New Focus for Inflammatory Skin Disease and Psoriasis: Topical Glucose Transport Inhibitors

MedicalResearch.com Interview with:

Richard Wang, M.D., Ph.D.  Assistant Professor Dermatology UT Southwestern Medical Center 

Richard Wang, M.D., Ph.D. 
Assistant Professor Dermatology
UT Southwestern Medical Center 

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Targeting cellular metabolism is currently being explored as a new way to diagnose and treat diseases. In particular, there has been increasing interest in specifically targeting metabolic pathways are preferentially altered in disease states, like cancer.  Although an increased dependence on glucose transport and metabolism has been well established for rapidly proliferating cells, attempts to target this conserved pathway have been limited by concerns about the high potential for side effects from the systemic inhibition of glucose transport.

To investigate the feasibility of targeting glucose transport in skin diseases, we investigated the effect of inhibiting glucose transport in the skin by deleting the primary glucose transporter in the skin, Glut1, in mouse keratinocytes. We confirmed that the Glut1-deficient keratinocytes showed metabolic and oxidative stress and impaired proliferation. However, the keratinocyte-specific ablation of Glut1 did not compromise mouse skin development and barrier function. Metabolomic profiling revealed sphingolipid, hexose, amino acid, and nucleotide adaptations in Glut1-deficient keratinocytes. However, Glut1 deficient skin did show defects in both proliferation and migration after physiologically relevant stressors like excisional wounds and UV-B irradiation.

Given its importance during stressors, we further tested whether Glut1 was important in the pathogenesis of psoriasis models. Notably, both the genetic and pharmacological inhibition of Glut1 decreased hyperplasia in mouse and human organic models of psoriasis. Moreover, the topical application of a Glut1 inhibitor further decreased inflammation in these models. The ability to deliver glucose transport inhibitors specifically to the skin may limit the adverse effects from the systemic inhibition of glucose transport and suggests that the topical inhibition of glucose transport may be a novel approach to treat hyperproliferative and inflammatory skin diseases.  Continue reading

Protein Associated with Metastatic Breast Cancer

MedicalResearch.com Interview with:
Yingfei Wang, Ph.D. and Weibo Luo, Ph.D.
Department of Pathology
UT Southwestern Medical Center
Dallas TX 75390

MedicalResearch.com: What is the background for this study?

Response: Breast cancer is the most commonly diagnosed cancer in women. Tumor metastasis is frequently found in breast cancer patients and causes more than 90% of cancer death. There is currently no cure for this deadly disease. We have known that breast tumor is not supplied with sufficient oxygen (a phenomenon known as hypoxia), which makes breast cancer cells more aggressive and may be responsible for tumor recurrence, metastasis, and therapy resistance. Hypoxia-inducible factor (HIF) is a master regulator frequently detected in the hypoxic regions and switches on many oncogenes needed for breast cancer cells to grow and spread around the body. The role of HIF in gene regulation is precisely controlled and shutting down of HIF’s activity would be a promising strategy for the treatment of metastatic breast cancer.

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Combination EGFR + TNF Inhibition May Knock Out Most Lung Cancers

MedicalResearch.com Interview with:

Amyn Habib, M.D. Associate Professor, Neurology & Neurotherapeutics UT Southwestern Medical Center

Dr. Amyn Habib

Amyn Habib, M.D.
Associate Professor, Neurology & Neurotherapeutics
UT Southwestern Medical Center

MedicalResearch.com: What is the background for this study?

Response: The epidermal growth factor receptor (EGFR) is expressed in most lung cancers and could play an important role in driving the growth of lung cancer.  Drugs are available that can block the activity of the EGFR. However, EGFR inhibitors are successful in only a small subset of lung cancers that have a mutant form of the EGFR, and do not work in the majority of lung cancers that have the normal form of the EGFR.  Continue reading

Adding Blood Biomarker To Ultrasound Improves Liver Cancer Detection

MedicalResearch.com Interview with:

Amit Singal MD MS David Bruton Jr. Professor in Clinical Cancer Research Associate Professor of Medicine Medical Director of Liver Tumor Program Clinical Chief of Hepatology University of Texas Southwestern

Dr. Amit Singal

Amit Singal MD MS
David Bruton Jr. Professor in Clinical Cancer Research
Associate Professor of Medicine
Medical Director of Liver Tumor Program
Clinical Chief of Hepatology
University of Texas Southwestern 

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Hepatocellular carcinoma, the most common form of primary liver cancer, often has a very poor prognosis because most cancers are found at a late stage when curative treatment is not available. However, if the cancer is found early, curative therapies are possible and patients can typically live longer than 5 years.

There is currently debate how at-risk patients with chronic liver disease should be screened – with an abdominal ultrasound alone or using a combination of abdominal ultrasound and a blood test called alpha fetoprotein. Many professional societies have traditionally recommended the former, i.e. ultrasound alone, given few data showing a benefit of adding alpha fetoprotein.

Our study examines all available literature examining this question and found using the two tests in combination significantly increases the likelihood of finding the cancer at an early stage. Whereas abdominal ultrasound misses over half of all cancers, using it in combination with alpha fetoprotein can detect two-thirds of cancers at an early stage. Continue reading

Phase I Study Successfully Targets Metastatic Kidney Cancer

MedicalResearch.com Interview with:

Kevin D. Courtney, M.D., Ph.D.  Assistant Professor UT Southwestern Medical Cente

Dr. Courtney

Kevin D. Courtney, M.D., Ph.D. 
Assistant Professor
UT Southwestern Medical Center

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Clear cell renal cell carcinoma (ccRCC) is the most common form of kidney cancer. Metastatic ccRCC does not respond to traditional chemotherapy.

Current standard treatments for metastatic ccRCC include drugs called vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR TKIs) that block the growth of new blood vessels that feed the cancer, as well as drugs that inhibit an enzyme called mTOR that is involved in ccRCC growth and immune therapies that rev up the body’s immune response to try to fight the cancer. Each of these treatments can have significant side effects for patients that can make them difficult to tolerate.

Metastatic ccRCC is largely incurable, and we need novel and better-tolerated treatments. A central driver of ccRCC is a protein called hypoxia inducible factor 2alpha (HIF-2alpha). This protein has been very difficult to try to target with a drug. This study is the first to test a drug that targets HIF-2alpha in patients with metastatic ccRCC. The study results showed that the HIF-2alpha inhibitor, PT2385 (Peloton Therapeutics) was active in fighting metastatic ccRCC and was well-tolerated.

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Early Studies Suggest Blood Pressure Medication Hydralazine May Slow Aging and Neurodegeneration

CrawlingCelegans Wikipedia

Crawling C. elegans
Wikipedia image

MedicalResearch.com Interview with:
Hamid Mirzaei, Ph.D.
Assistant Professor of Biochemistry
University of Texas Southwestern
Department of Biochemistry
Dallas, TX 75390

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Aging is a complex process at the cellular level with distinct organismal phenotypes. Despite millennia-old obsession with aging and relentless pursuits for ways to stop and reverse it, such elixir has not been found due to the complexity of the involved mechanisms and our limited understanding of the processes that lead to aging. Although progress has been made in recent years in slowing down the aging process in model organisms and human cells.

In this study, we report that and FDA approved antihypertensive drug, hydralazine, decelerates aging in C. elegans by mechanisms that seem to resemble dietary restriction. We show that hydralazine increases the median lifespan of the C. elegans by 25% which is comparable to or better than other known antiaging compounds.

We demonstrate that not only hydralazine-treated worms live longer, they appear to be healthier in general. Because aging is directly linked to neurodegenerative diseases, we tested our drug on both in vitro and in vivo models of neurodegenerative diseases using chemical and biological stressors (rotenone and tau fibrils) and show that hydralazine has neuroprotective properties as well.

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Common Antidepressant Sertraline Does Not Improve Depression in Chronic Kidney Disease Patients

MedicalResearch.com Interview with:

Dr. Susan Hedayati MD University of Texas Southwestern Dallas, Texas

Dr. Hedayati

Dr. Susan Hedayati MD
Yin Quan-Yuen Distinguished Professorship in Nephrology
University of Texas Southwestern
Dallas, Texas

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: We previously showed that Major Depression is associated with a significantly higher risk of death, dialysis initiation, and hospitalization among patients with Chronic Kidney Disease (CKD). Now we show that a common antidepressant medication, a selective serotonin reuptake inhibitors (SSRI), sertraline, does not improve depression in this patient population, a chronically ill group that is not only at significantly increased risk for developing depression but also its serious complications.

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Serotonin Receptors Tied To Weight Gain From Atypical Antipsychotic Medications

MedicalResearch.com Interview with:

Chen Liu, Ph.D. Assistant Professor Departments of Internal Medicine and Neuroscience Division of Hypothalamic Research The University of Texas Southwestern Medical Center Dallas, Texas 75390-9077

Dr. Chen Liu

Chen Liu, Ph.D.
Assistant Professor
Departments of Internal Medicine and Neuroscience
Division of Hypothalamic Research
The University of Texas Southwestern Medical Center
Dallas, Texas 75390-9077 

MedicalResearch.com: What is the background for this study?

Response: Atypical antipsychotics are second-generation antipsychotics (SGAs) that have been increasingly used to treat a variety of neuropsychiatric conditions such as schizophrenia, depression, and autism. Many patients taking these medications, however, are left in an agonizing dilemma.

On one hand, they rely on these drugs’ psychotropic effect for normal functioning in daily life. On the other, many SGAs, including the most widely prescribed olanzapine and clozapine, can cause a metabolic syndrome that is known for excessive weight gain, dyslipidemia, and type-2 diabetes_ENREF_2. Notably, while full-blown type 2 diabetes and morbid obesity typically take years to unfold in the general population, these conditions progress at a much faster pace (within months) following second-generation antipsychotics treatment. Other factors such as ethnicity, age, and sex can also aggravate SGA-induced metabolic syndrome. Together, these peculiar features strongly suggest a distinct etiology underlying SGA-induced metabolic syndrome that has yet been fully elucidated. Currently, there is no medication specifically targeting SGA-induced metabolic syndrome. For many youths and adults taking second-generation antipsychotics, metabolic complications are difficult to manage as lifestyle changes, nutritional consulting, and commonly used anti-diabetic medications only provide limited relief.

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Oral Treatment Option for RA Includes Tofacitinib (XELJANZ®) Plus Methotrexate

MedicalResearch.com Interview with:

Roy Fleischmann, MD MACR Medical Director Metroplex Clinical Research Center Clinical Professor of Medicine University of Texas Southwestern Medical Center Dallas, TX 75231

Dr. Fleischmann

Roy Fleischmann, MD MACR
Medical Director
Metroplex Clinical Research Center
Clinical Professor of Medicine
University of Texas Southwestern Medical Center
Dallas, TX 75231

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: In the phase 3 studies of tofacitinib, it was noted that the clinical responses to tofacitinib monotherapy were higher than the responses to tofaciotinib plus MTX and that tofacitinib plus methotrexate had numerically higher clinical responses compared to adalimumab plus methotrexate. This study was a non-inferiority design which compared tofacitinib monotherapy to tofacitinib + MTX and to adalimumab +MTX and tofacitinib monotherapy to tofacitinib +MTX in MTX incomplete responders. It was found that tofacitinib + MTX is non-inferior to adalimumab + MTX (and vice versa) and neither was superior to the other. The results of tofacitinib to either combination was non-conclusive showing neither non-inferiority or inferiority, but suggesting that either combination will be effective in more patients in a group of patients.

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Study Suggests Isolated Systolic Hypertension In Young Adults Should Be Treated To Prevent Damage To Aorta

MedicalResearch.com Interview with:

Wanpen Vongpatanasin, M.D.</strong> Professor of Medicine Norman & Audrey Kaplan Chair in Hypertension Fredric L. Coe Professorship in Nephrolithiasis and Mineral Metabolism Research Director, Hypertension Section, Cardiology Division, UT Southwestern Medical Center Dallas, TX 75390-8586

Dr. Vongpatanasin

Wanpen Vongpatanasin, M.D.
Professor of Medicine
Norman & Audrey Kaplan Chair in Hypertension
Fredric L. Coe Professorship in Nephrolithiasis and Mineral Metabolism Research
Director, Hypertension Section,
Cardiology Division,
UT Southwestern Medical Center
Dallas, TX 75390-8586

MedicalResearch.com: What is the background for this study?

Response: It is well know that treatment of isolated systolic hypertension (ISH), a subtype of hypertension with elevated systolic BP 140 or above but normal diastolic BP of < 90 mmHg, improves cardiovascular outcomes in older adults after the sixth decade of life. However, it is controversial if ISH in young adults requires treatment because it was suggested that elevated systolic BP in these individuals are related to high stroke volume, rather than increased aortic stiffness. In earlier case series, ISH in young adults were particularly common in athletes with long arms and legs, suggesting that pulse wave amplification coupled with high stroke volume were responsible for elevated brachial systolic blood pressure but the true central BP was normal. Thus,  isolated systolic hypertension was proposed to be a spurious condition in young adults that can be ignored.

However, previous studies used only indirect technique in assessing aortic structure and function. Furthermore, none of these studies were conducted in the U.S. Population.

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