liver disease. Inhibition of ROCK II ultimately blocks the phosphorylation of the myosin light chain (MLC) and thus inhibits stress fibre assembly and cell contraction. We investigated the effects of the ROCK inhibitors Y-33075 as well as Y-27632 in murine and human hepatic stellate cells. METHODS: Primary isolated HSC from FVB/NJ mice and the immortalized human HSC line TWNT-4 were culture-activated and incubated with Y-27632 and Y-33075 (10nM to 10µM) for 24h. Protein expression levels were analyzed by Western Blots and transcriptional levels of pro-fibrotic markers and proliferative markers were evaluated using real-time qPCR. Migration was investigated by wound-healing assay. Proliferation was assessed by BrdU assay. Contraction of HSC was measured using 3D collagen matrices after incubation with Y-27632 or Y-33075 in different doses. RESULTS: Both Rho-kinase inhibitors, Y-27632 and Y-33075, reduced contraction, fibrogenesis and proliferation in activated primary mouse HSC (FVB/NJ) and human HSC line (TWNT-4) significantly. Y-33075 demonstrated a 10-times increased potency compared to Y-27632. Surprisingly, both inhibitors mediated a substantial and unexpected increase in migration of HSC in FVB/NJ. CONCLUSION: ROCK inhibition by the tested compounds decreased contraction but increased migration. Y-33075 proved more potent than Y27632 in the inhibition of contraction of HSCs and should be further evaluated in chronic liver disease.

Fungal antigenic variation using mosaicism and reassortment of subtelomeric genes' repertoires.

Surface antigenic variation is crucial for major pathogens that infect humans. To escape the immune system, they exploit various mechanisms. Understanding these mechanisms is important to better prevent and fight the deadly diseases caused. Those used by the fungus Pneumocystis jirovecii that causes life-threatening pneumonia in immunocompromised individuals remain poorly understood. Here, though this fungus is currently not cultivable, our detailed analysis of the subtelomeric sequence motifs and genes encoding surface proteins suggests that the system involves the reassortment of the repertoire of ca. 80 non-expressed genes present in each strain, from which single genes are retrieved for mutually exclusive expression. Dispersion of the new repertoires, supposedly by healthy carrier individuals, appears very efficient because identical alleles are observed in patients from different countries. Our observations reveal a unique strategy of antigenic variation. They also highlight the possible role in genome rearrangements of small imperfect mirror sequences forming DNA triplexes.

Neprilysin-dependent neuropeptide Y cleavage in the liver promotes fibrosis by blocking NPY-receptor 1.

Development of liver fibrosis is paralleled by contraction of hepatic stellate cells (HSCs), the main profibrotic hepatic cells. Yet, little is known about the interplay of neprilysin (NEP) and its substrate neuropeptide Y (NPY), a potent enhancer of contraction, in liver fibrosis. We demonstrate that HSCs are the source of NEP. Importantly, NPY originates majorly from the splanchnic region and is cleaved by NEP in order to terminate contraction. Interestingly, NEP deficiency (Nep-/-) showed less fibrosis but portal hypertension upon liver injury in two different fibrosis models in mice. We demonstrate the incremental benefit of Nep-/- in addition to AT1R blocker (ARB) or ACE inhibitors for fibrosis and portal hypertension. Finally, oral administration of Entresto, a combination of ARB and NEP inhibitor, decreased hepatic fibrosis and portal pressure in mice. These results provide a mechanistic rationale for translation of NEP-AT1R-blockade in human liver fibrosis and portal hypertension.

Dyadic coping among couples with COPD: a pilot study.

COPD (chronic obstructive pulmonary disease) is associated with psychological distress for patients as well as their partners. Dyadic coping can be negatively impacted by stressors. This study's objective was to compare the dyadic coping of couples in which one partner suffered from COPD with healthy couples of the same age. A total of 43 complete couples with COPD and 138 healthy couples participated in this pilot study. The surveys were sent by mail. The response rate of the COPD sample was 24.3%. In order to analyze the effect of gender and role (patient vs. partner) on dyadic coping, linear mixed models were calculated. To analyze the effect of gender and group (COPD group vs. normative comparison group) on dyadic coping, two-way analyses of variance were calculated for independent samples. COPD patients and their partners indicated that the patients received more support and were less able to provide support to their partners. This difference was also evident in comparison with the normative comparison group. In addition, couples with COPD perceived higher levels of negative coping and provided a considerably lower assessment of their positive dyadic coping. The dyadic coping of couples with COPD is unbalanced and more negative when compared to that of healthy couples. Interventions aimed at supporting COPD couples should seek to improve couples' dyadic coping in addition to individual coping strategies.

Cell Fusion May Be Involved in the Homothallic Mating of Pneumocystis Species.

Pneumocystis species are obligate fungal biotrophs that colonize the lungs of mammals. They cause deadly pneumonia in immunocompromised hosts. The sexual phase seems obligate during their life cycle and essential for survival because it is believed to ensure proliferation and transmission between hosts. Here, we consider if the sexual phase is initiated by the fusion of two cells or by nucleus duplication in order to generate diploid cells that can undergo meiosis. The juxtaposition of the nucleus-associated organelles of pairs of cells with fused cytoplasmic membranes demonstrated that cell fusion can occur. Nevertheless, the frequency of cell fusion remains to be determined, and it cannot be excluded that both cell fusion and nucleus duplication are used to ensure the occurrence of the essential sexual phase. In vitro culturing of these fungi is a major milestone that could clarify the issue.

The impact of prehydration on the clearance and toxicity of high-dose methotrexate for pediatric patients.

Abstract High-dose methotrexate (HD-MTX) is an important chemotherapy for various pediatric malignancies. However, in contrast to precise recommendations on supportive care following the start of HD-MTX infusion, studies on the hydration regimen prior to HD-MTX infusion are lacking, and the local standard differs between pediatric oncology centers. Therefore, we prospectively evaluated the relevance of two common prehydration regimens on the clearance and toxicity of MTX in a randomized crossover study. There was no impact of the prehydration regimen on plasma levels and toxicity of MTX, but most parents preferred a fast prehydration regimen due to a significantly shorter inpatient treatment (mean duration 3.39 ± 0.79 days vs. 4.36 ± 0.70 days, p < 0.001). Based on our results, short prehydration seems safe, and may be recommended prior to the start of HD-MTX infusions instead of initiating hydration the preceding day.

[Helpful and stressful factors in coping with COPD in patients and their partners - a qualitative study]. / Hilfreiche und belastende Faktoren im Umgang mit COPD bei Patienten und ihren Partnern - eine qualitative Studie.

OBJECTIVE: To investigate helpful and stressful factors in coping with COPD of patients and their partners. METHOD: Nine COPD patients and their partners (9 couples) were interviewed. All interviews were audio taped and later transcribed and analysed using qualitative content analysis. RESULTS: Patients as well as partners reported high satisfaction with the professional support. The most helpful factor for COPD patients was the social support by the partner. In terms of stressful factors patients and partners reported psychological problems and physical complaints. Partners additionally reported about relationship conflicts. CONCLUSION: Partners of COPD patients are very important for patients to cope with the disease. Partners themselves are suffering from psychological stress and should therefore be included regularly in care programs.

Objectif: L'objectif de la présente étude était d'analyser les facteurs ayant une influence positive et ceux ayant une influence négative lors du traitement de la bronchopneumopathie obstructive chronique (BPCO) chez les patients et leurs partenaires. Méthode: Neuf patients atteints de BPCO ainsi que leurs partenaires se sont prêtés à un entretien semi-directif. Leurs réponses ont été exploitées au moyen d'une analyse qualitative. Résultats: Les patients ainsi que leurs partenaires se montrent satisfaits du soutien apporté par les professionnels. Le soutien apporté par le partenaire est crucial pour le patient. Les problèmes psychiques sont souvent évoqués comme facteur aggravant par les patients et leurs partenaires. Le principal facteur aggravant évoqué par les patients est celui de la limitation physique. Les partenaires ont quant à eux évoqué les conflits avec le patient. Conclusion: Les partenaires de patients atteints de BPCO semblent jouer un rôle important lors de la prise en charge de la maladie, mais ils sont eux-mêmes aussi souvent sollicités psychologiquement. Pour cette raison, ils devraient être davantage soutenus et impliqués dans le traitement de la maladie.

Contrast-enhanced dual-energy CT of gastrointestinal stromal tumors: is iodine-related attenuation a potential indicator of tumor response?

OBJECTIVES: To assess the correlation of true nonenhanced (TNE) and virtually nonenhanced (VNE) images of abdominal dual-energy computed tomography (DECT) in patients with metastatic gastrointestinal stromal tumors (GIST), and further to investigate the correlation of iodine-related attenuation (IRA) of DECT with the Choi criteria. MATERIAL AND METHODS: Twenty-four consecutive patients (5 women aged 61 ± 10 years) with metastatic GIST underwent DECT of the abdomen (80 kV, 140 kV) using first-generation dual-source computed tomography (CT). All patients had at least one or more liver lesions (median, 4; maximum, 9). Image data were processed with a dedicated DECT software algorithm designed for evaluation of iodine distribution in soft tissue lesions, and VNE CT images were generated. The tumor density (according to Choi criteria) and the maximum transverse diameter of the lesions (according to Response Evaluation Criteria in Solid Tumors [RECIST]) were determined. TNE and VNE lesion attenuation and Choi criteria and IRA were correlated with each other. RESULTS: A total of 291 liver lesions were evaluated, of which 220 were cystic and 71 were solid. The mean lesion size was 4.5 ± 3.2 cm (1.1-18.7 cm). The mean attenuation of all lesions was significantly higher in the TNE images than in the VNE images (P=0.0001). Pearson statistics revealed an excellent correlation of r=0.843 (P=0.0001) between IRA and Choi criteria for all lesions. DECT showed significantly higher IRA in progressive (23.3 ± 9.5 HU) lesions compared with stable or regressive (17.8 ± 9.1 HU) lesions (P=0.0185). Similarly, the Choi criteria differed significantly between progressive (39.9 ± 12.8 HU) and stable/regressive (31.1 ± 10.3 HU) lesions (P=0.0003). CONCLUSIONS: DECT is a promising imaging method for the assessment of treatment response in GIST, as IRA might be a more robust response parameter than the Choi criteria. VNE CT data calculated from DECT may eliminate the need for acquisition of a separate unenhanced data set.

Dyadic coping, quality of life, and psychological distress among chronic obstructive pulmonary disease patients and their partners.

BACKGROUND: Successfully coping with a chronic disease depends significantly on social support, particularly that of a significant other. Thus, it depends on the ways of dealing with stress within a couple (dyadic coping). In this study, the relationship between dyadic coping and well-being was investigated among couples in which one partner suffers from chronic obstructive pulmonary disease (COPD). METHODS: A total of 43 couples participated. They were mailed questionnaires on anxiety and depression (Hospital Anxiety and Depression Scale), quality of life (World Health Organization Quality of Life Questionnaire-BREF), and dyadic coping (Dyadic Coping Inventory). RESULTS: Low scores of positive and high scores of negative dyadic coping were associated with poorer quality of life and higher psychological distress among couples. Delegated coping (assistance with daily tasks) was higher among partners. When estimated by patients, high delegated partner coping (frequent provision of support by partners) and low delegated personal coping (low provision of support by patients) were associated with poorer quality of life for both patient and partner. COPD patients suffering from depression were supported more often and attributed deficits in dyadic coping primarily to themselves, whereas partners with higher scores of depression provided higher estimates of both their own negative coping and the negative coping of their partner. CONCLUSION: The higher the patient perceived the imbalance in delegated dyadic coping, the lower the couple's quality of life. More negative and less positive dyadic coping were associated with lower quality of life and higher psychological distress. Psychotherapeutic interventions to improve dyadic coping may lead to better quality of life and less psychological distress among COPD patients and their partners.

Enhancing emotion-regulation skills in police officers: results of a pilot controlled study.

Police officers are routinely exposed to situations that elicit intense negative emotions; thus, officers have a particularly strong need for effective methods of regulating such emotions. The main purpose of this study was to investigate whether a manualized emotion-regulation training (Integrative Training of Emotional Competencies; iTEC; Berking, 2010a) can improve the emotion-regulation skills of police officers. First, self-reports of 9 emotion-regulation skills were assessed in a sample of officers (N=31) and compared to those of a matched community-based control group. Then, the effects of the training on the emotion-regulation skills of officers were evaluated in a time-staggered design with a waitlist control condition. Results indicate that, compared to controls, officers have difficulties in accepting and tolerating negative emotions, supporting themselves in distressing situations, and confronting emotionally challenging situations. The training significantly enhanced successful skill application, especially some skills with which officers reported difficulty applying. These findings suggest that a focus on emotion-regulation skills may be an important component for programs aimed at preventing mental-health problems in police officers.