Effects of edge disorder on the stability of quantum oscillations in two-dimensional coupled systems.

This paper utilizes the theory of quantum diffusion to analyze the electron probability and spreading width of a wavepacket on each layer in a two-dimensional (2D) coupled system with edge disorder, aiming to clarify the effects of edge disorder on the stability of the electron periodic oscillations in 2D coupled systems. Using coupled 2D square lattices with edge disorder as an example, we show that, the electron probability and wavepacket spreading width exhibit periodic oscillations and damped oscillations, respectively, before and after the wavepacket reaches the boundary. Furthermore, these electron oscillations exhibit strong resistance against disorder perturbation with a longer decay time in the regime of large disorder, due to the combined influences of ordered and disordered site energies in the central and edge regions. Finally, we numerically verified the universality of the results through bilayer graphene, demonstrating that this anomalous quantum oscillatory behavior is independent of lattice geometry. Our findings are helpful in designing relevant quantum devices and understanding the influence of edge disorder on the stability of electron periodic oscillations in 2D coupled systems.

[Clinical therapeutic effects of acupuncture combined with Chinese herbal medicine on infertility of polycystic ovary syndrome in the patients with ovulation induction with letrozole].

OBJECTIVE: To evaluate the clinical therapeutic effects and safety on infertility of polycystic ovary syndrome (PCOS) in the patients with ovulation induction with letrozole in the treatment with the formula for regulating menstruation and removing phlegm and electroacupuncture (EA). METHODS: A total of 120 patients of PCOS infertility were randomized into 3 groups, 40 cases in each one. In the group A, diane-35 was prescribed for oral administration (one tablet a day since the 5th day of menstruation, continuously for 21 days). After 1 course of treatment (3 months), letrozole was used (one tablet a day since the 5th day of menstruation, continuously for 5 days) for ovulation induction for another 1 course (3 months). In the group B, on the basis of the treatment as the group A, since the 5th day of menstruation, the Chinese herbal formula was combined to regulate menstruation and remove phlegm, one dose a day and discontinued during menstruation. In the group C, on the basis of the treatment as the group B, EA was added since the 5th day of menstruation. The main acupoints were Guanyuan (CV 4), Zusanli (ST 36) and Fenglong (ST 40), etc. EA was applied once every 2 days and discontinued during menstruation. In all of the 3 groups, the treatment for 3 months was as 1 course and the 2 courses were required continuously. Before and after treatment, the menstruation improvements, body weight, body mass index (BMI), serum sex hormones [luteal production hormone (LH), follicle stimulating hormone (FSH), LH/FSH, total testosterone (T) and estradiol (E2)] were observed in the patients of each group. The enzyme linked immunosorbent assay was adopted to determine the content of anti-mullerian hormone (AMH) and inhibin B (IHNB). The therapeutic effects, safety, ovulation rate and pregnancy rate were compared among the 3 groups. RESULTS: (1) The differences were significant statistically in the total effective rate, ovulation rate and pregnancy rate in comparison of the 3 groups (all P<0.05). The results in the group C were the best and those in the group B were the better in the comparison of the 3 groups. (2) After treatment, the menstrual cycle was remarkably shortened in the 3 groups (all P<0.05). The result in the group C was better than that in the group A (P<0.05). After treatment, the body weight in the group B and group C was all reduced (both P<0.05). The reducing degree in the group C was better than that in the group A (P<0.05). The differences in BMI were not significant statistically before and after treatment in each group as well as in comparison among the groups (all P>0.05). (3) After treatment, the levels of LH and LH/FSH were all reduced remarkably in the 3 groups (all P<0.05). The differences were not significant statistically in comparison among the three groups (all P>0.05). After treatment, in the group B and group C, the levels of T and AMH were all reduced remarkably (all P<0.05), in which, T value in the group C was lower than that in the group A and group B, that in the group B was lower than the group A (all P<0.05). AMH value in the group C was lower than that in the group A (P<0.05). The differences were not significant statistically in FSH, E2 and IHNB before and after treatment in each group as well as in comparison among the 3 groups (all P>0.05). (4) The luteinized unreuptured follicle syndrome (LUFS) did not happen in the group C. There were 3 cases of LUFS (7.5%) in the group B and 5 cases (12.5%) in the group A. CONCLUSION: For PCOS infertility patients receiving ovulation induction with letrozole, the combined treatment with the Chinese herbal formula for regulating menstruation and removing phlegm and EA remarkably improves the menstrual cycle, reduces body weight and the levels of LH, LH/FSH, T and AMH, improves ovulation and pregnancy rates. This therapy does not induce adverse reactions and the therapeutic effects are better than the simple application of letrozole or the combined therapy of letrozole and Chinese herbal medicine.

Targeting Wnt-driven cancer through the inhibition of Porcupine by LGK974.

Wnt signaling is one of the key oncogenic pathways in multiple cancers, and targeting this pathway is an attractive therapeutic approach. However, therapeutic success has been limited because of the lack of therapeutic agents for targets in the Wnt pathway and the lack of a defined patient population that would be sensitive to a Wnt inhibitor. We developed a screen for small molecules that block Wnt secretion. This effort led to the discovery of LGK974, a potent and specific small-molecule Porcupine (PORCN) inhibitor. PORCN is a membrane-bound O-acyltransferase that is required for and dedicated to palmitoylation of Wnt ligands, a necessary step in the processing of Wnt ligand secretion. We show that LGK974 potently inhibits Wnt signaling in vitro and in vivo, including reduction of the Wnt-dependent LRP6 phosphorylation and the expression of Wnt target genes, such as AXIN2. LGK974 is potent and efficacious in multiple tumor models at well-tolerated doses in vivo, including murine and rat mechanistic breast cancer models driven by MMTV-Wnt1 and a human head and neck squamous cell carcinoma model (HN30). We also show that head and neck cancer cell lines with loss-of-function mutations in the Notch signaling pathway have a high response rate to LGK974. Together, these findings provide both a strategy and tools for targeting Wnt-driven cancers through the inhibition of PORCN.

The ITK-SYK fusion oncogene induces a T-cell lymphoproliferative disease in mice mimicking human disease.

Peripheral T-cell lymphomas (PTCL) constitute a major treatment problem with high mortality rates due to the minimal effectiveness of conventional chemotherapy. Recent findings identified ITK-SYK as the first recurrent translocation in 17% of unspecified PTCLs and showed the overexpression of SYK in more than 90% of PTCLs. Here, we show that the expression of ITK-SYK in the bone marrow of BALB/c mice causes a T-cell lymphoproliferative disease in all transplanted mice within 8 weeks after transplantation. The disease was characterized by the infiltration of spleen, lymph nodes, bone marrow, and skin with CD3+CD4+CD8- and CD3+CD4-CD8- ITK-SYK-positive T-cells accompanied by a systemic inflammatory reaction with upregulation of interleukin 5 and INF-gamma. ITK-SYK-positive T-cells showed enhanced apoptosis resistance and INF-gamma production in vitro. The disease was serially transplantable, inducing clonal T-cell expansion in secondary recipients. The action of ITK-SYK in vivo was dependent on SYK kinase activity and disease development could be inhibited by the treatment of mice with SYK inhibitors. Interestingly, the translocation of ITK-SYK from the membrane to the cytoplasm, using a point mutation in the pleckstrin homology domain (ITK-SYK R29C), did not abolish, but rather, enhanced disease development in transplanted mice. CBL binding was strongly enhanced in membrane-associated ITK-SYK E42K and was causative for delayed disease development. Our results show that ITK-SYK causes a T-cell lymphoproliferative disease in mice, supporting its role in T-cell lymphoma development in humans. Therefore, pharmacologic inhibition of SYK in patients with U-PTCLs carrying the ITK-SYK fusion protein might be an effective treatment strategy.

Note: Phase compensation in the fiber optical quadrature passive demodulation scheme.

A phase compensation technique in the fiber optical quadrature passive demodulation scheme is presented. The phase error between the two interferometric signals is calculated first, and a new signal is generated which has an accurate phase difference of 90 degrees with respect to another one. The experimental results show that the distortion in the demodulated signal is removed and the input signal is correctly recovered. The technique is successfully used in fiber optical interferometric sensors.

Targeting Bcr-Abl by combining allosteric with ATP-binding-site inhibitors.

In an effort to find new pharmacological modalities to overcome resistance to ATP-binding-site inhibitors of Bcr-Abl, we recently reported the discovery of GNF-2, a selective allosteric Bcr-Abl inhibitor. Here, using solution NMR, X-ray crystallography, mutagenesis and hydrogen exchange mass spectrometry, we show that GNF-2 binds to the myristate-binding site of Abl, leading to changes in the structural dynamics of the ATP-binding site. GNF-5, an analogue of GNF-2 with improved pharmacokinetic properties, when used in combination with the ATP-competitive inhibitors imatinib or nilotinib, suppressed the emergence of resistance mutations in vitro, displayed additive inhibitory activity in biochemical and cellular assays against T315I mutant human Bcr-Abl and displayed in vivo efficacy against this recalcitrant mutant in a murine bone-marrow transplantation model. These results show that therapeutically relevant inhibition of Bcr-Abl activity can be achieved with inhibitors that bind to the myristate-binding site and that combining allosteric and ATP-competitive inhibitors can overcome resistance to either agent alone.

Expansion of Bcr-Abl-positive leukemic stem cells is dependent on Hedgehog pathway activation.

Resistance of Bcr-Abl-positive leukemic stem cells (LSCs) to imatinib treatment in patients with chronic myeloid leukemia (CML) can cause relapse of disease and might be the origin for emerging drug-resistant clones. In this study, we identified Smo as a drug target in Bcr-Abl-positive LSCs. We show that Hedgehog signaling is activated in LSCs through upregulation of Smo. While Smo(-/-) does not impact long-term reconstitution of regular hematopoiesis, the development of retransplantable Bcr-Abl-positive leukemias was abolished in the absence of Smo expression. Pharmacological Smo inhibition reduced LSCs in vivo and enhanced time to relapse after end of treatment. Our results indicate that Smo inhibition might be an effective treatment strategy to reduce the LSC pool in CML.

Essential role of stromally induced hedgehog signaling in B-cell malignancies.

Interaction of cancer cells with their microenvironment generated by stromal cells is essential for tumor cell survival and influences the localization of tumor growth. Here we demonstrate that hedgehog ligands secreted by bone-marrow, nodal and splenic stromal cells function as survival factors for malignant lymphoma and plasmacytoma cells derived from transgenic Emu-Myc mice or isolated from humans with these malignancies. Hedgehog pathway inhibition in lymphomas induced apoptosis through downregulation of Bcl2, but was independent of p53 or Bmi1 expression. Blockage of hedgehog signaling in vivo inhibited expansion of mouse lymphoma cells in a syngeneic mouse model and reduced tumor mass in mice with fully developed disease. Our data indicate that stromally induced hedgehog signaling may provide an important survival signal for B- and plasma-cell malignancies in vitro and in vivo. Disruption of this interaction by hedgehog pathway inhibition could provide a new strategy in lymphoma and multiple myeloma therapy.

Rational design of solid aerosols for immunoglobulin delivery by modulation of aerodynamic and release characteristics.

Parenteral administration of immunoglobulins (Ig) for prevention or treatment of respiratory diseases achieves only modest concentrations of antibody in the pulmonary interstitial tissue and airways. Aerosols, including spray-dried particles, must overcome two limiting factors in order to be effective vehicles for pulmonary delivery of Ig: (i) Fc receptor (FcR)-mediated scavenging by macrophages and (ii) clearance by the mucociliary system. Ig-incorporated spray-dried lipid microparticles (SDLM), coformulated with or without a biocompatible surfactant (1% w:w) to modulate protein release, were designed and tested for their capability to deliver Ig to the respiratory tract. To determine efficacy, rodents were immunized with SDLM containing antiinfluenza antibody followed by virus challenge and clinical parameters measured. Control of the release kinetics resulted in enhanced delivery of immunoglobulins to the respiratory tract and interstitial tissue with slow translocation into the systemic circulation. As much as 60% of the IgG delivered from nonretentive SDLM could be recovered from the lung interstitial tissue within 1 h after aerosol administration at a dose of 1 mg of Ig/kg of body weight. In addition, nonretentive rather than slow-release particles loaded with antiinfluenza antibody were effective in curbing virus replication with a resulting positive clinical outcome. Thus, controlled release of Ig by manipulating aerosol characteristics and composition allows for a significant increase in the efficiency of pulmonary delivery of antibodies.