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FOXR2 Interacts with MYC to Promote Its Transcriptional Activities and Tumorigenesis.

Sat, 12/02/2017 - 16:46
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FOXR2 Interacts with MYC to Promote Its Transcriptional Activities and Tumorigenesis.

Cell Rep. 2016 07 12;16(2):487-497

Authors: Li X, Wang W, Xi Y, Gao M, Tran M, Aziz KE, Qin J, Li W, Chen J

Abstract
By combining the results of a large-scale proteomic analysis of the human transcription factor interaction network with knowledge databases, we identified FOXR2 as one of the top-ranked candidate proto-oncogenes. Here, we show that FOXR2 forms a stable complex with MYC and MAX and subsequently regulates cell proliferation by promoting MYC's transcriptional activities. We demonstrate that FOXR2 is highly expressed in several breast, lung, and liver cancer cell lines and related patient tumor samples, while reduction of FOXR2 expression in a xenograft model inhibits tumor growth. These results indicate that FOXR2 acts with MYC to promote cancer cell proliferation, which is a potential tumor-specific target for therapeutic intervention against MYC-driven cancers.

PMID: 27346356 [PubMed - indexed for MEDLINE]

CD105+-mesenchymal stem cells migrate into osteoarthritis joint: An animal model.

Fri, 12/01/2017 - 16:45

CD105+-mesenchymal stem cells migrate into osteoarthritis joint: An animal model.

PLoS One. 2017;12(11):e0188072

Authors: Fernandez-Pernas P, Rodríguez-Lesende I, de la Fuente A, Mateos J, Fuentes I, De Toro J, Blanco FJ, Arufe MC

Abstract
Mesenchymal stem cells are being the focus of connective tissue technology and regenerative medicine, presenting a good choice cell source for improving old and well recognized techniques of cartilage defect repair. For instance, the autologous chondrocyte transplantation using new concepts of regenerative medicine. The present study investigated the risk of xenogenicity of human synovial membrane-derived MSCs, injected into the monkeys using intravenous and intra-articular administration. The animal models used were adult monkeys Rhesus which had been injured into the left knee to create an Osteoarthritis (OA) animal model. CD105+-MSCs were injected twice into the OA monkeys with an interval of one week between them. The animals were euthanized one month after treatment. Immunohistochemistry analysis of different organs: spleen, heart, fat, liver, gut, pancreas, lung, skeletal muscle and kidney from the animals revealed that CD105+-MSCs migrated towards the injured knee joint. MSCs naive were found statistically significant increased in the injured knee in front of healthy one. CD105+-MSCs were negatives for CD68 and the area where CD105+-MSCs were found presented SDF-1 increased levels in front of healthy knee. We concluded that a characterized MSCs subset could be a safe alternative for cell therapy in clearly localized pathologies.

PMID: 29190645 [PubMed - in process]

Patterns and predictors of pain following lung transplantation.

Fri, 12/01/2017 - 16:45

Patterns and predictors of pain following lung transplantation.

Gen Hosp Psychiatry. 2017 Nov 21;50:125-130

Authors: Farquhar JM, Smith PJ, Snyder L, Gray AL, Reynolds JM, Blumenthal JA

Abstract
OBJECTIVE: Our objective was to examine variability in pain levels following lung transplantation, and examine individual biopsychosocial factors influencing changes in pain.
METHOD: We performed a retrospective study of a cohort of 150 patients transplanted and discharged from Duke University Hospital between January 2015 and September 2016. During hospitalization and at clinic visits up to two months after discharge, subjective pain ratings were obtained using a 0-10 Numeric Rating Scale. Psychiatric diagnoses of anxiety and depression and Center for Epidemiological Studies - Depression (CES-D) scores collected after hospital discharge were examined as predictors of post-surgery pain. Medical and surgical variables were examined as covariates.
RESULTS: During hospitalization, pain ratings decreased over time (p<0.001). Predictors of higher pain levels included pre-transplant history of depression (p=0.001) and anxiety (p=0.04), bilateral lung transplant (p=0.03), and lower six-minute walk distance (p=0.02). Two months after discharge, 18% of patients reported continued pain and 34% remained on opioid pain medications. Two months after discharge, more frequent post-operative complications predicted higher pain levels in a univariate analysis (p=0.02) although this relationship was attenuated after adjustment for depression. In a multivariate analysis, elevated CES-D scores (p=0.002), and greater opioid use (p=0.031) predicted higher pain levels 2-months post-discharge.
CONCLUSION: We conclude that patients with psychiatric comorbidities may be at risk for greater pain, and may require additional strategies for more effective pain management.

PMID: 29190571 [PubMed - as supplied by publisher]

Lung transplantation as a therapeutic option in acute respiratory distress syndrome.

Fri, 12/01/2017 - 16:45

Lung transplantation as a therapeutic option in acute respiratory distress syndrome.

Transplantation. 2017 Nov 17;:

Authors: Chang Y, Lee SO, Shim TS, Choi SH, Kim HR, Kim YH, Kim DK, Do KH, Choi IC, Hong SB, Park SI

Abstract
BACKGROUND: Lung transplantation (LTPL) is considered as a salvage therapeutic option in patients with end-stage lung disease. However, there is a lack of sufficient data on the use of LTPL in patients with acute respiratory distress syndrome (ARDS). While there are few case reports on lung transplant for ARDS, no case series exist up to date. The aim of this study was to evaluate the clinical outcomes of patients with ARDS in accordance with the LTPL status.
METHODS: Patients who had severe ARDS (PaO2/FiO2 ratio ≤ 100 mmHg with positive end expiratory pressure ≥ 5 cmH2O) and were listed for LTPL with no underlying end-stage lung disease were included in this single-center retrospective study. Demographic and clinical data of the patients were collected and analyzed.
RESULTS: Fourteen patients were listed for LTPL due to severe ARDS. All patients received mechanical ventilation, and 12 (86%) patients underwent extracorporeal membrane oxygenation. Of the nine patients who underwent LTPL, eight (89%) survived, whereas only one patient (20%) out of those who did not receive LTPL survived. The median survival time of the patients who underwent LTPL was 1996 days (interquartile range (IQR), 872-2239), compared with 49 days (IQR, 872-2239) in patients who did not undergo LTPL. The median survival time after LTPL was 64 months (IQR, 28-72). The three-year survival rate of the recipients was 78%.
CONCLUSIONS: LTPL may be considered as a therapeutic option in a select group of patients with severe ARDS. However, the irreversibility of the patient's lung status should be considered.

PMID: 29189633 [PubMed - as supplied by publisher]

Pre-operative neutrophil count and neutrophil-lymphocyte count ratio (NLCR) in predicting the histological grade of paediatric brain tumours: a preliminary study.

Fri, 12/01/2017 - 16:45

Pre-operative neutrophil count and neutrophil-lymphocyte count ratio (NLCR) in predicting the histological grade of paediatric brain tumours: a preliminary study.

Acta Neurochir (Wien). 2017 Nov 29;:

Authors: Wilson JRF, Saeed F, Tyagi AK, Goodden JR, Sivakumar G, Crimmins D, Elliott M, Picton S, Chumas PD

Abstract
INTRODUCTION: The neutrophil-lymphocyte count ratio (NLCR) is an established prognostic marker for renal, lung and colorectal carcinomas and has been suggested to be predictive of histological grade and outcome in adult intracranial tumours. The purpose of this study was to determine whether a correlation of the pre-operative neutrophil count (NC) and NLCR with the final histological grade exists in paediatric intracranial tumours.
METHODS: A retrospective analysis was undertaken at a single centre. Patients less than 18 years old at the time of surgery who underwent tumour-related procedures from 2006 to 2015 were included. Patients with recurrent tumours, previous bone marrow transplant and metastases were excluded. Pre-operative full blood counts (FBC), collected before the diagnosis of intracranial pathology and before administration of steroids, were matched with histological diagnosis for each patient. Post-operative FBC was also recorded, together with survival data where applicable.
RESULTS: A total of 116 patients (74 male, 42 female; mean age, 8 ± 0.9 years) with a diagnosis of primary intracranial tumours had pre-operative FBC that could be matched to final histological grade. Pre-operative NC and NLCR were higher with increasing grade of tumour: grade 1 (NC 4.29 109/l, NLCR 2.26), grade 2 (NC 4.59 109/l, NLCR 2.38), grade 3 (NC 5.67 109/l, NLCR 2.72) and grade 4 (NC 6.59 109/l, NLCR 3.31). Patients with WHO grade 1 and 2 tumours pooled together had a lower NC (4.37 95% CI ± 0.67 109/l) compared to WHO grade 3 and 4 patients (6.41 95% CI ± 0.99 109/l, p = 0.0013). The NLCR was lower in grade 1 and 2 tumours (2.29 ± 0.59) (compared to grade 3 and 4 tumours; 3.20 ± 0.76) but this did not reach significance (p = 0.069). The subgroup of patients with pilocytic astrocytoma had a significantly lower NC when compared to patients with high-grade tumours (p = 0.005). Medulloblastoma and supratentorial PNET subgroups had significantly higher NC compared to the low-grade group (p = 0.033, p = 0.002). Post-operative NC was significantly higher in the high-grade tumours (p = 0.034), but no difference was observed for NLCR (p = 0.28).
CONCLUSIONS: No evidence exists to support the correlation of pre-operative NC or NLCR to histological diagnosis in paediatric intracranial tumours. Our results indicate that a higher pre-operative NC/NLCR correlates with a higher histological grade of tumour. This suggests that immunological mechanisms may be involved in the pathogenesis of paediatric brain tumours, and a further prospective study is required to substantiate and expand these findings.

PMID: 29188366 [PubMed - as supplied by publisher]

Mutational Landscape of cfDNA Identifies Distinct Molecular Features Associated With Therapeutic Response to First-Line Platinum-Based Doublet Chemotherapy in Patients with Advanced NSCLC.

Fri, 12/01/2017 - 16:45

Mutational Landscape of cfDNA Identifies Distinct Molecular Features Associated With Therapeutic Response to First-Line Platinum-Based Doublet Chemotherapy in Patients with Advanced NSCLC.

Theranostics. 2017;7(19):4753-4762

Authors: Jiang T, Li X, Wang J, Su C, Han W, Zhao C, Wu F, Gao G, Li W, Chen X, Li J, Zhou F, Zhao J, Cai W, Zhang H, Du B, Zhang J, Ren S, Zhou C, Yu H, Hirsch FR

Abstract
Rationale To investigate whether the mutational landscape of circulating cell-free DNA (cfDNA) could predict and dynamically monitor the response to first-line platinum-based chemotherapy in patients with advanced non-small-cell lung cancer (NSCLC). Methods Eligible patients were included and blood samples were collected from a phase III trial. Both cfDNA fragments and fragmented genomic DNA were extracted for enrichment in a 1.15M size panel covering exon regions of 1,086 genes. Molecular mutational burden (MMB) was calculated to investigate the relationship between molecular features of cfDNA and response to chemotherapy. Results In total, 52 eligible cases were enrolled and their blood samples were prospectively collected at baseline, every cycle of chemotherapy and time of disease progression. At baseline, alterations of 17 genes were found. Patients with partial response (PR) had significantly lower baseline MMB of these genes than those patients with either stable disease (SD) (P = 0.0006) or progression disease (PD) (P = 0.0074). Further analysis revealed that the mutational landscape of cfDNA from pretreatment blood samples were distinctly different among patients with PR vs. SD/PD. For patients with baseline TP53 mutation, those with PR experienced a significant reduction in MMB whereas patients with SD or PD experienced an increase after two, three or four cycles of chemotherapy. Furthermore, patients with low MMB had superior response rate and significantly longer progression-free survival than those with high MMB. Conclusion This study indicated that the mutational landscape of cfDNA has potential clinical value to predict the therapeutic response to first-line platinum-based doublet chemotherapy in NSCLC patients. At the single gene level, dynamic change of molecular mutational burden of TP53 is valuable to monitor efficacy (and, therefore, might aid in early recognition of resistance and relapse) in patients harboring this mutation at baseline.

PMID: 29187901 [PubMed - in process]

Prevalence and characteristics of chronic kidney disease among Danish adults with cystic fibrosis.

Fri, 12/01/2017 - 16:45

Prevalence and characteristics of chronic kidney disease among Danish adults with cystic fibrosis.

J Cyst Fibros. 2017 Nov 27;:

Authors: Berg KH, Ryom L, Faurholt-Jepsen D, Pressler T, Katzenstein TL

Abstract
BACKGROUND: With improved prognosis of CF, comorbidities including chronic kidney disease (CKD) are becoming increasingly important. Identification of those at highest CKD risk is hence a priority.
METHODS: In this cross-sectional study, adults with CF attending the Copenhagen CF Centre at Rigshospitalet with ≥2 measurements of serum creatinine from 2013 to 2015 were included. Data was obtained from an electronic CF database, which contains anonymised clinical and laboratory data on all individuals attending the clinic. CKD was defined as a confirmed (≥3months apart) estimated glomerular filtration rate≤60mL/min/1.73m2.
RESULTS: Of 181 individuals, the CKD prevalence was 2.7% and increased to 11% after inclusion of lung transplanted patients. Individuals with CKD were generally older (median 39 (IQR, 36-45) vs. 31 (IQR, 24-39) years; p<0.001), diabetic (86% vs. 41%, p<0.001), with longer median duration of chronic pulmonary infection (28.3 (20.0-35.8) vs. 20.0 (9.9-34.7) years; p=0.008) and with longer intravenous aminoglycosides use (606 (IQR, 455-917) vs. 273 (IQR, 91-826) days, p=0.005).
CONCLUSIONS: The CKD prevalence is high and related to age, diabetes, chronic infection, transplantation and aminoglycosides use. These observations call for longitudinal studies investigating CKD predictors in adults with CF.

PMID: 29187303 [PubMed - as supplied by publisher]

Successful use of donor lungs after repairing severely injured pulmonary vein of donor lungs.

Fri, 12/01/2017 - 16:45

Successful use of donor lungs after repairing severely injured pulmonary vein of donor lungs.

Eur J Cardiothorac Surg. 2017 Nov 27;:

Authors: Shudo Y, Miller SL, Boyd JH, Woo YJ

PMID: 29186381 [PubMed - as supplied by publisher]

Development of an EliSPOT assay for HSV-1 and clinical validation in lung transplant patients.

Fri, 12/01/2017 - 16:45

Development of an EliSPOT assay for HSV-1 and clinical validation in lung transplant patients.

New Microbiol. 2017 Oct;40(4):251-257

Authors: Costa C, Di Nauta A, Rittà M, Sinesi F, Bianco G, Sidoti F, Solidoro P, Cavallo R

Abstract
Cellular immunity plays a major role in the control of HSV-1 infection/reactivation with a potential impact on the clinical-therapeutic management of immunocompromised patients, such as transplant recipients. Herein, we quantitatively evaluated T-cell response directed at HSV-1 by a newly developed IFN-γ EliSPOT assay in 53 patients (including 45 lung transplant recipients and eight subjects in waiting list). Overall, 62.2% of transplant patients and 62.5% of subjects on the waiting list showed a response to HSV-1 with no significant difference in the level of virus-specific cellular immunity. Response tended to be lower in the first three months posttransplantation with a progressive recovery of pretransplantation status by the second year and in the presence of HSV-1 DNA positivity in bronchoalveolar lavage. As expected, no response was found in seronegative patients. No significant difference in the level of response according to IgM and IgG status was found. Further studies are required to define the role of HSV-1 specific immune response for the clinical-therapeutic management of lung transplant patients and in other clinical settings and to define cut-off levels discriminating between absence/low and strong response to be related to the risk of viral infection/reactivation.

PMID: 29184964 [PubMed - in process]

Liver Transplantation From Donors With a History of Malignancy: A Single-Center Experience.

Fri, 12/01/2017 - 16:45

Liver Transplantation From Donors With a History of Malignancy: A Single-Center Experience.

Transplant Direct. 2017 Nov;3(11):e224

Authors: Benkö T, Hoyer DP, Saner FH, Treckmann JW, Paul A, Radunz S

Abstract
Background: The demand for transplantable organs exceeds donor organ supply. Transplantation of organs from donors with a history of malignancy remains controversial and the transmission of cancer in liver transplant recipients has not been sufficiently examined.
Methods: From 2002 until 2017, 83 livers from donors with a history of malignancy were transplanted at the University Hospital Essen, Germany. Donor and recipient data, type of malignancy, tumor-free interval at organ procurement, and follow-up data were analyzed.
Results: Nine different tumor sites (central nervous system [n = 27], genitourinary [n = 24], breast [n = 10], skin [n = 8], colorectal [n = 5], lung [n = 3], hemato-oncological [n = 3], thyroid [n = 2], and larynx [n = 1]) were detected in 83 donors. The majority (58%) of donors had tumor-free intervals of less than 5 years versus 19% of 6 to 10 years versus 23% over 10 years. The risk of tumor transmission from donors was assessed as low in 44 (53%), intermediate in 28 (34%), and high in 11 (13%) cases. During median follow-up of 19.9 (0-155) months, none of the recipients developed donor-transmitted malignancy.
Conclusions: Liver transplantation with organs from donors with a medical history of malignancy is feasible, and the risk of donor-transmitted malignancy appears to be low in this single-center analysis. A careful selection of donors remains mandatory and can expand the donor pool.

PMID: 29184912 [PubMed]

Comparative Assessment of Anti-HLA Antibodies Using Two Commercially Available Luminex-Based Assays.

Fri, 12/01/2017 - 16:45

Comparative Assessment of Anti-HLA Antibodies Using Two Commercially Available Luminex-Based Assays.

Transplant Direct. 2017 Nov;3(11):e218

Authors: Clerkin KJ, See SB, Farr MA, Restaino SW, Serban G, Latif F, Li L, Colombo PC, Vlad G, Ray B, Vasilescu ER, Zorn E

Abstract
Background: Allospecific anti-HLA antibodies (Abs) are associated with rejection of solid organ grafts. The 2 main kits to detect anti-HLA Ab in patient serum are commercialized by Immucor and One Lambda/ThermoFisher. We sought to compare the performance of both platforms.
Methods: Background-adjusted mean fluorescence intensity (MFI) values were used from both platforms to compare sera collected from 125 pretransplant and posttransplant heart and lung transplant recipients.
Results: Most HLA class I (94.5%) and HLA class II (89%) Abs with moderate to high MFI titer (≥4000) were detected by both assays. A modest correlation was observed between MFI values obtained from the 2 assays for both class I (r = 0.3, r2 = 0.09, P < 0.0001) and class II Ab (r = 0.707, r2 = 0.5, P < 0.0001). Both assays detected anti-class I and II Ab that the other did not; however, no specific HLA allele was detected preferentially by either of the 2 assays. For a limited number of discrepant sera, dilution resulted in comparable reactivity profiles between the 2 platforms.
Conclusions: Immucor and One Lambda/ThermoFisher assays have a similar, albeit nonidentical, ability to detect anti-HLA Ab. Although the correlation between the assays was present, significant variances exist, some of which can be explained by a dilution-sensitive "prozone" effect.

PMID: 29184907 [PubMed]

Isolated Peritoneal, Mesenteric, and Omental Hydatid Cyst: A Clinicopathologic Narrative Review.

Fri, 12/01/2017 - 16:45

Isolated Peritoneal, Mesenteric, and Omental Hydatid Cyst: A Clinicopathologic Narrative Review.

Iran J Med Sci. 2017 Nov;42(6):517-523

Authors: Geramizadeh B

Abstract
Hydatid disease (HD) is caused by Echinococcus granulosus and is endemic in many parts of the world. This parasitic tapeworm can produce cysts in almost every organ of the body, with the liver and lung being the most frequently targeted organs. Peritoneum, omentum, and mesentery are among these unusual locations, which can cause diagnostic challenge and treatment delay. This review provides information on the reported cases of the peritoneal, omental, and mesenteric hydatid cyst in the world during the last 20 years. During the last 20 years, there have been 49 published cases of hydatid cysts in the peritoneum, mesentery, and omentum. Among the reported cases in the English literature, the most common presenting symptom has been chronic abdominal pain and the method of primary diagnosis has been ELISA and ultrasonography. The best treatment modalities have been surgical excision, with and without adjuvant therapy, with albendazole and scolicidal agents. The published follow-up studies showed a low recurrence rate.

PMID: 29184259 [PubMed]

Hepatoblastoma in children aged less than six months at diagnosis: A report from the SIOPEL group.

Fri, 12/01/2017 - 16:45
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Hepatoblastoma in children aged less than six months at diagnosis: A report from the SIOPEL group.

Pediatr Blood Cancer. 2018 Jan;65(1):

Authors: Dall'Igna P, Brugieres L, Christin AS, Maibach R, Casanova M, Alaggio R, de Goyet JV, Zsiros J, Morland B, Czauderna P, Childs M, Aronson DC, Branchereau S, Brock P, Perilongo G

Abstract
BACKGROUND: The purpose of this study was to evaluate clinical characteristics, treatment, and survival of children, who were diagnosed with hepatoblastoma (HB) in their first 6 months of age, enrolled in the SIOPEL 2 and 3 protocols.
METHODS: Seventy-nine patients, treated between 1994 and 2006, were analyzed after stratification into three age groups: <1 month, between 1 and 3 months, and between 3 and 6 months. All received preoperative chemotherapy.
RESULTS: Clinical characteristics were similar in both trials: 4 patients had pulmonary metastases at diagnosis, 4 had α-fetoprotein <100 ng/ml, 68 were operated by partial hepatectomy, and 7 received liver transplant. Chemotherapy courses were delayed in 8.5%, 8.4%, and 11.8% of cycles in the three groups. Doses were calculated according to weight for children <5 and 5-10 kg, and further reduced in 18.1%, 6.8%, and 5.9% of cycles. Acute toxicity was manageable. Long-term hearing loss was the major problem at follow-up occurring in two-thirds of children. Ten patients experienced progression or relapse, and 5 of 10 died. After a median follow-up of 5.6 years, the 5-year overall survival (OS) and event-free survival (EFS) were 91% (95% confidence interval [CI]: 84-96%) and 87% (95% CI: 78-92%), respectively.
CONCLUSIONS: The 5-year OS and EFS of children <6 months of age affected by HB seem to be similar to those documented in the elder children. Dose reduction does not seem to jeopardize the long-term outcome and may explain the lower toxicity profile. Ototoxicity though appears as high as in the whole population of SIOPEL 2 and 3. The treatment for these children should be further explored in international studies, particularly focusing on prevention of hearing loss.

PMID: 28921839 [PubMed - indexed for MEDLINE]

Pulmonary Function and Pretransplant Evaluation of the Hematopoietic Cell Transplant Candidate.

Fri, 12/01/2017 - 16:45
Related Articles

Pulmonary Function and Pretransplant Evaluation of the Hematopoietic Cell Transplant Candidate.

Clin Chest Med. 2017 Jun;38(2):307-316

Authors: Cheng GS

Abstract
Pretransplant pulmonary function tests provide baseline data by which to reference subsequent respiratory impairment, as well as important prognostic information, for the hematopoietic cell transplant (HCT) recipient. Abnormalities in forced expiratory volume in 1 second and diffusing capacity of carbon monoxide are associated with early respiratory failure and increased all-cause mortality after allogeneic HCT. These parameters have been incorporated into risk assessment calculators that may aid in clinical decision making. This article discusses the clinical implications of pulmonary function parameters and other risk factors for pulmonary complications in the context of evolving allogeneic HCT practice.

PMID: 28477641 [PubMed - indexed for MEDLINE]

Pediatric sickle cell disease: past successes and future challenges.

Fri, 12/01/2017 - 16:45
Related Articles

Pediatric sickle cell disease: past successes and future challenges.

Pediatr Res. 2017 Jan;81(1-2):249-258

Authors: Meier ER, Rampersad A

Abstract
Once a fatal disease of childhood, more than 95% of patients born today with sickle cell disease (SCD) in developed countries are expected to survive into adulthood, largely because of improvements in supportive and preventive care (newborn screening, penicillin prophylaxis, transcranial Doppler (TCD) screening). Hydroxyurea (HU) therapy, the only oral medication currently available to prevent SCD complications, has become more widespread over the past 20 y. The NHLBI recommends that HU be offered to all patients with HbSS beginning at 9 mo of age, and the recently published Abnormal TCD with Transfusions Changing to HU (TWiTCH) trial has shown HU as an acceptable alternative to transfusion therapy for patients at high risk of stroke. While hematopoietic stem cell transplant (HSCT) is a curative option for SCD, less than 25% of patients have a suitable donor. Alternative stem cell sources from unrelated donors and haplo-identical donors are currently under investigation as are gene therapy trials. This review will focus on early efforts to elucidate SCD pathophysiology as well as supportive and preventive care improvements. Findings from recent multi-center studies (Silent Infarct Transfusion (SIT) Trial and TWiTCH) will be summarized. Finally, HSCT trials and gene therapy will be reviewed.

PMID: 27706129 [PubMed - indexed for MEDLINE]

Hypoxia-Induced Mesenchymal Stromal Cells Exhibit an Enhanced Therapeutic Effect on Radiation-Induced Lung Injury in Mice due to an Increased Proliferation Potential and Enhanced Antioxidant Ability.

Wed, 11/29/2017 - 16:49

Hypoxia-Induced Mesenchymal Stromal Cells Exhibit an Enhanced Therapeutic Effect on Radiation-Induced Lung Injury in Mice due to an Increased Proliferation Potential and Enhanced Antioxidant Ability.

Cell Physiol Biochem. 2017 Nov 29;44(4):1295-1310

Authors: Li B, Li C, Zhu M, Zhang Y, Du J, Xu Y, Liu B, Gao F, Liu H, Cai J, Yang Y

Abstract
BACKGROUND/AIMS: Radiation therapy is an important treatment for thoracic cancer; however, side effects accompanied with radiotherapy lead to limited tumor control and a decline in patient quality of life. Among these side effects, radiation-induced lung injury (RILI) is the most serious and common. Hence, an effective remedy for RILI is needed. Mesenchymal stromal cells (MSCs) are multipotent adult stem cells that have been demonstrated to be an effective treatment in some disease caused by tissue damage. However, unlike other injuries, RILI received limited therapeutic effects from implanted MSCs due to local hypoxia and extensive reactive oxygen species (ROS) in irradiated lungs. Since the poor survival of MSCs is primarily due to hypoxia and ROS generation, we hypothesize that persistent and adaptive hypoxia treatment induces enhanced resistance to hypoxic stress in implanted MSC. The aim of this study is to investigate whether persistent and adaptive hypoxia treatment of bmMSCs prior to their transplantation in injured mice enhanced survival and improved curative effects in RILI.
METHODS: Primary bmMSCs were obtained from the marrow of six-week-old male C57BL6/J mice and were cultured either under normoxic conditions (21% O2) or hypoxic conditions (2.5% O2). Mice were injected with normoxia/hypoxia MSCs after thoracic irradiation (20 Gy). The therapeutic effects of MSCs on RILI were assessed by pathological examinations that included H&E staining, Masson staining and α-SMA staining; meanwhile, inflammatory factors were measured using an ELISA. The morphology of MSCs in vitro was recorded using a microscope and identified by flow cytometry, cell viability was measured using the CCK-8 assay, the potential for proliferation was detected by the EdU assay, and ROS levels were measured using a ROS fluorogenic probe. In addition, HIF-1α and several survival pathway proteins (Akt, p-Akt, Caspase-3) were also detected by western blotting.
RESULTS: Implanted MSCs alleviated both early radiation-induced pneumonia and late pulmonary fibrosis. However, hypoxia MSCs displayed a more pronounced therapeutic effect compared to normoxia MSCs. Compared to normoxia MSCs, the hypoxia MSCs demonstrated greater cell viability, an enhanced proliferation potential, decreased ROS levels and increased resistance to hypoxia and ROS stress. In addition, hypoxia MSCs achieved higher activation levels of HIF-1α and Akt, and HIF-1α played a critical role in the development of resistance.
CONCLUSION: Hypoxia enhances the therapeutic effect of mesenchymal stromal cells on radiation-induced lung injury by promoting MSC proliferation and improving their antioxidant ability, mediated by HIF-1α.

PMID: 29183009 [PubMed - as supplied by publisher]

Expression of liver X receptors in normal and refractory carcinoma tissues of the human lung and pancreas.

Wed, 11/29/2017 - 16:49
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Expression of liver X receptors in normal and refractory carcinoma tissues of the human lung and pancreas.

Histol Histopathol. 2017 Nov 28;:11949

Authors: Kashiwagi K, Yanagida M, Matsui D, Tanaka M, Sugimoto K, Chen H, Ichikawa-Tomikawa N, Marubashi S, Suzuki H, Chiba H

Abstract
Liver X receptors (LXRs) participate not only in maintaining cholesterol homeostasis but also in controlling cellular growth in many types of normal and tumor cells. We previously reported that LXRα was aberrantly expressed in human oral squamous cell carcinoma (HOSCC) tissues and cell lines, and that LXR stimulation led to significant reduction of proliferation of HOSCC cells via accelerating cholesterol efflux. Since LXRs and downstream proteins involved in cholesterol metabolism could be also applied as therapeutic targets in small cell lung carcinoma (SCLC) and pancreatic ductal adenocarcinoma (PDAC), we herein analyzed the distribution of LXR proteins in these refractory cancers as well as in normal human lung and pancreatic tissues. LXRβ was observed in ciliated epithelial cells, bronchial gland epithelia, type II alveolar epithelia and alveolar macrophages of the lung, and was less expressed in bronchial basal cells and type I alveolar epithelia. In addition, LXRβ was detected in epithelium of the pancreatic duct and acinar cells of the pancreas, and was weakly expressed in pancreatic islet cells. By contrast, LXRα expression was restricted to alveolar macrophages, and was not evident in any types of epithelial cells in the lung and pancreas. We also demonstrated that LXRβ but not LXRα was abundantly expressed in nine cases of SCLC and twenty cases of PDAC tissues. These findings provide basic information for evaluating the efficacy of LXR-targeted treatment in SCLC and PDAC.

PMID: 29181837 [PubMed - as supplied by publisher]

High emergency organ allocation rule in lung transplantation: a simulation study.

Wed, 11/29/2017 - 16:49
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High emergency organ allocation rule in lung transplantation: a simulation study.

ERJ Open Res. 2017 Oct;3(4):

Authors: Riou J, Boëlle PY, Christie JD, Thabut G

Abstract
The scarcity of suitable organ donors leads to protracted waiting times and mortality in patients awaiting lung transplantation. This study aims to assess the short- and long-term effects of a high emergency organ allocation policy on the outcome of lung transplantation. We developed a simulation model of lung transplantation waiting queues under two allocation strategies, based either on waiting time only or on additional criteria to prioritise the sickest patients. The model was informed by data from the United Network for Organ Sharing. We compared the impact of these strategies on waiting time, waiting list mortality and overall survival in various situations of organ scarcity. The impact of a high emergency allocation strategy depends largely on the organ supply. When organ supply is sufficient (>95 organs per 100 patients), it may prevent a small number of early deaths (1 year survival: 93.7% against 92.4% for waiting time only) without significant impact on waiting times or long-term survival. When the organ/recipient ratio is lower, the benefits in early mortality are larger but are counterbalanced by a dramatic increase of the size of the waiting list. Consequently, we observed a progressive increase of mortality on the waiting list (although still lower than with waiting time only), a deterioration of patients' condition at transplant and a decrease of post-transplant survival times. High emergency organ allocation is an effective strategy to reduce mortality on the waiting list, but causes a disruption of the list equilibrium that may have detrimental long-term effects in situations of significant organ scarcity.

PMID: 29181383 [PubMed]

False-positive lung positron emission tomography-computed tomography result in a patient with a history of cancer.

Wed, 11/29/2017 - 16:49
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False-positive lung positron emission tomography-computed tomography result in a patient with a history of cancer.

Kardiochir Torakochirurgia Pol. 2017 Sep;14(3):206-208

Authors: Chrąchol J, Kubisa B, Dec P, Lesińska A, Waloszczyk P, Grodzki T

PMID: 29181051 [PubMed]

Redirecting TGF-β Signaling through the β-Catenin/Foxo Complex Prevents Kidney Fibrosis.

Wed, 11/29/2017 - 16:49
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Redirecting TGF-β Signaling through the β-Catenin/Foxo Complex Prevents Kidney Fibrosis.

J Am Soc Nephrol. 2017 Nov 27;:

Authors: Qiao X, Rao P, Zhang Y, Liu L, Pang M, Wang H, Hu M, Tian X, Zhang J, Zhao Y, Wang XM, Wang C, Yu H, Guo F, Cao Q, Wang Y, Wang YM, Zhang GY, Lee VW, Alexander SI, Zheng G, Harris DCH

Abstract
TGF-β is a key profibrotic factor, but targeting TGF-β to prevent fibrosis also abolishes its protective anti-inflammatory effects. Here, we investigated the hypothesis that we can redirect TGF-β signaling by preventing downstream profibrotic interaction of β-catenin with T cell factor (TCF), thereby enhancing the interaction of β-catenin with Foxo, a transcription factor that controls differentiation of TGF-β induced regulatory T cells (iTregs), and thus, enhance anti-inflammatory effects of TGF-β In iTregs derived from EL4 T cells treated with recombinant human TGF-β1 (rhTGF-β1) in vitro, inhibition of β-catenin/TCF transcription with ICG-001 increased Foxp3 expression, interaction of β-catenin and Foxo1, binding of Foxo1 to the Foxp3 promoter, and Foxo transcriptional activity. Moreover, the level of β-catenin expression positively correlated with the level of Foxo1 binding to the Foxp3 promoter and Foxo transcriptional activity. T cell fate mapping in Foxp3gfp Ly5.1/5.2 mice revealed that coadministration of rhTGF-β1 and ICG-001 further enhanced the expansion of iTregs and natural Tregs observed with rhTGF-β1 treatment alone. Coadministration of rhTGF-β1 with ICG-001 also increased the number of Tregs and reduced inflammation and fibrosis in the kidney fibrosis models of unilateral ureteric obstruction and ischemia-reperfusion injury. Notably, ICG-001 prevented the fibrosis in distant organs (lung and liver) caused by rhTGF-β1. Together, our results show that diversion of β-catenin from TCF- to Foxo-mediated transcription inhibits the β-catenin/TCF-mediated profibrotic effects of TGF-β while enhancing the β-catenin/Foxo-mediated anti-inflammatory effects. Targeting β-catenin/Foxo may be a novel therapeutic strategy in the treatment of fibrotic diseases that lead to organ failure.

PMID: 29180394 [PubMed - as supplied by publisher]

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