An Investigation of the Required MR Bone Attenuation Correction for Quantitative Whole-Body PET/MR Imaging Using Clinical NaF PET/CT Studies

Tissue-classification-based attenuation correction strategies have been previously proposed to correct for bone attenuation in PET/MR imaging and simulated using computed tomography. However, the complication of voxel averaging uniquely associated with bone has not been considered explicitly in the past. This study investigated the effect of voxel averaging between bone and soft tissue in attenuation images and determined how accurately bone must be detected in MR images in order to perform acceptable attenuation correction of PET data by using CT-simulated attenuation correction. We found out that treating bone as soft tissue caused a mean quantification difference of -9.9% ± 5.5% in all 119 bone lesions. There were no significant differences between lesions in the pelvis and the vertebrae. The nominal difference in lesions in the ribs was significantly lower, likely due to the spatial misregistration between the emission and attenuation images. Interestingly, a non-monotonic relationship between the bone imaging ability and the absolute PET quantification accuracy was observed, with the minimal quantification difference achieved at a BVF around 40% for skull lesions (2.6% ± 2.1%), and 30% for non-skull lesions (1.4% ± 1.1%) and all lesions (1.5% ± 1.3%). This study established that a bone classification sensitivity of approximately 30% BVF is required in order for MR-based attenuation correction methods to achieve optimal quantification in whole-body PET/MR studies. For this purpose, higher bone imaging ability of MR may not be necessary.

Detection of RASSF1A promoter hypermethylation in serum from gastric and colorectal adenocarcinoma patients

AIM:To evaluate the diagnostic role of serum RASSF1A promoter hypermethylation in gastric and colorectal ad- enocarcinoma. METHODS:Methylation-specific polymerase chain reac- tion (MSPCR) was used to examine the promoter meth- ylation status of the serum RASSF1A gene in 47 gastric adenocarcinoma patients, 45 colorectal adenocarcinoma patients, 60 patients with benign gastrointestinal dis- ease (30 with benign gastric disease and 30 with benign colorectal disease), and 30 healthy donor controls. Apaired study of RASSF1A promoter methylation status in primary tumor, adjacent normal tissue, and postopera- tive serum were conducted in 25 gastric and colorectal adenocarcinoma patients who later were underwent sur- gical therapy. RESULTS:The frequencies of detection of serum RASSF1A promoter hypermethylation in gastric (34.0%) and colorectal (28.9%) adenocarcinoma patients were significantly higher than those in patients with benign gastric (3.3%) or colorectal (6.7%) disease or in healthy donors (0%) (P < 0.01). The methylation status of RASSF1A promoter in serum samples was consistent with that in paired primary tumors, and the MSPCR results for RASSF1A promoter methylation status in paired preoperative samples were consistent with those in postoperative serum samples. The serum RASSF1A promoter hypermethylation did not correlate with patient sex, age, tumor differentiation grade, surgical therapy, or serum carcinoembryonic antigen level. Although the serum RASSF1A promoter hypermethylation frequency tended to be higher in patients with distant metastases, there was no correlation between methylation status and metastasis. CONCLUSION:Aberrant CpG island methylation within the promoter region of RASSF1A is a promising biomark- er for gastric and colorectal cancer.

Nonmetabolic functions of pyruvate kinase isoform M2 in controlling cell cycle progression and tumorigenesis

Pyruvate kinase catalyzes the rate-limiting final step of glycolysis, generating adenosine triphosphate (ATP) and pyruvate. The M2 tumor-specific isoform of pyruvate kinase (PKM2) promotes glucose uptake and lactate production in the presence of oxygen, known as aerobic glycolysis or the Warburg effect. As recently reported in Nature, PKM2, besides its metabolic function, has a nonmetabolic function in the direct control of cell cycle progression by activating β-catenin and inducing expression of the β-catenin downstream gene CCND1 (encoding for cyclin D1). This nonmetabolic function of PKM2 is essential for epidermal growth factor receptor (EGFR) activation-induced tumorigenesis.

Regulation of tumor cell migration by protein tyrosine phosphatase (PTP)-proline-, glutamate-, serine-,and threonine-rich sequence(PEST)

Protein tyrosine phosphatase (PTP)-proline-,glutamate-,serine-,and threonine-rich sequence (PEST) is ubiquitously expressed and is a critical regulator of cell adhesion and migration.PTP-PEST activity can be regulated transcriptionally via gene deletion or mutation in several types of human cancers or via post-translational modifications,including phosphorylation,oxidation,and caspase-dependent cleavage.PTP-PEST interacts with and dephosphorylates cytoskeletal and focal adhesion-associated proteins.Dephos-phorylation of PTP-PEST substrates regulates their enzymatic activities and/or their interaction with other proteins and plays an essential role in the tumor cell migration process.

Metabolic alterations in cancer cells and therapeutic implications

Cancer metabolism has emerged as an important area of research in recent years.Elucidation of the metabolic differences between cancer and normal cells and the underlying mechanisms will not only advance our understanding of fundamental cancer cell biology but also provide an important basis for the development of new therapeutic strategies and novel compounds to selectively eliminate cancer cells by targeting their unique metabolism.This article reviews several important metabolic alterations in cancer cells,with an emphasis on increased aerobic glycolysis (the Warburg effect) and glutamine addiction,and discusses the mechanisms that may contribute to such metabolic changes.In addition,metabolic alterations in cancer stem cells,mitochondrial metabolism and its influence on drug sensitivity,and potential therapeutic strategies and agents that target cancer metabolism are also discussed.

Patient-Specific and Generic Immobilization Devices for Prostate Radiotherapy

The purpose of our study was to compare interfractional bony setup variations in pelvic anatomy with two immobilization devices, the patient-specific Vac-Lok and the generic Dual Leg Positioner system (both Civco Medical Solutions, Kalona, IA), for bilateral proton radiotherapy of the prostate. Two groups of 10 patients were studied. Computed tomography (CT) was performed three times a week, yielding 233 CT image sets for the vacuum system group and 252 for the other group. The translational shifts of the pelvic bone and prostate and rotation of the upper femurs of the femoral heads with respect to the simulation CT images were analyzed. Along the anterior-posterior and lateral axes, mean and systematic translational variations of the pelvic bone and prostate, relative to skin fiducials, were significantly lower in the Vac-Lok group (all p 0.01) than in the Dual Leg Positioner group. Abduction of the upper femur, the dominant rotation, had random rotational variations of 1.9° and 2.0° and systematic rotations of 3.1&#176 and 2.9&#176 for the vacuum and generic system groups, respectively. Femoral abduction was highly correlated with anterior prostate displacement for both femurs in both groups (p tion introduced during simulation CT, particularly with the generic immobilization system. High degrees of femoral rotation may introduce prostate translation and distal misalignment of lateral proton beams with the prostate.

Dextran sulfate sodium-induced acute colitis impairs dermal lymphatic function in mice

AIM: To investigate whether dermal lymphatic function and architecture are systemically altered in dextran sulfate sodium(DSS)-induced acute colitis.METHODS: Balb/c mice were administered 4% DSS in lieu of drinking water ad libitum for 7 d and monitored to assess disease activity including body weight, diarrhea severity, and fecal bleeding. Control mice received standard drinking water with no DSS. Changes in mesenteric lymphatics were assessed following oral administration of a fluorescently-labelled fatty acid analogue, while dermal lymphatic function and architecture was longitudinally characterized using dynamic near-infrared fluorescence(NIRF) imaging following intradermal injection of indocyanine green(ICG) at the base of the tail or to the dorsal aspect of the left paw prior to, 4, and 7 d after DSSadministration. We also measured dye clearance rate after injection of Alexa680-bovine serum albumin(BSA). NIRF imaging data was analyzed to reveal lymphatic contractile activity after selecting fixed regions of interest(ROIs) of the same size in fluorescent lymphatic vessels on fluorescence images. The averaged fluorescence intensity within the ROI of each fluorescence image was plotted as a function of imaging time and the lymphatic contraction frequency was computed by assessing the number of fluorescent pulses arriving at a ROI. RESULTS: Mice treated with DSS developed acute inflammation with clinical symptoms of loss of body weight, loose feces/watery diarrhea, and fecal blood, all of which were aggravated as disease progressed to 7 d. Histological examination of colons of DSS-treated mice confirmed acute inflammation, characterized by segmental to complete loss of colonic mucosa with an associated chronic inflammatory cell infiltrate that extended into the deeper layers of the wall of the colon, compared to control mice. In situ intravital imaging revealed that mice with acute colitis showed significantly fewer fluorescent mesenteric lymphatic vessels, indicating impaired uptake of a lipid tracer within mesenteric lymphatics. Our in vivo NIRF imaging data demonstrated dilated dermal lymphatic vessels, which were confirmed by immunohistochemical staining of lymphatic vessels, and significantly reduced lymphatic contractile function in the skin of mice with DSS-induced acute colitis. Quantification of the fluorescent intensity remaining in the depot as a function of time showed that there was significantly higher Alexa680-BSA fluorescence in mice with DSSinduced acute colitis compared to pre-treatment with DSS, indicative of impaired lymphatic drainage.CONCLUSION: The lymphatics are locally and systemically altered in acute colitis, and functional NIRF imaging is useful for noninvasively monitoring systemic lymphatic changes during inflammation.

Survival and maintenance of regulatory T cells require the kinase TAK1

Regulatory T （Treg） cells play a central role in regulating peripheral immune tolerance and preventing autoimmunity. Despite the extensive studies on the development of Treg cells, the molecular mechanisms that maintain the population of committed Treg cells remain poorly understood. We show here that Treg-conditional ablation of the kinase TAK1 reduced the number of Treg cells in the peripheral lymphoid organs, causing abnormal activation of conventional T cells and autoimmune symptoms. Using an inducible gene knockout approach, we further demonstrate that TAK1 is crucial for the survival of Treg cells. Expression of a constitutively active IKB kinase partially restored the level of Treg cells in the TAKITreg-KO mice. These results suggest a crucial role for TAK1 for maintaining the survival of committed Treg cells under physiololzical conditions.

Dynamic Behavior and Function of Foxp3^+ Regulatory T Cells in Tumor Bearing Host

Regulatory T cells （Tregs） expressing forkhead/winged-helix transcription factor Foxp3 represent a distinct lineage of lymphocytes which play a central role in protecting the host from autoimmune diseases. However, Tregs also pose a major problem to anti-tumor immunity. Growing body of evidence from both laboratory and clinical investigations has demonstrated that expansion and accumulation of these immunosuppressive cells correlates with advanced tumor growth and predicts poor disease prognosis. How tumor development subverts normal self-tolerance function of Tregs thereby thwarts host anti-tumor immunity remains elusive. This review will discuss our current knowledge in understanding the dynamics and plasticity of Foxp3~ Treg activation and induction in tumor bearing hosts and their interaction with various antigen presenting cells （APCs） in tumor microenvironment leading to the establishment of active local and systemic immune suppression. Cellular ＆ Molecular Immunology.

Deubiquitinases as pivotal regulators of T cell functions

T cells efficiently respond to foreign antigens to mediate immune responses against infections but are tolerant to self-tissues. Defect in T cell activation is associated with severe immune deficiencies, whereas aberrant T cell activation contributes to the pathogenesis of diverse autoimmune and inflammatory diseases. An emerging mechanism that regulates T cell activation and tolerance is ubiquitination, a reversible process of protein modification that is counter-regulated by ubiquitinating enzymes and deubiquitinases （DUBs）. DUBs are isopeptidases that cleave polyubiquitin chains and remove ubiquitin from target proteins, thereby controlling the magnitude and duration of ubiquitin signaling. It is now well recognized that DUBs are crucial regulators of T cell responses and serve as potential therapeutic targets for manipulating immune responses in the treatment of immunological disorders and cancer. This review will discuss the recent progresses regarding the functions of DUBs in T cells.