Is MMTV associated with human breast cancer? Maybe, but probably not.

BACKGROUND: Conflicting results regarding the association of MMTV with human breast cancer have been reported. Published sequence data have indicated unique MMTV strains in some human samples. However, concerns regarding contamination as a cause of false positive results have persisted. METHODS: We performed PCR assays for MMTV on human breast cancer cell lines and fresh frozen and formalin fixed normal and malignant human breast epithelial samples. Assays were also performed on peripheral blood mononuclear cells from volunteer blood donors and subjects at risk for human retroviral infections. In addition, assays were performed on DNA samples from wild and laboratory mice. Sequencing of MMTV positive samples from both humans and mice were performed and phylogenetically compared. RESULTS: Using PCR under rigorous conditions to prevent and detect "carryover" contamination, we did detect MMTV DNA in human samples, including breast cancer. However, the results were not consistent and seemed to be an artifact. Further, experiments indicated that the probable source of false positives was murine DNA, containing endogenous MMTV, present in our building. However, comparison of published and, herein, newly described MMTV sequences with published data, indicates that there are some very unique human MMTV sequences in the literature. CONCLUSION: While we could not confirm the true presence of MMTV in our human breast cancer subjects, the data indicate that further, perhaps more traditional, retroviral studies are warranted to ascertain whether MMTV might rarely be the cause of human breast cancer.

Dorsal Onlay Urethroplasty for Membranous Urethral Strictures: Urinary and Erectile Functional Outcomes.

PURPOSE: We evaluated urinary and erectile functional outcomes after dorsal onlay urethroplasty for bulbomembranous urethral strictures. Our aim was to understand the functional implications of dissection of the posterior urethra. MATERIALS AND METHODS: We report on men who underwent membranous urethral stricture repair by buccal mucosal graft dorsal onlay substitution urethroplasty. Continence and erectile function were assessed preoperatively and postoperatively. Tissue routinely excised from the intercrural space during dissection of the dorsal aspect of the membranous urethra was evaluated for scar, striated muscle and nerves. RESULTS: A total of 16 consecutive men with a mean age of 48.3 years (range 26 to 72) who had strictures with a mean length of 56 mm (range 15 to 170) involving the membranous urethra were included in analysis. Of the 16 men 15 were continent preoperatively and remained continent postoperatively. Three of 10 men (30%) with a preoperative SHIM (Sexual Health Inventory for Men) score of 17 to 25 had a decrease after urethroplasty. All 16 men had an improved maximum urinary flow rate with a mean improvement of 22 ml per second. I-PSS (International Prostate Symptom Score) improved from a median of 23 to 4 postoperatively with a median bother score improvement of 5 to 0. Histopathological assessment identified striated muscle and nerves in 6 (46%) and 9 (69%) of 13 specimens. Overall nerves and muscle comprised an average of less than 15% of the specimen. CONCLUSIONS: The dorsal onlay technique with a buccal mucosal graft for membranous urethral stricture repair does not compromise continence or erectile function in most patients. Dissection at the level of the membranous urethra should be limited because striated muscle and cavernous nerves are present.

Novel Concept and Method of Endoscopic Urethral Stricture Treatment Using Liquid Buccal Mucosal Graft.

PURPOSE: We describe a novel method of urethral stricture treatment using liquid buccal mucosal grafts to augment direct vision internal urethrotomy. MATERIALS AND METHODS: A rabbit stricture model was used to test this method. In phase 1 the concept of endoscopic liquid buccal mucosal graft implantation was tested by performing direct vision internal urethrotomy in 3 rabbits with immediate intraurethral injection of autologous liquid buccal mucosal grafts suspended in fibrin glue. Animals were sacrificed at 2 to 3 weeks and the urethras were examined for the presence of buccal mucosa engraftment. In phase 2 strictures were induced by electroresection in 9 rabbits divided into 2 groups, including 1) 6 rabbits treated with direct vision internal urethrotomy and liquid buccal mucosal grafts, and 2) 3 controls that underwent direct vision internal urethrotomy and injection of fibrin glue only. Two treated and 1 control animals were sacrificed at 8, 16 and 24 weeks each. Prior to sacrifice the animals underwent retrograde urethrograms and urethroscopy. Histological specimens were examined for the presence of buccal mucosal engraftment. RESULTS: In phase 1, 2 of the 3 rabbits demonstrated engraftment of buccal mucosa in the urethra after injection of liquid buccal mucosal grafts. In phase 2 all 6 treated animals demonstrated engraftment with resolution/improvement of strictures on retrograde urethrograms and urethroscopy. Controls had no buccal engraftment and showed fibrosis and chronic inflammation. One of the 3 controls had persistent stricture on retrograde urethrograms and cystoscopy. CONCLUSIONS: This proof of concept study demonstrated the feasibility of using liquid buccal mucosal grafts for endoscopic urethral stricture repair. Such a method may allow for wide application of this novel concept of using liquid buccal mucosal grafts to augment direct vision internal urethrotomy.

Liver injury correlates with biomarkers of autoimmunity and disease activity and represents an organ system involvement in patients with systemic lupus erythematosus.

Liver disease (LD), defined as ≥ 2-fold elevation of aspartate aminotransferase (AST) or alanine aminotransferase (ALT), was examined in a longitudinal study of systemic lupus erythematosus (SLE) patients. Among 435 patients, 90 (20.7%) had LD with a greater prevalence in males (15/39; 38.5%) than females (75/396; 18.9%; p = 0.01). SLE disease activity index (SLEDAI) was greater in LD patients (7.8 ± 0.7) relative to those without (5.8 ± 0.3; p = 0.0025). Anti-smooth muscle antibodies, anti-DNA antibodies, hypocomplementemia, proteinuria, leucopenia, thrombocytopenia, and anti-phospholipid syndrome were increased in LD. An absence of LD was noted in patients receiving rapamycin relative to azathioprine, cyclosporine A, or cyclophosphamide. An absence of LD was also noted in patients treated with N-acetylcysteine. LFTs were normalized and SLEDAI was diminished with increased prednisone use in 76/90 LD patients over 12.1 ± 2.6 months. Thus, LD is attributed to autoimmunity and disease activity, it responds to prednisone, and it is potentially preventable by rapamycin or N-acetylcysteine treatment.

Gene expression profiles in granuloma tissue reveal novel diagnostic markers in sarcoidosis.

Sarcoidosis is an immune-mediated multisystem disease characterized by the formation of non-caseating granulomas. The pathogenesis of sarcoidosis is unclear, with proposed infectious or environmental antigens triggering an aberrant immune response in susceptible hosts. Multiple pro-inflammatory signaling pathways have been implicated in mediating macrophage activation and granuloma formation in sarcoidosis, including IFN-γ/STAT-1, IL-6/STAT-3, and NF-κB. It is difficult to distinguish sarcoidosis from other granulomatous diseases or assess disease severity and treatment response with histopathology alone. Therefore, development of improved diagnostic tools is imperative. Herein, we describe an efficient and reliable technique to classify granulomatous disease through selected gene expression and identify novel genes and cytokine pathways contributing to the pathogenesis of sarcoidosis. We quantified the expression of twenty selected mRNAs extracted from formalin-fixed paraffin embedded (FFPE) tissue (n = 38) of normal lung, suture granulomas, sarcoid granulomas, and fungal granulomas. Utilizing quantitative real-time RT-PCR we analyzed the expression of several genes, including IL-6, COX-2, MCP-1, IFN-γ, T-bet, IRF-1, Nox2, IL-33, and eotaxin-1 and revealed differential regulation between suture, sarcoidosis, and fungal granulomas. This is the first study demonstrating that quantification of target gene expression in FFPE tissue biopsies is a potentially effective diagnostic and research tool in sarcoidosis.

Repetitive percutaneous epididymal sperm aspirations (PESA's) resulted in asthenospermia and significant inflammation.

INTRODUCTION: In obstructive azoospermia, choosing a sperm retrieval method for intracytoplasmic sperm injection (ICSI) depends on the preference and expertise of both the urologist and the reproductive endocrinologist. Generally, a percutaneous epididymal sperm aspiration (PESA) is attempted first. Not uncommonly, multiple PESA's are necessary. This study utilizes a rat model to provide an understanding of sperm parameter and histological changes resulting from repetitive PESA procedures. MATERIALS AND METHODS: A cohort of 30 male Wistar rats of reproductive age (68-73 days) was divided into three groups of 10 (G1-G3). All three groups underwent a left epididymal head PESA using a 253/8 gauge needle. The untouched right epididymis acted as the control. At 14 day intervals, G2 and G3 underwent a second and third PESA respectively. Fourteen days after the final PESA, both epididymides and a 1 cm segment of both vas deferentia were harvested for sperm and histological evaluations. RESULTS: The percentage of vas specimens with a sperm count ≥ 5 x104/cc was 100%, 22%, and 20% for the G1, G2, G3 PESA samples respectively. Moreover, the percentage of the vas specimens with sperm motility ≥ 10% was 90%, 22%, and 20%, respectively. Epididymal granulomas were not seen in the control side, but formed in 70%, 100%, and 80% of G1, G2, G3 PESA specimens, respectively. CONCLUSIONS: In a rat model, PESA resulted in significant epididymal inflammation and a reduction in both sperm concentration and motility.

Large teratoma at aortic bifurcation: an unusual metastasis of testicular cancer.

A 29-year-old man presented with a right testicular mass. Serum tumor markers were within normal limits. When compared to a previous computed tomography (CT) scan, a new 4 cm presacral mass was present. He underwent radical right inguinal orchiectomy that demonstrated a mature teratoma and seminomatous components. The patient received four cycles of chemotherapy. Over the course of chemotherapy, the mass grew in size and therefore he underwent retroperitoneal lymph node dissection. Pathology confirmed it to be a teratoma with negative retroperitoneal lymph nodes. The unusual presentation of an isolated metastasis to the presacral region raises the question of altered lymphatic drainage.

Spatial distribution of fibrosis governs fibrillation wave dynamics in the posterior left atrium during heart failure.

Heart failure (HF) commonly results in atrial fibrillation (AF) and fibrosis, but how the distribution of fibrosis impacts AF dynamics has not been studied. HF was induced in sheep by ventricular tachypacing (220 bpm, 6 to 7 weeks). Optical mapping (Di-4-ANEPPS, 300 frames/sec) of the posterior left atrial (PLA) endocardium was performed during sustained AF (burst pacing) in Langendorff-perfused HF (n=7, 4 micromol/L acetylcholine; n=3, no acetylcholine) and control (n=6) hearts. PLA breakthroughs were the most frequent activation pattern in both groups (72.0+/-4.6 and 90.2+/-2.7%, HF and control, respectively). However, unlike control, HF breakthroughs preferentially occurred at the PLAs periphery near the pulmonary vein ostia, and their beat-to-beat variability was greater than control (1.93+/-0.14 versus 1.47+/-0.07 changes/[beats/sec], respectively, P<0.05). On histological analysis (picrosirius red), the area of diffuse fibrosis was larger in HF (23.4+/-0.4%) than control (14.1+/-0.6%; P<0.001, n=4). Also the number and size of fibrous patches were significantly larger and their location was more peripheral in HF than control. Computer simulations using 2-dimensional human atrial models with structural and ionic remodeling as in HF demonstrated that changes in AF activation frequency and dynamics were controlled by the interaction of electrical waves with clusters of fibrotic patches of various sizes and individual pulmonary vein ostia. During AF in failing hearts, heterogeneous spatial distribution of fibrosis at the PLA governs AF dynamics and fractionation.

Higher than expected association of clinical prostate and bladder cancers.

PURPOSE: In this study we evaluated the risk of a second malignancy of the bladder or prostate in patients with a previous diagnosis of prostate cancer (PCa) or urothelial cancer (TCC). MATERIALS AND METHODS: We retrospectively analyzed all cases of PCa and TCC diagnosed between January 1996 and June 2003. Only PCa diagnosed due to abnormal digital rectal examination or increased prostate specific antigen were included. All patients with TCC presented with hematuria or irritative voiding symptoms and the diagnoses were confirmed with a tissue diagnosis. The incidence of lung, colon and renal cancers was also analyzed. RESULTS: A total of 816 men were diagnosed with PCa and/or TCC. Of 673 men initially diagnosed with PCa 21 had TCC. Of 149 men initially diagnosed with TCC 18 had PCa. Average age at PCa and TCC diagnosis +/- SD was 68.2 +/- 7.9 and 68.2 +/- 10.4 years, respectively. The standardized incidence ratio (SIR) of TCC in patients with PCa (SIR 4.31, 95% CI 2.411 to 7.110) and of PCa in patients with TCC (SIR 3.83, 95% CI 1.911 to 6.858) was significantly increased. There was no statistical significant difference in SIR for TCC in men with or without radiotherapy. SIR for lung, renal or colon cancer was not significantly different from what was expected. CONCLUSIONS: Patients with PCa have higher incidence of bladder cancer and those with bladder cancer have a higher incidence of PCa. This study has clinical implications in the care of these patients and it may stimulate research interest that may identify common pathways of carcinogenesis.

Systemic calciphylaxis.

An 11-year-old male developed systemic calciphylaxis during induction therapy for acute lymphoblastic leukemia. His predisposing conditions were hypercalcemia, supplements for pamidronate-induced hypocalcemia and hypophosphatemia and renal insufficiency. He died of cardiorespiratory arrest on the 20th day of induction treatment. Autopsy revealed extensive calcium deposits in the heart, lungs and kidneys. He had diffused alveolar damage, acute tubular necrosis, chronic pancreatitis and marked hepatic steatosis. Systemic calcium deposition may progress rapidly in children with hypercalcemia of malignancy. Since pamidronate reduces mineral resorption from tissues, calcium and phosphate replacements increase systemic mineral deposits. Thus, mineral supplements should be considered only to combat symptoms.

The kinase Mirk/Dyrk1B mediates cell survival in pancreatic ductal adenocarcinoma.

Ductal adenocarcinoma of the pancreas is almost uniformly lethal as this cancer is invariably detected at an advanced stage and is resistant to treatment. The serine/threonine kinase Mirk/Dyrk1B has been shown to be antiapoptotic in rhabdomyosarcomas. We have now investigated whether Mirk might mediate survival in another cancer in which Mirk is widely expressed, pancreatic ductal adenocarcinoma. Mirk was an active kinase in each pancreatic cancer cell line where it was detected. Mirk knockdown by RNA interference (RNAi) reduced the clonogenicity of Panc1 pancreatic cancer cells 4-fold and decreased tumor cell number, showing that Mirk mediates survival in these cells. Mirk knockdown by synthetic duplex RNAis in Panc1, AsPc1, and SU86.86 pancreatic cancer cells induced apoptosis and enhanced the apoptosis induced by gemcitibine. Mirk knockdown did not increase the abundance or activation of Akt. However, four of five pancreatic carcinoma cell lines exhibited either elevated Mirk activity or elevated Akt activity, suggesting that pancreatic cancer cells primarily rely on Mirk or Akt for survival signaling. Mirk protein was detected by immunohistochemistry in 25 of 28 cases (89%) of pancreatic ductal adenocarcinoma, with elevated expression in 11 cases (39%). Increased expression of Mirk was seen in pancreatic carcinomas compared with primary cultures of normal ductal epithelium by serial analysis of gene expression and by immunohistochemistry. Thus, Mirk is a survival factor for pancreatic ductal adenocarcinoma. Because knockout of Mirk does not cause embryonic lethality, Mirk is not essential for normal cell growth and may represent a novel therapeutic target.

CHTM1, a novel metabolic marker deregulated in human malignancies.

A better understanding of the link between cellular metabolism and tumorigenesis is needed. Here, we report characterization of a novel protein named coiled-coil helix tumor and metabolism 1 (CHTM1). We have found that CHTM1 is associated with cancer and cellular metabolism. CHTM1 localizes to mitochondria and cytosol, and its deficiency in cancer cells results in decreased mitochondrial oxygen consumption and ATP levels as well as oxidative stress indicating mitochondrial dysfunction. CHTM1-deficient cancer cells display poor growth under glucose/glutamine-deprived conditions, whereas cells expressing increased levels of exogenous CHTM1 exhibit enhanced proliferation and survival under similar conditions. CHTM1 deficiency also leads to defects in lipid metabolism resulting in fatty acid accumulation, which explains poor growth of CHTM1-deficient cells under glucose/glutamine deprivation since nutrient deprivation increases dependency on lipids for energy generation. We also demonstrate that CHTM1 mediates its effect via the PKC, CREB, and PGC-1alpha signaling axis, and cytosolic accumulation of CHTM1 during nutrient deprivation appears to be important for its effect on cellular signaling events. Furthermore, analyses of tissue specimens from 71 breast and 97 colon cancer patients show CHTM1 expression to be upregulated in the majority of tumor specimens representing these malignancies. Collectively, our findings are highly significant because CHTM1 is a novel metabolic marker that is important for the growth of tumorigenic cells under limiting nutrient supplies and thus, links cellular metabolism and tumorigenesis.

Monoglyceride lipase gene knockout in mice leads to increased incidence of lung adenocarcinoma.

Monoglyceride lipase (MGL) is a recently discovered cancer-related protein. The role of MGL in tumorigenesis remains to be fully elucidated. We have previously shown that MGL expression was reduced or absent in multiple human malignancies, and overexpression of MGL inhibited cancer cell growth. Here, we have generated the MGL knockout mice to further investigate the role of MGL in tumorigenesis in vivo. Our results indicate that MGL-deficient (MGL+/-, MGL-/-) mice exhibited a higher incidence of neoplasia in multiple organs, including the lung, spleen, liver and lymphoid tissues. Interestingly, lung neoplasms were the most common neoplastic changes in the MGL-deficient mice. Importantly, MGL-deficient animals developed premalignant high-grade dysplasia and adenocarcinomas in their lungs. Investigation of the MGL expression status in lung cancer specimens from patients also revealed that MGL expression was significantly reduced in the majority of primary human lung cancers when compared to corresponding matched normal tissues. Furthermore, mouse embryonic fibroblasts (MEFs) from MGL-deficient animals showed characteristics of cellular transformation including increased cell proliferation, foci formation and anchorage-independent growth. Our results also indicate that MGL deficiency was associated with activation of EGFR and ERK. In addition, pro-inflammatory molecules COX-2 and TNF-α were also activated in the MGL-deficient lung tissues. Thus, our results provide new insights into the novel role of MGL as an important negative regulator of EGFR, COX-2 and TNF-α. Accordingly, EGFR and COX-2/TNF-α activation/induction is expected to play important roles in MGL deficiency-driven lung tumors. Collectively, our results implicate the tumor suppressive role of MGL in preventing tumor development in vivo, particularly in context to the lung cancer, and highlight its role as a potential tumor suppressor.

1500 gram suprarenal mass: a case report.

Adrenocortical carcinoma can have a clinical presentation that mimics a primary renal tumor. We describe a case of a 47-year-old male who presented with flank pain, weight loss, and a 14 cm mass arising from the upper pole of the right kidney on imaging. Upon surgical resection he was found to have a 1500 gram stage II adrenocortical carcinoma. The clinical features, pathologic findings, grading criteria, and differential diagnosis of adrenocortical carcinoma are reviewed.

Chemically modified tetracycline (COL-3) improves survival if given 12 but not 24 hours after cecal ligation and puncture.

Sepsis can result in excessive and maladaptive inflammation that is responsible for more than 215,00 deaths per year in the United State alone. Current strategies for reducing the morbidity and mortality associated with sepsis rely on treatment of the syndrome rather than prophylaxis. We have been investigating a modified tetracycline, COL-3, which can be given prophylactically to patients at high risk for developing sepsis. Our group has shown that COL-3 is very effect at preventing the sequelae of sepsis if given before or immediately after injury in both rat and porcine sepsis models. In this study, we wanted to determine the "treatment window" for COL-3 after injury at which it remains protective. Sepsis was induced by cecal ligation and puncture (CLP). Rats were anesthetized and placed into five groups: CLP (n = 20) = CLP without COL-3, sham (n = 5) = surgery without CLP or COL-3, COL3@6h (n = 10) = COL-3 given by gavage 6 h after CLP, COL3@12h (n = 10) = COL-3 given by gavage 12 h after CLP, and COL3@24h (n = 20) = COL-3 given by gavage 24 h after CLP. COL-3 that was given at 6 and 12 h after CLP significantly improved survival as compared with the CLP and the CLP@24h groups. Improved survival was associated with a significant improvement in lung pathology assessed morphologically. These data suggest that COL-3 can be given up to 12 h after trauma and remain effective.

Enteric cyst with epicardial attachment to the left ventricle.

Enteric cysts result from an anomaly of embryonic foregut development. In adults, these are frequently asymptomatic. The following is a case of an enteric cyst identified during routine coronary artery bypass attached directly to the epicardium of the left ventricle, a finding not previously reported. Approaches to the treatment of this rare lesion vary. Due to the patient's history of breast cancer, the lesion was excised for histopathological diagnosis.

Dynamic alveolar mechanics in four models of lung injury.

OBJECTIVE: To determine whether pathological alterations in alveolar mechanics (i.e., the dynamic change in alveolar size and shape with ventilation) at a similar level of lung injury vary depending on the cause of injury. DESIGN AND SETTING: Prospective controlled animal study in a university laboratory. SUBJECTS: 30 male Sprague-Dawley rats (300-550 g). INTERVENTIONS: Rats were separated into one of four lung injury models or control (n=6): (a) 2% Tween-20 (Tween, n=6), (b) oleic acid (OA, n=6), (c) ventilator-induced lung injury (VILI, PIP 40/ZEEP, n=6), (d) endotoxin (LPS, n=6). Alveolar mechanics were assessed at baseline and after injury (PaO2/FIO2 <300 mmHg) by in vivo microscopy. MEASUREMENTS: Alveolar instability (proportional change in alveolar size during ventilation) was used as a measurement of alveolar mechanics. RESULTS: Alveoli were unstable in Tween, OA, and VILI as hypoxemia developed (baseline vs. injury: Tween, 7+/-2% vs. 67+/-5%; OA: 3+/-2% vs. 82+/-9%; VILI, 4+/-2% vs. 72+/-5%). Hypoxemia after LPS was not associated with significant alveolar instability (baseline vs. injury: LPS, 3+/-2 vs. 8+/-5%). CONCLUSIONS: These data demonstrate that multiple pathological changes occur in dynamic alveolar mechanics. The nature of these changes depends upon the mechanism of lung injury.

Risk of post-operative intravesical mitomycin C instillation following transurethral bladder tumor resection.

Bladder cancer is the fifth most common cancer in the Western world and is on the rise. Most patients present with superficial disease and are treated by transurethral resection of bladder tumor. More than half of these patients experience recurrence with about 20% progressing to muscle invasive disease. Intravesical chemotherapy has been shown to decrease the risk of recurrence of bladder cancer. Mitomycin C has emerged as a major agent for an immediate post-resection intravesical instillation. This article reviews the literature on the mode of action, rationale for immediate adjuvant treatment with Mitomycin C and adverse effects associated with its use.

Mitochondrial Dysfunction in the Liver and Antiphospholipid Antibody Production Precede Disease Onset and Respond to Rapamycin in Lupus-Prone Mice.

OBJECTIVE: Antiphospholipid antibodies (aPL) constitute a diagnostic criterion of systemic lupus erythematosus (SLE), and aPL have been functionally linked to liver disease in patients with SLE. Since the mechanistic target of rapamycin (mTOR) is a regulator of oxidative stress, a pathophysiologic process that contributes to the development of aPL, this study was undertaken in a mouse model of SLE to examine the involvement of liver mitochondria in lupus pathogenesis. METHODS: Mitochondria were isolated from lupus-prone MRL/lpr, C57BL/6.lpr, and MRL mice, age-matched autoimmunity-resistant C57BL/6 mice as negative controls, and transaldolase-deficient mice, a strain that exhibits oxidative stress in the liver. Electron transport chain (ETC) activity was assessed using measurements of oxygen consumption. ETC proteins, which are regulators of mitochondrial homeostasis, and the mTOR complexes mTORC1 and mTORC2 were examined by Western blotting. Anticardiolipin (aCL) and anti-ß2 -glycoprotein I (anti-ß2 GPI) autoantibodies were measured by enzyme-linked immunosorbent assay in mice treated with rapamycin or mice treated with a solvent control. RESULTS: Mitochondrial oxygen consumption was increased in the livers of 4-week-old, disease-free MRL/lpr mice relative to age-matched controls. Levels of the mitophagy initiator dynamin-related protein 1 (Drp1) were depleted while the activity of mTORC1 was increased in MRL/lpr mice. In turn, mTORC2 activity was decreased in MRL and MRL/lpr mice. In addition, levels of aCL and anti-ß2 GPI were elevated preceding the development of nephritis in 4-week-old MRL, C57BL/6.lpr, and MRL/lpr mice. Transaldolase-deficient mice showed increased oxygen consumption, depletion of Drp1, activation of mTORC1, and elevated expression of NADH:ubiquinone oxidoreductase core subunit S3 (NDUFS3), a pro-oxidant subunit of ETC complex I, as well as increased production of aCL and anti-ß2 GPI autoantibodies. Treatment with rapamycin selectively blocked mTORC1 activation, NDUFS3 expression, and aPL production both in transaldolase-deficient mice and in lupus-prone mice. CONCLUSION: In lupus-prone mice, mTORC1-dependent mitochondrial dysfunction contributes to the generation of aPL, suggesting that such mechanisms may represent a treatment target in patients with SLE.

Mps1 Mediated Phosphorylation of Hsp90 Confers Renal Cell Carcinoma Sensitivity and Selectivity to Hsp90 Inhibitors.

The molecular chaperone Hsp90 protects deregulated signaling proteins that are vital for tumor growth and survival. Tumors generally display sensitivity and selectivity toward Hsp90 inhibitors; however, the molecular mechanism underlying this phenotype remains undefined. We report that the mitotic checkpoint kinase Mps1 phosphorylates a conserved threonine residue in the amino-domain of Hsp90. This, in turn, regulates chaperone function by reducing Hsp90 ATPase activity while fostering Hsp90 association with kinase clients, including Mps1. Phosphorylation of Hsp90 is also essential for the mitotic checkpoint because it confers Mps1 stability and activity. We identified Cdc14 as the phosphatase that dephosphorylates Hsp90 and disrupts its interaction with Mps1. This causes Mps1 degradation, thus providing a mechanism for its inactivation. Finally, Hsp90 phosphorylation sensitizes cells to its inhibitors, and elevated Mps1 levels confer renal cell carcinoma selectivity to Hsp90 drugs. Mps1 expression level can potentially serve as a predictive indicator of tumor response to Hsp90 inhibitors.