Inhibiting protein phosphatase 2A increases the antitumor effect of protein arginine methyltransferase 5 inhibition in models of glioblastoma

BackgroundDespite multi-model therapy of maximal surgical resection, radiation, chemotherapy, and tumor-treating fields, the median survival of glioblastoma (GBM) patients is less than 15 months. Protein arginine methyltransferase 5 (PRMT5) catalyzes the symmetric dimethylation of arginine residues and is overexpressed in GBM. Inhibition of PRMT5 causes senescence in stem-like GBM tumor cells. LB100, a first-in-class small molecular inhibitor of protein phosphatase 2A (PP2A), can sensitize therapy-resistant tumor cells. Here, we tested the anti-GBM effect of concurrent PRMT5 and PP2A inhibition.MethodsPatient-derived primary GBM neurospheres (GBMNS), transfected with PRMT5 target-specific siRNA, were treated with LB100 and subjected to in vitro assays including PP2A activity and western blot. The intracranial mouse xenograft model was used to test the in vivo antitumor efficacy of combination treatment.ResultsWe found that PRMT5 depletion increased PP2A activity in GBMNS. LB100 treatment significantly reduced the viability of PRMT5-depleted GBMNS compared to PRMT5-intact GBMNS. LB100 enhanced G1 cell cycle arrest induced by PRMT5 depletion. Combination therapy also increased the expression of phospho-MLKL. Necrostatin-1 rescued PRMT5-depleted cells from the cytotoxic effects of LB100, indicating that necroptosis caused the enhanced cytotoxicity of combination therapy. In the in vivo mouse tumor xenograft model, LB100 treatment combined with transient depletion of PRMT5 significantly decreased tumor size and prolonged survival, while LB100 treatment alone had no survival benefit.ConclusionOverall, combined PRMT5 and PP2A inhibition had significantly greater antitumor effects than PRMT5 inhibition alone.     

Introducing the health coach at a primary care practice: impact on quality and cost (Part 1)

The cost of healthcare in U.S. is a poor value proposition. One of the primary goals of the healthcare reform act is to reduce cost while improving healthcare quality. We believe that adding a health coach will help in achieving this goal. The health coach is a medical professional who supports both the physician and the patient by meeting previously established goals. This research presents and analyzes the key roles of a health coach in a primary care practice.     

Introducing the health coach at a primary care practice: a pilot study (part 2)

It is well known that the cost of healthcare in the United States is a poor value proposition. One of the primary goals of the healthcare reform act is to reduce cost while improving healthcare quality. The authors believe that adding a health coach helps to achieve this goal. In part I, the authors discuss the role of a health coach in the healthcare field. They present the findings from a pilot study at a primary care practice managing diabetes of patients using a health coach. The findings from the study suggest that adding a health coach helps in cost savings as well as improved health for the patients.     

Extramediastinal thymolipomas—challenges in diagnosis and dilemmas in approaches: a review

Objectives  

Thymolipomas are rare tumors, usually located in the anterior mediastinum and may extend into the chest cavity. But the thymolipomas presenting solely in the chest cavity without demonstrable mediastinal mass are extremely rare. They can be termed as extramediastinal thymolipomas and they present as diagnostic and technical challenge for surgeons.     

“Double cervical rib with uncommon presentation”

Double or Bilateral cervical ribs. Pseudo arthrosis of cervical rib with first rib causing neurovascular complication is a rare congenital anomaly. We report a case of young man who presented with intermittent claudication in the right hand and involvement of peripheral nerves. He had bilateral cervical ribs. Left side cervical rib was small. Right side cervical rib had pseudo arthrosis with first rib. There was total occlusion of subclavian artery beyond first part. Abnormal sensation in the inner aspect of hand and fingers. He was managed with subclavian to axillary artery bypass with 6 mm Goretex graft and excision of cervical rib on right side and division of all sclaenus muscles i.e. scelnus anterior, medium minimus with fibrous bands to free subclavian artery and nerves.     

Beta‐blockers improve survival outcomes in patients with multiple myeloma: a retrospective evaluation

A preclinical study demonstrated anti‐proliferative and apoptotic effect of propranolol on multiple myeloma (MM) cell. Clinical studies suggested that beta‐blocker (BB) might impact the prognosis of breast, prostate, colorectal, ovarian, lung, and skin cancer. This retrospective study evaluated the effect of BB in MM disease‐specific survival (DSS) and overall survival (OS). Among 1,971 newly diagnosed MM patients seen at Mayo Clinic between 1995 and 2010, usage of BB and other cardiac (or antihypertensive) medications were abstracted. Cumulative incidence function and Kaplan–Meier method were used to estimate 5‐year cumulative incidence rate (CIR) of MM death and OS rate, respectively. Nine hundred and thirty (47.2%) patients had no intake of cardiac medications; 260 (13.2%) used BB alone; 343 (17.4%) used both BB/non‐BB cardiac medications; and 438 (22.2%) had non‐BB cardiac drugs. Superior MM DSS was observed in BB only users, compared to patients without any cardiac drugs ( , 0.53, 95% confidence interval [CI], 0.42–0.67, P_adj.<0.0001) and non‐BB cardiac drugs users ( , 0.49, 95% CI, 0.38–0.63, P_adj.<0.0001). Patients on both BB and other cardiac drugs showed superior DSS than non‐cardiac drugs users ( , 0.54, 95% CI, 0.44–0.67, P_adj.<0.0001) and non‐BB cardiac drug users. ( , 0.50, 95% CI, 0.40–0.62, P_adj.<0.0001). MM DSS did not differ between BB users with and without other cardiac drugs (P_adj.=0.90). Multivariable analysis showed the same pattern for OS. In patients with MM, BB intake is associated with a reduced risk of disease‐specific death and overall mortality in comparison to non‐BB or no use of cardiac drugs. Am. J. Hematol. 92:50–55, 2017. © 2016 Wiley Periodicals, Inc.     

Squamous papilloma: case report and review of literature

Squamous papillomas are common lesions of the oral mueosa with a predilection for the mucosa of the hard and soft palate.As an oral lesion,it raises concern because of its clinical appearance,which may mimic exophytic carcinoma,verrucous carcinoma or condyloma acuminatum.Its pathogenesis is related to human papilloma virus but there is controversy regarding its viral origin.We present a case of squamous papilloma presenting as oral lesion along with a review of the literature.     

Extramedullary hematopoiesis within the clivus: an unusual cause of lower cranial nerve palsy

We report one year follow up of a case of extramedullary hematopoiesis within the clivus. The imaging findings, brief clinical course, and endoscopic transphenoidal approach are described. A 29-year-old female with thalassemia developed worsening cranial nerve signs. After imaging studies discovered a large clival mass, she underwent endoscopic transphenoidal biopsy of the lesion. Neural compression from exuberant erythrogenesis within tissue normally quiescent of red blood cell production was found to be the etiology of her neural deficit. Treatment for this condition is generally non-operative unless significant neural compression is present. Radiotherapy and anti-neoplastic agents have been used with success.     

Developments in technique and technology: the effect on the results of percutaneous nephrolithotomy for staghorn calculi

OBJECTIVE

To review the development of the technique of percutaneous nephrolithotomy (PCNL), for ease of learning and development of instrumentation for staghorn calculi at our centre since 1991, and to assess the results and outcomes.

PATIENTS AND METHODS

We retrospectively analysed the hospital records of 773 patients (632 males and 141 females, 834 renal units) who underwent PCNL for staghorn calculi at our centre from January 1991 to August 2008. We divided the patients into three groups depending on the changes in treatment policy, global trends and advances in equipment as follows: the first 200 cases (group I) from January 1991 to December 1996 (216 renal units); the next 200 (group II) from January 1997 to December 2001 (212 renal units); and the last 373 (group III) from January 2002 to August 2008 (406 renal units).

RESULTS

The mean (sd , range) operative duration in groups I, II and III, respectively, were 138.2 (52.7, 60–310), 121.4 (42.8, 70–250) and 112.5 (51.5, 55–310) min; the decrease in haemoglobin level was 3.2, 2.6 and 1.6 g/dL, respectively, and continued to decrease with improvements in technique. With increasing experience, the number of stages required for stone clearance and the number of tracts required decreased exponentially. Most of the severe complications occurred early in our experience. The stone clearance rate in groups I, II and III was 81%, 86% and 93%, respectively, after completing the procedure; the overall clearance rate with observation/auxiliary procedures was 86%, 89% and 96%, respectively. The mean hospital stay for groups I, II and III was 11.1 (3.9, 7–25), 9.5 (3.4, 5–22) and 7.1 (3.6, 4–28) days, respectively.

CONCLUSION

The percutaneous management of staghorn calculi requires considerable expertise. Our data suggest that ‘multiperc’ PCNL is difficult to learn and requires experience. Although over the years our results improved, complete clearance remains a challenge. A constant review and application of newer techniques and results will improve the overall clearance rates further.