The synergistic effect of radiation and inhibition of SPAK/OSR1 in the reduction of cell proliferation and clonogenic potential in patient-derived GBM cells in vitro

Glioblastoma (GBM) is the most aggressive brain tumor in adults. Cell invasion, migration and proliferation into the heathy brain parenchyma it’s one of the most important challenges in the treatment of this deadly tumor. One potential mechanism that GBM cells can utilize to enhance cell migration and evade pro-apoptotic signals is the tight regulation of cell volume by the STE20/SPS1-Related Proline-Alanine-Rich Protein Kinase (SPAK) and (Oxidative Stress Responsive Kinase 1) OSR1 kinases. Dynamic changes in cell volume can be used by GBM cells to disseminate through the narrow perivascular spaces of the brain. In addition, cancer cells could counteract pro-apoptotic reduction of cell volume by increasing the activity of these kinases. The objective of this project is to test the efficacy of SPAK and OSR1 inhibition alone or in combination with radiotherapy. For this purpose we evaluated the impact of this novel therapy on the proliferation, clonogenicity and apoptosis of primary patient-derived GBM cells in vitro. To achieve our goal we tested a novel SPAK/OSR1 inhibitor (a small molecule called YU566) in two patient derived GBM lines. Cell proliferation and colony formation were determined after treatment using 1uM YU566 alone or in combination with radiotherapy (at different doses 2, 4 Gray (Gy)). We found that radiation and inhibition of SPAK/OSR1 could act in a synergistic fashion, decreasing cell proliferation and clonogenic potential. The next steps in our research will be to determine the mechanisms of cell death and the implications of this therapy in vivo

A Lifelong Smoker with Hypopituitarism: Rethinking the Hypothesis of a Tumor in the Hypophysis

Pituitary adenomas are the most common cause of a sellar mass. Metastases to the pituitary gland, a rare occurrence, may mimic benign pituitary adenomas. We report here a case of a 61-year-old woman with an 80-pack-year smoking history who presented with headache and diplopia. Visual field testing demonstrated bitemporal hemianopsia. Pituitary MRI revealed a 2.0 cm sellar mass impinging upon the optic chiasm. Hypopituitarism was present, with no evidence of diabetes insipidus. The patient was referred to our service for transsphenoidal resection of a presumed pituitary macroadenoma. As part of her preoperative evaluation, a chest radiograph was obtained, which showed a large hilar mass. In light of the patient's extensive smoking history, the differential diagnosis was expanded to include metastatic lesion to the sella. Transsphenoidal resection of the tumor was performed and histopathology revealed small cell carcinoma. The patient received chemotherapy, but died 18 months later due to widespread brain metastases. Although the presence of diabetes insipidus may help to discriminate between pituitary adenomas and metastatic lesions, this is not a sensitive finding. This case illustrates the need for maintaining a high index of suspicion for pituitary metastasis in patients with known risk factors for malignancy

Harvey Cushing: early use of tendon transfers for repair of foot deformity: A historical case report

We describe 4 cases of tendon transfers for correction of foot deformities, which were performed by Harvey Cushing in 1898

Invasive adenoma and pituitary carcinoma: a SEER database analysis

Invasive pituitary adenomas and pituitary carcinomas are clinically indistinguishable until identification of metastases. Optimal management and survival outcomes for both are not clearly defined. The purpose of this study is to use the Surveillance, Epidemiology, and End Results (SEER) database to report patterns of care and compare survival outcomes in a large series of patients with invasive adenomas or pituitary carcinomas. One hundred seventeen patients diagnosed between 1973 and 2008 with pituitary adenomas/adenocarcinomas were included. Eighty-three invasive adenomas and seven pituitary carcinomas were analyzed for survival outcomes. Analyzed prognostic factors included age, sex, race, histology, tumor extent, and treatment. A significant decrease in survival was observed among carcinomas compared to invasive adenomas at 1, 2, and 5 years (p=0.047, 0.001, and 0.009). Only non-white race, male gender, and age ≥65 were significant negative prognostic factors for invasive adenomas (p=0.013, 0.033, and <0.001, respectively). There was no survival advantage to radiation therapy in treating adenomas at 5, 10, 20, or 30 years (p=0.778, 0.960, 0.236, and 0.971). In conclusion, pituitary carcinoma patients exhibit worse overall survival than invasive adenoma patients. This highlights the need for improved diagnostic methods for the sellar phase to allow for potentially more aggressive treatment approaches

Deferred Radiotherapy After Debulking of Non-functioning Pituitary Macroadenomas: Clinical Outcomes

Background: To describe the outcome for a cohort of patients with non-functioning pituitary macroadenomas (NFPMA), managed by debulking surgery with radiation therapy delayed until progression.Methods: Two hundred and sixty-seven patients were treated surgically for pituitary tumors at our institution between 1997 and 2005. One hundred and twenty-six patients met the inclusion criteria of NFPMA. They were followed for at least 2 years.Results: At presentation, 58% of patients had objectively decreased visual function, 66% had endocrine abnormalities, and 46% had headaches. Of the entire cohort, 75% of tumors abutted the optic chiasm and 87% had suprasellar extension. Over a median follow up of 112 months from surgery, 52% of patients had evidence of radiographic tumor progression, and 39% required additional treatment. There was a significant difference freedom from progression and in the number of patients receiving additional treatment with preoperative adenoma size of &lt; 2 vs. ≥2 cm (p &lt; 0.05).Conclusion: Close observation with radiation therapy delayed until the time of progression is an appropriate option for patients presenting with initial adenoma size &lt; 2 cm, and can be considered for those with initial sizes up to 4 cm, as the majority of patients do not require further intervention for 10 or more years, thereby meaningfully postponing the risks of radiotherapy

Mesoporous Silica-Coated Hollow Manganese Oxide Nanoparticles as Positive T1 Contrast Agents for Labeling and MRI Tracking of Adipose-Derived Mesenchymal Stem Cells

Mesoporous silica-coated hollow manganese oxide (HIVInO@ mSiO(2)) nanoparticles were developed as a novel T-1 magnetic resonance imaging (MRI) contrast agent. We hypothesized that the mesoporous structure of the nanopartide shell enables optimal access of water molecules to the magnetic core, and consequently, an effective longitudinal (R-1) relaxation enhancement of water protons, which value was measured to be 0.99 (mM(-1) s(-1)) at 11.7 T. Adipose-derived mesenchymal stem cells (MSCs) were efficiently labeled using electroporation, with much shorter T-1 values as compared to direct incubation without electroporation, which was also evidenced by signal enhancement on T-1-weighted MR images in vitro. Intracranial grafting of HMnO@mSiO(2)-labeled MSCs enabled serial MR monitoring of cell transplants over 14 days. These novel nanopartides may extend the arsenal of currently available nanoparticie MR contrast agents by providing positive contrast on T-1-weighted images at high magnetic field strengths.

Use of Mesenchymal Stem Cells in Pre-Clinical Models of Spinal Cord Injury

Spinal Cord Injury (SCI) is a devastating disease that causes disruption of sensorimotor function below the site of injury. Current management is based on surgical decompression of the neural tissue and pharmacotherapy; however, there is no gold standard treatment readily available for patients in the clinic. This indicates that novel therapeutic strategies for the treatment are still needed in the clinical setting. There are several alternatives that are currently under investigation for the treatment of this disease, with increasing focus in regenerative medicine treatments. Mesenchymal stem cells (MSCs) are one of the most promising candidates for stem cell therapy in SCI, as they are easily obtained, have high safety profiles, and help with neural regeneration in SCI mainly via release of trophic factors, neovascularization, and immunomodulation. In this work, authors provide an insight of the available MSC for neural regeneration, their therapeutic role, and the potential MSC-based therapies for SCI

In NPH, setting valve opening pressure close to lumbar puncture opening pressure decreases overdrainage

Background. The management of normal pressure hydrocephalus (NPH) can be difficult, partly because there are frequent treatment complications such as overdrainage which, when serious, may require surgical intervention. We previously reported a correlation between the difference of lumbar puncture opening pressure minus the valve opening pressure setting (LPOP–VOP) (which we refer to as the delta) and increased rates of overdrainage. This led to a modification in our practice, whereby we now set the VOP equal to, or close to, the LPOP, resulting in lower deltas. Objective. In this new study, our aim was to compare the rate of overdrainage in our patients with higher and lower deltas and assess the significance of setting the VOP equal, or close, to the patient’s LPOP. Methods. 1. We reproduced the association between delta and overdrainage. 2. We compared the incidence of overdrainage in those whose VOP was set close to LPOP (low delta) versus those with VOP setting distant from the LPOP (higher delta). 3. We compared symptom improvement in those with a low versus higher delta. Results. We confirmed the relation between high delta and an increased rate of overdrainage, lower rates of overdrainage in those whose VOP was set close to the LPOP (Delta Adjusted Practice), and better improvement of symptoms when the VOP was set closer to the LPOP. Conclusion. We propose that the initial VOP should be set as close as possible to the patient’s LPOP to decrease overdrainage without compromising symptom improvement

Shear Forces during Blast, Not Abrupt Changes in Pressure Alone, Generate Calcium Activity in Human Brain Cells

Blast-Induced Traumatic Brain Injury (bTBI) describes a spectrum of injuries caused by an explosive force that results in changes in brain function. The mechanism responsible for primary bTBI following a blast shockwave remains unknown. We have developed a pneumatic device that delivers shockwaves, similar to those known to induce bTBI, within a chamber optimal for fluorescence microscopy. Abrupt changes in pressure can be created with and without the presence of shear forces at the surface of cells. In primary cultures of human central nervous system cells, the cellular calcium response to shockwaves alone was negligible. Even when the applied pressure reached 15 atm, there was no damage or excitation, unless concomitant shear forces, peaking between 0.3 to 0.7 Pa, were present at the cell surface. The probability of cellular injury in response to a shockwave was low and cell survival was unaffected 20 hours after shockwave exposure