Gastric cancer (GC) is the second cause of cancer-related death. Cisplatin (CDDP) is widely used as the standard GC treatment, but relapse and metastasis are common because of intrinsic or acquired ...drug resistance. The mitogen-activated protein kinase phosphatases (MAPK)-extracellular signal regulated kinases (ERK) pathway contributes to GC progression and drug resistance, but targeting the MAPK-ERK pathway is challenging in GC therapy. Here, we demonstrated that dual-specificity phosphatases 6 (DUSP6) was overexpressed in GC and predicted poor overall survival and progression-free survival. Knockdown DUSP6 inhibited GC proliferation, migration, invasion and induced apoptosis. (E/Z)-BCI hydrochloride (BCI), a DUSP6 small molecule inhibitor, increased the activity of ERK but interestingly decreased the expression of ERK response genes in BGC823, SGC7901 and CDDP-resistant SGC7901/DDP cells. BCI also caused cell death through the DNA damage response (DDR) pathway. Moreover, BCI inhibited cell proliferation, migration and invasion in a receptor-independent manner and enhanced CDDP cytotoxicity at pharmacological concentrations in the GC cells. In vivo experiments further showed that BCI enhances the antitumor effects of CDDP in cell-based xenografts and PDX models. In summary, our findings indicated that disruption of DUSP6 by BCI enhanced CDDP-induced cell death and apoptosis in GC may partly through ERK and DDR pathways. Thus, this study suggests that DUSP6 is a potential prognostic biomarker and a promising target for GC therapy.
•DUSP6 was overexpressed and promote proliferation, metastasis and predict poor prognosis in GC.•BCI inhibited cell proliferation, migration and invasion and enhanced CDDP cytotoxicity in GC through DUSP6.•In vivo experiments showed that BCI enhances the antitumor effects of CDDP in cell-based xenografts and PDX models.•BCI enhanced CDDP-induced cell death and apoptosis may partly through ERK and DDR pathways in GC.
Energetic benefit and enhanced performance are considered among the most fascinating achievements of collective behaviours, e.g. fish schools and flying formations. The collective locomotion of two ...self-propelled flapping plates initially in a side-by-side arrangement is investigated numerically. Both in-phase and antiphase oscillations for the two plates are considered. It is found that the plates will spontaneously form some stable configurations as a result of the flow-mediated interaction, specifically, the staggered-following (SF) mode and the alternate-leading (AL) mode for the in-phase scenario and the moving abreast (MA) mode and the AL mode for the antiphase scenario. In the SF mode, the rear plate follows the front one with a staggered configuration. In the AL mode, the plates chase each other side-by-side alternately. In terms of propulsive speed and efficiency, the performance of the plates in the SF mode with small lateral spacing
$H$
is found to be better than those in the tandem following case (
$H=0$
) and the side-by-side case (i.e. the AL mode). To achieve higher propulsive efficiency, no matter in-phase or antiphase oscillations, the two plates with moderate bending stiffness, e.g.
$K\approx O(1)$
, are preferred and they should be close enough in the lateral direction. For the side-by-side configuration, the performance of each plate in the antiphase and in-phase scenarios is enhanced and weakened in comparison with that of the isolated plate, respectively. Besides the pressure and vorticity contours, the normal force and thrust acting on the plates are also analysed. It is revealed that the thrust is mainly contributed by the normal force at moderate bending stiffness. The normal force and thrust are critical to the propulsive speed and efficiency. For two self-propelled plates, in view of hydrodynamics, to achieve higher performance the in-phase SF mode and antiphase flappings in the side-by-side configuration are preferred.
Tumor cells often reprogram their metabolism for rapid proliferation. The roles of long noncoding RNAs (lncRNAs) in metabolism remodeling and the underlying mechanisms remain elusive. Through ...screening, we found that the lncRNA Actin Gamma 1 Pseudogene (AGPG) is required for increased glycolysis activity and cell proliferation in esophageal squamous cell carcinoma (ESCC). Mechanistically, AGPG binds to and stabilizes 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3). By preventing APC/C-mediated ubiquitination, AGPG protects PFKFB3 from proteasomal degradation, leading to the accumulation of PFKFB3 in cancer cells, which subsequently activates glycolytic flux and promotes cell cycle progression. AGPG is also a transcriptional target of p53; loss or mutation of TP53 triggers the marked upregulation of AGPG. Notably, inhibiting AGPG dramatically impaired tumor growth in patient-derived xenograft (PDX) models. Clinically, AGPG is highly expressed in many cancers, and high AGPG expression levels are correlated with poor prognosis, suggesting that AGPG is a potential biomarker and cancer therapeutic target.
The effect of trailing-edge shape on the self-propulsive performance of three-dimensional flexible plates is studied numerically. In our study, the trailing edges of the plates are symmetric chevron ...shapes, and the trailing-edge angle
$\unicodeSTIX{x1D719}$
varies from
$30^{\circ }$
(concave plate) to
$150^{\circ }$
(convex plate). Under different bending stiffnesses
$K$
, three regimes of the propulsive performance in terms of propulsive velocity
$U$
and efficiency
$\unicodeSTIX{x1D702}$
as a function of
$\unicodeSTIX{x1D719}$
are identified. When
$K$
is small, moderate and large, the square, convex and concave plate achieves the best performance, respectively. Analyses of vortical structures and velocity fields show that usually the jet behind the plate with the best performance is longest. Besides, the inclination angle of the jet may be small. The different propulsive performances at small and moderate
$K$
are mainly attributed to the phase lag of the trailing edge. The force acting on the plate is analysed and it is found that the thrust force is mainly contributed by the normal force. If
$U$
,
$\unicodeSTIX{x1D702}$
and
$K$
are rescaled by the normal force and the area moment of the plate, the curves for different
$\unicodeSTIX{x1D719}$
almost collapse into a single curve when the bending stiffness coefficient is small or moderate. The scaling confirms that the normal force should be the characteristic fluid force at small or moderate
$K$
and the
$\unicodeSTIX{x1D719}$
effect is governed by the area moment. The findings may shed some light on the propulsive performance of aquatic animals.
Droplet evaporation on heterogeneous or patterned surfaces has numerous potential applications, for example, inkjet printing. The effect of surface heterogeneities on the evaporation of a ...nanometer-sized cylindrical droplet on a solid surface is studied using molecular dynamics simulations of Lennard-Jones particles. Different heterogeneities of the surface were achieved through alternating stripes of equal width but two chemical types, which lead to different contact angles. The evaporation induced by the heated substrate instead of the isothermal evaporation is investigated. It is found that the whole evaporation process is generally dominated by the nonuniform evaporation effect. However, at the initial moment, the volume expansion and local evaporation effects play important roles. From the nanoscale point of view, the slow movement of the contact line during the pinning process is observed, which is different from the macroscopic stationary pinning. Particularly, we found that the speed of the contact line may be not only affected by the intrinsic energy barrier between the two adjacent stripes (ũ) but also relevant to the evaporation rate. Generally speaking, the larger the intrinsic energy barrier, the slower the movement of the contact line. At the specified temperature, when ũ is less than a critical energy barrier (ũ*), the speed of the contact line would increase with the evaporate rate. When ũ > ũ*, the speed of the contact line is determined only by ũ and no longer affected by the evaporation rate at different stages (the first stick and the second stick).
Anoikis is a critical obstacle to cancer metastasis. Colorectal cancer (CRC) exhibits a high rate of metastasis, leading to death, and the mechanisms involved in anoikis resistance are still unclear. ...We identified that the fatty acid oxidation (FAO) pathway was activated in detached CRC cells. Multiple genes in the FAO pathway, specifically the rate-limiting enzyme CPT1A, were upregulated in CRC cells grown in suspension. Reactive oxygen species elimination mediated by CPT1A in CRC cells was vital to anoikis resistance. In vivo experiments showed that CPT1A-suppressed CRC cells colonized the lung at a much lower rate than normal CRC cells, suggesting that CPT1A-mediated FAO activation increased metastatic capacity. In clinical tissue specimens from CRC patients, elevated expression of CPT1A was observed in metastatic sites compared with primary sites. Our results demonstrate that CPT1A-mediated FAO activation induces CRC cells to resist anoikis, suggesting that CPT1A is an attractive target for treating metastatic CRC.
Chemoresistance to temozolomide (TMZ) is a major challenge in the treatment of glioblastoma (GBM). We previously found that miR-519a functions as a tumor suppressor in glioma by targeting the signal ...transducer and activator of transcription 3 (STAT3)-mediated autophagy oncogenic pathway. Here, we investigated the effects of miR-519a on TMZ chemosensitivity and autophagy in GBM cells. Furthermore, the underlying molecular mechanisms and signaling pathways were explored.
In the present study, two stable TMZ-resistant GBM cell lines were successfully generated by exposure of parental cells to a gradually increasing TMZ concentration. After transfecting U87-MG/TMZ and U87-MG cells with miR-519a mimic or inhibitor, a series of biochemical assays such as MTT, apoptosis, and colony formation were performed to determine the chemosensitive response to TMZ. The autophagy levels in GBM cells were detected by transmission electron microscopy, LC3B protein immunofluorescence, and Western blotting analysis. Stable knockdown and overexpression of miR-519a in GBM cells were established using lentivirus. A xenograft nude mouse model and in situ brain model were used to examine the in vivo effects of miR-519a. Tumor tissue samples were collected from 48 patients with GBM and were used to assess the relationship between miR-519a and STAT3 expression.
TMZ treatment significantly upregulated miR-519a in U87-MG cells but not in U87-MG/TMZ cells. Moreover, the expression of miR-519a and baseline autophagy levels was lower in U87-MG/TMZ cells as compared to U87-MG cells. miR-519a dramatically enhanced TMZ-induced autophagy and apoptotic cell death in U87-MG/TMZ cells, while inhibition of miR-519a promoted TMZ resistance and reduced TMZ-induced autophagy in U87-MG cells. Furthermore, miR-519a induced autophagy through modification of STAT3 expression. The in vivo results showed that miR-519a can enhance apoptosis and sensitized GBM to TMZ treatment by promoting autophagy and targeting the STAT3/Bcl-2/Beclin-1 pathway. In human GBM tissues, we found an inverse correlation between miR-519a and STAT3 expression.
Our results suggested that miR-519a increased the sensitivity of GBM cells to TMZ therapy. The positive effects of miR-519a may be mediated through autophagy. In addition, miR-519a overexpression can induce autophagy by inhibiting STAT3/Bcl-2 pathway. Therefore, a combination of miR-519a and TMZ may represent an effective therapeutic strategy in GBM.
While hydrodynamic interactions for aggregates of swimmers have received significant attention in the low Reynolds number realm (
$Re\ll 1$
), there has been far less work at higher Reynolds numbers, ...in which fluid and body inertia are involved. Here we study the collective behaviour of multiple self-propelled plates in tandem configurations, which are driven by harmonic flapping motions of identical frequency and amplitude. Both fast modes with compact configurations and slow modes with sparse configurations were observed. The Lighthill conjecture that orderly configurations may emerge passively from hydrodynamic interactions was verified on a larger scale with up to eight plates. The whole group may consist of subgroups and individuals with regular separations. Hydrodynamic forces experienced by the plates near their multiple equilibrium locations are all springlike restoring forces, which stabilize the orderly formation and maintain group cohesion. For the cruising speed of the whole group, the leading subgroup or individual plays the role of ‘leading goose’.
The width effect on contact angle hysteresis in a microchannel with patterned heterogeneous surfaces is systematically investigated. In the model, identical defects periodically appear on the ...background surface. To this end, a droplet's evaporation and condensation processes inside the microchannel are studied by theoretical analysis and numerical simulation based on a diffuse-interface lattice Boltzmann method. The microchannel width effect on the system's equilibrium properties is studied. The results demonstrate that the number of equilibrium configurations increases linearly with the microchannel width ($b$), and has a quadratic relationship with the cosine of the reference contact angle and the heterogeneity strength ($\varepsilon$). The average most stable contact angle is independent of $b$ and is always equal to the contact angle predicted by the Cassie–Baxter equation. For contact angle hysteresis ($H$), when the microchannels are narrow and wide, there are individual-effect-dominated hysteresis (IDH) and collective-effect-dominated hysteresis (CDH), respectively. The IDH and CDH are hysteresis modes corresponding to the jumping behaviour of contact lines affected by individual defects and two neighbouring defects, respectively. Based on the graphical force balance approach, we establish a scaling law to quantify the connection between $H$, $b$ and $\varepsilon$. Specifically, in the IDH mode, $H\sim b \varepsilon ^2$, while in the CDH mode, $H$ increases linearly with $\varepsilon$ but nonlinearly with $b$.
A suspended ellipsoidal particle inside a Poiseuille flow with Reynolds number up to 360 is studied numerically. The effects of tube diameter (
$D$
), inertia of the particle and the flow, and the ...particle geometry (both prolate and oblate ellipsoids) are considered. When a prolate particle with
$a/b=2$
is inside a wider tube (e.g.
$D/A>1.9$
), where
$A=2a$
is the length of the major axis of the particle, the terminal stable state is tumbling. When the prolate particle is inside a narrower tube (
$1.0<D/A<1.9$
), log-rolling or kayaking modes may appear. Which mode occurs depends on the competition between fluid and particle inertia. When the fluid inertia is dominant, the log-rolling mode appears, otherwise, the kayaking mode appears. Inclined and spiral modes may appear when
$D/A<1$
and
$D/A=1$
, respectively. For a prolate ellipsoid with
$a/b=4$
, if
$1<D/A<1.9$
, there is only the kayaking mode and the log-rolling mode is not observed. When an oblate particle is inside a wider tube (e.g.
$D/A>3.5$
), it may adopt the log-rolling mode. Inclined and intermediate modes are firstly identified in narrower tubes. The phase diagram of the modes is also provided. The modes in the phase diagrams were not found to be affected by the initial state of the particle based on limited observation.
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