Recent Trends and Potential of Radiotherapy in the Treatment of Anaplastic Thyroid Cancer.

Anaplastic thyroid cancer (ATC) is a rare but highly aggressive malignancy characterized by advanced disease at diagnosis and a poor prognosis. Despite multimodal therapeutic approaches that include surgery, radiotherapy, and chemotherapy, an optimal treatment strategy remains elusive. Current developments in targeted therapies and immunotherapy offer promising avenues for improved outcomes, particularly for BRAF-mutant patients. However, challenges remain regarding overcoming drug resistance and developing effective treatments for BRAF-wild-type tumors. This comprehensive review examines the clinical and biological features of ATC, outlines the current standards of care, and discusses recent developments with a focus on the evolving role of radiotherapy. Moreover, it emphasizes the necessity of a multidisciplinary approach and highlights the urgent need for further research to better understand ATC pathogenesis and identify new therapeutic targets. Collaborative efforts, including large-scale clinical trials, are essential for translating these findings into improved patient outcomes.

Lived Bodily Experience of Worsening Heart Failure from Acute Exacerbation to Recovery: A Phenomenological Study.

Patients with heart failure have difficulty recognizing and identifying changes in bodily sensations, despite the importance of symptom monitoring. The way patients with heart failure experience their bodies from exacerbation to recovery is poorly understood. We aimed to describe the lived bodily experience of heart failure from exacerbation to recovery. Participatory observations and interviews were conducted in seven patients admitted to the intensive care unit with worsening heart failure. Benner's interpretive phenomenology was used for analysis. Four major themes were identified: a non-functional body becomes the central concern and an object; being conscious of bodily changes before hospitalization when asked; the central concern shifted to daily life and the body becomes the background; and having a feeling of death in the body that no longer functions or a weakened body after recovery. This study found that patients with heart failure were conscious and concerned about their bodies changing as they underwent rapid changes during exacerbations and recovery. In addition, immediately after their bodies recovered and until they were discharged from the hospital, they looked toward their daily lives through their bodily experiences during heart failure exacerbation. The lived bodily experience of heart failure, which is less conscious in daily life, is made conscious through storytelling in the period immediately following recovery from an acute exacerbation and can be the basis for subsequent self-care exploration.

Association of BRAF or TERT Promoter Mutations and Advanced Papillary Thyroid Carcinoma.

BACKGROUND/AIM: BRAF and TERT promoter mutations are associated with the poor prognosis of papillary thyroid carcinoma. This single-center retrospective study investigated the influence of these genes on advanced cases. PATIENTS AND METHODS: Advanced cases who underwent gene panel testing and cases who underwent complete resection were classified as groups A and C, respectively. The gene mutations were determined using gene panel testing or Sanger sequencing using tumor DNA. RESULTS: The study included 51 cases in group A and 44 cases in group C. In group A, all cases had unresectable lesions or distant metastasis; 82.4% of cases showed no accumulation of radioactive iodine in metastasis and 47.1% of cases were administered drug therapy. Meanwhile, all cases of group C did not have distant metastasis. The prevalence of TERT promoter mutations was significantly higher in group A compared to group C (70.6% vs. 18.2%, p<0.001). However, there was no significant difference in the prevalence of BRAF mutations between the two groups (86.3% vs. 90.9%). In Group C, disease-free survival was significantly shorter in patients harboring the TERT promoter mutations (p<0.001), despite no significant difference in that according to the BRAF mutation status. In addition, there was no significant difference in overall survival in group A according to the TERT promoter mutation status. CONCLUSION: Advanced papillary thyroid carcinoma was associated with the TERT promoter mutations, but not with BRAF mutation. Meanwhile, TERT promoter mutations did not affect overall survival among the advanced cases.

Effect of Daily Activity Record-Based Self-monitoring Intervention on the Perception of Physical Sensations in Patients With Chronic Heart Failure: A Randomized Controlled Trial.

BACKGROUND: To prevent rehospitalization for heart failure (HF), patients need to be able to perceive physical changes that occur at the onset of HF exacerbation and seek early help. OBJECTIVE: The aim of this study was to evaluate the effect of a self-monitoring intervention on patients' perceptions of physical sensations during daily activities in the context of HF via a randomized controlled trial. METHODS: Participants (N = 70) were randomly assigned to the intervention (received daily activity record-based self-monitoring intervention support; group A) or control (only explained the measured results from the records; group B) group. Group A reflected on and described the physical sensations in their daily activities within 1 month after discharge. Outcome measures were assessed at 1 month after the intervention using the European Heart Failure Self-care Behavior Scale, Evaluation Scale for Self-Monitoring by patients with Heart Failure, clinical events, physical activity, and sleep. RESULTS: There was no significant difference in the change in the "asking for help" subscale score of the European Heart Failure Self-care Behavior Scale between the groups (+0.7 vs +0.4 points, P = .716). Group A had improved score on the self-monitoring subscale related to "concern about how movements affect body" from baseline (from 12.7 to 14.0 points, P = .026). There was no significant effect of self-monitoring intervention support on the first rehospitalization related to HF and all-cause death (log-rank χ2 = 0.432, P = .511). A significant difference in moderate-intensity physical activity between the groups was observed (+4.6 vs -0.5 minutes, P = .029). CONCLUSIONS: A focused strategy that enables patients to perceive their physical sensations and promotes early help-seeking behavior is needed.

Validation of EZH2 Inhibitor Efficiency in Anaplastic Thyroid Carcinoma Cell Lines.

BACKGROUND/AIM: The prognosis of anaplastic thyroid carcinoma (ATC) is poor, and there is currently no established treatment to improve its outcome. We previously reported that enhancer of zeste homolog 2 (EZH2) was highly expressed in ATC, and may be a therapeutic target; however, the effects of EZH2 on ATC growth currently remain unknown. MATERIALS AND METHODS: We investigated the effects of an EZH2 inhibitor (DZNep) on four ATC cell lines (8305C, KTA1, TTA1 and TTA2). We performed a gene panel analysis of all ATC cell lines to identify differences in DZNep sensitivity between the cell lines. To investigate the effects of DZNep on the recovery of differentiation, we assessed changes in thyroid differentiation markers (TDMs) before and after the DZNep treatment using PCR. RESULTS: EZH2 was expressed in all ATC cell lines. The cell-reducing effects of DZNep were detected in all ATC cell lines, and were the strongest in KTA1 cells followed by TTA2 cells. The TTA1 and 8305C cell lines, which showed weak cell-reducing effects, had TP53 mutations. No changes in TDMs were observed in any ATC cell line. CONCLUSION: DZNep, an EZH2 inhibitor, exerted suppressive effects on the growth of ATC cell lines and has potential as a therapeutic strategy; however, its effects may be attenuated in ATC with TP53 mutations.

Evaluation of X-ray and carbon-ion beam irradiation with chemotherapy for the treatment of cervical adenocarcinoma cells in 2D and 3D cultures.

BACKGROUND: Cervical cancer is the second most common cancer in women and causes more than 250,000 deaths worldwide. Among these, the incidence of cervical adenocarcinomas is increasing. Cervical adenocarcinoma is not only difficult to detect and prevent in the early stages with screening, but it is also resistant to chemotherapy and radiotherapy, and its prognosis worsens significantly as the disease progresses. Furthermore, when recurrence or metastasis is observed, treatment options are limited and there is no curative treatment. Recently, heavy-particle radiotherapy has attracted attention owing to its high tumor control and minimal damage to normal tissues. In addition, heavy particle irradiation is effective for cancer stem cells and hypoxic regions, which are difficult to treat. METHODS: In this study, we cultured cervical adenocarcinoma cell lines (HeLa and HCA-1) in two-dimensional (2D) or three-dimensional (3D) spheroid cultures and evaluated the effects of X-ray and carbon-ion (C-ion) beams. RESULTS: X-ray irradiation decreased the cell viability in a dose-dependent manner in 2D cultures, whereas this effect was attenuated in 3D spheroid cultures. In contrast, C-ion irradiation demonstrated the same antitumor effect in 3D spheroid cultures as in 2D cultures. In 3D spheroid cultures, X-rays and anticancer drugs are attenuated because of hypoxia inside the spheroids. However, the impact of the C-ion beam was almost the same as that of the 2D culture, because heavy-particle irradiation was not affected by hypoxia. CONCLUSION: These results suggest that heavy-particle radiotherapy may be a new therapeutic strategy for overcoming the resistance of cervical adenocarcinoma to treatment.

Effectiveness of daily activity record-based self-monitoring intervention for patients with chronic heart failure: A study protocol.

Background: The prevention of recurrent readmission among heart failure (HF) patients requires support for appropriate self-care behaviors to prevent exacerbation of HF and self-monitoring to allow for patients' early perception of physical changes during exacerbations. Such support may enable patients to seek early consultation. This study developed a self-monitoring intervention that aimed at increasing the perception of patient-unique physical sensations caused by HF, based on daily activity records of patients. Method: A parallel two-arm randomized controlled trial is being conducted with 68 HF patients early after their discharge. Participants in both groups wear a wristwatch activity tracker from time-of-discharge. Participants in the self-monitoring intervention group receive support to reflect on their actual daily activities and the associated physical sensations they experienced, based on their daily activity records. The primary outcome is participants' "Asking for Help" dimension of self-care behavior, measured using the European Heart Failure Self-Care Behavior Scale at one month follow-up after intervention. Conclusion: This study is the first trial to use an activity tracker as a tool for symptom perception among HF patients. The problem of delayed consultations during exacerbations may be resolved by assisting patients in improving their perception of their unique physical sensations associated with specific daily activities, based on their daily activity records. If the effect is clarified, it could lead to the construction of new nursing interventions for continuous disease management that aim towards re-hospitalization prevention.

Possible Involvement of the Upregulation of ΔNp63 Expression Mediated by HER2-Activated Aryl Hydrocarbon Receptor in Mammosphere Maintenance.

Cancer stem cells (CSCs) contribute to the drug resistance, recurrence, and metastasis of breast cancers. Recently, we demonstrated that HER2 overexpression increases mammosphere formation via the activation of aryl hydrocarbon receptor (AHR). In this study, the objective was to identify the mechanism underlying mammosphere maintenance mediated by HER2 signaling-activated AHR. We compared the chromatin structure of AHR-knockout (AHRKO) HER2-overexpressing MCF-7 (HER2-5) cells with that of wild-type HER2-5 cells; subsequently, we identified TP63, a stemness factor, as a potential target gene of AHR. ΔNp63 mRNA and protein levels were higher in HER2-5 cells than in HER2-5/AHRKO cells. Activation of HER2/HER3 signaling by heregulin treatment increased ΔNp63 mRNA levels, and its induction was decreased by AHR knockdown in HER2-5 cells. The results of the chromatin immunoprecipitation assay revealed an interaction between AHR and the intronic region of TP63, which encodes ΔNp63. A luciferase reporter gene assay with the intronic region of TP63 showed that AHR expression increased reporter activity. Collectively, our findings suggest that HER2-activated AHR upregulates ΔNp63 expression and that this signaling cascade is involved in CSC maintenance in HER2-expressing breast cancers.

Differential DNA-binding and cofactor recruitment are possible determinants of the synthetic steroid YK11-dependent gene expression by androgen receptor in breast cancer MDA-MB 453 cells.

Recently, selective androgen receptor modulators (SARMs), which bind to AR and act in a tissue/effect-specific manner, have been developed, but the selective mechanism is not well understood. In this study, we investigated the selective mechanism using the synthetic steroid YK11, which showed AR-mediated gene-selective transactivation. In the AR-positive human breast cancer MDA-MB-453 cells, different patterns of AR-mediated target gene expression and AR recruitment to their enhancer regions were observed between DHT and YK11. A docking study suggested the helices 11 and 12 was moved by the sterically hindered C17-group of YK11. Furthermore, the mutational studies of AR Gln902 and mammalian two-hybrid assays suggested different cofactor recruitment between DHT and YK11. The results of this study suggest that gene selective regulation by SARMs results from differential DNA-binding and/or cofactor recruitment by ligands. These results provide novel insights into the mechanism of action of SARMs.

TROP-2, Nectin-4, GPNMB, and B7-H3 Are Potentially Therapeutic Targets for Anaplastic Thyroid Carcinoma.

BACKGROUND: Anaplastic thyroid carcinoma (ATC) is a highly aggressive thyroid tumor with a poor prognosis. However, there are limited choices for ATC treatment. Recently, the effectiveness of antibody-drug conjugates has been demonstrated in various carcinomas. Whether the targets of antibody-drug conjugates are expressed in anaplastic thyroid carcinoma remains unclear. METHODS: Fifty-four patients with ATC were enrolled in this study. Tissue microarrays were constructed using the archives of formalin-fixed paraffin-embedded tissue blocks. All sections were stained with the following antibody-drug conjugate targets: human epidermal growth factor receptor 2 (HER2), nectin-4, trophoblast cell surface antigen 2 (TROP-2), glycoprotein non-metastatic B (GPNMB), and B7-H3. RESULTS: HER2 was negative in all tissues, whereas GPNMB and B7-H3 were expressed in most ATC tissues. TROP-2 and nectin-4 were expressed in 65% and 59% of ATC tissues, respectively. TROP-2 was expressed at significantly higher levels in ATC undifferentiated from papillary thyroid carcinoma than in ATC undifferentiated from follicular thyroid carcinoma and de novo ATC. In contrast, nectin-4 expression was markedly higher in patients with de novo ATC than in those with papillary and follicular thyroid carcinoma. CONCLUSIONS: TROP-2 and nectin-4 are potential therapeutic targets for ATC undifferentiated from papillary thyroid carcinoma and de novo ATC, respectively. GPNMB and B7-H3 potential for treating all types of ATC.

Two new glycosidic acids, calyhedic acids E and F, in crude resin glycoside fraction from Calystegia hederacea.

Two new glycosidic acids, calyhedic acids E (1a) and F (2a), were isolated from the glycosidic acid fraction afforded by alkaline hydrolysis of the crude resin glycoside fraction obtained from whole plants of Calystegia hederacea Wall. Compounds 1a and 2a were characterised as 11S-hydroxyhexadecanoic acid 11-O-ß-D-glucopyranosyl-(1→6)-O-ß-D-glucopyranosyl-(1→6)-O-ß-D-glucopyranosyl-(1→3)-[O-α-L-rhamnopyranosyl-(1→2)]-O-ß-D-glucopyranosyl-(1→2)-ß-D-quinovopyranoside and an isomer of 1a, in which the 11S-hydroxyhexadecanoyl residue of 1a was replaced by a 12S-hydroxyhexadecanoyl residue, respectively, on the basis of spectroscopic data.

Device nurse intervention facilitates the patients' adaptation to cardiac shock devices in the remote monitoring era.

BACKGROUND: A substantial number of patients with shock devices (implantable cardioverter defibrillators [ICDs] or ICDs with resynchronization [CRTDs]) experience psychological distress. OBJECTIVE: We investigated the device nurse telephone intervention's effect on improving the patient's adaptation to shock devices, quality of life (QOL), and anxiety in the remote monitoring era. METHODS: The patient's adaptation to the device, health-related QOL, and anxiety were investigated by the modified Implanted Devices Adjustment-Japan score (IDAS), Short Form-36, and State-Trait Anxiety Inventory (STAI) before and 1-year after the device nurse telephone intervention, performed every 3 months. A total of 95 patients (median age 69 years and 25 females) participated. Sixty patients had ICDs and 35 CRTDs. Structural heart disease was observed in 72 patients, and idiopathic ventricular arrhythmias in the others. The mean left ventricular ejection fraction was 46% ± 15%. The median duration since the device implantation was 5.2 years. RESULTS: The total IDAS score significantly improved from 28.42 ± 7.11 at baseline to 26.77 ± 7.68 (p = 0.0076) at 1 year. Both the state and trait anxiety significantly improved (from 38.9 ± 9.6 to 35.3 ± 9.0 [<0.0001] and 38.8 ± 10.3 to 36.2±9.8 [p = 0.0044], respectively). The prevalence of patients with a state and trait anxiety of more than 40 decreased from 44 (46%) and 38 (40%) patients before the study to 27 (28 %) and 32 (34 %) at 1 year. The SF-36 mental component summary score significantly increased (50.8 ± 8.3 at baseline to 53.1 ± 7.7 at 1 year, p = 0.0031). CONCLUSIONS: The device nurse intervention facilitated the patient's adaptation to the shock device, increased the health-related QOL, and reduced the patient's anxiety.

The Differential Selectivity of Aryl Hydrocarbon Receptor (AHR) Agonists towards AHR-Dependent Suppression of Mammosphere Formation and Gene Transcription in Human Breast Cancer Cells.

We had previously reported that treatment with the aryl hydrocarbon receptor (AHR) agonist ß-naphthoflavone (ßNF) suppressed mammosphere formation derived from cancer stem cells in human breast cancer MCF-7 cells (Cancer Lett., 317, 2012, Zhao et al.). Here, using several AHR agonists, we have investigated the association of this suppression with the classical ability to induce AHR-mediated gene transcription in the xenobiotic response element (XRE). The mammosphere formation assays were performed using wild-type and AHR-knockout MCF-7 cells in the presence of AHR agonists including 3-methylcholanthrene (3MC), benzo[a]pyrene (BaP), 7,12-dimethylbenz[a]anthracene (DMBA), 6-formylindolo[3,2-b]carbazole (FICZ), indirubin, indole-3-carbinol (I3C), indole-3-acetic acid (IAA), and kynurenine (KYN), followed by the XRE-reporter gene assays of the agonists. We showed that treatments with 3MC, BaP, and DMBA strongly suppressed mammosphere formation of the stem cells in an AHR-dependent manner, while other agonists showed weaker suppression. In reporter gene assays, the strength or duration of AHR/XRE-mediated gene transcription was found to be dependent on the agonist. Although strong transcriptional activation was observed with 3MC, FICZ, indirubin, I3C, IAA, or KYN after 6 h of treatment, only weak activation was seen with BaP or DMBA. While transcriptional activation was sustained or increased at 24 h with 3MC, BaP, or DMBA, appreciable reduction was observed with the other agonists. In conclusions, the results demonstrated that the suppressive effects of AHR agonists on mammosphere formation do not necessarily correlate with their abilities to induce AHR-mediated gene transcription. Hence, different AHR functions may be differentially induced in an agonist-dependent manner.

Preoperative circadian physical activity rhythm and postoperative delirium in cardiovascular surgery patients.

Postoperative delirium, a common perioperative complication, is frequently observed in elderly surgical patients. Few studies have investigated the life rhythm of preoperative patients, and whether or not the preoperative life rhythm is associated with the development of postoperative delirium. The purpose of this study was to investigate the relationship between the preoperative circadian physical activity rhythm and postoperative delirium in cardiovascular surgery patients. A total of 43 patients who underwent cardiovascular surgery were included in this prospective study between July 2016 and September 2017 at Kobe University Hospital. All subjects used a "Life Microscope" wristband (a wristwatch-type terminal incorporating a 3-axis accelerometer monitoring) for 3-7 days at home before the planned surgery. Hourly mean values were calculated for the metabolic equivalents from the obtained activity amounts, and subsequently evaluated using cosine periodic regression analysis. The circadian rhythm parameters of mesor (24 h time series mean), amplitude (half the peak-trough variation), and acrophase (peak time) for the metabolic equivalents were obtained. The intensive care delirium screening checklist was used to assess for postoperative delirium. The acrophase significantly advanced in the postoperative delirium group (median, 11:55 h [interquartile range, 11:06-12:27 h]) compared to the group without postoperative delirium (median, 13:25 h [interquartile range, 12:52-14:13 h]) (p < .001). Furthermore, binary logistic regression analysis showed that advances in the physical activity phase remained independently associated with postoperative delirium (odds ratio, 0.003 [95% confidence interval, 0-0.63]). These results suggest that misalignment between advanced life rhythm before hospitalization and life rhythm after hospitalization might be associated with risk for developing postoperative delirium. Our results led us to speculate that adequate consideration of the patient's life rhythm before hospitalization is needed to prevent postoperative delirium.

Identification and characterization of organic and glycosidic acids in crude resin glycoside fraction from Calystegia hederacea.

Resin glycosides are well known as the purgative ingredients, which are characteristic of convolvulaceous plants. Calystegia hederacea Wall. is a perennial herbaceous vine that is widespread throughout India and East Asia. All parts of this plant are used for the treatment of menoxenia, gonorrhea, etc. Alkaline hydrolysis of the crude resin glycoside fraction of the whole plants of C. hederacea yielded four new glycosidic acids, calyhedic acids A, B, C, and D, along with two known glycosidic acids, calysolic acids A and C, and three known organic acids, 2S-methylbutyric, tiglic, and 2R,3R-nilic acids. Their structures were characterized on the basis of spectroscopic data and chemical evidence. Calyhedic acids A, B, and D were penta-, hexa-, and hepta-glycosides of 12S-hydroxyhexadecanoic acid, respectively, and cayhedic acid C was an isomer of calyhedic acid D, in which the 12S-hydroxyhexadecanoyl residue of calyhedic acid D was replaced by a 11S-hydroxyhexadecanoyl residue. Additionally, cytotoxic activity toward HL-60 human promyelocytic leukemia cells of the crude resin glycoside fraction, the glycosidic acid fraction, calyhedic acid A, and calysolic acid A from C. hederacea was evaluated. Furthermore, to clarify the structure-activity relationship of resin glycosides, the activities of six genuine resin glycosides with calysolic acid A or calysolic acid C as the glycosidic acid, which were isolated from C. soldanella, were examined. Among them, the crude resin glycoside fraction and five genuine resin glycosides with macrolactone structures demonstrated clear cytotoxic activities, while the glycosidic acid fraction, calyhedric acid A, calysolic acid A, and a genuine non-macrolactone-type resin glycoside were either inactive or exhibited weaker activity than the tested macrolactone-type resin glycosides.

Aryl hydrocarbon receptor counteracts pharmacological efficacy of doxorubicin via enhanced AKR1C3 expression in triple negative breast cancer cells.

Triple-negative breast cancer (TNBC) is associated with poor prognosis, because of no effective targeted therapy. In the present study, we demonstrated the crucial role of the aryl hydrocarbon receptor (AhR) in mediating the effects of the chemotherapeutic agent doxorubicin (DOX) in the chemotherapeutic sensitivity of TNBC. Firstly, we established AhR knockout (KO) MDA-MB 231 TNBC cells. The cytotoxic effects of DOX were more pronounced in AhR KO cells than in parental cells. In addition, our results indicated that AhR KO cells showed downregulated expression of DOX-metabolism enzyme, aldo-keto reductase (AKR) 1C3, relative to those of parental cells. Furthermore, AhR was found to enhance AKR1C3 promoter reporter activity, suggesting that AKR1C3 mRNA transcription is activated by AhR. Additionally, our findings confirmed that the downregulation of AKR1C3 expression enhanced DOX sensitivity in MDA-MB 231 cells. Finally, AhR and AKR1C3 expression were positively correlated in human breast cancer. Taken together, our results suggested that AhR is involved in DOX sensitivity by regulating AKR1C3 expression in TNBC cells.

Identification of 10-dehydrooxyglycyuralin E as a selective human estrogen receptor alpha partial agonist.

Selective estrogen receptor modulators (SERMs) act as either agonist or antagonist of estrogen receptor (ER) in a tissue selective manner and have been used in several diseases such as breast cancer, postmenopausal syndrome, osteoporosis, and cardiovascular diseases. However, current SERMs may also increase the risk of serious side effects and trigger drug resistance. Herein, a screening program, that was designed to search for novel SERMs, resulted in the identification of a series of 2-arylbenzofuran-containing compounds that are ligands for ERα, when applying the Gaussia-luciferase reporter assay. One of these compounds, 10-dehydrooxyglycyuralin E (T9) was chemically synthesized. T9 showed anti-estrogenic/proliferative activity in ERα-positive breast cancer cells. Pretreatment of T9 prevented the mRNA expression of GREB1, which is an estrogen response gene. Furthermore, by an in silico docking simulation study we demonstrated that T9 showed interactions directly to ERα. Taken together, these results demonstrated that T9 is a candidate of SERMs and a useful seed compound for the foundation of the selective activity of SERMs.

Lifestyle of Patients with Alcoholic Liver Disease and Factors Leading to Hospital Readmission: A Prospective Observational Study.

The objective of this study was to clarify the lifestyle characteristics of patients with alcoholic liver disease (ALD) who were readmitted to the hospital, and to identify the background factors associated with these characteristics. This was a prospective observational study. Over a period of 3 months following hospital discharge, we conducted structured interviews to investigate the following five lifestyle characteristics based on our previous research: dietary intake, alcohol consumption or abstinence, psycho-emotional status, regularity of life habits, adherence to treatment. We also collected data on background factors from medical records and questionnaires. The analysis was performed using conceptual cluster matrices, with participants divided into two groups (at-home recovery and readmission). Lifestyle, health status, and background factors were compared between the two groups. Of the 34 patients with ALD recruited, 21 completed the one-month follow-up and were included in the analysis-14 patients were in the at-home recovery group and 7 in the readmission group. The at-home group's lifestyle was characterized by controlled alcohol consumption, but with maintenance of regular life and eating habits and adherence to treatment. In contrast, irregular eating habits (p=0.006) and the development of irregular life habits or the discontinuation of treatment very quickly after hospital discharge characterized the readmission group's lifestyle. Experiences of loss were a lifestyle-related background factor that was associated with readmission (p=0.017). Based on these findings, supporting patients with ALD in maintaining regular eating habits and taking experiences of loss into consideration would be important in avoiding readmission over the short-term.

Cell Cycle and Apoptosis Regulator 1, CCAR1, Regulates Enhancer-Dependent Nuclear Receptor CAR Transactivation.

The constitutive active/androstane receptor (CAR) controls genes involved in xenochemical metabolism. Although numerous cofactors have been reported to be involved in CAR-mediated transactivation, unknown and poorly defined proteins recruited by CAR have yet to be characterized. In this study, a novel CAR-interacting protein, cell cycle and apoptosis regulator 1 (CCAR1), was identified by coimmunoprecipitation analysis using human hepatocarcinoma HepG2 cells expressing FLAG epitope-tagged CAR. We demonstrated that CCAR1 can act as an enhancer-dependent coactivator of CAR. First, we showed that overexpression of CCAR1 enhanced CAR-induced reporter gene activity with triplicate consensus direct repeat 4 motif (DR4-Luc), xenobiotic-responsive enhancer module (XREM)-enhancer of CYP3A4 (XREM-Luc), and phenobarbital-responsive enhancer module of UDP-glucuronosyltransferases 1A1 (UGT1A1) (gtPBREM)-enhancer of UGT1A1 (gtPBREM-Luc)-driven reporter plasmids but not PBREM-enhancer of CYP2B6 (PBREM-Luc)-driven reporter activity. Furthermore, we showed that knockdown of CCAR1 suppressed CAR-induced UGT1A1 mRNA expression but did not affect CAR-induced CYP2B6 mRNA expression in HepTR/CAR and HepaRG cells. Moreover, CCAR1 could be recruited to the gtPBREM of the UGT1A1 enhancer by CAR but not to the PBREM of the CYP2B6 enhancer. Moreover, we showed that CCAR1 can act as a secondary coactivator by cooperating with the p160 family of steroid receptor coactivators (SRCs). These findings demonstrated CCAR1 to be a novel transcriptional cofactor for CAR and provided insight regarding the mechanism of CAR-mediated gene-selective transactivation.

RIPK1 downregulation in keratinocyte enhances TRAIL signaling in psoriasis.

BACKGROUND: Psoriasis, a common inflammatory skin disorder characterized by scaly erythema and plaques, is induced by dysregulation of dendritic cell- and T cell-mediated immune reaction. Receptor-interacting protein kinase 1 (RIPK1) regulates inflammatory signaling in response to stimuli such as TNF-α, TRAIL, and TLRs, resulting in apoptosis, necroptosis and NF-κB activation. However, the physiological relevance in human epidermis remains elusive. OBJECTIVE: In this study, we examined whether RIPK1 is involved in the pathogenesis of psoriasis vulgaris. METHODS: Skin samples of eight patients with psoriasis vulgaris were investigated by western blotting and immunohistochemistry. The functions of RIPK1 in keratinocytes were examined by RT-PCR and ELISA in vitro. TRAIL-neutralization-experiment was employed in an imiquimod-induced murine psoriasis model. RESULTS: In lesional psoriatic epidermis, RIPK1-expression was decreased compared with that in normal epidermis. Cytokines involved in the pathomechanism of psoriasis, such as IL-1ß, IL-17A, IL-22 and TRAIL, reduced RIPK1-expression in normal human epidermal keratinocytes (HEK) in vitro. In addition, RIPK1-knockdown enhanced TRAIL-mediated expression of psoriasis-relating cytokines, such as IL-1ß, IL-6, IL-8, TNF-α, in HEK. Numerous TRAIL-positive cells were detected in the dermis of lesional psoriatic skin, and TRAIL receptors were expressed in psoriatic epidermis and HEK in conventional cultures. Moreover, TRAIL-neutralization in an imiquimod-induced murine psoriasis model remarkably improved skin phenotypes, such as ear thickness, and TNF-α expression in lesional skin. CONCLUSIONS: These results lead us to conclude that RIPK1-downregulation in keratinocytes increases their susceptibility to TRAIL stimulation, and plays a role in the pathogenesis of psoriasis vulgaris.