Liver cancer is the fourth most common cause of cancer‐related death worldwide, with hepatocellular carcinoma (HCC) being the main primary malignancy affecting the liver. Unfortunately, there are ...still limited therapeutic options for HCC, and even the latest advances have only increased the overall survival modestly. Thus, new treatment strategies and rational drug combinations are urgently needed. Reactivation of receptor tyrosine kinases (RTK) has been described as a mechanism of intrinsic resistance to targeted therapies in a variety of cancers, including inhibitors of mTOR. The design of rational combination therapies to overcome this type of resistance is complicated by the notion that multiple RTK can be upregulated during the acquisition of resistance. SHP2, encoded by the gene PTPN11, acts downstream of virtually all RTK, and has proven to be a good target for small molecule inhibitors. Here, we report activation of multiple RTK upon mTOR inhibition in HCC which, through SHP2, leads to reactivation of the mTOR pathway. We show that co‐inhibition of both mTOR and SHP2 is highly synergistic in vitro by triggering apoptosis. More importantly, the combination is well‐tolerated and outperforms the monotherapies in impairing tumor growth in multiple HCC mouse models. Our findings suggest a novel rational combination therapy for the treatment of HCC.
We show that, upon mTOR inhibition with AZD8055, there is upregulation of several receptor tyrosine kinases. As consequence, SHP2 signals through the mTOR pathway. Hence, dual blockade of SHP2 and mTOR can effectively suppress the mTOR pathway and drive anti‐cancer response, both in vitro and in vivo, in several hepatocellular carcinoma models.
Degradation of the mechanical properties of vinylester and epoxy matrix composites exposed to water has been approached by monitoring the strengths of glass and carbon fibers and resins. In addition, ...the fiber/matrix (F/M) interface strengths and debond lengths of single-fiber composites were determined and test results were compared to test results of macroscopic composite specimens. The single-fiber tensile test results indicate a substantial loss of the tensile strength of glass fibers and the fragmentation tests reveal loss of F/M shear strength and substantial debonding for both glass and carbon fiber composites after water exposure. The transverse strengths of the composites are also degraded to large extents. The tests results identify water degradation of the F/M interface as a major strength limiting mechanism.
Aims.
Gamma-ray burst (GRB) 190829A (
z
= 0.0785) was detected by
Fermi
and
Swift
and also at very high energy (VHE) by the High-Energy Stereoscopic System (H.E.S.S.) telescopes. The prompt emission ...displayed two emission episodes separated by a quiescent gap of ∼40 s. We present the 10.4 m Gran Telescopio Canarias (GTC) observations of the afterglow of GRB 190829A and its underlying supernova. We also compare GRB 190829A to GRB 180728A, a GRB with similar behaviour, and discuss the implications on underlying physical mechanisms producing these two GRBs.
Methods.
We present multi-band photometric data along with spectroscopic follow-up observations taken with the 10.4 m GTC telescope. Together with the data from the prompt emission, the 10.4 m GTC data are used to understand the emission mechanisms and possible progenitor.
Results.
A detailed analysis of the multi-band observations of the afterglow requires the cooling frequency to pass between the optical and X-ray bands at early epochs. The afterglow then transitions to the underlying supernova (SN) 2019oyw, which dominates later on.
Conclusions.
Although the prompt emission temporal properties of GRB 190829A and GRB 180728A are similar, the two pulses are different in the spectral domain. We find that SN 2019oyw associated with GRB 190829A is powered by Ni decay and is a Type Ic-BL SN. The spectroscopic and photometric properties of this SN are consistent with those observed for SN 1998bw, but evolved earlier.
Photo-catalysts based on BiVO4 (BV) and Eco-graphene (EG) were synthesized and obtained in a single step with high-quality properties. These nanostructures (NEs) were obtained through a green ...chemistry route and by adding 2, 3, and 5 wt% of a homemade EG. The BV/X EG NEs (where X = corresponds to the weight % of EG) demonstrated high photocatalytic activity, obtaining Sulfamethoxazole degradation percentages of 40, 45, 52, and 57 for BV, BV/2 EG, BV/3 EG, and BV/5 EG respectively, using a blue LED light. In addition, it was observed that the presence of EG slightly affected the surface area and porosity of BV. Moreover, it was observed that the presence of EG stabilized the scheelite monoclinic phase (m-s), and decreased the crystal size and band-gap values of BV-based samples. It was detected that EG contents increased the BV reduction, creating oxygen vacancies and V4+ states, which favored electron transfer, enhanced the photo-catalytic activity, and decreased the recombination rate. The adsorption influence of the BV/EG system was also studied. Finally, the stability tests of these materials after four cycles of reuse allowed keeping practically the full degradation capacity, demonstrating that these NEs represent a promising material driven by visible light that can be used for wastewater decontamination in the presence of drugs.
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•A green, one-step method was applied to obtain BiVO4/Eco-graphene-based catalysts.•Eco-graphene improved the optical properties of the nanostructures.•BiVO4/5 EG catalyst improved SMX photodegradation reaching 57% in 480 min.•Low-cost blue LEDs were used as an irradiation source.•Eco-graphene effect on the photocatalytic activity of the BV/EG system.
The cavitation erosion (CE) resistance of an UNS S32205 duplex stainless steel (DSS) was improved through microstructural modification using friction stir processing (FSP). As-received material was ...processed using 200rpm and 100mm/min spindle and travel speeds, respectively. The cavitation erosion tests were performed in a vibratory apparatus according to ASTM G32 standard. The incubation period, the maximum erosion rate and the variation of surface roughness during the tests are reported and the results are compared with those obtained for the base metal samples (BMS). The worn surfaces were characterized using roughness measurements and scanning electron microscopy (SEM). After a CE testing time of 10h, FSP samples showed a 70% diminution of the mass loss when compared to the BMS. Moreover, a 200% enhancement of incubation time and 100% reduction in the erosion rate were achieved after FPS. The improvement of CE performance is related to the recrystallized and refined microstructure, as well as to the modification of the elongated α/γ interfaces.
► The CE resistance of a DSS was improved through microstructural modification using FSP. ► A 200% improvement on the incubation time and 100% on the erosion rate was achieved after FSP. ► RsmRq−1, Rku and RaRq−1 showed a good agreement with incubation time. ► The wear resistance enhancement was related to the α/γ interface continuity rupture. ► The reduction of grain size and the improvement of mechanical properties.
Antimicrobial resistance has become a major problem over the years and threatens to remain in the future, at least until a solution is found. Silver nanoparticles (Ag-NPs) and antimicrobial polymers ...(APs) are known for their antimicrobial properties and can be considered an alternative approach to fighting resistant microorganisms. Hence, the main goal of this research is to shed some light on the antimicrobial properties of Ag-NPs and APs (chitosan (CH), poly-L-lysine (PLL), ε-poly-L-lysine (ε-PLL), and dopamine (DA)) when used alone and complexed to explore the potential enhancement of the antimicrobial effect of the combination Ag-NPs + Aps. The resultant nanocomplexes were chemically and morphologically characterized by UV-visible spectra, zeta potential, transmission electron microscopy, and Fourier-transform infrared spectroscopy. Moreover, the Ag-NPs, APs, and Ag-NPs + APs nanocomplexes were tested against Gram-positive
(
) and the Gram-negative
(
) bacteria, as well as the fungi
(
). Overall, the antimicrobial results showed potentiation of the activity of the nanocomplexes with a focus on
. For the biofilm eradication ability, Ag-NPs and Ag-NPs + DA were able to significantly remove
preformed biofilm, and Ag-NPs + CH were able to significantly destroy
biofilm, with both performing better than Ag-NPs alone. Overall, we have proven the successful conjugation of Ag-NPs and APs, with some of these formulations showing potential to be further investigated for the treatment of microbial infections.
Human bronchial epithelial (HBE) cells play an essential role during bacterial infections of the airways by sensing pathogens and orchestrating protective immune responses. We here sought to ...determine which metabolic pathways are utilized by HBE cells to mount innate immune responses upon exposure to a relevant bacterial agonist. Stimulation of HBE cells by the bacterial component flagellin triggered activation of the mTOR pathway resulting in an increased glycolytic flux that sustained the secretory activity of immune mediators by HBE cells. The mTOR inhibitor rapamycin impeded glycolysis and limited flagellin-induced secretion of immune mediators. The role of the mTOR pathway was recapitulated in vivo in a mouse model of flagellin-triggered lung innate immune responses. These data demonstrate that metabolic reprogramming via the mTOR pathway modulates activation of the respiratory epithelium, identifying mTOR as a potential therapeutic target to modulate mucosal immunity in the context of bacterial infections.
Polybrominated diphenyl ethers (PBDEs) are widely distributed compounds in all types of matrices. In the northern portion of the Southern California Bight (SCB), there were reports of some of the ...largest PBDE concentrations in marine mammals and mussels. Because of this, we decided to analyze the status of PBDEs in the southern part of the SCB. An analysis of 91 samples of marine surface sediment was carried out. All of the 91 samples contained measurable amounts of PBDEs, which is a manifestation of the widespread distribution of these chemical substances. However, the levels detected are between one and two orders of magnitude smaller than those reported in southern California. Currents appear to control the distribution of PBDEs along the coast and the sedimentation sites with largest concentrations are favored by local bathymetry. Maximum concentrations were located in the middle and deeper platforms ranging from 0.02 to 5.90 (with a median 0.71) ng·g−1 d.w. Deca-BDE mixture is largely predominant in the sediments followed by the penta-BDE mixture. The mass balance for the latitudinal strata shows the largest concentrations in the north where the largest population centers are present and with a very clear southward gradient. The mass balance calculation values showed about 36kg of PBDEs for the north, 22kg for the center, and 10kg for the south strata. In terms of depth, the PBDEs are mainly located on the middle and deep platforms rather than near point discharges, which is different than that reported by other authors.
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•PBDEs were reported as very high just north of our study area in California•Consequently, PBDEs were measured for the first time on these coastal sediments.•PBDE concentrations are two orders of magnitude smaller than those reported in sediments up north.•Their distribution was found not close to the coast but rather in deeper sediments.•Only within Todos Santos Bay and Estuary, PBDEs distribution followed grain size.•Deca-BDE mixture is largely predominant followed by the Penta-BDE mixture in most samples.
Introduction
Increased risk of postmenopausal breast cancer associated with anthropometric measures including Body Mass Index (BMI), adult weight gain, and waist circumference has been observed in ...North American and European populations, but little evidence is available for Hispanic women. Breast cancer is the leading type of cancer, and leading cause of cancer-related deaths among Hispanic women in Puerto Rico (PR). However, compared with the United States, breast cancer incidence rates are lower but increasing more rapidly.
Purpose
To examine associations between anthropometric characteristics and breast cancer risk in Hispanic women in PR.
Methods
Data from a population-based case–control study in the San Juan metropolitan region (cases = 315; controls = 348) were used to examine associations between anthropometric measures and breast cancer risk, also considering menopausal status and hormone therapy (HT).
Results
Among premenopausal participants, there was a significant trend for lower odds of breast cancer with higher BMI and borderline significant with higher waist to height ratio (WHtR). For postmenopausal participants, a significant trend for lower odds of breast cancer was observed with higher WHtR, and waist to hip ratio (WHR), borderline significant with higher BMI, and higher odds with height. Among postmenopausal participants using HT, a significant trend for lower odds of breast cancer was observed with higher waist circumference, WHtR, WHR, and body shape index.
Conclusion
Our study provides evidence of anthropometric differences in relation to breast cancer risk in PR compared to previous studies. Future studies should include analyses of fat and lean mass distribution, and hormone receptor status to further understand anthropometry and breast cancer risk among Hispanic women.
It has been hypothesized that insulin resistance plays a role in the development of the loss of skeletal muscle; however, no cohort studies on insulin resistance and low relative appendicular ...skeletal muscle mass (ASM) have been published to date. Thus, we examined whether insulin resistance is associated with low relative ASM after a 4.6-year follow-up period among apparently healthy older men and women participants.
This is a combined retrospective-prospective cohort study, which includes 147 community-dwelling older men and women participants. ASM was measured by dual-energy x-ray absorptiometry at baseline and follow-up. Participants with a relative change in ASM below the sex-specific 15th value were classified as the low relative ASM group. Homeostatic model assessment was used to quantify insulin resistance. Logistic regression calculated odds ratios and 95% confidence intervals for development of low relative ASM, adjusted for covariates.
The loss of ASM in the low relative ASM and normal groups was -1.8kg and -0.35kg, respectively (p ≤ .05). The low relative ASM group was older and had higher insulin and homeostatic model assessment of insulin resistance values at baseline. The risk of developing low relative ASM at 4.6-year follow-up was 2.9 times higher (95% CI, 1.00-7.8; p = .04) among the participants with homeostatic model assessment of insulin resistance levels more than 2.3. After adjusting for age, the risk increased to 3.9 times higher (95% CI, 1.3-11.5; p = .03).
Insulin resistance was associated with low relative ASM at 4.6-year follow-up after accounting for several covariates in a cohort of apparently healthy, well-functioning young older men and women.
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