A mouse xenograft long-term replication yields a SARS-CoV-2 Delta mutant with increased lethality.

We recently established a long-term SARS-CoV-2 infection model using lung-cancer xenograft mice and identified mutations that arose in the SARS-CoV-2 genome during long-term propagation. Here, we applied our model to the SARS-CoV-2 Delta variant, which has increased transmissibility and immune escape compared with ancestral SARS-CoV-2. We observed limited mutations in SARS-CoV-2 Delta during long-term propagation, including two predominant mutations: R682W in the spike protein and L330W in the nucleocapsid protein. We analyzed two representative isolates, Delta-10 and Delta-12, with both predominant mutations and some additional mutations. Delta-10 and Delta-12 showed lower replication capacity compared with SARS-CoV-2 Delta in cultured cells; however, Delta-12 was more lethal in K18-hACE2 mice compared with SARS-CoV-2 Delta and Delta-10. Mice infected with Delta-12 had higher viral titers, more severe histopathology in the lungs, higher chemokine expression, increased astrocyte and microglia activation, and extensive neutrophil infiltration in the brain. Brain tissue hemorrhage and mild vacuolation were also observed, suggesting that the high lethality of Delta-12 was associated with lung and brain pathology. Our long-term infection model can provide mutant viruses derived from SARS-CoV-2 Delta and knowledge about the possible contributions of emergent mutations to the properties of new variants.

Prophylactic effect of pilocarpine on acute sialadenitis following radioactive iodine therapy in thyroid cancer patients.

Purpose: Our aim was to evaluate the effect of prophylactic pilocarpine on acute salivary symptoms after radioactive iodine (RAI) therapy in patients with differentiated thyroid cancer. Methods: We enrolled 88 patients (76 women and 12 men; mean age: 47 years; range: 20-74 years) with differentiated thyroid cancer who received RAI. Patients were divided into pilocarpine (51 patients) and control (37 patients) groups. Pilocarpine was given orally, at a dose of 5 mg three times a day, from 2 days before and 12 days after RAI therapy. Symptoms and signs of acute sialadenitis within 3 months of RAI therapy were recorded. Results: During the 3 months after RAI therapy, 13 of the 88 patients (14.7%) developed acute symptomatic sialadenitis (swelling or pain of salivary glands). Acute salivary symptoms were reported by 4 (7.8%) and 9 (24.3%) patients in the pilocarpine and control groups, respectively. Acute salivary symptoms were less frequent in the pilocarpine than control group (p = 0.04), but did not differ by age, sex, or RAI dose (p = 0.3357, p = 0.428, and p = 0.2792). Conclusions: Pilocarpine reduced the likelihood of acute sialadenitis after RAI therapy in patients with differentiated thyroid cancer.

Effects of parental holding on pain response in young children during cystometry: A randomized controlled trial.

INTRODUCTION: Cystometry is essential for evaluating bladder function. However, children may react negatively to the physical pain of urethral catheterization or anxiety and fear of an unfamiliar environment. These pain responses during the cystometry procedure may interfere with the cystometry procedure and make it difficult to interpret the cystometry result. In this regard, the International Children's Continence Society has advised performing cystometry while holding infants as an effective nonpharmacological pain management method, but there is insufficient evidence to support this. PURPOSE: This study aimed to analyze the effect of parental holding on reducing pain in children during cystometry. METHODS: This was an experimental study in a randomized controlled pre-post test design. A total of 64 participants aged 6-18 months were recruited. During cystometry, the participants in the experimental group were placed on the parent's laps and held in the parents' arms. The participants in the control group were laid down on the examination table. During the procedure, both groups of parents were allowed to touch their children in all ways except holding them and to use the pacifier if they wished. The behavioral (face, leg, activity, cry, consolability scale) and physiological (oxygen saturation and heart rate) pain responses were measured at three-time points (immediately, 3, and 10 min after urethral catheter insertion). RESULTS: Comparing the two groups, in the experimental group, the behavioral pain response at 3 min after urethral catheter insertion (t = -2.165, p = 0.034) and 10 min after (t = -3.155, p = 0.002) was decreased compared with that immediately after urethral catheter insertion. In addition, oxygen saturation increased more (t = 2.021, p = 0.048), and the heart rate decreased more (t = -2.033, p = 0.047) at 10 min than at 3 min after urethral catheter insertion in the experimental group. CONCLUSIONS: This study revealed that parental holding could reduce pain responses during cystometry in children. Further research is required to confirm the applicability and usefulness of parental holding during cystometry.

Prognostic Value of FDG PET/CT in Patients with Nodal Peripheral T-Cell Lymphoma.

This study evaluated the prognostic significance of FDG PET/CT in patients with nodal peripheral T-cell lymphoma (PTCL). We retrospectively reviewed patients with histologically confirmed nodal PTCL who underwent FDG PET/CT at baseline, after three cycles of first-line chemotherapy (interim), and at the end of therapy. Response was assessed visually using the Deauville 5-point scale (D5PS); scores of 1, 2, and 3 were considered PET-negative, and scores of 4 and 5 were considered PET-positive. The associations between FDG PET/CT findings and survival were assessed using Cox regression analysis. A total of 79 patients (44 males and 35 females; median age 56 years) were included in this study. In response assessment, 17 (22%) had an interim PET-positive result and 10 (13%) had an end-of-therapy PET-positive result. During a median follow-up of 50 months, 37 patients (47%) presented with disease progression and 30 patients (38%) died. The estimated 5-year progression-free survival (PFS) and overall survival (OS) were 57% and 64%, respectively. An interim PET-positive result was the only significant indicator of PFS. Higher International Prognostic Index and end-of-therapy PET-positive result were significant independent prognostic factors of OS. Interim and end-of-therapy FDG PET/CT responses based on D5PS are meaningful in predicting the outcomes of patients with nodal PTCL.

Radotinib Decreases Prion Propagation and Prolongs Survival Times in Models of Prion Disease.

The conversion of cellular prion protein (PrPC) into pathogenic prion isoforms (PrPSc) and the mutation of PRNP are definite causes of prion diseases. Unfortunately, without exception, prion diseases are untreatable and fatal neurodegenerative disorders; therefore, one area of research focuses on identifying medicines that can delay the progression of these diseases. According to the concept of drug repositioning, we investigated the efficacy of the c-Abl tyrosine kinase inhibitor radotinib, which is a drug that is approved for the treatment of chronic myeloid leukemia, in the treatment of disease progression in prion models, including prion-infected cell models, Tga20 and hamster cerebellar slice culture models, and 263K scrapie-infected hamster models. Radotinib inhibited PrPSc deposition in neuronal ZW13-2 cells that were infected with the 22L or 139A scrapie strains and in cerebellar slice cultures that were infected with the 22L or 263K scrapie strains. Interestingly, hamsters that were intraperitoneally injected with the 263K scrapie strain and intragastrically treated with radotinib (100 mg/kg) exhibited prolonged survival times (159 ± 28.6 days) compared to nontreated hamsters (135 ± 9.9 days) as well as reduced PrPSc deposition and ameliorated pathology. However, intraperitoneal injection of radotinib exerted a smaller effect on the survival rate of the hamsters. Additionally, we found that different concentrations of radotinib (60, 100, and 200 mg/kg) had similar effects on survival time, but this effect was not observed after treatment with a low dose (30 mg/kg) of radotinib. Interestingly, when radotinib was administered 4 or 8 weeks after prion inoculation, the treated hamsters survived longer than the vehicle-treated hamsters. Additionally, a pharmacokinetic assay revealed that radotinib effectively crossed the blood-brain barrier. Based on our findings, we suggest that radotinib is a new candidate anti-prion drug that could possibly be used to treat prion diseases and promote the remission of symptoms.

Development and effects of an internet-based family resilience-promoting program for parents of children with cancer: A randomized controlled trial.

PURPOSE: The diagnosis of cancer in children can negatively impact their parents, owing to the complex treatment processes. Families with high levels of resilience can overcome these difficulties and thus perform higher family functions. We aimed to develop an internet-based family resilience-promoting program for parents of children with cancer and evaluate its effect on the levels of family resilience, depression, and family function. METHODS: This prospective, parallel-group, randomized-controlled study that was conducted at Yonsei Cancer Center from June to October 2021 included 41 parents of children with cancer. In total, four sessions of the internet-based family resilience-promoting program, led by a nurse, were conducted individually for parents. Levels of family resilience, depression, and family function were measured before, immediately after, and 4 weeks after the program. The data were analyzed using the linear mixed-effect model, and program satisfaction was evaluated through an internet-based questionnaire and interview. RESULTS: The experimental group (the family resilience-promoting program participants) differed more significantly from the control group in the level of change in family resilience (ß = 13.214, p = 0.003, effect size = 0.374) and family function (ß = 1.256, p = 0.018, effect size = 0.394). However, there was no significant difference between the groups in the level of depression (ß = 2.133, p = 0.187, effect size = 0.416). All the program participants showed a high program satisfaction score of 4.75 out of 5.00 points overall. CONCLUSIONS: The applicability of the internet-based family resilience-promoting program as an appropriate nursing intervention was verified. Its application can help the families of children with cancer adapt to the stressful situation of their children's cancer diagnosis and treatment.

8-Methoxypsoralen Induces Apoptosis by Upregulating p53 and Inhibits Metastasis by Downregulating MMP-2 and MMP-9 in Human Gastric Cancer Cells.

Furanocoumarin 8-methoxypsoralen (8-MOP) is the parent compound that naturally occurs in traditional medicinal plants used historically. 8-MOP has been employed as a photochemotherapeutic component of Psoralen + Ultraviolet A (PUVA) therapy for the treatment of vitiligo and psoriasis. Although the role of 8-MOP in PUVA therapy has been studied, little is known about the effects of 8-MOP alone on human gastric cancer cells. In this study, we observed anti-proliferative effect of 8-MOP in several human cancer cell lines. Among these, the human gastric cancer cell line SNU1 is the most sensitive to 8-MOP. 8-MOP treated SNU1 cells showed G1-arrest by upregulating p53 and apoptosis by activating caspase-3 in a dose-dependent manner, which was confirmed by loss-of-function analysis through the knockdown of p53-siRNA and inhibition of apoptosis by Z-VAD-FMK. Moreover, 8-MOPinduced apoptosis is not associated with autophagy or necrosis. The signaling pathway responsible for the effect of 8-MOP on SNU1 cells was confirmed to be related to phosphorylated PI3K, ERK2, and STAT3. In contrast, 8-MOP treatment decreased the expression of the typical metastasis-related proteins MMP-2, MMP-9, and Snail in a p53-independent manner. In accordance with the serendipitous findings, treatment with 8-MOP decreased the wound healing, migration, and invasion ability of cells in a dose-dependent manner. In addition, combination treatment with 8-MOP and gemcitabine was effective at the lowest concentrations. Overall, our findings indicate that oral 8-MOP has the potential to treat early human gastric cancer, with fewer side effects.

Brown fat activation demonstrated on FDG PET/CT predicts survival outcome.

PURPOSE: The purpose of this study was to compare the survival of patients with and without BAT activity on FDG PET/CT. METHODS: PET/CT exams from 3937 breast cancer patients were retrospectively reviewed for bilateral symmetric elongated FDG activity in the neck and chest, typical of BAT activation. A control group of age-matched (± 1 year) breast cancer patients who underwent PET/CT the same week was also enrolled for comparison. Kaplan-Meier curves of progression-free survival (PFS) and overall survival (OS) for BAT positive patients and the control group were calculated. Further sub-analysis was performed to account for the hormonal changes associated with menopause. RESULTS: 2.0% (80/3937) of the breast cancer patients who underwent PET/CT demonstrated BAT activation, and 80 additional patients were analyzed for comparison as the group without BAT activity. Mean follow-up was 76 months (range 1-225 months). There were 4 recurrences in the BAT group, compared to 12 in the control. The mean PFS for the BAT group was 127 months, which was significantly lower than the mean PFS of 180 months in the control (p = 0.047). Sub-analysis of premenopausal women again showed longer PFS for the BAT group (129 vs. 196 months, p = 0.095) while no difference was found in postmenopausal women (mean 102 vs. 135 months, p = 0.360). Presence of BAT activity was also a significant predictor variable for PFS on Cox regression. CONCLUSION: Patients with BAT activity showed longer progression-free survival than those without, emphasizing the need for further evaluation of its role in metabolism, treatment response, tumor microenvironment and long-term prognosis.

Impairment of Neuronal Mitochondrial Quality Control in Prion-Induced Neurodegeneration.

Mitochondrial dynamics continually maintain cell survival and bioenergetics through mitochondrial quality control processes (fission, fusion, and mitophagy). Aberrant mitochondrial quality control has been implicated in the pathogenic mechanism of various human diseases, including cancer, cardiac dysfunction, and neurological disorders, such as Alzheimer's disease, Parkinson's disease, and prion disease. However, the mitochondrial dysfunction-mediated neuropathological mechanisms in prion disease are still uncertain. Here, we used both in vitro and in vivo scrapie-infected models to investigate the involvement of mitochondrial quality control in prion pathogenesis. We found that scrapie infection led to the induction of mitochondrial reactive oxygen species (mtROS) and the loss of mitochondrial membrane potential (ΔΨm), resulting in enhanced phosphorylation of dynamin-related protein 1 (Drp1) at Ser616 and its subsequent translocation to the mitochondria, which was followed by excessive mitophagy. We also confirmed decreased expression levels of mitochondrial oxidative phosphorylation (OXPHOS) complexes and reduced ATP production by scrapie infection. In addition, scrapie-infection-induced aberrant mitochondrial fission and mitophagy led to increased apoptotic signaling, as evidenced by caspase 3 activation and poly (ADP-ribose) polymerase cleavage. These results suggest that scrapie infection induced mitochondrial dysfunction via impaired mitochondrial quality control processes followed by neuronal cell death, which may have an important role in the neuropathogenesis of prion diseases.

Cellular Prion Protein Is Closely Associated with Early Recurrence and Poor Survival in Patients with Hepatocellular Carcinoma.

The cellular prion protein (PrPC) is known to play a role in cancer proliferation and metastasis. However, the role of PrPC expression in hepatocellular carcinoma (HCC) is unknown. This study investigated whether overexpression of PrPC affects recurrence after surgical resection and survival in HCC. A total of 110 HCC patients who underwent hepatic resection were included. They were followed up for a median of 42 months (range 1-213 months) after hepatectomy. The relationships between PrPC expression and the HCC histologic features, recurrence of HCC following surgical resection, and survival of the patients were examined. Seventy-one cases (64.5%) of HCC demonstrated higher expression of PrPC. The expression of PrPC was only correlated with diabetes mellitus. There was no association between PrPC expression and age, sex, hypertension, hepatitis B virus positivity, alcohol consumption, Child-Pugh class, major portal vein invasion, serum alpha-fetoprotein, and HCC size or number. The 1-year recurrence rates in patients with higher PrPC expression were higher than those with lower PrPC expression. The cumulative survival rates of patients with higher PrPC expression were significantly shorter than those of patients with lower PrPC expression. In conclusion, PrPC expression is closely associated with early recurrence and poor survival of HCC patients following surgical resection.

Resilience-Promoting Programs in Families of Children With Cancer: A Systematic Review.

Purpose: Pediatric cancer is a difficult experience for children and their families. It is thus necessary to promote family resilience for the effective treatment and quality of life improvement among children with cancer. The aim of this systematic review was to identify the components of a resilience-promoting program for children with cancer and their families and to synthesize the literature findings on the outcomes of the resilience-promoting program. Method: A systematic search of the literature was conducted using five databases (PubMed, CHIAHL, PsycINFO, Web of Science, and Research Information Sharing Service) up to July 22, 2020. The search was limited to studies published in English and Korean, and to grey literature published in Korea. Studies were critically appraised using the Mixed Methods Appraisal Tool and Cochrane Risk of Bias tool. Extracted data were summarized as tables. Results: Eight studies were selected. The main components of the resilience-promoting program were providing information (on strategies, medical and psychoeducation, and community resources) and emotional coping (expressing feeling, reappraising cognition about adversity, and stress management). The main outcomes of these programs were reinforced outcomes (resilience, benefit finding, coping, positive affect, problem-solving skills, family adaptation, and self-concept) and improved outcomes (in depression, posttraumatic stress, anxiety, impact of illness of the family, and mood). Conclusion: As the components and outcomes of family resilience-promoting programs vary, it is necessary to consistently use valid tools to effectively identify interventions. Additionally, various methodological studies are required to further analyze the effect of these programs.

Improvement in obstructive sleep apnea in a child with Down syndrome with rapid palatal expansion.

Children with Down syndrome (DS) have distinct orofacial structures that predispose them to sleep-disordered breathing. The management options for obstructive sleep apnea include continuous positive airway pressure, adenotonsillectomy, mandibular advancement, and maxillary expansion. However, most of these treatment options are less effective or less viable for children with DS. Rapid maxillary expansion with a fixed orthodontic appliance is a viable alternative for DS patients because it separates the midpalatal suture and dilates the airway, regardless of the patient's compliance. We present a case of a 15-year-old boy with DS and severe obstructive sleep apnea, which dramatically improved with rapid maxillary expansion and subsequent orthodontic treatment. Although only the short-term changes have been presented in this report, this case emphasizes the need for further discussions on the viability of rapid maxillary expansion for treating obstructive sleep apnea in children with DS. CITATION: Kim A, Cho HJ, Choi EK, Choi YJ. Improvement in obstructive sleep apnea in a child with Down syndrome with rapid palatal expansion. J Clin Sleep Med. 2022;18(7):1885-1888.

Prognostic Impact of Total Lesion Glycolysis (TLG) from Preoperative 18F-FDG PET/CT in Stage II/III Colorectal Adenocarcinoma: Extending the Value of PET/CT for Resectable Disease.

We investigated the prognostic role of metabolic parameters from preoperative 18F-FDG PET/CT in stage II/III colorectal adenocarcinoma. A total of 327 stage II/III colorectal adenocarcinoma patients who underwent curative resection were included. The maximal standard uptake value (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) were analyzed for optimal cut-offs and their effect on DFS. Differences in DFS rates and hazard ratios for DFS between cut-offs were statistically significant in SUVmax, MTV2.5, MTV3, TLG 2.5, TLG3, and TLG30%. Factors significantly related to DFS in univariate Cox regression were age, sex, stage, preoperative CEA, SUVmax, MTV2.5, MTV3, TLG2.5, TLG3, and TLG30%. Age, sex, preoperative CEA, and TLG2.5 (p = 0.009) sustained statistically significant difference in multivariate analysis. The 1-, 3-, and 5-year DFS rates for TLG2.5 ≤ 448.5 were 98.1%, 79.6%, and 74.8%, significantly higher than 78.4%, 68.5%, and 61.1% of TLG2.5 > 448.5, respectively (p = 0.012). TLG, a parameter indicating both the metabolic activity and metabolic volume, was the strongest predictor independently associated with DFS, among several PET parameters with statistical significance. These results suggest the potential prognostic value of preoperative 18F-FDG PET/CT in stage II/III resectable colorectal cancer.

Family resilience factors affecting family adaptation of children with cancer: A cross-sectional study.

PURPOSE: Pediatric cancer impacts all family members, including parents and siblings, who strive to adjust to a multitude of changes brought about by the illness. Family resilience is an important factor in the successful adaptation of families of children with cancer. Therefore, we aimed to identify risk and protective factors for family resilience at the child, family, and community levels that affect the adaptation of families of children with cancer. METHOD: This study employed a descriptive survey design, and data were collected from 111 parents of children undergoing treatment for cancer between April and May 2020 at a university hospital in South Korea. Based on Patterson's family resilience model, risk factors-severity of child's condition, parental depression, and stigma and discrimination-and protective factors-the child's temperament, family communication skills, and supportive health services-for family adaptation were analyzed using multiple regression analyses. RESULTS: Among family resilience factors affecting the adaptation of families of children with cancer, parental depression (ß = -0.290, p = 0.004) and family communication skills (ß = 0.403, p < 0.001) were identified as risk and protective factors, respectively. These variables accounted for 29.3% of the variance in family adaptation (F = 7.503, p < 0.001). CONCLUSIONS: There is a need to develop strategies such as intervention programs that focus on reducing parental depression and strengthening family communication skills to promote the adaptation of families to pediatric cancer.

G-749 Promotes Receptor Tyrosine Kinase TYRO3 Degradation and Induces Apoptosis in Both Colon Cancer Cell Lines and Xenograft Mouse Models.

G-749 is an FLT3 kinase inhibitor that was originally developed as a treatment for acute myeloid leukemia. Some FLT3 kinase inhibitors are dual kinase inhibitors that inhibit the TAM (Tyro3, Axl, Mer) receptor tyrosine kinase family and are used to treat solid cancers such as non-small cell lung cancer (NSCLC) and triple-negative breast cancer (TNBC). AXL promotes metastasis, suppression of immune response, and drug resistance in NSCLC and TNBC. G-749, a potential TAM receptor tyrosine kinase inhibitor, and its derivative SKI-G-801, effectively inhibits the phosphorylation of AXL at nanomolar concentration (IC50 = 20 nM). This study aimed to investigate the anticancer effects of G-749 targeting the TAM receptor tyrosine kinase in colon cancer. Here, we demonstrate the potential of G-749 to effectively inhibit tumorigenesis by degrading TYRO3 via regulated intramembrane proteolysis both in vitro and in vivo. In addition, we demonstrated that G-749 inhibits the signaling pathway associated with cell proliferation in colon cancer cell lines HCT15 and SW620, as well as tumor xenograft mouse models. We propose G-749 as a new therapeutic agent for the treatment of colon cancer caused by abnormal TYRO3 expression or activity.

Increased Expression of S100B and RAGE in a Mouse Model of Bile Duct Ligation-induced Liver Fibrosis.

BACKGROUND: Liver fibrosis is defined as the accumulation of the extracellular matrix and scar formation. The receptor for advanced glycation end products (RAGE) has been demonstrated to participate in fibrogenesis. S100B is a ligand of RAGE and exerts extracellular functions by inducing a series of signal transduction cascades. However, the involvement of S100B and RAGE in cholestasis-induced liver fibrosis remains unclear. In this study, we investigated S100B and RAGE expression during liver fibrosis in mice that underwent common bile duct ligation (BDL). METHODS: BDL was performed in 10-week-old male C57BL/6J mice with sham control (n = 26) and BDL (n = 26) groups. Expression levels of S100B, RAGE and fibrotic markers in the livers from both groups at week 1 and 3 after BDL were examined by western blot and quantitative real-time reverse transcription polymerase chain reaction analysis. Liver fibrotic changes were examined by histological and ultrastructural analysis. RESULTS: Histological staining with Sirius Red and the evaluation of the messenger RNA expression of fibrotic markers showed noticeable periportal fibrosis and bile duct proliferation. S100B was mainly present in bile duct epithelial cells, and its expression was upregulated in proportion to the ductular reaction during fibrogenesis by BDL. RAGE expression was also increased, and interestingly, triple immunofluorescence staining and transmission electron microscopy showed that both S100B and RAGE were expressed in proliferating bile duct epithelial cells and activated hepatic stellate cells (HSCs) of the BDL livers. In addition, in rat HSCs (HSC-T6), treatment with recombinant S100B protein significantly increased fibrotic markers in a dose-dependent manner, and RAGE small interfering RNA (siRNA) suppressed S100B-stimulated upregulation of fibrotic markers compared with cells treated with scramble siRNA and S100B. CONCLUSION: These findings suggest that the increased expression of S100B and RAGE and the interaction between S100B and RAGE may play an important role in ductular reaction and liver fibrosis induced by BDL.

Involvement of Cellular Prion Protein in Invasion and Metastasis of Lung Cancer by Inducing Treg Cell Development.

The cellular prion protein (PrPC) is a cell surface glycoprotein expressed in many cell types that plays an important role in normal cellular processes. However, an increase in PrPC expression has been associated with a variety of human cancers, where it may be involved in resistance to the proliferation and metastasis of cancer cells. PrP-deficient (Prnp0/0) and PrP-overexpressing (Tga20) mice were studied to evaluate the role of PrPC in the invasion and metastasis of cancer. Tga20 mice, with increased PrPC, died more quickly from lung cancer than did the Prnp0/0 mice, and this effect was associated with increased transforming growth factor-beta (TGF-ß) and programmed death ligand-1 (PD-L1), which are important for the development and function of regulatory T (Treg) cells. The number of FoxP3+CD25+ Treg cells was increased in Tga20 mice compared to Prnp0/0 mice, but there was no significant difference in either natural killer or cytotoxic T cell numbers. In addition, mice infected with the ME7 scrapie strain had decreased numbers of Treg cells and decreased expression of TGF-ß and PD-L1. These results suggest that PrPC plays an important role in invasion and metastasis of cancer cells by inducing Treg cells through upregulation of TGF-ß and PD-L1 expression.

Prognostic value of pretreatment F-18 fluorodeoxyglucose PET/CT in colorectal cancer with unresectable metastasis.

PURPOSE: The aim of the study was to assess the prognostic value of pretreatment PET/computed tomography (CT) scans in colorectal cancer (CRC) patients with unresectable metastasis. MATERIALS AND METHODS: We retrospectively reviewed the pretreatment PET/CT images of 82 CRC patients with unresectable metastasis and their medical records. On PET/CT images, maximum standardized uptake value (SUVmax) of primary tumor, highest SUVmax of metastatic tumors and number of metastatic organs were identified. The patients were further divided into single and multiple organ metastases groups according to the extent of disease. Survival analysis was performed with the clinical variables and metabolic parameters from PET/CT. RESULTS: In a total of 82 patients, the age of patients, highest SUVmax of metastatic tumors and number of metastatic organs were independent prognostic factors for overall survival (OS) (all P < 0.05), whereas the SUVmax of primary tumor was not. On multivariate analysis, only the SUVmax of metastatic tumor was a significant prognostic factor in the single organ metastasis group (P = 0.047), whereas the age and highest SUVmax of metastatic tumors were independent prognostic factors in the multiple organ metastases group (all P < 0.05). CONCLUSION: The highest SUVmax of metastatic tumors was an independent prognostic factor for OS in CRC patients with unresectable metastasis.

Co-treatment of birinapant with TRAIL synergistically induces apoptosis by downregulating cFLIP(L) in MDA-MB-453 cell lines.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has received much attention owing to its ability to specifically induce cell death in cancer. However, several types of cancer, including some forms of breast cancer, are resistant to TRAIL. Various chemotherapeutic agents, phytochemicals, and TRAIL combination therapies have been proposed to resolve TRAIL resistance. Here, we explored the sensitization effect of birinapant on TRAIL-induced apoptosis in the MDA-MB-453 cell line. Although neither birinapant nor TRAIL showed any cytotoxic effect when used alone, apoptosis was induced when birinapant and TRAIL were used together. Our data suggest that the combination of birinapant and TRAIL induces downregulation of FLICE-like inhibitory protein (cFLIP) (L) protein expression. Interestingly, cFLIP(L) overexpression reversed apoptosis caused by co-treatment with TRAIL. Taken together, our results indicate that a combination of birinapant and TRAIL may be a promising treatment for TRAIL-resistant breast cancer.

The matricellular protein CCN5 prevents adverse atrial structural and electrical remodelling.

Atrial structural remodelling including atrial hypertrophy and fibrosis is a key mediator of atrial fibrillation (AF). We previously demonstrated that the matricellular protein CCN5 elicits anti-fibrotic and anti-hypertrophic effects in left ventricles under pressure overload. We here determined the utility of CCN5 in ameliorating adverse atrial remodelling and arrhythmias in a murine model of angiotensin II (AngII) infusion. Advanced atrial structural remodelling was induced by AngII infusion in control mice and mice overexpressing CCN5 either through transgenesis (CCN5 Tg) or AAV9-mediated gene transfer (AAV9-CCN5). The mRNA levels of pro-fibrotic and pro-inflammatory genes were markedly up-regulated by AngII infusion, which was significantly normalized by CCN5 overexpression. In vitro studies in isolated atrial fibroblasts demonstrated a marked reduction in AngII-induced fibroblast trans-differentiation in CCN5-treated atria. Moreover, while AngII increased the expression of phosphorylated CaMKII and ryanodine receptor 2 levels in HL-1 cells, these molecular features of AF were prevented by CCN5. Electrophysiological studies in ex vivo perfused hearts revealed a blunted susceptibility of the AAV9-CCN5-treated hearts to rapid atrial pacing-induced arrhythmias and concomitant reversal in AngII-induced atrial action potential prolongation. These data demonstrate the utility of a gene transfer approach targeting CCN5 for reversal of adverse atrial structural and electrophysiological remodelling.