Local steroid injection versus wrist splinting for carpal tunnel syndrome: A randomized clinical trial.

AIM: We conducted a prospective randomized parallel clinical trial comparing the efficacy of local steroid injection and nocturnal wrist splinting in patients with carpal tunnel syndrome (CTS). METHODS: The well-validated and disease-specific Boston Carpal Tunnel Questionnaire (BCTQ) was employed and its score at 4 weeks after treatment was used as the primary outcome measure. Important secondary outcomes included patient satisfaction, the change of an objective finger dexterity test and the side effects. RESULTS: Twenty-five patients in the local steroid group and 25 patients in the wrist splinting group completed the study procedures. At 4 weeks after treatment, there was significant improvement of the BTCQ scores in both the steroid group and splinting group. There was improvement of the finger dexterity test only in the steroid group but not in the splinting group. However, there was no statistically significant difference in the changes of BTCQ scores between the two groups after treatment. Patient satisfaction score was higher in the steroid group. Patients in the steroid group took fewer painkillers after treatment. Four patients developed side effects after splinting and three after local steroid injection, which was not statistically significant. CONCLUSION: Although local steroid injection and nocturnal wrist splinting were equally effective in the treatment of patients with CTS, only the former improved objective hand function. Local steroid injection also resulted in better patient satisfaction and less painkiller use without causing more side effects.

Neuroimaging and sexual behavior: identification of regional and functional differences.

The neuroanatomical correlates of human sexual desire, arousal, and behavior have been characterized in recent years with functional brain imaging techniques such as magnetic resonance imaging (MRI) and positron emission tomography (PET). Here, we briefly review the results of functional neuroimaging studies in humans, whether healthy or suffering from sexual disorders, and the current models of regional and network activation in sexual arousal. Attention is paid, in particular, to findings from both regional and network studies in the past 3 years. We also identify yet unanswered and pressing questions of interest to areas of ongoing investigations for psychiatric, scientific, and forensic disciplines.

Sphingosine 1-Phosphate Receptor 2 Regulates the Migration, Proliferation, and Differentiation of Mesenchymal Stem Cells.

Mesenchymal stem cells (MSCs) are a multipotent cell population acquired most prominently from bone marrow with the capacity to differentiate into osteoblasts, chondrocytes, adipocytes, and others. MSCs demonstrate the capacity to home to sites of injury and contribute to tissue repair. Sphingosine 1-phosphate (S1P) is a biologically active sphingolipid impacting proliferation, apoptosis, inflammation, and angiogenesis with changes in S1P concentration providing significant implications for various disease conditions including cancer, diabetes, and cardiac disease. These functions are primarily mediated by interactions with 5 G-protein coupled S1P receptors (S1PR1-5). In this paper, we demonstrate that inhibition of S1PR2 results in increased MSC clonogenicity, migration, and proliferation; features dependent on Erk phosphorylation. Furthermore, decreased S1PR2 expression decreases the differentiation of MSCs into adipocytes and mature osteoblasts that may be the result of increased expression of MSC pluripotency factors including Nanog, Sox-9, and Oct-4. Inhibition of S1PR1 and S1PR3 in contrast does not impact MSC migration or Erk activation although increased proliferation is observed. In the study, we describe the essential role of S1PR2 in MSC differentiation pathways through modification of pluripotency factors. We propose a MAPK dependent mechanism through S1PR2 inhibition that promotes equally multipotent MSC proliferation.

Radiation-induced acid ceramidase confers prostate cancer resistance and tumor relapse.

Escape of prostate cancer (PCa) cells from ionizing radiation-induced (IR-induced) killing leads to disease progression and cancer relapse. The influence of sphingolipids, such as ceramide and its metabolite sphingosine 1-phosphate, on signal transduction pathways under cell stress is important to survival adaptation responses. In this study, we demonstrate that ceramide-deacylating enzyme acid ceramidase (AC) was preferentially upregulated in irradiated PCa cells. Radiation-induced AC gene transactivation by activator protein 1 (AP-1) binding on the proximal promoter was sensitive to inhibition of de novo ceramide biosynthesis, as demonstrated by promoter reporter and ChIP-qPCR analyses. Our data indicate that a protective feedback mechanism mitigates the apoptotic effect of IR-induced ceramide generation. We found that deregulation of c-Jun induced marked radiosensitization in vivo and in vitro, which was rescued by ectopic AC overexpression. AC overexpression in PCa clonogens that survived a fractionated 80-Gy IR course was associated with increased radioresistance and proliferation, suggesting a role for AC in radiotherapy failure and relapse. Immunohistochemical analysis of human PCa tissues revealed higher levels of AC after radiotherapy failure than those in therapy-naive PCa, prostatic intraepithelial neoplasia, or benign tissues. Addition of an AC inhibitor to an animal model of xenograft irradiation produced radiosensitization and prevention of relapse. These data indicate that AC is a potentially tractable target for adjuvant radiotherapy.

Acid ceramidase promotes nuclear export of PTEN through sphingosine 1-phosphate mediated Akt signaling.

The tumor suppressor PTEN is now understood to regulate cellular processes at the cytoplasmic membrane, where it classically regulates PI3K signaling, as well as in the nucleus where multiple roles in controlling cell cycle and genome stability have been elucidated. Mechanisms that dictate nuclear import and, less extensively, nuclear export of PTEN have been described, however the relevance of these processes in disease states, particularly cancer, remain largely unknown. We investigated the impact of acid ceramidase on the nuclear-cytoplasmic trafficking of PTEN. Immunohistochemical analysis of a human prostate tissue microarray revealed that nuclear PTEN was lost in patients whose tumors had elevated acid ceramidase. We found that acid ceramidase promotes a reduction in nuclear PTEN that is dependent upon sphingosine 1-phosphate-mediated activation of Akt. We were further able to show that sphingosine 1-phosphate promotes formation of a complex between Crm1 and PTEN, and that leptomycin B prevents acid ceramidase and sphingosine 1-phosphate mediated loss of nuclear PTEN, suggesting an active exportin-mediated event. To investigate whether the tumor promoting aspects of acid ceramidase in prostate cancer depend upon its ability to export PTEN from the nucleus, we used enforced nuclear expression of PTEN to study docetaxel-induced apoptosis and cell killing, proliferation, and xenoengraftment. Interestingly, while acid ceramidase was able to protect cells expressing wild type PTEN from docetaxel, promote proliferation and xenoengraftment, acid ceramidase had no impact in cells expressing PTEN-NLS. These findings suggest that acid ceramidase, through sphingosine 1-phosphate, promotes nuclear export of PTEN as a means of promoting tumor formation, cell proliferation, and resistance to therapy.

Interdiction of sphingolipid metabolism to improve standard cancer therapies.

Non-surgical therapies for human malignancies must negotiate complex cell signaling pathways to impede cancer cell growth, ideally promoting death of cancer cells while sparing healthy tissue. For most of the past half century, medical approaches for treating cancer have relied primarily on cytotoxic chemotherapeutics that interfere with DNA replication and cell division, susceptibilities of rapidly dividing cancer cells. As a consequence, these therapies exert considerable cell stress, promoting the generation of ceramide through de novo synthesis and recycling of complex glycosphingolipids and sphingomyelin into apoptotic ceramide. Radiotherapy of cancer exerts similar geno- and cytotoxic cell stresses, and generation of ceramide following ionizing radiation therapy is a well-described feature of radiation-induced cell death. Emerging evidence now describes sphingolipids as mediators of death in response to newer targeted therapies, cementing ceramide generation as a common mechanism of cell death in response to cancer therapy. Many studies have now shown that dysregulation of ceramide accumulation-whether by reduced generation or accelerated metabolism-is a common mechanism of resistance to standard cancer therapies. The aims of this chapter will be to discuss described mechanisms of cancer resistance to therapy related to dysregulation of sphingolipid metabolism and to explore clinical and preclinical approaches to interdict sphingolipid metabolism to improve outcomes of standard cancer therapies.

LCL124, a cationic analog of ceramide, selectively induces pancreatic cancer cell death by accumulating in mitochondria.

Treatment of pancreatic cancer that cannot be surgically resected currently relies on minimally beneficial cytotoxic chemotherapy with gemcitabine. As the fourth leading cause of cancer-related death in the United States with dismal survival statistics, pancreatic cancer demands new and more effective treatment approaches. Resistance to gemcitabine is nearly universal and appears to involve defects in the intrinsic/mitochondrial apoptotic pathway. The bioactive sphingolipid ceramide is a critical mediator of apoptosis initiated by a number of therapeutic modalities. It is noteworthy that insufficient ceramide accumulation has been linked to gemcitabine resistance in multiple cancer types, including pancreatic cancer. Taking advantage of the fact that cancer cells frequently have more negatively charged mitochondria, we investigated a means to circumvent resistance to gemcitabine by targeting delivery of a cationic ceramide (l-t-C6-CCPS [LCL124: ((2S,3S,4E)-2-N-[6'-(1″-pyridinium)-hexanoyl-sphingosine bromide)]) to cancer cell mitochondria. LCL124 was effective in initiating apoptosis by causing mitochondrial depolarization in pancreatic cancer cells but demonstrated significantly less activity against nonmalignant pancreatic ductal epithelial cells. Furthermore, we demonstrate that the mitochondrial membrane potentials of the cancer cells were more negative than nonmalignant cells and that dissipation of this potential abrogated cell killing by LCL124, establishing that the effectiveness of this compound is potential-dependent. LCL124 selectively accumulated in and inhibited the growth of xenografts in vivo, confirming the tumor selectivity and therapeutic potential of cationic ceramides in pancreatic cancer. It is noteworthy that gemcitabine-resistant pancreatic cancer cells became more sensitive to subsequent treatment with LCL124, suggesting that this compound may be a uniquely suited to overcome gemcitabine resistance in pancreatic cancer.

Effects of reference objects and extra-retinal information about pursuit eye movements on curvilinear path perception from retinal flow.

We have previously shown that when traveling on a circular path, observers use the rotation in the retinal velocity field for path curvature estimation and recover their path of forward travel relative to their perceived instantaneous heading (L. Li, & J. C. K. Cheng, 2011). Here, we examined the contribution of reference objects and extra-retinal information about pursuit eye movements to curvilinear path perception. In Experiment 1, the display simulated an observer traveling on a circular path over a textured ground with and without tall posts while looking at a fixed target on the future path, along heading, or along a fixed axis in the world. We found that reference objects did not help path perception. In Experiment 2, extra-retinal signals about pursuit eye movements were introduced in two viewing conditions: one that corresponded to the natural case of traveling on a circular path when the body orientation is aligned with the instantaneous heading and one that corresponded to the unnatural case of traveling when the body orientation is fixed relative to the world. We found that extra-retinal signals support accurate path perception only for the natural case of self-motion when the body orientation is aligned with heading such that pursuit compensation helps stabilize the heading in the body-centric coordinate system.

Acid ceramidase-mediated production of sphingosine 1-phosphate promotes prostate cancer invasion through upregulation of cathepsin B.

Invasiveness is one of the key features of aggressive prostate cancer; however, our understanding of the precise mechanisms effecting invasion remains limited. The ceramide hydrolyzing enzyme acid ceramidase (AC), overexpressed in most prostate tumors, causes an aggressive and invasive phenotype through downstream effectors that have not yet been well characterized. Here, we demonstrate that AC, through generation of sphingosine-1-phosphate (S1P), promotes Ets1 nuclear expression and binding to the promoter region of matrix-degrading protease cathepsin B. Through confocal microscopy and flow cytometry, we found that AC overexpression promotes pericellular localization of cathepsin B and its translocation to the outer leaflet of the cell membrane. AC overexpressing cells have an increased abundance of cathepsin B-enriched invasive structures and enhanced ability to invade through a collagen matrix, but not in the presence of an inhibitor of cathepsin B. In human prostate tissues, AC and cathepsin B overexpression were strongly associated and may relate to poor outcome. These results demonstrate a novel pathway by which AC, through S1P, promotes an invasive phenotype in prostate cancer by causing overexpression and secretion of cathepsin B through activation and nuclear expression of Ets1. As prostate cancer prognosis is dramatically worse when invasion has occurred, this study provides critical insight into the progression toward lethal prostate cancer.

Heading but not path or the tau-equalization strategy is used in the visual control of steering toward a goal.

The visual strategies for the control of steering toward a goal include aligning one's instantaneous direction of travel (i.e., heading; J. J. Gibson, 1950) or the future path (J. P. Wann & D. K. Swapp, 2000) specified by optic flow with the target, equating the time to closure of the target-heading angle with the time to passage of the target (tau equalization, B. Fajen, 2001), or using the target egocentric direction and steering to center the target in the straight ahead or cancel the target optical drift (S. K. Rushton, J. M. Harris, M. Lloyd, & J. P. Wann, 1998). Supporting evidences for the use of these strategies in guiding steering or walking toward a goal were reported, but no consensus has been reached. In this study, by presenting participants with displays in which target egocentric direction was fixed and thus unavailable for steering to force participants to rely on information from optic flow for the control of self-motion, we systematically examined the use of the optic flow-based strategies in the visual control of steering toward a goal. We found that participants steered to align their heading with the target, supporting the use of the heading strategy. We found no evidence to support the use of the path or the tau-equalization strategy in the visual control of steering toward a goal.

Perceiving path from optic flow.

We examined how people perceive their path of traveling from optic flow. Observers viewed displays simulating their traveling on a circular path over a textured ground, a random-dot ground, or a dynamic random-dot ground display in which dots were periodically redrawn to remove extended dot motion trajectories (flow lines) in the flow field. Five viewing conditions were tested in which the simulated observer gaze direction was pointed to (1) a target on the path at 30° away from the initial heading, (2) a target at 15° outside of the path, (3) a target at 15° inside of the path, (4) along the instantaneous heading, or (5) along the Z-axis of the simulated environment. Path performance was similar for all three display conditions, indicating that observers did not rely on flow lines to perceive path from optic flow. Furthermore, contrary to the idea that looking where you want to go provides accurate path perception, path perception was accurate only when the simulated observer gaze direction pointed in the instantaneous heading direction. In contrast, heading perception was accurate and not affected by path curvature regardless of the simulated gaze direction. The results suggest that heading perception is more robust than path perception.

Optimal combination of form and motion cues in human heading perception.

We examined what role motion-streak-like form information plays in heading perception. We presented observers with an integrated form and motion display in which random-dot pairs in a 3D cloud were oriented toward one direction on the screen (the form FOE) to form a radial Glass pattern while moving in a different direction in depth (the motion FOE). Observers' heading judgments were strongly biased toward the form FOE direction (weight: 0.78), and this bias decreased with the reduction of the salience of the global form structure in the Glass pattern. At the local level, the orientation of dot pairs in the Glass pattern can affect their perceived motion direction, leading to a shift of the perceived motion FOE direction in optic flow. However, this shift accounted for about half of the total bias. Using the measurements of the shifted motion FOE and the perceived form FOE directions, we found that at the global level, an optimal combination of these two cues could accurately predict the heading bias observed for the integrated display. Our findings support the claim that motion streaks are effective cues for self-motion perception, and humans make optimal use of both form and motion cues for heading perception.

Targeting sphingolipid metabolism in head and neck cancer: rational therapeutic potentials.

IMPORTANCE OF THE FIELD: Ceramide accumulation has been shown to be a conserved mechanism of apoptosis initiation in normal physiological processes as well as in response to cancer treatments. Therefore, it is unsurprising that many cancers develop aberrations of sphingolipid metabolism that prevent the accumulation of ceramide, whether by reduction of ceramide generation or by enhanced ceramide catabolism, particularly dangerous when catabolism leads to generation of pro-tumor sphingosine-1-phosphate and ceramide-1-phosphate. Numerous studies have now implicated dysregulation of sphingolipid metabolism in head and neck cancers. AREAS COVERED IN THIS REVIEW: This review highlights the importance of sphingolipid metabolism and brings sphingolipid metabolism to the forefront in the investigation of novel therapies for head and neck cancer. It reviews sphingolipid-centric therapies under investigation in preclinical and clinical trials of cancers of the head and neck. WHAT THE READER WILL GAIN: The roles of sphingolipids and sphingolipid metabolism in cancer are reviewed and the reader will be brought up to date with discoveries in the field of sphingolipid metabolism in head and neck cancer. TAKE HOME MESSAGE: As treatments for head and neck cancers are currently limited, the potential of targeting sphingolipid metabolism should be taken into consideration as we seek novel ways to combat this group of tumors.

Acid ceramidase upregulation in prostate cancer: role in tumor development and implications for therapy.

Bioactive sphingolipids, such as ceramide, sphingosine and sphingosine-1-phosphate are known bio-effector molecules which play important roles in various aspects of cancer biology including cell proliferation, growth arrest, apoptosis, metastasis, senescence and inflammation. Therefore, enzymes involved in ceramide metabolism are gaining recognition as being critical regulators of cancer cell growth and/or survival. We previously observed that the ceramide metabolizing enzyme, acid ceramidase (AC) is upregulated in tumor tissues. Studies have now concluded that this creates a dysfunctional ceramide pathway, which is responsible for tumor progression and resistance to chemotherapy and radiation. This suggests that development of small-molecule drugs that inhibit AC enzyme activity is a promising approach for improving standard cancer therapy and patient's clinical outcomes.

Acid ceramidase upregulation in prostate cancer cells confers resistance to radiation: AC inhibition, a potential radiosensitizer.

Radiation resistance in a subset of prostate tumors remains a challenge to prostate cancer radiotherapy. The current study on the effects of radiation on prostate cancer cells reveals that radiation programs an unpredicted resistance mechanism by upregulating acid ceramidase (AC). Irradiated cells demonstrated limited changes of ceramide levels while elevating levels of sphingosine and sphingosine-1-phosphate. By genetically downregulating AC with small interfering RNA (siRNA), we observed radiosensitization of cells using clonogenic and cytotoxicity assays. Conversely, AC overexpression further decreased sensitivity to radiation. We also observed that radiation-induced AC upregulation was sufficient to create cross-resistance to chemotherapy as demonstrated by decreased sensitivity to Taxol and C(6) ceramide compared to controls. Lower levels of caspase 3/7 activity were detected in cells pretreated with radiation, also indicating increased resistance. Finally, utilization of the small molecule AC inhibitor, LCL385, sensitized PPC-1 cells to radiation and significantly decreased tumor xenograft growth. These data suggest a new mechanism of cancer cell resistance to radiation, through upregulation of AC that is, in part, mediated by application of the therapy itself. An improved understanding of radiotherapy and the application of combination therapy achieved in this study offer new opportunities for the modulation of radiation effects in the treatment of cancer.

New insights on the use of desipramine as an inhibitor for acid ceramidase.

Treatment of different cancer cell lines with desipramine induced a time- and dose-dependent downregulation of acid ceramidase. Desipramine's effect on acid ceramidase appeared specific for amphiphilic agents (desipramine, chlorpromazine, and chloroquine) but not other lysomotropic agents such as ammonium chloride and bafilomycin A1, and was not transcriptionally regulated. The cathepsin B/L inhibitor, CA074ME, but not the cathepsin D inhibitor, pepstatin A, blocked desipramine's effect on acid ceramidase. Desipramine led to a more pronounced downregulation of sphingosine compared to ceramide suggesting acid ceramidase inhibition is important to desipramine's mechanism of action. This study reveals a new mechanism of action for desipramine.

Detection of chromosomal aneuploidies and gene copy number changes in fine needle aspirates is a specific, sensitive, and objective genetic test for the diagnosis of breast cancer.

Fine needle aspiration cytology is central to the evaluation of clinically or mammographically detected suspicious lesions of the breast. On the basis of results from studies of >500 breast cancers by comparative genomic hybridization we have developed protocols and designed probe sets that allow one to visualize recurrent chromosomal aneuploidies, amplification of oncogenes, and deletion of tumor suppressor genes directly in cytological preparations using multicolor fluorescence in situ hybridization. The fluorescence in situ hybridization probes are specific for chromosome arm 1q, the c-MYC and HER2 oncogenes, the tumor suppressor gene p53 and, as controls for chromosome ploidy of each cell, the centromeres of chromosomes 8, 10, and 17. Application of these diagnostic mixtures to 20 invasive breast cancers, 7 mastopathias, and 2 fibroadenomas demonstrates that a highly sensitive, specific, and objective diagnosis of breast cancer is now possible on cytological preparations obtained by minimally invasive fine needle aspiration.