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Article ; Online: Effect of SARS-CoV-2 Entry Factors on Myeloid Cancers.

Alshareef, Abdulraheem

Journal of Nippon Medical School = Nippon Ika Daigaku zasshi

2022 Volume 89, Issue 1, Page(s) 95–101

Abstract: Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel, highly pathogenic coronavirus that has spread rapidly worldwide and caused an international public health emergency. Patients with hematological cancers are regarded as ...

Abstract	Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel, highly pathogenic coronavirus that has spread rapidly worldwide and caused an international public health emergency. Patients with hematological cancers are regarded as a high-risk group for coronavirus disease 2019 (COVID-19). However, few reports have investigated factors that might account for the differential severity of COVID-19 disease in these patients. Methods: Gene expression of SARS-CoV-2 entry-promoting factors and entry-restricting factors and the associated effects on myeloid malignancies were evaluated. Gene expression levels of 11 SARS-CoV-2 entry-promoting factors and 4 SARS-CoV-2 entry-restricting factors were analyzed in patients with myelodysplastic syndromes (MDS), chronic myeloid leukemia (CML), and acute myeloid leukemia and its subtypes. Results: Expression levels of promoting and restricting factors were most affected in MDS. Specifically, 4 of the 11 analyzed SARS-CoV-2 entry-promoting factors were significantly increased (TMPRSS4, CD209, CLEC4G, and CTSB), and 2 of the 4 analyzed SARS-CoV-2 entry-restricting factors were significantly decreased (IFITM1 and IFITM2) in MDS. Patients with CML also exhibited a pattern of significant changes in SARS-CoV-2 entry-promoting and entry-restricting factors. Five of the 11 analyzed SARS-CoV-2 entry-promoting factors were significantly increased (ACE2, TMPRSS2, TMPRSS4, ANPEP, CD209), and 1 of the 4 analyzed SARS-CoV-2 entry-restricting factors was significantly decreased (LY6E) in CML. Conclusions: The present and past results highlight the importance of investigating SARS-CoV-2 entry-promoting factors and entry-restricting factors, because of their crucial role in determining the differential severity of COVID-19 disease.
MeSH term(s)	Angiotensin-Converting Enzyme 2 ; COVID-19 ; Cell Line ; Humans ; Membrane Proteins ; Neoplasms ; Peptidyl-Dipeptidase A/genetics ; Peptidyl-Dipeptidase A/metabolism ; SARS-CoV-2 ; Serine Endopeptidases/genetics
Chemical Substances	IFITM2 protein, human ; Membrane Proteins ; Peptidyl-Dipeptidase A (EC 3.4.15.1) ; Angiotensin-Converting Enzyme 2 (EC 3.4.17.23) ; Serine Endopeptidases (EC 3.4.21.-) ; TMPRSS4 protein, human (EC 3.4.21.-)
Language	English
Publishing date	2022-03-10
Publishing country	Japan
Document type	Journal Article
ZDB-ID	2091563-9
ISSN	1347-3409 ; 1345-4676
ISSN (online)	1347-3409
ISSN	1345-4676
DOI	10.1272/jnms.JNMS.2022_89-204
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Article: Novel Molecular Challenges in Targeting Anaplastic Lymphoma Kinase in ALK-Expressing Human Cancers.

Alshareef, Abdulraheem

Cancers

2017 Volume 9, Issue 11

Abstract: Targeting anaplastic lymphoma kinase (ALK), a receptor tyrosine kinase receptor initially identified as a potent oncogenic driver in anaplastic large-cell lymphoma (ALCL) in the form of nucleophosmin (NPM)-ALK fusion protein, using tyrosine kinase ... ...

Abstract	Targeting anaplastic lymphoma kinase (ALK), a receptor tyrosine kinase receptor initially identified as a potent oncogenic driver in anaplastic large-cell lymphoma (ALCL) in the form of nucleophosmin (NPM)-ALK fusion protein, using tyrosine kinase inhibitors has shown to be a promising therapeutic approach for ALK-expressing tumors. However, clinical resistance to ALK inhibitors invariably occurs, and the molecular mechanisms are incompletely understood. Recent studies have clearly shown that clinical resistance to ALK inhibitors is a multifactorial and complex mechanism. While few of the mechanisms of clinical resistance to ALK inhibitors such as gene mutation are well known, there are others that are not well covered. In this review, the molecular mechanisms of cancer stem cells in mediating resistance to ALK inhibitors as well as the current understanding of the molecular challenges in targeting ALK in ALK-expressing human cancers will be discussed.
Language	English
Publishing date	2017-10-28
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers9110148
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Article ; Online: Cancer Research Challenges and Potential Solutions in Saudi Arabia: A Qualitative Discussion Group Study.

Alessy, Saleh A / Almotlak, Abdulaziz A / Alattas, Maha / Alshareef, Abdulraheem / Alwosaibai, Kholoud / Alghamdi, Majed A / Razack, Habeeb I A / Alqahtani, Saleh A

JCO global oncology

2024 Volume 10, Page(s) e2300189

Abstract: Purpose: Cancer incidence in Saudi Arabia has recently shown an upward trend. Research efforts within the different cancer continuum are pivotal to strengthening control measures. Since cancer research is evolving in the country, it is crucial to ... ...

Abstract	Purpose: Cancer incidence in Saudi Arabia has recently shown an upward trend. Research efforts within the different cancer continuum are pivotal to strengthening control measures. Since cancer research is evolving in the country, it is crucial to understand the current challenges and implement defined interventions to overcome them. The present qualitative study aimed to assess cancer research barriers among researchers and identify potential solutions from their perspectives. Methods: We conducted a focus group discussion among 17 Saudi-based cancer researchers from diverse research backgrounds, provinces, and institutions. We used descriptive-interpretive thematic analysis following an open-ended approach to investigate the challenges in conducting cancer research. We also captured the solutions suggested based on the researchers' experiences. Results: Six major themes emerged from the analysis: requirements of the data landscape, organizational support, national research roadmap, sustainable funding, clearer policies and regulations, and capacity building. To address challenges in these areas, researchers stressed the need for improved interinstitutional collaborations, immediate availability of research materials, and unlimited and easy access to research data. Conclusion: Improving health research is one of the primary goals of Saudi Vision 2030. It is, therefore, essential to overcome the current challenges in cancer research, enabling research findings to inform policies related to cancer control and care provision.
MeSH term(s)	Humans ; Saudi Arabia/epidemiology ; Qualitative Research ; Delivery of Health Care ; Neoplasms/epidemiology ; Neoplasms/prevention & control
Language	English
Publishing date	2024-01-02
Publishing country	United States
Document type	Journal Article
ISSN	2687-8941
ISSN (online)	2687-8941
DOI	10.1200/GO.23.00189
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Article ; Online: Mitigation of patients with hematologicaldisorders during the COVID-19 pandemicthrough telemedicine

Abdulraheem Alshareef / Hawazen Balkhair / Arwa Abbas / Maha Rizq / Hani Alhashmi

Saudi Journal of Emergency Medicine, Vol 2, Iss 1, Pp 77-

the physicians perspectives

2021 Volume 84

Abstract: Background: Patients with hematological disorders are among the highly affected patient groups during the COVID-19 pandemic worldwide. Therefore, this study aimed to evaluate how physicians mitigated patients with hematological disorders during the COVID- ...

Abstract	Background: Patients with hematological disorders are among the highly affected patient groups during the COVID-19 pandemic worldwide. Therefore, this study aimed to evaluate how physicians mitigated patients with hematological disorders during the COVID-19 pandemic in Saudi Arabia. In addition, the impact of the lockdown on hematologists and their recommendations according to their current experience was also assessed. Methods: This was a questionnaire-based cross-sectional survey conducted among 62 hematologists in Saudi Arabia during the COVID-19 pandemic from 6th to 29th June 2020. Results: The most common method of contact between physicians and their patients was the use of actual and virtual clinics and WhatsApp (22.6%). In addition, the most common cases that contacted the physicians were those suffering from hematological malignancies (such as lymphoma and leukemia) (37.1%), followed by sickle cell anemia (17.7%). Interestingly, majority of patients had contacted their physicians for general concerns (41.9%), followed by assurance purposes (35.5%). Furthermore, 53.2% of the physicians were satisfied with the experience of handling patients during curfew. Around 71% of the physicians thought that social media had a positive impact on communication with their patients, which was significantly correlated with male participants and those in the age group of 46-55 years (p-values 0.03 and 0.002, respectively). Conclusion: Telemedicine is one of the most useful solutions utilized during the COVID-19 pandemic. However, it needs to be improved and should be used routinely as a part of the healthcare system in Saudi Arabia. [SJEMed 2021; 2(1.000): 77-84]
Keywords	hematologists ; hematological disorders ; covid-19 ; telemedicine ; saudi arabia ; Medicine ; R
Language	English
Publishing date	2021-06-01T00:00:00Z
Publisher	Discover STM Publishing Ltd
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Clinico-Pathological Study of K-ras Mutations in Colorectal Tumors: A Single-Center Retrospective Study of 51 Patients in Madinah, Saudi Arabia.

Mulla, Nasser / Alshareef, Abdulraheem / Syed, Abdul Rahman / Al-Jahel, Majid

Cureus

2020 Volume 12, Issue 8, Page(s) e9978

Abstract: Background Colorectal cancer (CRC) is one of the leading types of cancer worldwide and in Saudi Arabia. At the molecular level, CRC is very complicated and requires establishing comprehensive patient stratification models through identification of ... ...

Abstract	Background Colorectal cancer (CRC) is one of the leading types of cancer worldwide and in Saudi Arabia. At the molecular level, CRC is very complicated and requires establishing comprehensive patient stratification models through identification of patients who will benefit or will not benefit from targeted therapy. We retrospectively investigated and analyzed the frequency of Kirsten-ras (K-ras) mutation and its correlation with patients' characteristics as weel as its association with clinicopathological features (i.e age, gender, clinical stage, anatomical site, histological subtype, degree of histological differentiation and metastatic site) in patients with CRC. Methods Medical records and paraffin-embedded tumor samples from 51 patients with histologically proven colorectal adenocarcinoma referred to Madinah center in Saudi Arabia were analyzed for the occurrence of rat sarcoma virus (RAS) mutations. Results RAS mutations occurred in 43% of the patients; 91% of these mutations were in K-ras. Seventy-five percent of these K-ras mutations were in codon 12, most commonly p.G12D. Codon 13 mutations occurred in 20% of tumors: all of these were p.G13D (100%). The percentage of K-ras mutations occurrence was higher in young patients (≤50) compared with the older patients (>50) (54.5% and 35%, respectively). Similarly, the percentage of K-ras mutations occurrence was higher in the right-sided tumors compared with the left-sided tumors (57.1% and 32.4%, respectively). Patients' characteristics and clinicopathological features were not significantly associated with K-ras mutations. Conclusions K-ras mutations are common among Saudi patients diagnosed with CRC in Madinah, especially pG12V and pG12D in codon 12. Further investigation would be required to establish correlation of K-ras mutations in larger cohorts.
Language	English
Publishing date	2020-08-24
Publishing country	United States
Document type	Journal Article
ZDB-ID	2747273-5
ISSN	2168-8184
ISSN	2168-8184
DOI	10.7759/cureus.9978
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Article ; Online: Gene Methylation and Silencing of WIF1 Is a Frequent Genetic Abnormality in Mantle Cell Lymphoma.

Alshareef, Abdulraheem / Peters, Anthea C / Gélébart, Pascal / Chen, Will / Lai, Raymond

International journal of molecular sciences

2021 Volume 22, Issue 2

Abstract: We have previously shown that the Wnt canonical pathway (WCP) is constitutively active in most cases of mantle cell lymphoma (MCL). Here, we aimed to elucidate the mechanisms underlying this biochemical deregulation. We hypothesized that gene methylation/ ...

Abstract	We have previously shown that the Wnt canonical pathway (WCP) is constitutively active in most cases of mantle cell lymphoma (MCL). Here, we aimed to elucidate the mechanisms underlying this biochemical deregulation. We hypothesized that gene methylation/silencing of WIF1 (Wnt inhibitory factor-1), a physiologic inhibitor of WCP, contributes to the deregulation of WCP and promotes cell growth in MCL. In support of this hypothesis, we found that the expression of WIF1 was detectable in none of the 4 MCL cell lines, and in only 2 of 5 tumors (40%) examined. Using methylation-specific PCR, we found evidence of gene methylation of WIF1 in 4 of 5 cell lines (80%) and in 24 of 29 (82%) tumors. The addition of the demethylation agent 5-aza-2'-deoxycytidine to Mino and JeKo-1, two WIF1-negative cell lines, restored the expression of WIF1 mRNA in these cells. Gene transfection of WIF1 into JeKo-1 and Mino cells significantly reduced cell growth, and this finding correlated with substantial downregulations of various proteins in WCP, such as β-catenin and pGSK-3β. In conclusion, our results support the concept that gene methylation/silencing of WIF1 is a frequent event in MCL, and this abnormality contributes to the aberrant activation of WCP. These results have provided further evidence that aberrant Wnt signaling is pathogenetically important in MCL and it may represent a potential therapeutic target.
MeSH term(s)	Adaptor Proteins, Signal Transducing/genetics ; Cell Line, Tumor ; Cell Proliferation/genetics ; DNA Methylation/genetics ; Decitabine/pharmacology ; Demethylation/drug effects ; Epigenesis, Genetic/genetics ; Gene Expression Regulation, Neoplastic/genetics ; Gene Silencing ; Glycogen Synthase Kinase 3 beta/genetics ; Humans ; Lymphoma, Mantle-Cell/genetics ; Lymphoma, Mantle-Cell/pathology ; Wnt Signaling Pathway/genetics ; beta Catenin/genetics
Chemical Substances	Adaptor Proteins, Signal Transducing ; CTNNB1 protein, human ; WIF1 protein, human ; beta Catenin ; Decitabine (776B62CQ27) ; Glycogen Synthase Kinase 3 beta (EC 2.7.11.1)
Language	English
Publishing date	2021-01-18
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms22020893
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Article ; Online: Gene Methylation and Silencing of WIF1 Is a Frequent Genetic Abnormality in Mantle Cell Lymphoma

Abdulraheem Alshareef / Anthea C. Peters / Pascal Gélébart / Will Chen / Raymond Lai

International Journal of Molecular Sciences, Vol 22, Iss 2, p

2021 Volume 893

Abstract	We have previously shown that the Wnt canonical pathway (WCP) is constitutively active in most cases of mantle cell lymphoma (MCL). Here, we aimed to elucidate the mechanisms underlying this biochemical deregulation. We hypothesized that gene methylation/silencing of WIF1 (Wnt inhibitory factor-1), a physiologic inhibitor of WCP, contributes to the deregulation of WCP and promotes cell growth in MCL. In support of this hypothesis, we found that the expression of WIF1 was detectable in none of the 4 MCL cell lines, and in only 2 of 5 tumors (40%) examined. Using methylation-specific PCR, we found evidence of gene methylation of WIF1 in 4 of 5 cell lines (80%) and in 24 of 29 (82%) tumors. The addition of the demethylation agent 5-aza-2′-deoxycytidine to Mino and JeKo-1, two WIF1-negative cell lines, restored the expression of WIF1 mRNA in these cells. Gene transfection of WIF1 into JeKo-1 and Mino cells significantly reduced cell growth, and this finding correlated with substantial downregulations of various proteins in WCP, such as β-catenin and pGSK-3β. In conclusion, our results support the concept that gene methylation/silencing of WIF1 is a frequent event in MCL, and this abnormality contributes to the aberrant activation of WCP. These results have provided further evidence that aberrant Wnt signaling is pathogenetically important in MCL and it may represent a potential therapeutic target.
Keywords	mantle cell lymphoma ; Wnt canonical pathway ; Wnt inhibitory factor-1 ; gene methylation ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	570
Language	English
Publishing date	2021-01-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Brucellosis causing subacute motor polyradiculopathy and the pathological correlation of pseudomyopathic electromyography: A case report.

Abuzinadah, Ahmad R / Milyani, Haneen A / Alshareef, Aysha / Bamaga, Ahmed K / Alshehri, Abdulraheem / Kurdi, Maher E

Clinical neurophysiology practice

2020 Volume 5, Page(s) 130–134

Abstract: Introduction: Brucellosis is a rare cause of polyradiculopathy. We aim to present a case of subacute motor polyradiculopathy (SAMPR), along with the electromyographic pseudomyopathic changes, and their histopathological correlation.: Case presentation! ...

Abstract	Introduction: Brucellosis is a rare cause of polyradiculopathy. We aim to present a case of subacute motor polyradiculopathy (SAMPR), along with the electromyographic pseudomyopathic changes, and their histopathological correlation. Case presentation: A 24-year-old man presented with gradually progressive bilateral lower limb weakness for three weeks that progressed to a loss of ambulation in seven weeks. He had no ocular, facial, or sphincteric weakness and no sensory symptoms. He showed normal cognitive, cranial nerve, and upper limb exams. His lower limb power was medical research council (MRC) grade 3 proximally, and 4 distally. His reflexes were grade 2+ in the upper limbs and grade 0 in the lower limbs. The nerve conduction studies were normal. Electromyography (EMG) showed active denervation with a short-duration motor unit potential (MUP) and early recruitment. MRI showed a diffuse enhancement of the lumbosacral nerve roots. Cerebrospinal fluid (CSF) showed a protein of 2.7 g/L and a white blood cells (WBC) count of 420 cells per microliter. Muscle biopsy revealed neurogenic changes with secondary degenerating and regenerating fibers, explaining the small and short MUPs in the EMG. CSF grew Brucella after fourteen days of incubation. Serum showed high antibody titers for the Brucella species "Melitensis" and "Abortus". The patient started to walk again, ten months after starting a course of antibiotics. Conclusion: Neurobrucellosis can present primarily as SAMPR, sparing the sensory system. SAMPR, with ongoing degenerating and regenerating muscle fibers, may explain the pseudomyopathic changes found in electromyographic studies.
Language	English
Publishing date	2020-06-11
Publishing country	Netherlands
Document type	Case Reports
ISSN	2467-981X
ISSN (online)	2467-981X
DOI	10.1016/j.cnp.2020.05.003
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Article: Hypoxia Induces the Acquisition of Cancer Stem-like Phenotype Via Upregulation and Activation of Signal Transducer and Activator of Transcription-3 (STAT3) in MDA-MB-231, a Triple Negative Breast Cancer Cell Line.

Soleymani Abyaneh, Hoda / Gupta, Nidhi / Alshareef, Abdulraheem / Gopal, Keshav / Lavasanifar, Afsaneh / Lai, Raymond

Cancer microenvironment : official journal of the International Cancer Microenvironment Society

2018 Volume 11, Issue 2-3, Page(s) 141–152

Abstract: The finding that hypoxia can induce cancer stemness in various experimental models is in agreement with the conceptual basis of cancer cell plasticity. Here, we aimed to gain insights into the molecular basis of hypoxia-induced cancer cell plasticity in ... ...

Abstract	The finding that hypoxia can induce cancer stemness in various experimental models is in agreement with the conceptual basis of cancer cell plasticity. Here, we aimed to gain insights into the molecular basis of hypoxia-induced cancer cell plasticity in triple negative breast cancer (TNBC). To achieve this goal, we employed our previously published in-vitro model of TNBC, in which a small subset of stem-like cells can be distinguished from the bulk cell population based on their responsiveness to a Sox2 reporter. In MDA-MB-231, a TNBC cell line, we observed that hypoxia significantly increased the expression of luciferase and green fluorescence protein (GFP), the readouts of the Sox2 reporter. Upon hypoxic challenge, the bulk, reporter unresponsive (RU) cells acquired stem-like features, as evidenced by the significant increases in the proportion of CD44
Language	English
Publishing date	2018-09-25
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	2422345-1
ISSN	1875-2284 ; 1875-2292
ISSN (online)	1875-2284
ISSN	1875-2292
DOI	10.1007/s12307-018-0218-0
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Article ; Online: High expression of β-catenin contributes to the crizotinib resistant phenotype in the stem-like cell population in neuroblastoma.

Alshareef, Abdulraheem / Gupta, Nidhi / Zhang, Hai-Feng / Wu, Chengsheng / Haque, Moinul / Lai, Raymond

Scientific reports

2017 Volume 7, Issue 1, Page(s) 16863

Abstract: ALK has been identified as a novel therapeutic target in neuroblastoma (NB), but resistance to ALK inhibitors (such as crizotinib) is well recognized. We recently published that the crizotinib sensitivity in NB cells strongly correlates with the ... ...

Abstract	ALK has been identified as a novel therapeutic target in neuroblastoma (NB), but resistance to ALK inhibitors (such as crizotinib) is well recognized. We recently published that the crizotinib sensitivity in NB cells strongly correlates with the crizotinib-ALK binding, and β-catenin effectively hinders this interaction and confers crizotinib resistance. Here, we asked if these observations hold true for the stem-like cells in NB cells, which were purified based on their responsiveness to a Sox2 reporter. Compared to bulk, reporter unresponsive (RU) cells, reporter responsive (RR) cells had significantly higher neurosphere formation ability, expression of CD133/nestin and chemo-resistance. Using the cellular thermal shift assay, we found that RR cells exhibited significantly weaker crizotinib-ALK binding and higher crizotinib resistance than RU cells. The suboptimal crizotinib-ALK binding in RR cells can be attributed to their high β-catenin expression, since siRNA knockdown of β-catenin restored the crizotinib-ALK binding and lowered the crizotinib resistance to the level of RU cells. Enforced expression of β-catenin in RU cells resulted in the opposite effects. To conclude, high expression of β-catenin in the stem-like NB cells contributes to their crizotinib resistance. Combining β-catenin inhibitors and ALK inhibitors may be useful in treating NB patients.
MeSH term(s)	AC133 Antigen/metabolism ; Anaplastic Lymphoma Kinase/antagonists & inhibitors ; Anaplastic Lymphoma Kinase/metabolism ; Cell Line, Tumor ; Cell Survival/drug effects ; Crizotinib/pharmacology ; Drug Resistance, Neoplasm ; Gene Expression/drug effects ; Humans ; Neuroblastoma/metabolism ; Neuroblastoma/pathology ; Phenotype ; Protein Binding ; Protein Kinase Inhibitors/pharmacology ; RNA Interference ; RNA, Small Interfering/metabolism ; beta Catenin/antagonists & inhibitors ; beta Catenin/genetics ; beta Catenin/metabolism
Chemical Substances	AC133 Antigen ; Protein Kinase Inhibitors ; RNA, Small Interfering ; beta Catenin ; Crizotinib (53AH36668S) ; Anaplastic Lymphoma Kinase (EC 2.7.10.1)
Language	English
Publishing date	2017-12-04
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-017-17319-9
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