Skip directly to content

PubMed Liver Transplant

Subscribe to PubMed Liver Transplant feed PubMed Liver Transplant
NCBI: db=pubmed; Term=liver transplant
Updated: 2 hours 46 min ago

Isolated intraductal variant of hepatocellular carcinoma.

Sun, 08/13/2017 - 12:45
Related Articles

Isolated intraductal variant of hepatocellular carcinoma.

BMJ Case Rep. 2017 Aug 11;2017:

Authors: Philips CA, Paramaguru R, Mahadevan P, Augustine P

PMID: 28801513 [PubMed - in process]

Isolated clival metastasis: a rare presentation of renal cell carcinoma.

Sun, 08/13/2017 - 12:45
Related Articles

Isolated clival metastasis: a rare presentation of renal cell carcinoma.

BMJ Case Rep. 2017 Aug 11;2017:

Authors: Mani A, Yadav P, Paliwal VK, Lal H

Abstract
Renal cell carcinoma accounts for 3% of all adult malignancies. Usual sites of metastasis are lymph nodes, lungs, bone, liver and brain. We describe a patient who presented with complaints of holocranial headache and diplopia. MRI of the head showed a clival-based lesion with associated bony erosion. With suspicion of a metastatic lesion, an ultrasonogram of the abdomen was done which showed a left renal mass that enhanced on contrast-enhanced CT. There were no other metastatic foci. Patient underwent radiotherapy for the clival lesion. This case report emphasises on the evaluation of clival lesion with cranial neuropathies for a possibility of a renal primary tumour.

PMID: 28801336 [PubMed - in process]

Obesity as predictor of postoperative outcomes in liver transplant candidates: Review of the literature and future perspectives.

Sun, 08/13/2017 - 12:45
Related Articles

Obesity as predictor of postoperative outcomes in liver transplant candidates: Review of the literature and future perspectives.

Dig Liver Dis. 2017 Jul 22;:

Authors: Barone M, Viggiani MT, Avolio AW, Iannone A, Rendina M, Di Leo A

Abstract
BACKGROUND: Current American and European guidelines consider a pre-transplant BMI ≥40kg/m(2) as a relative contraindication for liver transplantation but this recommendation is graded as uncertain and requires further research. Moreover, conflicting results are reported on the predictive value of BMI 30-39.9kg/m(2) on post-transplant complication and mortality risk.
AIM: This study analyzed the data of the literature on the effect of all three BMI classes of obesity on postoperative outcomes in liver transplantation.
MATERIALS AND METHODS: A PubMed and Cochrane Library search was conducted from inception to October 2015.
RESULTS: Analysis of the literature demonstrates that discrepancies among studies are mainly either due to limitations of BMI per se, the different BMI cut-offs used to select patients with obesity or reference group and the different outcomes considered. Moreover, the evaluation of visceral adipose tissue and the detrimental effect of muscle mass reduction in presence of obesity are never considered.
CONCLUSIONS: BMI assessment should be used as a preliminary method to evaluate obesity. Subsequently, the assessment of visceral adipose tissue and muscle mass should complete the preoperative evaluation of liver transplant candidates. This innovative approach could represent a new field of research in liver transplantation.

PMID: 28801180 [PubMed - as supplied by publisher]

Rational Heart Transplant From Hepatitis C Donor: New Antiviral Weapons Conquer the Trojan.

Sun, 08/13/2017 - 12:45
Related Articles

Rational Heart Transplant From Hepatitis C Donor: New Antiviral Weapons Conquer the Trojan.

J Card Fail. 2017 Aug 08;:

Authors: Gottlieb RL, Sam T, Wada SY, Trotter JF, Asrani SK, Lima B, Joseph SM, Gonzalez-Stawinski G, Hall SA

Abstract
BACKGROUND: Donors with hepatitis C (HCV) viremia are rarely utilized for orthotopic heart transplantation (OHTx) due to post-transplant risks. New, highly effective HCV antivirals may alter the landscape.
METHODS: An adult patient unsuitable for bridging mechanical support therapy accepted a heart transplant offer from a donor with HCV viremia. Upon daily logarithmic rise in HCV viral load and adequate titers to ensure successful genotyping, once daily sofosbuvir 400 mg / velpatasvir 100 mg (Epclusa) was initiated empirically pending HCV genotype (genotype 3a confirmed after initiation of therapy).
RESULTS: We report the kinetics of acute Hepatitis C viremia and therapeutic response to treatment with a new pangenotypic antiviral agent after donor-derived acute HCV infection transmitted incidental to successful cardiac transplant into a HCV negative OHTx recipient. Prompt resolution of viremia was noted by the first week of a 12 week course of antiviral therapy. Sustained virologic remission continues beyond 12 weeks after completion of HCV therapy (SVR-12).
CONCLUSIONS: The availability of effective pangenotypic therapy for HCV may expand donor availability. The feasibility of early versus late treatment of HCV remains to be determined through formalized protocols. We hypothesize pharmacoeconomics to be the greatest limitation to widespread availability of this promising tool.

PMID: 28801074 [PubMed - as supplied by publisher]

JC Virus-Related Progressive Multifocal Leukoencephalopathy After Living-Donor Liver Transplant: A Rare Case.

Sun, 08/13/2017 - 12:45
Related Articles

JC Virus-Related Progressive Multifocal Leukoencephalopathy After Living-Donor Liver Transplant: A Rare Case.

Exp Clin Transplant. 2017 Aug 12;:

Authors: Rastogi A, Gulati N, Bihari C, Chaudhary A, Bansal K, Sasturkar S, Thapar S, Pamecha V

Abstract
Progressive multifocal leukoencephalopathy caused by polyoma JC virus is a rare and severe demyelinating disease of the central nervous system. It occurs in immunocompromised patients and is scarcely reported in liver transplant recipients. Brain biopsy demonstrating demyelination with presence of foamy macrophages, relative preservation of axons, astrogliosis, and typical polyomavirus inclusions in the enlarged oligodendroglial nuclei is essential for diagnosis. Here, we report a case of JC virus-associated progressive multifocal leukoencephalopathy in a living-donor liver transplant recipient who was transplanted for hepatitis C virus-related decompensated cirrhosis. Brain biopsy with immunohistochemistry confirmed the diagnosis of progressive multifocal leukoencephalopathy secondary to JC virus. JC virus related-progressive multifocal leukoencephalopathy is associated with extremely poor prognosis. Awareness and consideration of this entity in liver transplant recipients who present with sudden progressive neurologic manifestations can help in prompt diagnosis and timely treatment.

PMID: 28800720 [PubMed - as supplied by publisher]

Intracerebroventricular Streptozotocin Induces Obesity and Dementia in Lewis Rats: Rat Model of Dementia Associated with Obesity.

Sat, 08/12/2017 - 12:45
Related Articles

Intracerebroventricular Streptozotocin Induces Obesity and Dementia in Lewis Rats: Rat Model of Dementia Associated with Obesity.

J Alzheimers Dis. 2017 Aug 08;:

Authors: Bloch K, Gil-Ad I, Vanichkin A, Hornfeld SH, Koroukhov N, Taler M, Vardi P, Weizman A

Abstract
BACKGROUND: Animal models of dementia associated with metabolic abnormalities play an important role in understanding the bidirectional relationships between these pathologies. Rodent strains develop cognitive dysfunctions without alteration of peripheral metabolism following intracerebroventricular administration of streptozotocin (icv-STZ).
OBJECTIVE: We aimed to estimate the effect of icv-STZ on cognitive functions and peripheral metabolism in Lewis rats, which are rarely used for the induction of cognitive abnormalities.
METHODS: Inbred adult Lewis rats were treated with single icv-STZ (3 mg/kg). Cognitive functions were assessed using Morris water maze (MWM) test and locomotion by the Open Field test. Metabolic alterations were studied using histological and biochemical analysis of brain and peripheral tissues.
RESULTS: The icv-STZ induced rapid weight decline during the first two weeks. Thereafter, the rats showed an accelerated weight gain. Three months after the icv-STZ treatment, the rats were severely obese and revealed fatty liver, pancreatic islet hypertrophy, significantly elevated levels of blood insulin, leptin, and adiponectin, but intact peripheral glucose homeostasis. The icv-STZ rats expressed amyloid-β deposits in blood vessels of leptomeningeal area, microgliosis, astrogliosis, and spongiosis in fimbria-fornix area of hippocampus. Locomotor activities of icv-STZ treated and sham-operated rats were similar. In the MWM test, the icv-STZ treated rats demonstrated severely impaired spatial learning during both acquisition and reversal phases.
CONCLUSIONS: Icv-STZ treated Lewis rats develop severe dementia associated with obesity and peripheral metabolic abnormalities. This animal model may be useful for exploring the pathophysiological relationship between obesity and dementia and provides a new tool for development of effective therapy.

PMID: 28800326 [PubMed - as supplied by publisher]

The impact of chemotherapy-associated hemoglobin on prognosis of colorectal cancer patients receiving adjuvant chemotherapy.

Sat, 08/12/2017 - 12:45
Related Articles

The impact of chemotherapy-associated hemoglobin on prognosis of colorectal cancer patients receiving adjuvant chemotherapy.

Cancer Biomark. 2017 Aug 01;:

Authors: Wei YS, Zhou YG, Wang GY, Liang ZH, Luo MR, Yang TA, Huang J

Abstract
BACKGROUND AND OBJECTIVE: The association of chemotherapy-associated hemoglobin and survival of colorectal cancer (CRC) receiving adjuvant chemotherapy is uncertain. We sought to explore the prognostic value of chemotherapy-associated hemoglobin in CRC receiving adjuvant chemotherapy and the best cut point affecting prognosis.
METHODS: Three hundred and twenty stage II and III CRC patients receiving adjuvant FOLFOX chemotherapy from March 2003 to March 2012 were enrolled. The associations between chemotherapy-associated hemoglobin (the absolute levels of post-chemotherapy) or chemotherapy-associated hemoglobin change (change between the pre- and post-chemotherapy hemoglobins) and disease free survival (DFS) or overall survival (OS) of CRC, and the best cut point were investigated.
RESULTS: Log rank test showed the best cut points for chemotherapy-associated hemoglobin and chemotherapy-associated hemoglobin change were respectively 90 g/L, 30 g/L. Cox regression model showed chemotherapy-associated hemoglobin < 90 g/L was the independent prognostic factor for DFS (HR, 2.221; 95% CI = 1.157-4.262), OS (HR, 2.058; 95% CI = 1.009-4.197), respectively, but no association of chemotherapy-associated hemoglobin change ⩾ 30g/L and DFS (HR, 2.063; 95% CI = 0.929-4.583), OS (HR, 1.386; 95% CI = 0.553-3.471) was found.
CONCLUSIONS: Chemotherapy-associated hemoglobin < 90 g/L has a significant prognostic value in CRC receiving adjuvant chemotherapy, which is a significant biomarker in the individualized management and may suggest the simple indication for the treatment of anemia in adjuvant chemotherapy in CRC.

PMID: 28800321 [PubMed - as supplied by publisher]

The Italian Compassionate use of Sofosbuvir (ITACOPS) observational cohort study for the treatment of recurrent hepatitis C: clinical and virological outcomes.

Sat, 08/12/2017 - 12:45
Related Articles

The Italian Compassionate use of Sofosbuvir (ITACOPS) observational cohort study for the treatment of recurrent hepatitis C: clinical and virological outcomes.

Transpl Int. 2017 Aug 11;:

Authors: Carrai P, Morelli C, Cordone G, Romano A, Tamé M, Lionetti R, Pietrosi G, Lenci I, Piai G, Russo FP, Coppola C, Melazzini M, Montilla S, Pani L, Petraglia S, Russo P, Trotta MP, Martini S, Toniutto P, ITACOPS study group

Abstract
Direct antivirals are available for treating recurrent hepatitis C (RHC). This study reported outcomes of 424 patients with METAVIR F3-F4 RHC who were treated for 24 weeks with sofosbuvir/ribavirin and followed for 12 weeks within the Italian sofosbuvir compassionate use program. In 55 patients, daclatasvir or simeprevir were added. Child-Pugh class and MELD scores were evaluated at baseline and 36 weeks after the start of therapy. The sustained viral response (SVR) was 86.7% (316/365) in patients who received sofosbuvir/ribavirin and 98.3% (58/59) in patients who received a second antiviral (p<0.01). In patients treated with sofosbuvir/ribavirin, a significant difference in SVR was observed between patients diagnosed with METAVIR F4 (211/250; 84.4%), METAVIR F3 (95/105; 90.5%) and fibrosing cholestatic hepatitis (10/10; 100%) (p=0.049). A significant association was found between patients who worsened from Child-Pugh class A and who experienced viral relapse (4/26 vs 8/189, p=0.02). In patients with a baseline MELD score <15, a significant association was found between maintaining a final MELD score <15 and the achievement of SVR (187/219 vs 6/10, p=0.031). This real-world study indicates that sofosbuvir/ribavirin treatment for 24 weeks was effective, and the achievement of SVR was associated with a reduced probability of developing worsening liver function. This article is protected by copyright. All rights reserved.

PMID: 28799277 [PubMed - as supplied by publisher]

Bleeding Recurrence and Mortality Following Interventional Management of Spontaneous HCC Rupture: Results of a Multicenter European Study.

Sat, 08/12/2017 - 12:45
Related Articles

Bleeding Recurrence and Mortality Following Interventional Management of Spontaneous HCC Rupture: Results of a Multicenter European Study.

World J Surg. 2017 Aug 10;:

Authors: Schwarz L, Bubenheim M, Zemour J, Herrero A, Muscari F, Ayav A, Riboud R, Ducerf C, Regimbeau JM, Tranchart H, Lermite E, Petrovai G, Suhol A, Doussot A, Capussotti L, Tuech JJ, Le Treut YP, FRENCH association

Abstract
BACKGROUND: The incidence of spontaneous rupture of hepatocellular carcinoma (HCC) is low in Europe, at less than 3%. HCC rupture remains a life-threatening complication, with mortality reported between 16 and 30%. The risk of bleeding recurrence has never been clearly evaluated in such clinical situation. The objectives of this study were to evaluate the current risk of mortality related to HCC rupture and to focus on the risk of bleeding recurrence following interventional management.
METHODS: All patients admitted to 14 French-Italian surgical centers for spontaneous rupture of HCC between May 2000 and May 2012 were retrospectively included. Clinical data, imaging features, relevant laboratory data, treatment strategies, and prognoses were analyzed.
RESULTS: Overall, 58 of the 138 included patients (42%) had cirrhosis. Thirty-five patients (25%) presented with hemorrhagic shock, and 19% with organ(s) dysfunction. Bleeding control was obtained by interventional hemostasis, emergency liver resection, and conservative medical management in 86 (62%), 24 (18%), and 21 (15%) patients, respectively. Best supportive care was chosen for 7 (5%) patients. The mortality rate following rupture was 24%. The bleeding recurrence rate was 22% with related mortality of 52%. In multivariate analysis, a bilirubin level >17 micromol/L (HR 3.768; p = 0.006), bleeding recurrence (HR 5.400; p < 0.0001), and ICU admission after initial management (HR 8.199; p < 0.0001) were associated with in-hospital mortality.
CONCLUSION: This European, multicenter, large-cohort study confirmed that the prognosis of ruptured HCC is poor with an overall mortality rate of 24%, despite important advances in endovascular techniques. Overall, the rate of bleeding recurrence was more than 20%, with a related high risk of mortality.

PMID: 28799103 [PubMed - as supplied by publisher]

Mucosa-associated invariant T cells infiltrate hepatic metastases in patients with colorectal carcinoma but are rendered dysfunctional within and adjacent to tumor microenvironment.

Sat, 08/12/2017 - 12:45
Related Articles

Mucosa-associated invariant T cells infiltrate hepatic metastases in patients with colorectal carcinoma but are rendered dysfunctional within and adjacent to tumor microenvironment.

Cancer Immunol Immunother. 2017 Aug 10;:

Authors: Shaler CR, Tun-Abraham ME, Skaro AI, Khazaie K, Corbett AJ, Mele T, Hernandez-Alejandro R, Haeryfar SMM

Abstract
Mucosa-associated invariant T (MAIT) cells are innate-like T lymphocytes that are unusually abundant in the human liver, a common site of colorectal carcinoma (CRC) metastasis. However, whether they contribute to immune surveillance against colorectal liver metastasis (CRLM) is essentially unexplored. In addition, whether MAIT cell functions can be impacted by chemotherapy is unclear. These are important questions given MAIT cells' potent immunomodulatory and inflammatory properties. Herein, we examined the frequencies and functions of peripheral blood, healthy liver tissue, tumor-margin and tumor-infiltrating MAIT cells in 21 CRLM patients who received no chemotherapy, FOLFOX, or a combination of FOLFOX and Avastin before they underwent liver resection. We found that MAIT cells, defined as CD3ε(+)Vα7.2(+)CD161(++) or CD3ε(+)MR1 tetramer(+) cells, were present within both healthy and tumor-afflicted hepatic tissues. Paired and grouped analyses of samples revealed the physical proximity of MAIT cells to metastatic lesions to drastically influence their functional competence. Accordingly, unlike those residing in the healthy liver compartment, tumor-infiltrating MAIT cells failed to produce IFN-γ in response to a panel of TCR and cytokine receptor ligands, and tumor-margin MAIT cells were only partially active. Furthermore, chemotherapy did not account for intratumoral MAIT cell insufficiencies. Our findings demonstrate for the first time that CRLM-penetrating MAIT cells exhibit wide-ranging functional impairments, which are dictated by their physical location but not by preoperative chemotherapy. Therefore, we propose that MAIT cells may provide an attractive therapeutic target in CRC and that their ligands may be combined with chemotherapeutic agents to treat CRLM.

PMID: 28798979 [PubMed - as supplied by publisher]

Heme-Oxygenase-1 Expression Contributes to the Immunoregulation Induced by Fasciola hepatica and Promotes Infection.

Sat, 08/12/2017 - 12:45
Related Articles

Heme-Oxygenase-1 Expression Contributes to the Immunoregulation Induced by Fasciola hepatica and Promotes Infection.

Front Immunol. 2017;8:883

Authors: Carasi P, Rodríguez E, da Costa V, Frigerio S, Brossard N, Noya V, Robello C, Anegón I, Freire T

Abstract
Fasciola hepatica, also known as the liver fluke, is a trematode that infects livestock and humans causing fasciolosis, a zoonotic disease of increasing importance due to its worldwide distribution and high economic losses. This parasite immunoregulates the host immune system by inducing a strong Th2 and regulatory T immune response by immunomodulating dendritic cell (DC) maturation and alternative activation of macrophages. In this paper, we show that F. hepatica infection in mice induces the upregulation of heme-oxygenase-1 (HO-1), the rate-limiting enzyme in the catabolism of free heme that regulates the host inflammatory response. We show and characterize two different populations of antigen presenting cells that express HO-1 during infection in the peritoneum of infected animals. Cells that expressed high levels of HO-1 expressed intermediate levels of F4/80 but high expression of CD11c, CD38, TGFβ, and IL-10 suggesting that they correspond to regulatory DCs. On the other hand, cells expressing intermediate levels of HO-1 expressed high levels of F4/80, CD68, Ly6C, and FIZZ-1, indicating that they might correspond to alternatively activated macrophages. Furthermore, the pharmacological induction of HO-1 with the synthetic metalloporphyrin CoPP promoted F. hepatica infection increasing the clinical signs associated with the disease. In contrast, treatment with the HO-1 inhibitor SnPP protected mice from parasite infection, indicating that HO-1 plays an essential role during F. hepatica infection. Finally, HO-1 expression during F. hepatica infection was associated with TGFβ and IL-10 levels in liver and peritoneum, suggesting that HO-1 controls the expression of these immunoregulatory cytokines during infection favoring parasite survival in the host. These results contribute to the elucidation of the immunoregulatory mechanisms induced by F. hepatica in the host and provide alternative checkpoints to control fasciolosis.

PMID: 28798750 [PubMed]

NEDD4-family E3 ligase dysfunction due to PKHD1/Pkhd1 defects suggests a mechanistic model for ARPKD pathobiology.

Sat, 08/12/2017 - 12:45
Related Articles

NEDD4-family E3 ligase dysfunction due to PKHD1/Pkhd1 defects suggests a mechanistic model for ARPKD pathobiology.

Sci Rep. 2017 Aug 10;7(1):7733

Authors: Kaimori JY, Lin CC, Outeda P, Garcia-Gonzalez MA, Menezes LF, Hartung EA, Li A, Wu G, Fujita H, Sato Y, Nakanuma Y, Yamamoto S, Ichimaru N, Takahara S, Isaka Y, Watnick T, Onuchic LF, Guay-Woodford LM, Germino GG

Abstract
Autosomal recessive polycystic kidney disease (ARPKD) is an important childhood nephropathy, occurring 1 in 20,000 live births. The major clinical phenotypes are expressed in the kidney with dilatation of the collecting ducts, systemic hypertension, and progressive renal insufficiency, and in the liver with biliary dysgenesis, portal tract fibrosis, and portal hypertension. The systemic hypertension has been attributed to enhanced distal sodium reabsorption in the kidney, the structural defects have been ascribed to altered cellular morphology, and fibrosis to increased TGF-β signaling in the kidney and biliary tract, respectively. The pathogenic mechanisms underlying these abnormalities have not been determined. In the current report, we find that disrupting PKHD1 results in altered sub-cellular localization and function of the C2-WWW-HECT domain E3 family of ligases regulating these processes. We also demonstrate altered activity of RhoA and increased TGF-β signaling and ENaC activity. Linking these phenomena, we found that vesicles containing the PKHD1/Pkhd1 gene product, FPC, also contain the NEDD4 ubiquitin ligase interacting protein, NDFIP2, which interacts with multiple members of the C2-WWW-HECT domain E3 family of ligases. Our results provide a mechanistic explanation for both the cellular effects and in vivo phenotypic abnormalities in mice and humans that result from Pkhd1/PKHD1 mutation.

PMID: 28798345 [PubMed - in process]

Healthcare Costs for Chronic Hepatitis C in South Korea from 2009 to 2013: An Analysis of the National Health Insurance Claims' Data.

Sat, 08/12/2017 - 12:45
Related Articles

Healthcare Costs for Chronic Hepatitis C in South Korea from 2009 to 2013: An Analysis of the National Health Insurance Claims' Data.

Gut Liver. 2017 Aug 14;:

Authors: Ki M, Choi HY, Kim KA, Jang ES, Jeong SH

Abstract
Background/Aims: The introduction of direct-acting antivirals (DAA) in 2013 revolutionized hepatitis C virus (HCV) treatment, offering a cure rate >90%. However, this therapy is expensive, and estimations of the number of chronic HCV-infected (CHC) patients and their treatment costs pre-2013 are therefore essential for creating policies and expanding drug access. Herein, we aimed to investigate the number of HCV-related liver disease patients, their healthcare utilization, their annual direct medical costs, and the interferon-based antiviral treatment rates and costs from 2009 to 2013 in South Korea.
Methods: The National Health Insurance database was reviewed, and patients diagnosed with CHC from 2009 to 2013 were extracted. Data regarding detailed healthcare utilization, prescribed drugs, and direct medical costs were obtained. For annual direct healthcare cost calculations, a prevalence-based approach was used.
Results: Overall, 181,768 CHC patients were identified. In 2013, the annual per-patient costs for chronic hepatitis, liver cirrhosis, hepatocellular carcinoma, and the first year post-liver transplant were 895, 1,873, 6,945, and 67,359 USD, respectively. Interferon-based antiviral therapeutics were prescribed to 25,223 patients (13.9%).
Conclusions: Healthcare costs have increased remarkably with increasing liver disease severity. Thus, efforts to stop disease progression are needed. Moreover, the low rate of interferon-based therapy indicates an unmet need for DAA.

PMID: 28798283 [PubMed - as supplied by publisher]

NKT cells are important mediators of hepatic ischemia-reperfusion injury.

Sat, 08/12/2017 - 12:45
Related Articles

NKT cells are important mediators of hepatic ischemia-reperfusion injury.

Transpl Immunol. 2017 Aug 07;:

Authors: Richards JA, Wigmore SJ, Anderton SM, Howie SEM

Abstract
INTRODUCTION: IRI results from the interruption then reinstatement of an organ's blood supply, and this poses a significant problem in liver transplantation and resectional surgery. In this paper, we explore the role T cells play in the pathogenesis of this injury.
MATERIALS & METHODS: We used an in vivo murine model of warm partial hepatic IRI, genetically-modified mice, in vivo antibody depletion, adoptive cell transfer and flow cytometry to determine which lymphocyte subsets contribute to pathology. Injury was assessed by measuring serum alanine aminotransfersase (ALT) and by histological examination of liver tissue sections.
RESULTS: The absence of T cells (CD3εKO) is associated with significant protection from injury (p=0.010). Through a strategy of antibody depletion it appears that NKT cells (p=0.0025), rather than conventional T (CD4+ or CD8+) (p=0.11) cells that are the key mediators of injury.
DISCUSSION: Our results indicate that tissue-resident NKT cells, but not other lymphocyte populations are responsible for the injury in hepatic IRI. Targeting the activation of NKT cells and/or their effector apparatus would be a novel approach in protecting the liver during transplantation and resection surgery; this may allow us to expand our current criteria for surgery.

PMID: 28797737 [PubMed - as supplied by publisher]

Transplantation of the Patient with Human Immunodeficiency Virus.

Sat, 08/12/2017 - 12:45
Related Articles

Transplantation of the Patient with Human Immunodeficiency Virus.

Adv Surg. 2017 Sep;51(1):65-76

Authors: Jackson KR, Cameron A

PMID: 28797346 [PubMed - in process]

A new model of multi-visceral and bone metastatic prostate cancer with perivascular niche targeting by a novel endothelial specific adenoviral vector.

Sat, 08/12/2017 - 12:45
Related Articles

A new model of multi-visceral and bone metastatic prostate cancer with perivascular niche targeting by a novel endothelial specific adenoviral vector.

Oncotarget. 2017 Feb 14;8(7):12272-12289

Authors: Lu ZH, Kaliberov S, Sohn RE, Kaliberova L, Du Y, Prior JL, Leib DJ, Chauchereau A, Sehn JK, Curiel DT, Arbeit JM

Abstract
While modern therapies for metastatic prostate cancer (PCa) have improved survival they are associated with an increasingly prevalent entity, aggressive variant PCa (AVPCa), lacking androgen receptor (AR) expression, enriched for cancer stem cells (CSCs), and evidencing epithelial-mesenchymal plasticity with a varying extent of neuroendocrine transdifferentiation. Parallel work revealed that endothelial cells (ECs) create a perivascular CSC niche mediated by juxtacrine and membrane tethered signaling. There is increasing interest in pharmacological metastatic niche targeting, however, targeted access has been impossible. Here, we discovered that the Gleason 7 derived, androgen receptor negative, IGR-CaP1 cell line possessed some but not all of the molecular features of AVPCa. Intracardiac injection into NOD/SCID/IL2Rg -/- (NSG) mice produced a completely penetrant bone, liver, adrenal, and brain metastatic phenotype; noninvasively and histologically detectable at 2 weeks, and necessitating sacrifice 4-5 weeks post injection. Bone metastases were osteoblastic, and osteolytic. IGR-CaP1 cells expressed the neuroendocrine marker synaptophysin, near equivalent levels of vimentin and e-cadherin, all of the EMT transcription factors, and activation of NOTCH and WNT pathways. In parallel, we created a new triple-targeted adenoviral vector containing a fiber knob RGD peptide, a hexon mutation, and an EC specific ROBO4 promoter (Ad.RGD.H5/3.ROBO4). This vector was expressed in metastatic microvessels tightly juxtaposed to IGR-CaP1 cells in bone and visceral niches. Thus, the combination of IGR-CaP1 cells and NSG mice produces a completely penetrant metastatic PCa model emulating end-stage human disease. In addition, the metastatic niche access provided by our novel Ad vector could be therapeutically leveraged for future disease control or cure.

PMID: 28103576 [PubMed - indexed for MEDLINE]

Humanized Mouse Xenograft Models: Narrowing the Tumor-Microenvironment Gap.

Sat, 08/12/2017 - 12:45
Related Articles

Humanized Mouse Xenograft Models: Narrowing the Tumor-Microenvironment Gap.

Cancer Res. 2016 Nov 01;76(21):6153-6158

Authors: Morton JJ, Bird G, Refaeli Y, Jimeno A

Abstract
Cancer research has long been hampered by the limitations of the current model systems. Both cultured cells and mouse xenografts grow in an environment highly dissimilar to that of their originating tumor, frequently resulting in promising treatments that are ultimately clinically ineffective. The development of highly immunodeficient mouse strains into which human immune systems can be engrafted can help bridge this gap. Humanized mice (HM) allow researchers to examine xenograft growth in the context of a human immune system and resultant tumor microenvironment, and recent studies have highlighted the increased similarities in attendant tumor structure, metastasis, and signaling to those features in cancer patients. This setting also facilitates the examination of investigational cancer therapies, including new immunotherapies. This review discusses recent advancements in the generation and application of HM models, their promise in cancer research, and their potential in generating clinically relevant treatments. This review also focuses on current efforts to improve HM models by engineering mouse strains expressing human cytokines or HLA proteins and implanting human bone, liver, and thymus tissue to facilitate immune cell maturation and trafficking. Finally, we discuss how these improvements may help direct future HM model cancer studies. Cancer Res; 76(21); 6153-8. ©2016 AACR.

PMID: 27587540 [PubMed - indexed for MEDLINE]

Preclinical Activity of ARQ 087, a Novel Inhibitor Targeting FGFR Dysregulation.

Sat, 08/12/2017 - 12:45
Related Articles

Preclinical Activity of ARQ 087, a Novel Inhibitor Targeting FGFR Dysregulation.

PLoS One. 2016;11(9):e0162594

Authors: Hall TG, Yu Y, Eathiraj S, Wang Y, Savage RE, Lapierre JM, Schwartz B, Abbadessa G

Abstract
Dysregulation of Fibroblast Growth Factor Receptor (FGFR) signaling through amplifications, mutations, and gene fusions has been implicated in a broad array of cancers (e.g. liver, gastric, ovarian, endometrial, and bladder). ARQ 087 is a novel, ATP competitive, small molecule, multi-kinase inhibitor with potent in vitro and in vivo activity against FGFR addicted cell lines and tumors. Biochemically, ARQ 087 exhibited IC50 values of 1.8 nM for FGFR2, and 4.5 nM for FGFR1 and 3. In cells, inhibition of FGFR2 auto-phosphorylation and other proteins downstream in the FGFR pathway (FRS2α, AKT, ERK) was evident by the response to ARQ 087 treatment. Cell proliferation studies demonstrated ARQ 087 has anti-proliferative activity in cell lines driven by FGFR dysregulation, including amplifications, fusions, and mutations. Cell cycle studies in cell lines with high levels of FGFR2 protein showed a positive relationship between ARQ 087 induced G1 cell cycle arrest and subsequent induction of apoptosis. In addition, ARQ 087 was effective at inhibiting tumor growth in vivo in FGFR2 altered, SNU-16 and NCI-H716, xenograft tumor models with gene amplifications and fusions. ARQ 087 is currently being studied in a phase 1/2 clinical trial that includes a sub cohort for intrahepatic cholangiocarcinoma patients with confirmed FGFR2 gene fusions (NCT01752920).

PMID: 27627808 [PubMed - indexed for MEDLINE]

Stem-cell Based Engineered Immunity Against HIV Infection in the Humanized Mouse Model.

Sat, 08/12/2017 - 12:45
Related Articles

Stem-cell Based Engineered Immunity Against HIV Infection in the Humanized Mouse Model.

J Vis Exp. 2016 Jul 02;(113):

Authors: Zhen A, Rezek V, Youn C, Rick J, Lam B, Chang N, Zack J, Kamata M, Kitchen S

Abstract
With the rapid development of stem cell-based gene therapies against HIV, there is pressing requirement for an animal model to study the hematopoietic differentiation and immune function of the genetically modified cells. The humanized Bone-marrow/Liver/Thymus (BLT) mouse model allows for full reconstitution of a human immune system in the periphery, which includes T cells, B cells, NK cells and monocytes. The human thymic implant also allows for thymic selection of T cells in autologous thymic tissue. In addition to the study of HIV infection, the model stands as a powerful tool to study differentiation, development and functionality of cells derived from hematopoietic stem cells (HSCs). Here we outline the construction of humanized non-obese diabetic (NOD)-severe combined immunodeficient (SCID)-common gamma chain knockout (cγ(-/-))-Bone-marrow/Liver/Thymus (NSG-BLT) mice with HSCs transduced with CD4 chimeric antigen receptor (CD4CAR) lentivirus vector. We show that the CD4CAR HSCs can successfully differentiate into multiple lineages and have anti-HIV activity. The goal of the study is to demonstrate the use of NSG-BLT mouse model as an in vivo model for engineered immunity against HIV. It is worth noting that, because lentivirus and human tissue is used, experiments and surgeries should be performed in a Class II biosafety cabinet in a Biosafety Level 2 (BSL2) with special precautions (BSL2+) facility.

PMID: 27404517 [PubMed - indexed for MEDLINE]

Low renal but high extrarenal phenotype variability in Schimke immuno-osseous dysplasia.

Fri, 08/11/2017 - 12:45
Related Articles

Low renal but high extrarenal phenotype variability in Schimke immuno-osseous dysplasia.

PLoS One. 2017;12(8):e0180926

Authors: Lipska-Ziętkiewicz BS, Gellermann J, Boyer O, Gribouval O, Ziętkiewicz S, Kari JA, Shalaby MA, Ozaltin F, Dusek J, Melk A, Bayazit AK, Massella L, Hyla-Klekot L, Habbig S, Godron A, Szczepańska M, Bieniaś B, Drożdż D, Odeh R, Jarmużek W, Zachwieja K, Trautmann A, Antignac C, Schaefer F, PodoNet Consortium

Abstract
Schimke immuno-osseous dysplasia (SIOD) is a rare multisystem disorder with early mortality and steroid-resistant nephrotic syndrome (SRNS) progressing to end-stage kidney disease. We hypothesized that next-generation gene panel sequencing may unsurface oligosymptomatic cases of SIOD with potentially milder disease courses. We analyzed the renal and extrarenal phenotypic spectrum and genotype-phenotype associations in 34 patients from 28 families, the largest SMARCAL1-associated nephropathy cohort to date. In 11 patients the diagnosis was made unsuspectedly through SRNS gene panel testing. Renal disease first manifested at median age 4.5 yrs, with focal segmental glmerulosclerosis or minimal change nephropathy on biopsy and rapid progression to end-stage kidney disease (ESKD) at median age 8.7 yrs. Whereas patients diagnosed by phenotype more frequently developed severe extrarenal complications (cerebral ischemic events, septicemia) and were more likely to die before age 10 years than patients identified by SRNS-gene panel screening (88 vs. 40%), the subgroups did not differ with respect to age at proteinuria onset and progression to ESKD. Also, 10 of 11 children diagnosed unsuspectedly by Next Generation Sequencing were small at diagnosis and all showed progressive growth failure. Severe phenotypes were usually associated with biallelic truncating mutations and milder phenotypes with biallelic missense mutations. However, no genotype-phenotype correlation was observed for the renal disease course. In conclusion, while short stature is a reliable clue to SIOD in children with SRNS, other systemic features are highly variable. Our findings support routine SMARCAL1 testing also in non-syndromic SRNS.

PMID: 28796785 [PubMed - in process]

Pages