Cancer is a common comorbidity of diabetic patients; however, little is known about the effects that anti-diabetic drugs have on tumors. We discovered that common classes of drugs used in type 2 diabetes mellitus, the hypoglycemic dipeptidyl peptidase-4 inhibitors (DPP-4i) saxagliptin and sitagliptin, as well as the antineuropathic alpha-lipoic acid (ALA), do not increase tumor incidence but increase the risk of metastasis of existing tumors. Specifically, these drugs induce prolonged activation of the nuclear factor-E2-related factor 2 (NRF2)-mediated antioxidant response via inhibition of KEAP1-C151-dependent ubiquitination and subsequent degradation of NRF2, resulting in up-regulated expression of metastasis-associated proteins, increased cancer cell migration, and promotion of metastasis in xenograft mouse models. Accordingly, knockdown of NRF2 attenuated naturally-occurring and DPP-4i-induced tumor metastasis, whereas NRF2 activation accelerated metastasis. Furthermore, in human liver cancer tissue samples, increased NRF2 expression correlated with metastasis. Our findings suggest that antioxidants that activate NRF2 signaling may need to be administered with caution in cancer patients, such as diabetic patients with cancer. Moreover, NRF2 may be a potential biomarker and therapeutic target for tumor metastasis.

BackgroundAcupuncture has been commonly used for preventing migraine attacks and relieving pain during a migraine, although there is limited knowledge on the physiological mechanism behind this method. The objectives of this study were to compare the differences in brain activities evoked by active acupoints and inactive acupoints and to investigate the possible correlation between clinical variables and brain responses.Methods and ResultsA randomized controlled trial and resting-state functional magnetic resonance imaging (fMRI) were conducted. A total of eighty migraineurs without aura were enrolled to receive either active acupoint acupuncture or inactive acupoint acupuncture treatment for 8 weeks, and twenty patients in each group were randomly selected for the fMRI scan at the end of baseline and at the end of treatment. The neuroimaging data indicated that long-term active acupoint therapy elicited a more extensive and remarkable cerebral response compared with acupuncture at inactive acupoints. Most of the regions were involved in the pain matrix, lateral pain system, medial pain system, default mode network, and cognitive components of pain processing. Correlation analysis showed that the decrease in the visual analogue scale (VAS) was significantly related to the increased average Regional homogeneity (ReHo) values in the anterior cingulate cortex in the two groups. Moreover, the decrease in the VAS was associated with increased average ReHo values in the insula which could be detected in the active acupoint group.ConclusionsLong-term active acupoint therapy and inactive acupoint therapy have different brain activities. We postulate that acupuncture at the active acupoint might have the potential effect of regulating some disease-affected key regions and the pain circuitry for migraine, and promote establishing psychophysical pain homeostasis.Trial RegistrationChinese Clinical Trial Registry ChiCTR-TRC-13003635

No abstract

SUMMARY We have constructed a 3-D shear wave velocity (Vs) model for the crust and uppermost mantle beneath the Middle East using Rayleigh wave records obtained from ambient-noise cross-correlations and regional earthquakes. We combined one decade of data collected from 852 permanent and temporary broad-band stations in the region to calculate group-velocity dispersion curves. A compilation of >54 000 ray paths provides reliable group-velocity measurements for periods between 2 and 150 s. Path-averaged group velocities calculated at different periods were inverted for 2-D group-velocity maps. To overcome the problem of heterogeneous ray coverage, we used an adaptive grid parametrization for the group-velocity tomographic inversion. We then sample the period-dependent group-velocity field at each cell of a predefined grid to generate 1-D group-velocity dispersion curves, which are subsequently inverted for 1-D Vs models beneath each cell and combined to approximate the 3-D Vs structure of the area. The Vs model shows low velocities at shallow depths (5–10 km) beneath the Mesopotamian foredeep, South Caspian Basin, eastern Mediterranean and the Black Sea, in coincidence with deep sedimentary basins. Shallow high-velocity anomalies are observed in regions such as the Arabian Shield, Anatolian Plateau and Central Iran, which are dominated by widespread magmatic exposures. In the 10–20 km depth range, we find evidence for a band of high velocities (>4.0 km s–1) along the southern Red Sea and Arabian Shield, indicating the presence of upper mantle rocks. Our 3-D velocity model exhibits high velocities in the depth range of 30–50 km beneath western Arabia, eastern Mediterranean, Central Iranian Block, South Caspian Basin and the Black Sea, possibly indicating a relatively thin crust. In contrast, the Zagros mountain range, the Sanandaj-Sirjan metamorphic zone in western central Iran, the easternmost Anatolian plateau and Lesser Caucasus are characterized by low velocities at these depths. Some of these anomalies may be related to thick crustal roots that support the high topography of these regions. In the upper mantle depth range, high-velocity anomalies are obtained beneath the Arabian Platform, southern Zagros, Persian Gulf and the eastern Mediterranean, in contrast to low velocities beneath the Red Sea, Arabian Shield, Afar depression, eastern Turkey and Lut Block in eastern Iran. Our Vs model may be used as a new reference crustal model for the Middle East in a broad range of future studies.

Highlights d BA synergizes with RT to overcome tumor immune evasion via TME reprogramming d Reconstitution of tumor immunosurveillance by BART induces abscopal effects d In fibrotic lungs, PD-L1 + endothelial cells and M2-like lipofibroblasts express TGF-b d BA attenuates lung fibrosis by neutralizing TGF-b in the relevant PD-L1 + compartments

No abstract

No abstract

A positive MIR in association with a positive FIR decreases the risk of RDS, but increases the risk of IVH Grade 2 or greater in preterm infants with a gestational age of less than 34 weeks. However, a positive MIR alone has little effect on neonatal outcome.