Detection of primary sites in unknown primary tumors using FDG-PET or FDG-PET/CT

<p>Abstract</p> <p>Background</p> <p>Carcinoma of unknown primary tumors (CUP) is present in 0.5%-9% of all patients with malignant neoplasms; only 20%-27% of primary sites are identified before the patients die. Currently, 18F-fluorodeoxy-glucose positron-emission tomography (18F-FDG PET) or PET combined with computed tomography (PET/CT) is widely used for the diagnosis of CUP. However, the diagnostic yield of the primary site varies. The aim of this study was to determine whether PET or PET/CT has additional advantages over the conventional diagnostic workup in detecting the primary origin of CUP.</p> <p>Findings</p> <p>Twenty patients with unknown primary tumors that underwent PET or PET/CT were included in this study. For all patients, the conventional diagnostic workup was unsuccessful in detecting the primary sites. Among 20 patients, 11 had PET scans. The remaining nine patients had PET/CT. In all 20 patients, neither the PET nor PET/CT identified the primary site of the tumor, including six cases with cervical lymph node metastases. The PET and PET/CT revealed sites of FDG uptake other than those associated with known metastases in seven patients, but these findings did not influence patient management or therapy. Two patients had unnecessary invasive diagnostic procedures due to false positive results on the PET or PET/CT.</p> <p>Conclusions</p> <p>Although it is inconclusive because of small sample size of the study, the additional value of PET or PET/CT for the detection of primary sites in patients with CUP might be less than expected; especially in patients that have already had extensive conventional diagnostic workups. Further study is needed to confirm this finding.</p

Representation of cognitive reappraisal goals in frontal gamma oscillations

Recently, numerous efforts have been made to understand the neural mechanisms underlying cognitive regulation of emotion, such as cognitive reappraisal. Many studies have reported that cognitive control of emotion induces increases in neural activity of the control system, including the prefrontal cortex and the dorsal anterior cingulate cortex, and increases or decreases (depending upon the regulation goal) in neural activity of the appraisal system, including the amygdala and the insula. It has been hypothesized that information about regulation goals needs to be processed through interactions between the control and appraisal systems in order to support cognitive reappraisal. However, how this information is represented in the dynamics of cortical activity remains largely unknown. To address this, we investigated temporal changes in gamma band activity (35-55 Hz) in human electroencephalograms during a cognitive reappraisal task that was comprised of three reappraisal goals: To decease, maintain, or increase emotional responses modulated by affect-laden pictures. We examined how the characteristics of gamma oscillations, such as spectral power and large-scale phase synchronization, represented cognitive reappraisal goals. We found that left frontal gamma power decreased, was sustained, or increased when the participants suppressed, maintained, or amplified their emotions, respectively. This change in left frontal gamma power appeared during an interval of 1926 to 2453 ms after stimulus onset. We also found that the number of phase-synchronized pairs of gamma oscillations over the entire brain increased when participants regulated their emotions compared to when they maintained their emotions. These results suggest that left frontal gamma power may reflect cortical representation of emotional states modulated by cognitive reappraisal goals and gamma phase synchronization across whole brain regions may reflect emotional regulatory efforts to achieve these goals. Our study may provide the basis for an electroencephalogram-based neurofeedback system for the cognitive regulation of emotion.open0

Late time behaviors of the expanding universe in the IIB matrix model

Recently we have studied the Lorentzian version of the IIB matrix model as a nonperturbative formulation of superstring theory. By Monte Carlo simulation, we have shown that the notion of time ---as well as space---emerges dynamically from this model, and that we can uniquely extract the real-time dynamics, which turned out to be rather surprising: after some "critical time", the SO(9) rotational symmetry of the nine-dimensional space is spontaneously broken down to SO(3) and the three-dimensional space starts to expand rapidly. In this paper, we study the same model based on the classical equations of motion, which are expected to be valid at later times. After providing a general prescription to solve the equations, we examine a class of solutions, which correspond to manifestly commutative space. In particular, we find a solution with an expanding behavior that naturally solves the cosmological constant problem.Comment: 25 pages, 3 figure

Inhibition of glucose metabolism selectively targets autoreactive follicular helper T cells.

Follicular helper T (TFH) cells are expanded in systemic lupus erythematosus, where they are required to produce high affinity autoantibodies. Eliminating TFH cells would, however compromise the production of protective antibodies against viral and bacterial pathogens. Here we show that inhibiting glucose metabolism results in a drastic reduction of the frequency and number of TFH cells in lupus-prone mice. However, this inhibition has little effect on the production of T-cell-dependent antibodies following immunization with an exogenous antigen or on the frequency of virus-specific TFH cells induced by infection with influenza. In contrast, glutaminolysis inhibition reduces both immunization-induced and autoimmune TFH cells and humoral responses. Solute transporter gene signature suggests different glucose and amino acid fluxes between autoimmune TFH cells and exogenous antigen-specific TFH cells. Thus, blocking glucose metabolism may provide an effective therapeutic approach to treat systemic autoimmunity by eliminating autoreactive TFH cells while preserving protective immunity against pathogens

Deficiency of the Mitochondrial Electron Transport Chain in Muscle Does Not Cause Insulin Resistance

It has been proposed that muscle insulin resistance in type 2 diabetes is due to a selective decrease in the components of the mitochondrial electron transport chain and results from accumulation of toxic products of incomplete fat oxidation. The purpose of the present study was to test this hypothesis.Rats were made severely iron deficient, by means of an iron-deficient diet. Iron deficiency results in decreases of the iron containing mitochondrial respiratory chain proteins without affecting the enzymes of the fatty acid oxidation pathway. Insulin resistance was induced by feeding iron-deficient and control rats a high fat diet. Skeletal muscle insulin resistance was evaluated by measuring glucose transport activity in soleus muscle strips. Mitochondrial proteins were measured by Western blot. Iron deficiency resulted in a decrease in expression of iron containing proteins of the mitochondrial respiratory chain in muscle. Citrate synthase, a non-iron containing citrate cycle enzyme, and long chain acyl-CoA dehydrogenase (LCAD), used as a marker for the fatty acid oxidation pathway, were unaffected by the iron deficiency. Oleate oxidation by muscle homogenates was increased by high fat feeding and decreased by iron deficiency despite high fat feeding. The high fat diet caused severe insulin resistance of muscle glucose transport. Iron deficiency completely protected against the high fat diet-induced muscle insulin resistance.The results of the study argue against the hypothesis that a deficiency of the electron transport chain (ETC), and imbalance between the ETC and β-oxidation pathways, causes muscle insulin resistance

Discovery of Q203, a potent clinical candidate for the treatment of tuberculosis

New therapeutic strategies are needed to combat the tuberculosis pandemic and the spread of multidrug-resistant (MDR) and extensively drug-resistant (XDR) forms of the disease, which remain a serious public health challenge worldwide1, 2. The most urgent clinical need is to discover potent agents capable of reducing the duration of MDR and XDR tuberculosis therapy with a success rate comparable to that of current therapies for drug-susceptible tuberculosis. The last decade has seen the discovery of new agent classes for the management of tuberculosis3, 4, 5, several of which are currently in clinical trials6, 7, 8. However, given the high attrition rate of drug candidates during clinical development and the emergence of drug resistance, the discovery of additional clinical candidates is clearly needed. Here, we report on a promising class of imidazopyridine amide (IPA) compounds that block Mycobacterium tuberculosis growth by targeting the respiratory cytochrome bc1 complex. The optimized IPA compound Q203 inhibited the growth of MDR and XDR M. tuberculosis clinical isolates in culture broth medium in the low nanomolar range and was efficacious in a mouse model of tuberculosis at a dose less than 1 mg per kg body weight, which highlights the potency of this compound. In addition, Q203 displays pharmacokinetic and safety profiles compatible with once-daily dosing. Together, our data indicate that Q203 is a promising new clinical candidate for the treatment of tuberculosis

Inhibitory effect of 4-O-methylhonokiol on lipopolysaccharide-induced neuroinflammation, amyloidogenesis and memory impairment via inhibition of nuclear factor-kappaB in vitro and in vivo models

<p>Abstract</p> <p>Background</p> <p>Neuroinflammation is important in the pathogenesis and progression of Alzheimer disease (AD). Previously, we demonstrated that lipopolysaccharide (LPS)-induced neuroinflammation caused memory impairments. In the present study, we investigated the possible preventive effects of 4-<it>O</it>-methylhonokiol, a constituent of <it>Magnolia officinalis</it>, on memory deficiency caused by LPS, along with the underlying mechanisms.</p> <p>Methods</p> <p>We investigated whether 4-<it>O</it>-methylhonokiol (0.5 and 1 mg/kg in 0.05% ethanol) prevents memory dysfunction and amyloidogenesis on AD model mice by intraperitoneal LPS (250 μg/kg daily 7 times) injection. In addition, LPS-treated cultured astrocytes and microglial BV-2 cells were investigated for anti-neuroinflammatory and anti-amyloidogenic effect of 4-<it>O</it>-methylhonkiol (0.5, 1 and 2 μM).</p> <p>Results</p> <p>Oral administration of 4-<it>O</it>-methylhonokiol ameliorated LPS-induced memory impairment in a dose-dependent manner. In addition, 4-<it>O</it>-methylhonokiol prevented the LPS-induced expression of inflammatory proteins; inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) as well as activation of astrocytes (expression of glial fibrillary acidic protein; GFAP) in the brain. In <it>in vitro </it>study, we also found that 4-<it>O</it>-methylhonokiol suppressed the expression of iNOS and COX-2 as well as the production of reactive oxygen species, nitric oxide, prostaglandin E₂, tumor necrosis factor-α, and interleukin-1β in the LPS-stimulated cultured astrocytes. 4-<it>O</it>-methylhonokiol also inhibited transcriptional and DNA binding activity of NF-κB via inhibition of IκB degradation as well as p50 and p65 translocation into nucleus of the brain and cultured astrocytes. Consistent with the inhibitory effect on neuroinflammation, 4-<it>O</it>-methylhonokiol inhibited LPS-induced Aβ_1-42generation, β- and γ-secretase activities, and expression of amyloid precursor protein (APP), BACE1 and C99 as well as activation of astrocytes and neuronal cell death in the brain, in cultured astrocytes and in microglial BV-2 cells.</p> <p>Conclusion</p> <p>These results suggest that 4-<it>O</it>-methylhonokiol inhibits LPS-induced amyloidogenesis via anti-inflammatory mechanisms. Thus, 4-<it>O</it>-methylhonokiol can be a useful agent against neuroinflammation-associated development or the progression of AD.</p

Microstructural Abnormalities in Subcortical Reward Circuitry of Subjects with Major Depressive Disorder

Previous studies of major depressive disorder (MDD) have focused on abnormalities in the prefrontal cortex and medial temporal regions. There has been little investigation in MDD of midbrain and subcortical regions central to reward/aversion function, such as the ventral tegmental area/substantia nigra (VTA/SN), and medial forebrain bundle (MFB).We investigated the microstructural integrity of this circuitry using diffusion tensor imaging (DTI) in 22 MDD subjects and compared them with 22 matched healthy control subjects. Fractional anisotropy (FA) values were increased in the right VT and reduced in dorsolateral prefrontal white matter in MDD subjects. Follow-up analysis suggested two distinct subgroups of MDD patients, which exhibited non-overlapping abnormalities in reward/aversion circuitry. The MDD subgroup with abnormal FA values in VT exhibited significantly greater trait anxiety than the subgroup with normal FA values in VT, but the subgroups did not differ in levels of anhedonia, sadness, or overall depression severity.These findings suggest that MDD may be associated with abnormal microstructure in brain reward/aversion regions, and that there may be at least two subtypes of microstructural abnormalities which each impact core symptoms of depression