Impact of disseminated tumor cells in the bone marrow on survival and disease progression in patients with left-sided colorectal cancer.

INTRODUCTION: Disseminated tumor cells (DTCs) are a subset of circulating tumor cells that migrate to the bone marrow. Colorectal cancer is a heterogeneous disease depending on the site of the primary tumor. OBJECTIVES: We aimed to assess the association between the presence of DTCs in the bone marrow and tumor characteristics as well as long­term treatment outcomes in patients with left­sided colorectal cancer. PATIENTS AND METHODS: This prospective study included 91 patients with left­sided colorectal cancer (37 with colon cancer and 54 with rectal cancer) treated between 2007 and 2012 in a single tertiary center. Fifteen patients had stage I cancer; 26, stage II; 26, stage III; and 24, stage IV. Overall survival and cancer relapse rates were compared between patients with different cancer stages and DTC status. RESULTS: Bone marrow DTCs were identified in 42 patients (46.1%). The prevalence of DTCs was not related to tumor infiltration depth, nodal involvement, distant metastasis, tumor stage, or primary tumor site. The 5­year overall survival rates were 59.5% and 53% in the DTC­positive and DTC­negative groups, respectively (P = 0.19). There was a notable trend favoring survival in patients with DTCs with stage II and III disease (both separately and when combined). The number of metachronous distant metastases was significantly lower in DTC­positive patients. CONCLUSIONS: The presence of DTCs in the bone marrow is not associated with primary tumor characteristics and seems to reduce metastasis formation in left­sided colorectal cancer. There is also a trend for improved overall survival in DTC­positive patients. These results are intriguing and warrant further confirmation.

The first reported case of vincristine-induced unilateral vocal cord palsy in an adult patient with HIV-associated Burkitt-like lymphoma being treated with dose-escalated R-EPOCH.

Vincristine-induced vocal cord palsy (VCP) is a rare but critical complication. Prompt recognition of VCP is imperative. Vincristine-induced VCP is reversible, and a complete remission of a lymphoma is still feasible upon withdrawal of vincristine from the chemotherapeutic regimen early in the course of treatment.

A rare case of hepatosplenic gamma-delta T-cell lymphoma and secondary hemophagocytic lymphohistiocytosis.

Hepatosplenic gamma-delta T-cell lymphoma with concurrent hemophogocytic lymphohistiocytosis is a rare but well-recognized clinical scenario, associated with a grim prognosis. Clinicians must be aware of this aggressive type of lymphoma so that a prompt diagnosis can be made with timely initiation of systemic therapy and referral for bone marrow transplant.

The Impact of Postoperative Enteral Immunonutrition on Postoperative Complications and Survival in Gastric Cancer Patients - Randomized Clinical Trial.

BACKGROUND: Immunomodulating enteral nutrition in the perioperative period may reduce postoperative complications in cancer patients. Little is known if this effect translates to the better survival. The aim of study was to assess the impact of postoperative immunomodulating enteral nutrition on postoperative complications and survival of gastric cancer patients. METHODS: A group of 98 gastric cancer patients was randomly assigned for postoperative immunomodulating enteral nutrition n = 44 (Reconvan, Fresenius Kabi, Bad Homburg, Germany), or standard enteral nutrition n = 54 (Peptisorb, Nutricia, Schipol, The Netherlands). Postoperative complications, mortality, 6-mo and 1-yr survival were analyzed. RESULTS: The overall postoperative morbidity did not differ between the groups. The rate of pulmonary complications (excluding pneumonia) was significantly lower in immunomodulation group (0% vs 9.3%, p = 0.044), as well as 60-day mortality (0% vs. 11.1%, p = 0.037). There was no difference in 6-mo and 1-yr survival between the groups. CONCLUSIONS: Postoperative immunomodulating enteral nutrition may reduce respiratory complications and postoperative mortality in comparison to standard enteral nutrition. Despite this effect, it did not improve 6-mo and 1-yr survival in immunomodulation group. Probably the beneficial effect of immunomodulating enteral nutrition is too weak to be significant in such a number of patients.

Induced Chemical Defense of a Mushroom by a Double-Bond-Shifting Polyene Synthase.

The antilarval mushroom polyenes 18-methyl-19-oxoicosaoctaenoic acid and 20-methyl-21-oxodocosanonaenoic acid appear in response to injury of the mycelium of the stereaceous mushroom BY1. We identified a polyketide synthase (PPS1) which belongs to a hitherto completely uncharacterized clade of polyketide synthases. Expression of the PPS1 gene is massively upregulated following mycelial damage. The synthesis of the above polyenes was reconstituted in the mold Aspergillus niger as a heterologous host. This demonstrates that PPS1 1) synchronously produces branched-chain polyketides of varied lengths, and 2) catalyzes the unprecedented shift of eight or nine double bonds. This study represents the first characterization of a reducing polyketide synthase from a mushroom. We also show that injury-induced de novo synthesis of polyketides is a fungal response strategy.

Unexpected Metabolic Versatility in a Combined Fungal Fomannoxin/Vibralactone Biosynthesis.

The secondary metabolome of an undescribed stereaceous basidiomycete (BY1) was investigated for bioactive compounds. Along with a known fomannoxin derivative and two known vibralactones, we here describe three new compounds of these natural product families, whose structures were elucidated using 1D and 2D NMR spectroscopy and high-resolution mass spectrometry. The new compound vibralactone S (4) shows a 3,6-substituted oxepin-2(7H)-one ring system, which is unprecedented for the vibralactone/fomannoxin class of compounds. Stable isotope labeling established a biosynthetic route that is dissimilar to the two published cascades of oxepinone formation. Another new compound, the antifungal methyl seco-fomannoxinate (6), features a 2-methylprop-1-enyl ether moiety, which is only rarely observed with natural products. The structure of 6 was confirmed by total synthesis. (13)C-labeling experiments revealed that the unusual 2-methylprop-1-enyl ether residue derives from an isoprene unit. The diversity of BY1's combined fomannoxin/vibralactone metabolism is remarkable in that these compound families, although biosynthetically related, usually occur in different organisms.

Preoperative serum chemokine (C-C motif) ligand 2 levels and prognosis in colorectal cancer.

INTRODUCTION: Chemokines are cytokines with chemotactic functions in the initiation and maintenance of immune reactions. They have also been shown to regulate other processes such as cancer progression and cancer cell migration. OBJECTIVES: The aim of this study was to determine the prognostic role of serum levels of chemokine (C-C motif) ligand 2 (CCL2) and chemokine (C-C motif) ligand 5 (CCL5) in patients with colorectal cancer. PATIENTS AND METHODS: The study included a group of 45 patients with colorectal cancer. The serum concentrations of CCL2 and CCL5 were measured preoperatively. Peripheral blood mononuclear cells (PBMC) from patients' blood were isolated and cultured alone or with cancer cells. The concentrations of chemokines in serum and culture supernatants were measured using the cytometric bead array method. The cut-off points for serum chemokine levels were set based on the receiver-operating characteristic curve analysis at a level of 103.6 pg/ml for CCL2 and of 11933.2 pg/ml for CCL5. The survival analysis and multivariate analysis of prognostic factors were performed. RESULTS: The 5-year survival was 57.5% for the group with low CCL2 levels and 23.87% for the group with high CCL2 levels. For the groups with low and high CCL5 levels, the survival was 18.3% and 49.3%, respectively. For CCL2, the survival of the low-level group was significantly better than that of the highlevel group (P = 0.0028). In the Cox proportional hazard model, radicality of resection (P = 0.001) and CCL2 levels (P = 0.029) were independent prognostic factors. CONCLUSIONS: The serum level of CCL2 in patients with colorectal cancer may have prognostic value. One of the possible mechanisms of CCL2 production is the interaction of PBMC with cancer cells.

Clusters of bound Ca(2+) initiate contraction in fast skeletal muscle.

Ca(2+)-binding to troponin C ultimately controls force in muscle leading to the expectation that the two curves, pCa/force and pCa/Ca(2+) binding, will coincide. Using an improved fluorescence apparatus to measure Ca(2+)-binding, we confirm a displacement between the position and shape of the pCa/Ca(2+)-binding and pCa/force curves. This displacement may be part of a mechanism that reduces the noise inherent in the control process. There must always be some Ca(2+)-binding events even at 10 or 100nM, well below threshold for muscle contraction. To minimize the response to such random binding events we suggest that clusters of adjacent Ca(2+)-binding sites must be filled before contraction is initiated. Clusters promote the reconfiguration of the thin filament to the "On" state; this simultaneously increases thin filaments' affinity for myosin heads and of troponin C for Ca(2+) producing the highly cooperative pCa/force curve. The cluster requirement displaces the Ca(2+)-binding from the force curve as observed. The thin filament conformational changes and the accompanying affinity increases introduce a discontinuity in the pCa/Ca(2+)-binding curve. The curve, therefore, is most appropriately fit by two separate Hill equations, a simple non-cooperative one (midpoint, pK1, n1∼1) for the foot and a second cooperative one (pK2, n2∼2.5) for the upper part. With this fit pK2 is larger than pK1 as our argument requires, in contrast to fitting to the sum of two Hill equations. It also expresses the idea that there may be three states of the thin filament.

The troponin I: inhibitory peptide uncouples force generation and the cooperativity of contractile activation in mammalian skeletal muscle.

Hodges and his colleagues identified a 12 amino acid fragment of troponin I (TnI-ip) that inhibits Ca(2+)-activated force and reduces the effectiveness Ca(2+) as an activator. To understand the role of troponin C (TnC) in the extended cooperative interactions of thin filament activation, we compared the effect of TnI-ip with that of partial troponin TnC extraction. Both methods reduce maximal Ca(2+)-activated force and increase [Ca(2+)] required for activation. In contrast to TnC extraction, TnI-ip does not reduce the extended cooperative interactions between adjacent thin filament regulatory units as assessed by the slope of the pCa/force relationship. Additional evidence that TnI-ip does not interfere with extended cooperativity comes from studies that activate muscle by rigor crossbridges (RXBs). TnI-ip increases both the cooperativity of activation and the concentration of RXBs needed for maximal force. This shows that TnI-ip binding to TnC increases the stability of the relaxed state of the thin filament. TnI-ip, therefore, uncouples force generation from extended cooperativity in both Ca(2+) and RXB activated muscle contraction. Because maximum force can be reduced with no change-or even an increase-in cooperativity, force-generating crossbridges do not appear to be the primary activators of cooperativity between thin filament regulatory units of skeletal muscle.

Microscopic theory for anisotropic pair correlations in driven binary mixtures.

A self-consistent microscopic approach to calculate non-equilibrium pair correlations in strongly interacting driven binary mixtures is presented. The theory is derived from the many-body Smoluchowski equation for interacting Brownian particles by employing Kirkwood's superposition approximation as a closure relation. It is shown that the pair correlations can exhibit notable anisotropy and a strong tendency to laning in the driving direction. Furthermore, there are strong indications that pair correlations are characterized by a long-range decay along the drive. The theoretical results are in good quantitative agreement with the complementary Brownian dynamics computer simulations.

Expression and function of the C-class chemokine lymphotactin (XCL1) in Wegener's granulomatosis.

OBJECTIVE: In Wegener's granulomatosis (WG), vasculitic lesions are characterized by prominent infiltration of polymorphonuclear neutrophils (PMN) and T cells, but underlying pathogenic mechanisms remain to be defined. We analyzed the expression and functional role of the C-class chemokine lymphotactin, XCL1, in WG. METHODS: Sera and peripheral blood mononuclear cells (PBMC) were obtained from 16 patients with WG and healthy controls. Serum XCL1 concentrations were measured by ELISA. PBMC were subjected to flow cytometry for activation markers and immunophenotype of XCL1+ T cells. Renal biopsies were analyzed by double-label immunohistochemistry. In vitro stimulation of PMN with XCL1 was performed to study its function. RESULTS: Flow cytometry demonstrated coexpression of the activation markers CD25, CD69, and HLA-DR in a significantly higher proportion of T cells in WG patients in comparison to controls. XCL1 was found to be mainly expressed in CD4+CD28- T cells in WG patients. In renal biopsies, the presence of XCL1 was only detected within interstitial CD4+ and CD8+ T cells. Functional studies demonstrated a significant enhancement of IL-8 production in isolated PMN after in vitro stimulation with XCL1. There were no significant differences in XCL1 serum concentrations between WG patients and controls (p = 0.88). CONCLUSION: Our data indicated increased expression of XCL1 in CD4+ and CD8+ T cells in WG. Considering its function as a lymphocyte-specific chemoattractant, XCL1 might be a key modulator of T cell recruitment in WG. Functional studies further suggest that XCL1 may support vascular inflammation by induction of release of interleukin 8 in PMN.

Solid phases in electro- and magnetorheological systems.

Ensembles of particles with a spherically symmetric repulsive Yukawa interaction and additional dipole-dipole interaction induced by an external field exhibit numerous solid-solid phase transitions controlled by the magnitude of the field. Such interactions emerge most notably in electro- and magnetorheological fluids and plasmas. We propose a simple variational approach based on the Bogoliubov inequality for determining equilibrium solid phases. Phase diagrams for several regimes are calculated and compared with previously performed Monte Carlo and molecular dynamics simulations.

Stiffness and fraction of Myosin motors responsible for active force in permeabilized muscle fibers from rabbit psoas.

The stiffness of the single myosin motor (epsilon) is determined in skinned fibers from rabbit psoas muscle by both mechanical and thermodynamic approaches. Changes in the elastic strain of the half-sarcomere (hs) are measured by fast mechanics both in rigor, when all myosin heads are attached, and during active contraction, with the isometric force (T0) modulated by changing either [Ca2+] or temperature. The hs compliance is 43.0+/-0.8 nm MPa-1 in isometric contraction at saturating [Ca2+], whereas in rigor it is 28.2+/-1.1 nm MPa-1. The equivalent compliance of myofilaments is 21.0+/-3.3 nm MPa-1. Accordingly, the stiffness of the ensemble of myosin heads attached in the hs is 45.5+/-1.7 kPa nm-1 in isometric contraction at saturating [Ca2+] (e0), and in rigor (er) it rises to 138.9+/-21.2 kPa nm-1. Epsilon, calculated from er and the lattice molecular dimensions, is 1.21+/-0.18 pN nm-1. epsilon estimated, using a thermodynamic approach, from the relation of T0 at saturating [Ca2+] versus the reciprocal of absolute temperature is 1.25+/-0.14 pN nm-1, similar to that estimated for fibers in rigor. Consequently, the ratio e0/er (0.33+/-0.05) can be used to estimate the fraction of attached heads during isometric contraction at saturating [Ca2+]. If the osmotic agent dextran T-500 (4 g/100 ml) is used to reduce the lateral filament spacing of the relaxed fiber to the value before skinning, both e0 and er increase by approximately 40%. Epsilon becomes approximately 1.7 pN nm-1 and the fraction and the force of myosin heads attached in the isometric contraction remain the same as before dextran application. The finding that the fraction of myosin heads attached to actin in an isometric contraction is 0.33 rules out the hypothesis of multiple mechanical cycles per ATP hydrolyzed.