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Quinta-feira, 28.05.15



Clinical Trials: The NCCN recommends cancer patient participation in clinical trials as the gold standard for treatment.

Cancer therapy selection, dosing, administration, and the management of related adverse events can be a complex process that should be handled by an experienced healthcare team. Clinicians must choose and verify treatment options based on the individual patient; drug dose modifications and supportive care interventions should be administered accordingly. The cancer treatment regimens below may include both U.S. Food and Drug Administration-approved and unapproved indications/regimens. These regimens are only provided to supplement the latest treatment strategies.

These Guidelines are a work in progress that may be refined as often as new significant data becomes available. The NCCN Guidelines® are a consensus statement of its authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult any NCCN Guidelines® is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient's care or treatment. The National Comprehensive Cancer Network makes no warranties of any kind whatsoever regarding their content, use, or application and disclaims any responsibility for their application or use in any way.

General treatment notes:1

• Targeted therapy using tyrosine kinase inhibitors is now widely used as first- and second-line treatments in renal cell carcinoma (RCC). To date, seven such agents have been approved by the FDA for the treatment of advanced RCC: sunitinib, bevacizumab (+ interferon), pazopanib, temsirolimus, sorafenib, everolimus, and axitinib.

• Prior to targeted therapies, systemic treatment options were limited to cytokine therapy, notably interleukin-2 (IL-2) and interferon-α-2A (IFN-α-2a).

First-line Therapy for Patients with Predominantly Clear Cell Histology1

Note: All recommendations are Category 2A unless otherwise indicated.

(Revised 2/2015)

© 2015 Haymarket Media, Inc.



Sunitinib (Category 1)2,3

Sunitinib 50mg PO daily for 4 weeks, followed by 2 weeks off.

Temsirolimus (Category 1: poor-prognosis patients; Category 2B: selected patients of other risk groups)4,5

Temsirolimus 25mg IV over 30–60 minutes once weekly.

Bevacizumab + Interferon (Category 1)6-8

Bevacizumab 10mg/kg IV every 2 weeks + IFN-α-2a 9 million IU SQ three times a week.

Pazopanib(Category 1)9,10

Pazopanib 800mg PO once daily.

High-dose IL-211,12‡

IL-2 720,000 IU/kg IV every 8 hours (max 15 consecutive doses/cycle)


Days 1–5 and 15–19: IL-2 600,000 IU/kg IV every 8 hours (max 14 doses).

Repeat cycle every 4 weeks for max 3 cycles.


Axitinib 5mg PO every 12 hours.


Sorafenib 400mg PO twice daily.

Subsequent Therapy for Patients with Predominantly Clear Cell Carcinoma1

High-dose IL-211,12‡

IL-2 720,000 IU/kg IV every 8 hours (max 15 consecutive doses/cycle)


Days 1–5 and 15–19: IL-2 600,000 IU/kg IV every 8 hours (max 14 doses).

Repeat cycle every 4 weeks for max 3 cycles.

After Tyrosine Kinase Inhibitor Therapy

Everolimus (Category 1)16,17

Everolimus 10mg PO once daily.

Axitinib (Category 1)13,14*

Axitinib 5mg PO every 12 hours.


Sorafenib 400mg PO twice daily.


Sunitinib 50mg PO daily for 4 weeks, followed by 2 weeks off.


Pazopanib 800mg PO once daily.

Temsirolimus (Category 2B)24,25

Temsirolimus 25mg IV over 30-60 minutes weekly.

Bevacizumab (Category 2B)26

Bevacizumab 10mg/kg IV every 2 weeks.

After Cytokine Therapy

Axitinib (Category 1)13,14*

Axitinib 5mg PO every 12 hours.

Sorafenib (Category 1)18-21

Sorafenib 400mg PO twice daily.

Sunitinib (Category 1)2,22,23

Sunitinib 50mg PO daily for 4 weeks, followed by 2 weeks off.

Pazopanib (Category 1)9,10

Pazopanib 800mg PO once daily.


Temsirolimus 25mg IV over 30-60 minutes weekly.


Bevacizumab 10mg/kg IV every 2 weeks.

Systemic Therapy for Patients with Non-Clear Cell Histology

Temsirolimus (Category 1: poor-prognosis patients; Category 2A: selected patients of other risk groups)24,25

Temsirolimus 25mg IV over 30–60 minutes weekly.


Sorafenib 400mg PO twice daily.


Sunitinib 50mg PO daily for 4 weeks, followed by 2 weeks off.


Pazopanib 800mg PO once daily.


Axitinib 5mg PO every 12 hours.


Everolimus 10mg PO once daily.


Bevacizumab 10mg/kg IV every 2 weeks.


Erlotinib 150mg PO once daily.

* May increase to 7mg every 12 hours after 2 weeks based on criteria; may increase to 10mg every 12 hours after 2 weeks based on criteria.

† Patients who progressed were dose-escalated to 600 mg twice daily.

‡ Treatments divided into 60-day courses, with each IV treatment course consisting of 2 cycles of therapy, separated by approximately7–10 days of rest with no other therapy during the remainder of the 60 days.


1. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology™. Kidney. v 3.2015. Available at: kidney.pdf. Accessed February 4, 2015.

2. Sutent [package insert]. New York, NY: Pfizer Labs; 2014.

3. Gore ME, Szczylik C, Porta C, et al. Safety and efficacy of sunitinib for metastatic renal-cell carcinoma: an expanded-access trial.Lancet Oncol. 2009;10:757–763.

4. Torisel [package insert]. Philadelphia, PA: Wyeth; 2014.

5. Hudes G, Carducci M, Tomczak P, et al; Global ARCC Trial. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med. 2007;356:2271–2281.

6. Avastin [package insert]. San Francisco, CA: Genentech; 2014.

7. Escudier B, Pluzanska A, Koralewski P, et al; AVOREN Trial investigators. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet. 2007;370:2103–2111.

8. Rini BI, Halabi S, Rosenberg JE, et al. Phase III trial of bevacizumab plus interferon alfa versus interferon alfa monotherapy in patients with metastatic renal cell carcinoma: final results of CALGB 90206. J Clin Oncol. 2010;28:2137–2143.

9. Votrient [package insert]. Research Triangle Park, NC: GSK; 2014.

10. Sternberg CN, Davis ID, Mardiak J et al. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol. 2010;28:1061–1068.

11. Yang JC, Sherry RM, Steinberg SM, et al. Randomized study of high-dose and low-dose interleukin-2 in patients with metastatic renal cancer. J Clin Oncol. 2003;21:3127–3132.

12. McDermott DF, Regan MM, Clark JI, et al. Randomized phase III trial of high-dose interleukin-2 versus subcutaneous interleukin-and interferon in patients with metastatic renal cell carcinoma. J Clin Oncol. 2005;23:133–141.

13. Inlyta [package insert]. New York, NY: Pfizer Inc; 2014.

14. Rini BI, Escudier B, Tomczak P, et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomized phase 3 trial. Lancet. 2011;378:1931–1939.

15. Escudier B, Szczylik C, Hutson TE, et al. Randomized phase II trial of first-line treatment with sorafenib versus interferon Alfa-2a in patients with metastatic renal cell carcinoma. J Clin Oncol. 2009;27(8):1280–1289.

16. Afinitor [package insert]. East Hanover, NJ: Novartis; 2015.

17. Motzer RJ, Escudier B, Oudard S, et al; RECORD-1 Study Group. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet. 2008;372:449–456.

18. Nexavar [package insert]. Wayne, NJ: Bayer HealthCare; 2014.

19. Escudier B, Eisen T, Stadler WM, et al. Sorafenib in advanced clear cell renal-cell carcinoma. N Engl J Med. 2007;356(2): 125–134.

20. Di Lorenzo G, Carteni G, Autorino R, et al. Phase II study of sorafenib in patients with sunitinib-refractory metastatic renal cell cancer. J Clin Oncol. 2009;27(27):4469–4474.

21. Garcia JA, Hutson TE, Elson P, et al. Sorafenib in patients with metastatic renal cell carcinoma refractory to either sunitinib or bevacizumab. Cancer. 2010;116(23):5383–5390.

22. Motzer RJ, Michaelson MD, Redman BG, et al. Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J Clin Oncol. 2006;24(1):16–24.

23. Motzer RJ, Rini BI, Bukowski RM, et al. Sunitinib in patients with metastatic renal cell carcinoma. JAMA. 2006;295(21): 2516–2524.

24. Atkins MB, Hidalgo M, Stadler WM, et al. Randomized phase II study of multiple dose levels of CCI-779, a novel mammalian target of rapamycin kinase inhibitor, in patients with advanced refractory renal cell carcinoma. J Clin Oncol. 2004;22(5): 909–918.

25. Hutson TE, Escudier B, Esteban E, et al. Temsirolimus vs Sorafenib as Second Line Therapy in Metastatic Renal Cell Carcinoma: Results from the INTORSECT Trial [abstract]. Ann Oncol. 2012;23:Abstract: LBA22.

26. Yang JC, Haworth L, Sherry RM, et al. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody,for metastatic renal cancer. N Engl J Med. 2003; 349(5):427–434.

27. Gordon MS, Hussey M, Nagle RB, et al. Phase II study of erlotinib in patients with locally advanced or metastatic papillary histology renal cell cancer: SWOG S0317. J Clin Oncol. 2009;27:5788-5793.

Genitourinary Cancer Drug Monographs

Bladder, Kidney, And Other Urologic Cancers

Adriamycin Adriamycin Solution Afinitor
Avastin Cosmegen Nexavar
Proleukin Sutent Theracys
Tice BCG Torisel Valstar
Vincasar PFS Votrient  

Prostate And Other Male Cancers

Casodex Cosmegen Delestrogen
Eligard 22.5mg 3-Month Eligard 30mg 4-Month Eligard 45mg 6-Month
Eligard 7.5mg 1-Month Emcyt Estrace
Etopophos Firmagon Ifex
Ifex w. Mesnex Combination Pack Jevtana Lupron Depot 7.5mg
Lupron Depot-3 Month 22.5mg Lupron Depot-4 Month 30mg Lupron Depot-6 Month 45mg
Menest Nilandron Novantrone
Provenge Taxotere Toposar
Trelstar Vantas Vinblastine for injection
Vinblastine injection Zoladex Zoladex 3-Month 10.8mg

Data provided by the Monthly Prescribing Reference (MPR) Hematology/Oncology Edition.

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por cyto às 19:56

Quinta-feira, 28.05.15

Tumor suppressor turns activator

Tumor suppressor turns activator

A gene that inhibits tumor growth is shown to promote aggressive breast cancers

Published online 27 May 2015

Expression of the gene RASAL2 can be used as a biomarker to distinguish between breast cancer patients with low (top) and high (bottom) expression levels and guide subsequent treatment.

© 2015 A*STAR Genome Institute of Singapore

A*STAR researchers have shown that theRASAL2 gene, which is known to inhibit tumor growth in some breast cancers, actually advances tumor formation and metastasis in more aggressive forms of breast cancer and have suggested its use as a diagnostic marker1.

Breast cancer is often characterized by an overexpression of cell surface proteins that bind hormones and trigger the disruption of cell division and DNA repair. Typically, cancer treatments that inhibit the activity of hormone receptors have a high rate of success, except in the case of triple-negative breast cancer (TNBC), which accounts for approximately 15 per cent of all breast cancer cases. TNBC tumor cells lose the ability to express hormone receptors, making the cancer more difficult to treat.

Qiang Yu’s research at the A*STAR Genome Institute of Singapore focuses on finding the key molecules in a cancer cell’s network responsible for making tumor cells more aggressive. “Identifying biomarkers which can define high-risk TNBC patients is one of our main interests,” he says.

Leading a team of international scientists, Yu focused on the targets of small RNA molecules, or microRNAs, which often act as tumor suppressors and control the expression of genes that can promote cancer. If the levels of these microRNAs go down, the oncogenes’ levels come up and tumors form. The researchers found reduced levels of a microRNA in TNBC and determined that its target was a gene called RASAL2.

Higher RASAL2 expression in TNBC correlates with a more aggressive tumor, a finding that intrigued Yu since it could not be easily explained by the gene’s function. In tumors that express hormone receptors, the RASAL2 gene was shown to inhibit disease progression by inactivatingRas, one of the most common genes to contribute to human cancer.

Yu showed that the mechanism by which RASAL2 made TNBC cells more invasive does not require the inhibition of Ras. Instead RASAL2 binds a protein that inactivates Rac, another cancer-promoting protein, thus leading to higher Rac activity, which in turn makes tumor cells more prone to invading the surrounding tissue.

Yu does not see RASAL2 as a therapeutic target since its function might not be easily inhibited by a drug. “I think more likely RASAL2 can be pursued as a diagnostic marker for aggressive TNBC,” he says (see image).

Identifying the molecular signaling pathways in cancer cells and understanding how networks change and proteins take on opposite functions is critical for reliable diagnosis that will lead to effective therapy geared toward a patient’s particular type of cancer.


The A*STAR-affiliated researchers contributing to this research are from the Genome Institute of Singapore.


Related Links

Cancer biology: Understanding aggressive behavior

Cancer biology: The two faces of a cancer signal

Cancer biology: Aggravating tumor aggressiveness




  1. Feng, M., Bao, Y., Li, Z., Li, J., Gong, M. et al. RASAL2 activates RAC1 to promote triple-negative breast cancer progression. The Journal of Clinical Investigation 124, 5291–5304 (2014). | article

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por cyto às 19:54

Quinta-feira, 28.05.15

Link found in regulation of blood glucose


Link found in regulation of blood glucose

Insight into a molecular mechanism for regulating blood sugar could enhance our understanding of diabetes

Published online 27 May 2015

Insulin released into the blood when levels of glucose are high activates mechanisms to reduce glucose levels, including the transport of GLUT4 to the membranes of muscle and fat cells.

© Ugreen/iStock/Thinkstock

A key mechanism in the regulation of blood sugar levels has been identified in work led by A*STAR researchers1. The findings could help us understand the mechanisms of diabetes and might lead to new treatments.

Blood levels of the sugar glucose increase after a meal. In response, the body releases insulin, which activates mechanisms to return these levels to normal. One such mechanism involves transport of the protein GLUT4 to the membranes of muscle and fat cells, enabling the uptake of glucose from the blood into the cells.

“Defects in glucose uptake in response to insulin generally manifest as type 2 diabetes,” explains Han Weiping from the Laboratory of Metabolic Medicine at A*STAR Singapore Bioimaging Consortium who led the study. “Insulin-stimulated GLUT4 translocation is central to the maintenance of blood glucose levels. An understanding of the mechanisms that underlie this process will help us to work out what goes wrong in diabetes.”

Previous studies had identified two important elements involved in the transport of GLUT4: an insulin-activated kinase called Akt2 and rearrangement of the cell’s skeleton, which consists of fibers of the protein actin. Han, his graduate student Lim Chun-Yan and collaborators investigated the molecular pathway that connects these two elements.

They did this by screening proteins in fat cells to identify those involved in the delivery of GLUT4 to cell membranes. They identified one — tropomodulin3 (Tmod3) — that is also involved in the rearrangement of the cell’s actin skeleton. The researchers showed that Tmod3 is modified by insulin-activated Akt2 and that GLUT4 translocation and glucose uptake are impaired in cells with reduced Tmod3 levels.

By making cells with fluorescently labeled actin, the team also found that low expression of Tmod3 reduced the ability of a cell to rearrange its skeleton in response to insulin; the same effect was seen in cells that expressed a form of Tmod3 that cannot be modified by Akt2. The fluorescently labeled actin also revealed that modification of Tmod3 by Akt2 potentiates the insulin-induced actin reorganization.

“Our study highlights a direct link between Akt2 signaling and the actin skeleton that is essential for insulin-stimulated GLUT4 translocation,” says Han. “But the identification of Tmod3 might represent the tip of the iceberg of a vast signaling network involved in glucose uptake. A complete understanding of the mechanism of GLUT4 transport would help to pinpoint the key molecular nodes that underlie this process and to develop a therapeutic intervention to help clear glucose more efficiently from the body.”


The A*STAR-affiliated researchers contributing to this research are from the Singapore Bioimaging Consortium, the Bioprocessing Technology Institute and the Institute of Molecular and Cell Biology.


Related Links

Molecular biology: Taking full control of diabetes

Metabolism: Striking a balance

Cell biology: Cellular damage control’s link with diabetes




  1. Lim, C.-Y., Bi, X., Wu, D., Kim, J. B., Gunning, P. W. et al. Tropomodulin3 is a novel Akt2 effector regulating insulin-stimulated GLUT4 exocytosis through cortical actin remodeling.Nature Communications 6, 5951 (2015). | article

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por cyto às 19:52

Segunda-feira, 25.05.15

Protein With Therapeutic Potential for Brain Cancer

MD Anderson Researchers Identify Protein With Therapeutic Potential for Brain Cancer

In a recent study entitled “FGL2 as a Multimodality Regulator of Tumor-Mediated Immune Suppression and Therapeutic Target in Gliomas,” researchers at The University of Texas MD Anderson Cancer Center showed that FGL2 protein is a crucial immune-suppressive factor in glioblastoma multiforme (GBM) cancer. As such, blocking FGL2 may promote GBM patients’ enhanced survival. The study was published in the Journal of the National Cancer Institute.

In this study, a research team at The University of Texas MD Anderson Cancer Center showed that FGL2 (short forFibrinogen-like protein 2), commonly expressed in cancers, acts as an immune-suppressor in glioblastoma multiforme (GBM), allowing the tumor to grow by suppressing tumor-targeted immune responses. FGL2 acts by enhancing the expression of genes encoding for immune checkpoints, i.e., a collection of factors that are key for maintaining body self-tolerance by controlling the duration and amplitude of the immune responses.

The team used mouse models but also human tumor samples and The Cancer Genome Atlas (TCGA) glioma database, a comprehensively project launched in 2006 with the objective to characterize the genomic and molecular characteristics of both ovarian cancer and glioblastoma multiforme.

The authors found that patients with high levels of FGL2 expression in glioma tissues exhibited lower overall survival. To evaluate the functional relevance of blocking FGL2 expression, authors treated mouse models for glioblastoma with an anti-FGL2 antibody. They observed mice median survival increased; specifically mice lived 27 days more when compared to 17 days of the control antibody. 


The team highlights that because FGL2 functions as a key immune-suppressive modulator developing future immunotherapeutics against FGL2 may promote patients’ survival.

Shulin Li, Ph.D., professor of Pediatrics and study lead author commented, “It is well known that cancer evades immune surveillance by exploiting a series of editing mechanisms to avoid immune detection and eradication. One such mechanism is to hijack an immune cell’s checkpoints, subverting the immune system and allowing tumor growth.”

Amy Heimberger, M.D., professor of Neurosurgery and also an author added, “The average survival time in mice treated with the antibody was significantly longer than those receiving an alternative control antibody. Interestingly, four of 17 mice treated with FGL2 antibody were completely tumor free.”

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por cyto às 18:24

Segunda-feira, 25.05.15

CD151—A Striking Marker for Cancer Therapy

CD151—A Striking Marker for Cancer Therapy


Studies have shown cluster of differentiation 151 (CD151), a member of the mammalian tetraspanin family, is involved in various cellular functions such as angiogenesis, cell motility, cell-to-cell communication, maintaining normal cellular integrity, platelet aggregation, trafficking, and wound healing; however, overexpression of CD151 contributes to the invasion and metastasis of cancer cells through its interaction with α3β1 and α6β4 integrins via palmitoylation.

Of note, CD151 has been found to be highly expressed in tumors, such as breast, colon, and lung cancers, compared with non-solid tumors like Burkitt lymphoma, and high CD151 gene expression in cancer has been associated with poor prognosis, particularly in colon, endometrial, esophageal, lung, and pancreatic cancers.

The role of CD151 in cancer cell migration, invasion, and metastasis suggests that CD151 is an important target for cancer therapy.

Inhibiting CD151 may alter the signaling pathway involved in cancer cell survival and progression, thereby potentially halting tumor growth.

Possible strategies to target CD151 may include treatment with monoclonal antibodies, small hairpin RNA molecules, or gene knockout, and a better understanding of how palmitoylation affects the association of CD151 with integrins and non-integrin proteins may lead to new developments in cancer research.



Cluster of differentiation 151 (CD151) is a member of the mammalian tetraspanin family, which is involved in diverse functions such as maintaining normal cellular integrity, cell-to-cell communication, wound healing, platelet aggregation, trafficking, cell motility and angiogenesis. CD151 also supports de novo carcinogenesis in human skin squamous cell carcinoma (SCC) and tumor metastasis.

CD151 interacts with α3β1 and α6β4 integrins through palmitoylation where cysteine plays an important role in the association of CD151 with integrins and non-integrin proteins.

Invasion and metastasis of cancer cells were diminished by decreasing CD151 association with integrins. CD151 functions at various stages of cancer, including metastatic cascade and primary tumor growth, thus reinforcing the importance of CD151 as a target in oncology.

The present review highlights the role of CD151 in tumor metastasis and its importance in cancer therapy.


Insight on CD151 (Cluster of Differentiation 151)

Tetraspanins are four-transmembrane-spanning proteins with short cytoplasmic N- and C-termini and one small and one large extracellular domain, namely (EC1 and EC2), with a unique cysteine motif in EC2 domain.1

They are highly expressed on cell surface and/or intracellular vesicle. Palmitoylation of intracellular and juxtamembrane cysteine of tetraspanins along with specific integrins contributes to tetraspanin complex formation.

This complex formation protects tetraspanins from lysosomal degradation and promotes increased cell–cell interaction.2

CD151 (glycoprotein-27 (GP-27)/Red blood cell antigen MER 2 (MER 2)/platelet-endothelial tetraspan antigen-3 (PETA-3)/Raph blood group antigen (RAPH)/Membrane Glycoprotein SFA-1 (SFA-1)./tetraspanin-24 (TSPAN-24)) is a plasma membrane protein that belongs to tetraspanin superfamily.

CD151 forms tetraspanin web with integrins such as α3β1, α6β1, α7β1, and α6β4;2 membrane receptors; intracellular signaling molecules such as phosphoinositide 4-kinase (PI4K) and protein kinase C (PKC);3,4 immunoglobulin super family proteins and other tetraspanins such as CD9, CD81 and CD63. These tetraspanin-enriched microdomains (TEMs) serve as molecular facilitator.5

CD151 contains a potential tyrosine-based sorting motif in the C-terminal domain. The YXXφ (tyrosine linked with hydrophobic amino acid) motif (where φ is a hydrophobic residue) is required for endocytosis and sorting of proteins from the trans-Golgi network (TGN) to lysosomes for degradation. A mutation in the CD151 YXXφ motif diminishes CD151 internalization and affects integrin-dependent cell migration.6,7

The major functions of CD151 are maintenance of epithelial cell integrity, wound healing, platelet aggregation, regulation of membrane fusion, trafficking, cell motility, angiogenesis and tumor metastasis.8

It is normally expressed in endothelial cells and platelets and frequently overexpressed in cancer cells where it is functionally associated with cancer progression and metastasis.9


Genetics of CD151

CD151 (Raph blood group) gene is represented as CD151, which is located on the short (p) arm of chromosome 11 at position 15.5. More precisely, CD151 gene is located from base pair 832, 951 to base pair 838, 834 on chromosome 11.10

It is an autosomal gene with sexually dimorphic expression, involved in signal transduction, cell proliferation and death. It is also involved in differential neural development, cognitive function and neurological diseases.11

Association of CD151 with Integrins and Other Proteins

Metastasis is facilitated by cell–cell interactions between tumor cells and endothelium in which cell-adhesion molecules, such as integrins and selectins, play an important role.

Hemler12 has demonstrated that CD151 interacts directly with α3β1 and α6β4 integrins through their palmitoylated cysteine residues. CD151 acts as master regulators of α6β4, α6β1 and α3β1 integrin-assembly into TEMs.13

The major laminin-332 cellular receptors with α3β1 and α6β4 integrins-dependent adhesion, migration and signaling are impaired or altered by CD151 excision, indicating the vital role of CD151 in association with integrins.14,15

Mapping of the integrin-CD151 association was performed using chimeric α6/α3 integrins and CD151/NAG2 TM4SF proteins, which showed an interaction of amino acids from 570 to 705 at the extracellular sites of α3 integrin and amino acids from 186 to 217 on a large extracellular loop of CD151.16

Devbhandari et al17 reviewed the role of CD151/integrin β1 complex in cancer metastasis. Yauch et al3 reported that specific site on the large extracellular loop of CD151 associates with α3β1 integrin with unusually high stoichiometry, proximity and stability.

In the same year, Sterk et al18 reported that CD151 uses the same site for interaction with α6β1, α6β4 and other integrins.

Role of CD151 in De Novo Carcinogenesis

CD151, in association with laminin and laminin-binding integrins, involves in the regulation of carcinogenesis. Li et al19 evaluated the role of CD151 in de novo carcinogenesis, multiplicity and progression of skin squamous cell carcinoma (SCC) in comparison with normal cells.

CD151 supports survival and proliferation of keratinocytes by activation of transcription factor STAT3, a regulator of cell proliferation and apoptosis. CD151 regulates α6β4 distribution by enhancing protein kinase Cα (PKCα)—α6β4 integrin association and PKC-dependent β4 S1424 phosphorylation. CD151 in complex with PKCα enhances invasive behavior by phoshorylating β4 integrin, thus affects subcellular localization and epithelial disruption.

In addition, CD151 knockout mice showed a decrease in tumor latency, tumor incidence, multiplicity and size. Hence, CD151 targeting may be therapeutically beneficial in cancer therapy.


CD151 and Cancer Metastasis

Deregulation of various tetraspanins is reported in human malignancy.20Overexpression of CD151 was also reported to associate with poor prognosis of lung,21 colon,22 esophageal,23pancreatic24 and endometrial cancers.25

In addition, several evidences have supported the contribution of CD151 in cancer metastasis.26 Loss of CD151 decreased the integrin-mediated cell migration, spreading, and invasion through FAK and Rac1-mediated signaling.13

Earlier reports have shown that down-regulation of CD151 by short-hairpin RNA decreased the tumorigenicity and communication between tumor and endothelial cells. This emphasizes CD151 as a potential prognostic marker.27

CD151 also modulates the activity of cytokine-like transforming growth factor-β (TGF-β). CD151 in association with dimerized TGF-β receptor promotes invasion and metastasis through the activation of Smad2/3, c-Akt, Erk1/2, JNK, JUN and matrix metalloproteinase-9 (MMP-9) signaling pathways (Figure 1). Sadej et al reported that CD151 is a positive regulator of TGF-β-induced signaling in cancer metastasis.28


Studies on CD151-null mice showed impaired pathological angiogenesis without vascular defect during normal development.29

Adhesion-dependent activation of endothelial cells caused diminished expressions of PKC/c-Akt, e-NO, Rac and Cdc42, which are important signaling pathways of angiogenesis and cytoskeleton reorganization without altering the expression of Raf, ERK, p38, MAP kinase, FAK and Src.

CD151 regulates cytoskeletal reorganization, invasion and cell-adhesion functions of endothelial cells during pathological angiogenesis by modulating laminin-binding integrins-mediated activation of PI3K/Akt, JNK and PKC pathways29 (Figure 2).

Evaluation of prognostic significance of CD151 expression with estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor-2 “(HER-2) and E-cadherin indicated a strong concordance of CD151 with E-cadherin in type 2 endometrial cancer. Kohno et al demonstrated that CD151 also enhanced cell motility, invasion and metastasis through focal adhesion kinase (FAK).30


Haeuw et al31 reported that monoclonal antibodies (mAbs) targeted to CD151 inhibited cell motility. Similarly, Fei et al32 reported that CD151-AAA mutant inhibited cell-proliferation, migration and chemotaxis in HepG2 cells. 

Genetic ablation of CD151 inhibited metastasis in a transgenic mouse model without showing any noticeable effect on expression of markers associated with proliferation, apoptosis or angiogenesis in primary tumors.33

Shanmukhappa et al have demonstrated for the first time that CD151siRNA and anti-CD151 antibodies significantly reduced the porcine reproductive and respiratory syndrome virus (PRRSV) infection.34

One recent study showed that simultaneous inhibition of CD9/CD81 and CD151 has a profound inhibitory effect on cancer metastasis through α3β1-PKCα-mediated signaling in MDA-MB 231 breast cancer cells.35

Several studies have demonstrated that CD151 is involved in cell-adhesion and formation of hemidesmosomes; thus, inhibition of CD151 expression by hypoxia decreased the cell–cell interaction and cell–matrix adhesion.36

A study by RR Malla et al have demonstrated that silencing of cathepsin B and uPAR using siRNA decreased the interactions of CD151 with laminin-binding integrin α3β1 and inhibits cell-adhesion and invasion in glioma.37

CD151 Pathogenesis and Clinical Studies

CD151 is implicated in pathological processes associated with cancer progression, neoangiogenesis and epithelial-mesenchymal transition (EMT).38–41 CD151 overexpressing cancer cells acquired high migratory abilities, which are crucial for tumor cell invasion.42

Overexpression of CD151 was also reported to associate with intercellular adhesiveness and wound healing.43 CD151 plays a crucial role in the interaction of podocyte-GBM binding adhesion receptor and integrin α3β1. Deletion of CD151 leads to reduced adhesiveness at cell–matrix interface, leading to glomerular nephropathy.44

CD151-null mice showed diminished tumor cell residence in the lungs after injection with Lewis lung carcinoma, which may be because of inhibition of angiogenesis.45

In vitro studies showed that tumor-endothelial adhesion, tumor-transendothelial migration and tumor –induced permeability were defective in CD151-null endothelial cells.46

Blocking of CD151 using specific mAbs inhibited invasion without affecting primary tumor growth and tumor cell arrest or growth at the secondary site.26 Knockdown of CD151 inhibited downstream signaling through Akt, ErK1/2 and FAK and markedly sensitizes ErbB2+ cancers.47

Kwon et al reported that overexpression of CD151 may be a potential molecular therapeutic target in advanced stages of breast cancer.48 Recent clinical studies have demonstrated that a positive correlation exists between CD151 expression and progression of cancer cells.33

An interesting fact has been reported recently that integrin-free CD151 can promote tumor cell migration without binding to integrin. This study suggests that CD151 can control migration, independent of integrin association.49

Expression Levels of CD151

Comparative analysis of tetraspanin expression in various types of cancers revealed that CD151 is highly expressed in solid tumor compared with non-solid tumor (Table 1). CD151 is usually localized to the basal and lateral junctions of tumor cells.50

Solid tumors exhibit heterogeneity of neoplastic and normal cells at histological, genetic and gene expression levels. Considerable heterogeneity of CD151 expression was reported in various tumor tissues. The intensity of staining was noticeably weaker in well-differentiated cells of oral SCC.

The gradient of CD151 expression was particularly prominent in the invasive front of tumors.51Overexpression of CD151 can be correlated with large tumor size, depth of invasion and advanced stage of tumor.52

A number of investigations have suggested that high CD151 gene expression in cancer is associated with poor prognosis.53 Tokuhara et al have reported that survival rate of patients with CD151-positive tumors was much lower than that of CD151-negative patients.21

For optimal separation between low and high risk for overall survival, prognostic factors are usually considered as an optimized cutoff point.53 The cutoff point of CD151 in ER negative breast cancer patients was reported as 14%48 and 31%,13 in lung cancer patients as 50%,21 and in gastric cancer patients as >50%,52 using immunohistochemical and RT-PCR analysis.

These studies show the cutoff values to identify CD151 positivity, which may vary based on cancer type. However, large-scale prospective and retrospective studies on various cancers established CD151 as a prognostic marker for cancer therapy with minimal side effects on normal cells.13

Table 1. Expression of tetraspanins in different cancers

Type of Cancer CD9 CD63 CD81 CD82 CD151 Reference
Breast cancer ++ + +++ + +++ Penas et al, 200054
Lung cancer +++ ++ ++ +++ +++ Funakoshi et al, 200355
Colon cancer +++ + +++ ++ +++ Le Naour et al, 200656
Burkitt lymphoma + +++ + + + Ferrer et al, 199857
Notes: Expression levels of tetraspanin proteins (CD9, CD63, CD81, CD82, and CD151) involved in cancer progression in different cancer cells. +, low; ++, medium; +++, high.

Future Prospects

This review explores the importance of CD151 in the maintenance of cellular integrity and cell communication. It also imparts the role of CD151 in cancer cell migration, invasion, and metastasis. Thus, CD151 is a crucial target for cancer therapy.

Disruption of tetraspanin web by targeting CD151 may affect the signaling pathways involved in cell survival and cancer progression. CD151 can be downregulated using mAbs, shRNA or gene knockout, which may find application in cancer therapy. Understanding the mechanism of palmitoylation of CD151 may give a wide scope for cancer research.

Studying the role of CD151 in molecular mechanisms associated with self-renewal, differentiation, DNA damage response, epigenetic mechanisms and anchorage-dependent and -independent tumor cell survival using gene silencing methods may provide an ample scope for future cancer research.


CD151 cluster of differentiation 151
GP-27 glycoprotein-27
PETA-3 platelet-endothelial tetraspan antigen-3
TSPAN-24 tetraspanin-24
TEM tetraspanin-enriched microdomains
ECM extracellular membrane
MMP matrix metalloproteinase


ACADEMIC EDITOR: Barbara Guinn, Editor in Chief

FUNDING: This review was supported by the Department of Science and Technology, Ministry of Science and Technology, India, and by GITAM University. The authors confirm that the funder had no influence over the study design, content of the article, or selection of this journal.

COMPETING INTERESTS: Authors disclose no potential conflicts of interest.

Paper subject to independent expert blind peer review by minimum of two reviewers. All editorial decisions made by independent academic editor. Upon submission manuscript was subject to anti-plagiarism scanning.

Prior to publication all authors have given signed confirmation of agreement to article publication and compliance with all applicable ethical and legal requirements, including the accuracy of author and contributor information, disclosure of competing interests and funding sources, compliance with ethical requirements relating to human and animal study participants, and compliance with any copyright requirements of third parties. This journal is a member of the Committee on Publication Ethics (COPE).

Author Contributions

Conceived and designed the experiments: RM. Analyzed the data: SK. Wrote the first draft of the manuscript: GV. Contributed to the writing of the manuscript: AB.

Agree with the manuscript results and conclusions: SK. Jointly developed the structure and arguments for the paper: RM. Made critical revisions and approved final version: RM and VRD.

All authors reviewed and approved of the manuscript.


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Source: Biomarkers In Cancer


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por cyto às 18:02

Sexta-feira, 22.05.15

Possible treatment identified for lethal pediatric brain cancer

Possible treatment identified for lethal pediatric brain cancer

Gene-regulating drugs may be effective at treating diffuse intrinsic pontine gliomas.
Gene-regulating drugs may be effective at treating diffuse intrinsic pontine gliomas.

The drug panobinostat and similar gene-regulating drugs may be effective at treating diffuse intrinsic pontine gliomas (DIPG), an aggressive and lethal form of pediatric cancer. These findings, from brain tumor samples collected from children in the United States and Europe, were published in Nature Medicine (2015; doi:10.1038/nm.3855).

"Our results provide a glimmer of hope for treating this heartbreaking disease," said Michelle Monje, MD, PhD, assistant professor of neurology and neurological sciences, Stanford University School of Medicine, California, a senior author of the study and a specialist in DIPG. "Caring for DIPG patients drives me to find new ways to treat them."

DIPG typically attacks children 4 to 9 years of age. Children progressively lose muscle control as the tumor rapidly attacks the pons, a region deep inside the brain that connects the brain to the spinal cord, and is difficult to reach and surgically remove. Despite radiation treatment, children usually survive for about 9 months, and less than 1% survive longer than 5 years.

Six years ago, Monje started to create and share cell cultures of patients' DIPG cells that could be studied in laboratories. In this study, she and her colleagues used cell cultures collected from 16 patients in the United States and Europe to search for drugs that could kill or stop the growth of DIPG cells. By performing experiments in petri dishes and with mice, they found that panobinostat, a drug designed to change the way cells regulate genes, may be effective at inhibiting DIPG growth and extending survival rates.

"It's astounding. In only 6 years, scientists have gone from knowing virtually nothing about this tumor to understanding its underlying genetics and finding a potential therapy," said Jane Fountain, PhD, program director, at the National Institute of Neurological Disorders and Stroke (NINDS), part of the National Institutes of Health. "This study epitomizes collaborative medicine at work. It took a dedicated team of international scientists working with patients, families, and foundations to get to this point."

"All roads lead to histones," said Monje. "Our results support the idea that histone modifications are the keys to understanding and treating DIPG."

The scientists showed that panobinostat may be effective at treating a variety of DIPG tumors. Approximately 80% of DIPG tumors have a specific mutation, H3K27M, in a histone gene. Panobinostat slowed the growth of a line of cells that had the mutation and also slowed the growth of DIPG cells that do not have that mutation.

Finally the scientists showed that panobinostat may work in combination with other treatments. Studying H3K27M cells that developed resistance to panobinostat over time, they showed that GSKJ4, a drug that blocks the removal of methyl groups from histones, slowed tumor growth. Combining panobinostat and GSKJ4 appeared to slow growth further, suggesting the two compounds work synergistically.

"This may be a first step to finally improving the prognosis of this seemingly untreatable disease," said Monje.

The study was partially funded by the National Institutes of Health, the Department of Defense, and more than 25 nonprofit foundations devoted to finding cures for childhood brain cancer.

Video resource

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por cyto às 20:06

Sexta-feira, 22.05.15

Uncovering Mechanisms of Replication in Human Papillomavirus

Uncovering Mechanisms of Replication in Human Papillomavirus

ImageJ=1.47i unit=inch

Scientists used immunofluorescence to show active proteins (green and red dots) in differentiated HPV-positive cells.

Northwestern Medicine scientists have identified proteins that mediate aspects of virus replication in the lifecycle of human papillomavirus (HPV), a finding that may lead to new therapeutic targets for treatment of infections caused by the virus.

“What we show, for the first time, are the proteins that hold chromatin together during mitosis, or cell replication, are the same proteins that play an important role in the DNA damage response in these viral infections,” said Laimonis Laimins, PhD, chair of Microbiology-Immunology.

The study, recently published in PLOS Pathogens, describes two cell proteins as critical regulators of viral replication; SMC1, a protein that bridges DNA together when cells divide, and CTCF, a protein that binds together strands of DNA to form loops that can either repress or enhance gene expression.

When the scientists reduce the genetic expression of these proteins, they found HPV was unable to replicate. They also confirmed that CTCF and SMC1 binding was critical to genome amplification, through mutating CTCF sites on the HPV genome. Reduction in the expression of CTCF resulted in the loss of the ability for SMC1 to interact with the HPV genome.

“This research is interesting because it show the ways in which the virus may interact with our own DNA,” said Kavi Mehta, first author of the paper and a third-year graduate student in the Walter S. and Lucienne Driskill Graduate Program in Life Sciences. “The importance of this research is understanding the life cycle of this virus. Now that we have a little bit of a greater understanding of how the virus maintains itself through the cell lifecycle, we might be able to find ways to prevent or understand how the virus evades the immune system.”

Next, Mehta plans to investigate how HPV uses these proteins to bring in other factors that allow the virus to replicate.

“These are small steps to figuring out this entire virus life cycle that is important for HPV biology,” Mehta said. “Once we know more about that, then this knowledge could be used as a base for developing therapeutics.”

The research was funded by National Cancer Institute grants CA59655 and CA142861, and the Cellular and Molecular Basis of Disease Training Grant T32 NIH T32 GM08061

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por cyto às 20:02

Sexta-feira, 22.05.15

Telomere Changes Predict Cancer



Change in telomeres may forecast cancer risk

Signal on Telomeres May Point to Cancer Risk Earlier
Signal on Telomeres May Point to Cancer Risk Earlier

(HealthDay News) -- For the first time, researchers have identified a pattern of change in DNA that may signal the development of cancer long before a standard diagnosis can be made. The study findings were published in EBioMedicine.

The current study revealed that telomeres start to age at a faster pace than normal in people who eventually develop cancer. The study authors said that telomeres belonging to future cancer patients may shorten in length to such a degree that they resemble telomeres belonging to people 15 years older. "Understanding this pattern of telomere growth may mean it can be a predictive biomarker for cancer," lead author Lifang Hou, M.D., Ph.D., a professor of preventive medicine at the Northwestern University Feinberg School of Medicine in Chicago, said in a university news release.

In all, the study team spent 13 years tracking telomere measurements among 792 people. Eventually, 135 were diagnosed with a variety of different cancers. Investigators found that while telomeres notably shortened well in advance of a cancer diagnosis, that shortening process actually came to a stop roughly three to four years before the cancer diagnosis.

Exactly why remains unclear. But the team suggested that the point at which shrinkage halts may coincide with the point at which a patient's as yet-undiagnosed cancer cells start to take control. "We saw the inflection point at which rapid telomere shortening stabilizes," Hou explained. "We found cancer has hijacked the telomere shortening in order to flourish in the body."


Telomere Changes Predict Cancer


Lifang Hou, MD, PhD, associate professor in Preventive Medicine-Cancer Epidemiology and Prevention, was the lead author of the study that showed how changes in telomere length may predict future cancers.

A distinct pattern in the changing length of blood telomeres, the protective end caps on our DNA strands, can predict cancer many years before actual diagnosis, according to a new study from Northwestern Medicine in collaboration with Harvard University.

The pattern – a rapid shortening followed by a stabilization three or four years before cancer is diagnosed – could ultimately yield a new biomarker to predict cancer development with a blood test. This is the first reported trajectory of telomere changes over the years in people developing cancer.

Scientists have been trying to understand how blood cell telomeres, considered a marker of biological age, are affected in people who are developing cancer. But the results have been inconsistent: some studies find they are shorter, some longer and some show no correlation at all.

The paper was published April 30 in EBioMedicine, a new a new journal from Elsevier in collaboration with The Lancet and Cell Press.

The Northwestern and Harvard study shows why previous results were confusing.

In the new study, scientists took multiple measurements of telomeres over a 13-year period in 792 persons, 135 of whom were eventually diagnosed with different types of cancer, including prostate, skin, lung, leukemia and others.

Initially, scientists discovered telomeres aged much faster (indicated by a more rapid loss of length) in individuals who were developing but not yet diagnosed with cancer. Telomeres in persons developing cancer looked as much as 15 years chronologically older than those of people who were not developing the disease.

But then scientists found the accelerated aging process stopped three to four years before the cancer diagnosis.

“Understanding this pattern of telomere growth may mean it can be a predictive biomarker for cancer,” said Lifang Hou, MD, PhD, the lead study author and associate professor in Preventive Medicine-Cancer Epidemiology and Prevention. “Because we saw a strong relationship in the pattern across a wide variety of cancers, with the right testing these procedures could be used to eventually diagnose a wide variety of cancers.” Hou also is a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.

The Northwestern and Harvard study is believed to be the first to look at telomere length at more than one time point before diagnosis. That’s significant because cancer treatment can shorten telomeres. Post treatment, it’s uncertain whether their length has been affected by the cancer or the treatment.

“This likely explains why the previous studies have been so inconsistent,” Dr. Hou said. “We saw the inflection point at which rapid telomere shortening stabilizes. We found cancer has hijacked the telomere shortening in order to flourish in the body.”

Telomeres shorten every time a cell divides. The older you are, the more times each cell in your body has divided and the shorter your telomeres. Because cancer cells divide and grow rapidly, scientists would expect the cell would get so short it would self-destruct. But that’s not what happens, scientists discovered. Somehow, cancer finds a way to halt that process.

If scientists can identify how cancer hijacks the cell, Dr. Hou said, perhaps treatments could be developed to cause cancer cells to self-destruct without harming healthy cells.

Other authors include Frank Penedo, Roswell Park Professor in in Medical Social Sciences and Psychiatry and Behavioral Sciences; Lei Liu, PhD, associate professor in Preventive Medicine-Biostatistics; Wei Zhang, PhD, associate professor in Preventive Medicine; Brian Thomas Joyce; Tao Gao; Yinan Zheng; and Siran Liu. Andrea Baccarelli, of the Harvard School of Public Health, is the senior author.

The research was supported by grants R01ES021733 and R01ES015172 from the National Institute of Environmental Health Sciences of the National Institutes of Health.

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por cyto às 19:55

Sexta-feira, 22.05.15

Brain Institute to Open at UT Southwestern

Peter O’Donnell Jr. Brain Institute to Open at UT Southwestern

The creation of the new Peter O’Donnell Jr. Brain Institute at the recognized University of Texas (UT) Southwestern Medical Center, has been approved by the University of Texas System Board of Regents, as announced in a press release. The new institute will be created thanks to a $36 million gift granted by the O’Donnell Foundation.

Focused on neuroscience, the new institute is designed to work as a comprehensive center, while it is expected to improve knowledge about the basic molecular function of the brain, as well as translate these findings into new methods to prevent and treat brain injuries or conditions. UT Southwestern is also committed to recruiting world leaders in the field to join the institute.

A team led by the recently hired professor of Neurology and Neurotherapeutics, Marc Diamond is already working to advance basic understanding of debilitating brain conditions. In addition, the university is planning to search for new investors to support advance technology and multidisciplinary clinical programs.“The Institute will serve as the umbrella to bring together the Medical Center’s historic advances in basic research and therapeutic care,” stated UT Southwestern’s president, Daniel K. Podolsky.

“UT Southwestern draws exceptionally talented investigators to a highly collaborative, technically sophisticated environment. These investigators have consistently made groundbreaking discoveries in medicine, and now, thanks to the incredible generosity of the O’Donnell Foundation, they will be positioned to make even more dramatic advances throughout the entire realm of neuroscience,” added Podolsky, who is also the Philip O’Bryan Montgomery, Jr., M.D. Distinguished Presidential Chair in Academic Administration, as well as Doris and Bryan Wildenthal Distinguished Chair in Medical Science.

UT Southwestern, which is already an established center in the field of neuroscience, expects the new Peter O’Donnell Jr. Brain Institute to enhance their capacities in basic and translation research, as well as in clinical care. The funding granted by the foundation is based on Peter and Edith O’Donnell’s belief in the center’s talent and its ability to build a unique and expert medical school in the region.

“UT Southwestern’s enormous talent in neuroscience and neurotechnology provides an important opportunity to invest in this critical field,” said Peter O’Donnell Jr. “The medical school consistently tackles some of the most difficult scientific challenges with enormous success, benefitting patients today and patients for generations to come. I have every confidence that the field of neuroscience will make great strides at UT Southwestern. I look forward to seeing the next discoveries that are made, and meeting the next extraordinary scientists and researchers who will be recruited to the Brain Institute.”

The O’Donnell Foundation has been supporting UT Southwestern, among other elite facilities in the country, to support promising research. Among the funded research projects is included work being developed by six Nobel Laureates and numerous members of the National Academy of Sciences and the Institute of Medicine at the medical school.


“The support of the O’Donnell Foundation recognizes that one of the greatest challenges of our time is brain injury in its various forms. The gift enables UT Southwestern to accelerate progress in injury prevention, novel brain preservation strategies, and restoring brain function lost by injury and disease,” stated Podolsky.

In addition, the UT Southwestern Medical Center recently announced the inauguration of another new facility, the Harold C. Simmons Comprehensive Cancer Center, focused on providing the most advanced clinical care and research progress for cancer patients in Tarrant and ten other local counties. The new Moncrief Cancer Institute in Fort Worth integrates the UT institution, which is the only cancer center in the region and is among the only 68 in the country designated by theNational Cancer Institute.

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por cyto às 19:54

Quinta-feira, 21.05.15

Accelerated brain aging related to cognitive complications observed in people with type 1 diabetes

Accelerated brain aging related to cognitive complications observed in people with type 1 diabetes

Published on May 5, 2015 at 10:07 AM 

The brains of people with type 1 diabetes show signs of accelerated aging that correlate with slower information processing, according to research led by the University of Pittsburgh Graduate School of Public Health.

The findings indicate that clinicians should consider screening middle-aged patients with type 1 diabetes for cognitive difficulties. If progressive, these changes could influence their ability to manage their diabetes. The study, funded by the National Institutes of Health (NIH), is online and will be published in the May 19 issue of the journal Neurology.

"The severity of cognitive complications and cerebral small vessel disease -- which can starve the brain of oxygen -- is much more intense than we expected, but it can be measured in a clinical setting," said senior author Caterina Rosano, M.D., M.P.H., associate professor in Pitt Public Health's Department of Epidemiology. "Further study in younger patients is needed, but it stands to reason that early detection and intervention -- such as controlling cardiometabolic factors and tighter glycemic control, which help prevent microvascular complications -- also could reduce or delay these cognitive complications."

Type 1 diabetes usually is diagnosed in children and young adults and happens when the body does not produce insulin, a hormone that is needed to convert sugar into energy.

Dr. Rosano and her co-authors examined brain MRIs, cognitive assessments, physical exams and medical histories on 97 people with type 1 diabetes and 81 of their non-diabetic peers.

The people with type 1 diabetes were all participants in the Pittsburgh Epidemiology of Diabetes Complications Study, an ongoing investigation led by Pitt Public Health epidemiologist and study co-author Trevor Orchard, M.D., to document long-term complications of type 1 diabetes among patients diagnosed at Children's Hospital of Pittsburgh of UPMC between 1950 and 1980.

The MRIs showed that 33 percent of the people with type 1 diabetes had moderate to severe levels of white matter hyperintensities (markers of damage to the brain's white matter, present in normal aging and neurological disorders) compared with 7 percent of their non-diabetic counterparts.

On three cognitive tests that measure abilities such as information-processing speed, manual dexterity and verbal intelligence, the people with type 1 diabetes averaged lower scores than those without the condition.

Among only the participants with type 1 diabetes, those with greater volumes of white matter hyperintensities averaged lower cognitive scores than those with smaller volumes, though the difference was less pronounced.

The associations held even when the researchers adjusted for high blood pressure and glucose control, which are conditions that can worsen diabetes complications.

The study identified signs of nerve damage, such as numbness or tingling in extremities, as a risk factor for greater volumes of white matter hyperintensities.

"People with type 1 diabetes are living longer than ever before, and the incidence of type 1 diabetes is increasing annually," said lead author Karen A. Nunley, Ph.D., postdoctoral fellow in Pitt Public Health's neuroepidemiology program. "We must learn more about the impact of this disease as patients age. Long-term studies are needed to better detect potential issues and determine what interventions may reduce or prevent accelerated brain aging and cognitive decline."


University of Pittsburgh Schools of the Health Sciences

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Maio 2015