Miracle-dz/UniFAR-FTUs huggingface dataset:
Targeting the HER Family with Pan-HER Effectively Overcomes Resistance to Cetuximab

Cetuximab, an antibody against the EGFR, has shown efficacy in treating head and neck squamous cell carcinoma (HNSCC), metastatic colorectal cancer, and non–small cell lung cancer (NSCLC). Despite the clinical success of cetuximab, many patients do not respond to cetuximab. Furthermore, virtually all patients who do initially respond become refractory, highlighting both intrinsic and acquired resistance to cetuximab as significant clinical problems. To understand mechanistically how cancerous cells acquire resistance, we previously developed models of acquired resistance using the H226 NSCLC and UM-SCC1 HNSCC cell lines. Cetuximab-resistant clones showed a robust upregulation and dependency on the HER family receptors EGFR, HER2, and HER3. Here, we examined pan-HER, a mixture of six antibodies targeting these receptors on cetuximab-resistant clones. In cells exhibiting acquired or intrinsic resistance to cetuximab, pan-HER treatment decreased all three receptors' protein levels and downstream activation of AKT and MAPK. This correlated with decreased cell proliferation in cetuximab-resistant clones. To determine whether pan-HER had a therapeutic benefit in vivo, we established de novo cetuximab-resistant mouse xenografts and treated resistant tumors with pan-HER. This regimen resulted in a superior growth delay of cetuximab-resistant xenografts compared with mice continued on cetuximab. Furthermore, intrinsically cetuximab-resistant HNSCC patient-derived xenograft tumors treated with pan-HER exhibited significant growth delay compared with vehicle/cetuximab controls. These results suggest that targeting multiple HER family receptors simultaneously with pan-HER is a promising treatment strategy for tumors displaying intrinsic or acquired resistance to cetuximab. Mol Cancer Ther; 15(9); 2175–86. ©2016 AACR.
Impact of Mobility on the Uplink Sum Rate of MIMO-OFDMA Cellular Systems

With the fast development of vehicular technologies, the number of mobile terminals as well as their moving speeds has increased conspicuously, making it meaningful to re-examine the impact of mobility on communication performance of the existing cellular systems. In this paper, the uplink sum rate of a multiple-input multiple-output orthogonal frequency-division multiple access (MIMO-OFDMA) cellular system with nodes moving randomly at different speeds is studied. In such a multi-user environment, mobility not only causes inter sub-carrier interferences (ICI) among different users, but also brings the so-called channel aging which together with the above interferences incur outdated and inaccurate channel estimation and thus entail additional pilot overhead. Here, we first derive the relationship between the users’ mobility and the ICI power, characterize the channel aging, and derive the overall multi-user interference caused by the outdated and inaccurate channel state information as a function of mobility. Then, by capitalizing on the above results, the sum rate of the MIMO-OFDMA uplink is theoretically analyzed. Moreover, an adaptive transmission scheme in which the users adjust the pilot percentage according to mobility statistics is proposed to maximize the sum rate. Finally, numerical results are provided to validate our analyses.
Comparative Study of Antidiabetic Activity and Oxidative Stress Induced by Zinc Oxide Nanoparticles and Zinc Sulfate in Diabetic Rats

In the current study, antidiabetic activity and toxic effects of zinc oxide nanoparticles (ZnO) were investigated in diabetic rats compared to zinc sulfate (ZnSO4) with particular emphasis on oxidative stress parameters. One hundred and twenty male Wistar rats were divided into two healthy and diabetic groups, randomly. Each major group was further subdivided into five subgroups and then orally supplemented with various doses of ZnO (1, 3, and 10 mg/kg) and ZnSO4 (30 mg/kg) for 56 consecutive days. ZnO showed greater antidiabetic activity compared to ZnSO4 evidenced by improved glucose disposal, insulin levels, and zinc status. The altered activities of erythrocyte antioxidant enzymes as well as raised levels of lipid peroxidation and a marked reduction of total antioxidant capacity were observed in rats receiving ZnO. ZnO nanoparticles acted as a potent antidiabetic agent, however, severely elicited oxidative stress particularly at higher doses.
Water storage dynamics across different types of vegetated patches in rocky highlands of central Argentina

Rivers originating in the granitic highlands of seasonally dry central Argentina provide water to 2 million people. These highlands comprise a complex landscape where a matrix of outcropping rock hosts vegetated patches that vary in response to long‐term grazing and fire. We characterized water storage dynamics across 20 sites representing 6 vegetation‐soil conditions with similar mid‐upslope positions in the landscape. We measured temporal and spatial variability of water inputs (rain and fog) and water stored at the unsaturated and saturated zones. We found that rainfall was highly seasonal, but fog occurred year‐round, likely representing an extra water source in areas with complex vegetation structure. Moreover, fog seems to regulate evapotranspiration/topsoil water dynamics. Water was stored in the saturated zone only during the rainy season. Piezometric response to rainfall was rapid but transient (dropping an average 15 cm/day), possibly buffering peak stormflows, reducing sediment yield, and delivering subsurface water downslope for potential storing throughout the year. Spatially, a reduction in soil depth (from 100 up to 9 cm) and vegetation structure (from woodlands to stonelands), with a degradation of topsoil conditions for infiltration were accompanied by a decline in water storage at the unsaturated (from 32% up to 14%) and saturated (from 46.3 up to 0 cm) zones. Taken together, our results support the infiltration trade‐off hypothesis, which states that vegetation structure benefits fog interception, soil properties that enhance water infiltration, subsurface flow paths, and storage. Long‐term disturbances have likely triggered a degradation of the hydrological function of seasonal highlands in central Argentina.
Toll-Like Receptor Expression and Induction of Type I and Type III Interferons in Primary Airway Epithelial Cells

ABSTRACT Interferons (IFNs) are a critical component of the first line of antiviral defense. The activation of Toll-like receptors (TLRs) expressed by dendritic cells triggers different signaling cascades that result in the production of large amounts of IFNs. However, the functional consequences of TLR activation and differential IFN production in specific cell populations other than antigen-presenting cells have not yet been fully elucidated. In this study, we investigated TLR expression and polarization in airway epithelial cells (AECs) and the consequences of TLR agonist stimulation for the production of type I (IFN-α/β) and type III (IFN-λ) IFNs. Our results show that the pattern of expression and polarization of all TLRs in primary AEC cultures mirrors that of the human airways ex vivo and is receptor specific. The antiviral TLRs (TLR3, TLR7, and TLR9) are mostly expressed on the apical cell surfaces of epithelial cells in the human trachea and in primary polarized AECs. Type III IFN is the predominant IFN produced by the airway epithelium, and TLR3 is the only TLR that mediates IFN production by AECs, while all TLR agonists tested are capable of inducing AEC activation and interleukin-8 production. In response to influenza virus infection, AECs can produce IFN-λ in an IFNAR- and STAT1-independent manner. Our results emphasize the importance of using primary well-differentiated AECs to study TLR and antiviral responses and provide further insight into the regulation of IFN production during the antiviral response of the lung epithelium.
On the 2007 July flare of the blazar 3C 454.3

In 2007 July, the blazar 3C 454.3 underwent a flare in the optical, reaching R∼ 13 on July 19. Then the optical flux decreased by one magnitude, being R∼ 14 when the source was detected by the gamma-ray satellite AGILE, which observed the source on July 24–30. At the same time, the Swift satellite performed a series of snapshots. We can construct the simultaneous spectral energy distribution using optical, ultraviolet, X-ray and gamma-ray data. These show that an increased gamma-ray flux is accompanied by a weaker optical/X-ray flux with respect to the flare observed in the spring of 2005 by INTEGRAL and Swift. This confirms earlier suggestions about the behaviour of the jet of 3C 454.3.
Effects of long-lasting raloxifene treatment on serum prolactin and gonadotropin levels in postmenopausal women.

OBJECTIVE To evaluate the effects of a 6 month administration of raloxifene hydrochloride, a selective estrogen receptor modulator which was recently approved for the prevention of osteoporosis, on serum gonadotropin and prolactin (PRL) levels and on TRH-stimulated PRL responsiveness in postmenopausal women who have not undergone estrogen replacement therapy. DESIGN AND METHODS Sixteen healthy postmenopausal women were divided into two groups on the basis of their bone status, evaluated by dual energy X-ray absorptiometry at the lumbar level. Eight women (chronological age 52.4+/-4.1 (s.d.) years, menopausal age 42.4+/-3.9 years), in whom T-score L2-L4 was less than -2.5 s.d. , were treated with raloxifene (60 mg p.o.) administered daily for 6 months (group 1), while the other eight women (chronological age 52.6+/-2.5 years, menopausal age 42.1+/-3.6 years), in whom the T-score L2-L4 ranged between -1 and -2.5 s.d. , were used as a control group (group 2). Serum PRL, FSH, LH and 17beta-estradiol (E2) levels were evaluated at baseline and after 3 and 6 months of treatment. In all subjects, PRL responsiveness to TRH (200 microg i.v.) administration was evaluated at baseline and at the end of the study. RESULTS At baseline, mean PRL, LH and FSH levels were not significantly different in the two groups (PRL 133.6+/-21.7 vs 136.7+/-28.1 mIU/l (NS), LH 25.1+/-6.8 vs 24.4+/-6.7 mIU/ml (NS), FSH 74.4+/-25.0 vs 71.1+/-24.1 mIU/ml (NS), in group 1 and group 2 respectively). No significant variations in serum FSH and LH values, in either group, or in serum PRL levels in group 2, were observed at the 3 and 6 month examinations. On the contrary, serum PRL values decreased significantly in group 1 after 3 months (100.1+/-47.7 mIU/l, P<0.05) and 6 months (81.5+/-30.2 mIU/l, P<0.001). At baseline, no significant differences were observed in the TRH-stimulated serum PRL peak between the groups (1015.4+/-30.5 vs 1030.2+/-25.7 mIU/l in group 1 and in group 2 respectively), while it decreased significantly at the 6 month examination in group 1 (770.5+/-47.4 mIU/l, P<0.001) and it was significantly lower than in group 2 (1068.1+/-301.8 mIU/l, P=0.02). Serum E2 was not detected at baseline and at each examination, in all patients. CONCLUSIONS The decrease of PRL values induced by long-term raloxifene administration in postmenopausal women could be explained by a direct antiestrogenic effect of raloxifene on lactotrope cells or by the recently suggested increase of opiatergic tone on the hypothalamic-pituitary region.
Novel Oral Anticoagulant Use Among Patients With Atrial Fibrillation Hospitalized With Ischemic Stroke or Transient Ischemic Attack

Background—Novel oral anticoagulants (NOACs) have been shown to be at least as good as warfarin for preventing stroke or transient ischemic attack in patients with atrial fibrillation, yet diffusion of these therapies and patterns of use among atrial fibrillation patients with ischemic stroke and transient ischemic attack have not been well characterized. Methods and Results—Using data from Get With The Guidelines-Stroke, we identified a cohort of 61 655 atrial fibrillation patients with ischemic stroke or transient ischemic attack hospitalized between October 2010 and September 2012 and discharged on warfarin or NOAC (either dabigatran or rivaroxaban). Multivariable logistic regression was used to identify factors associated with NOAC versus warfarin therapy. In our study population, warfarin was prescribed to 88.9%, dabigatran to 9.6%, and rivaroxaban to 1.5%. NOAC use increased from 0.04% to a 16% to 17% plateau during the study period, although anticoagulation rates among eligible patients did not change appreciably (93.7% versus 94.1% from first quarter 2011 to second quarter 2012), suggesting a trend of switching from warfarin to NOACs rather than increased rates of anticoagulation among eligible patients. Several bleeding risk factors and CHA2DS2-VASc scores were lower among those discharged on NOAC versus warfarin therapy (47.9% versus 40.9% with CHA2DS2-VASc ⩽5, P<0.001 for difference in CHA2DS2-VASc). Conclusions—NOACs have had modest but growing uptake over time among atrial fibrillation patients hospitalized with stroke or transient ischemic attack and are prescribed to patients with lower stroke risk compared with warfarin.
Roles of neutrophil gelatinase-associated lipocalin (NGAL) in human cancer

Cancer remains one of the major cause of death in the Western world. Although, it has been demonstrated that new therapies can improve the outcome of cancer patients, still many patients relapse after treatment. Therefore, there is a need to identify novel factors involved in cancer development and/or progression. Recently, neutrophil gelatinase-associated lipocalin (NGAL) has been suggested as a key player in different cancer types. Its oncogenic effect may be related to the complex NGAL/MMP-9. In the present study, NGAL was analyzed at both transcript and protein levels in different cancer types by analysing 38 public available microarray datasets and the Human Protein Atlas tool. NGAL transcripts were significantly higher in the majority of solid tumors compared to the relative normal tissues for every dataset analyzed. Furthermore, concordance of NGAL at both mRNA and protein levels was observed for 6 cancer types including bladder, colorectal, liver, lung, ovarian, and pancreatic. All metastatic tumors showed a decrease of NGAL expression when compared to matched primary lesions. According to these results, NGAL is a candidate marker for tumor growth in a fraction of solid tumors. Further investigations are required to elucidate the function of NGAL in tumor development and metastatic processes.
A Survey of Physical Activity Programming and Counseling Preferences in Young-Adult Cancer Survivors

Background:Few research studies have focused on physical activity in young-adult cancer survivors despite the potential long-term health consequences of inactivity in this population. Objective:Understanding the unique physical activity programming and counseling preferences of young-adult cancer survivors may inform future research as well as nursing practice. Methods:Participants were 588 young-adult cancer survivors (20–44 years old) who completed a mailed survey in the province of Alberta, Canada, that assessed physical activity preferences and standard demographic and medical variables. Results:Most young-adult cancer survivors indicated that they were interested (78%) and able (88%) to participate in an activity program. Young-adult cancer survivors also preferred receiving activity counseling from a fitness expert at the cancer center (49.6%), information by brochure (64%), starting activity after treatment (64%), walking (51%), doing activity with others (49%), and doing activity at a community fitness center (46%). The &khgr;2 analyses indicated that younger cancer survivors (20–29 vs 30–39 vs 40–44 years) were less likely to prefer walking (P < .001), more interested in receiving information (P = .002), and more likely to prefer receiving information by e-mail (P = .044) or Internet (P = .006). Conclusions:Young-adult cancer survivors show interest in receiving physical activity counseling. There were some consistent programming preferences, although other preferences varied by demographic and medical factors. Implications for Practice:Nurses may play a key role in promoting physical activity in young-adult cancer survivors. Understanding the physical activity preferences of young-adult cancer survivors may help nurses make practical recommendations and referrals.
Next Generation of Optical Access Network Based on Reflective-SOA

Communication networks have evolved in order to fulfil the growing demand of our bandwidth-hungry world. First, the coaxial cable has replaced the copper cable since 1950 for longand medium-range communication networks. The Bit rate-distance product (BL) is commonly used as figure of merit for communication systems, where the B is the bit rate (bit/sec) and L is the repeater spacing (km). A suitable medium for transmission needed to be available and optical fibres were selected as the best option to guide the light (Kao & Hockham, 1966). A radical change occurred, the information was transmitted using pulses of light. Thus further increase in the BL product was possible using this new transmission medium because the physical mechanisms of the frequency-dependent losses are different for copper and optical fibres. The bit-rate was increased in the core network by the introduction of a new technique: Wavelength-Division Multiplexing (WDM). The use of WDM revolutionized the system capacity since 1992 and in 1996, they were used in the Atlantic and Pacific fibre optic cables (Otani et al., 1995). While WDM techniques were mostly used in long-haul systems employing EDFA for online amplification, access networks were using more and more bandwidth. Access network includes the infrastructures used to connect the end users (Optical Network Unit ONU) to one central office (CO). The CO is connected to the metropolitan or core network. The distance between the two network units is up to 20 km. The evolution of access network was very different from in the core network. High bit-rate transmissions are a recent need. At the beginning, it provided a maximum bandwidth of 3 kHz (digitised at 64 kbit/s) for voice transmission and was based on copper cable. Today, a wide range of services need to be carried by our access network and new technologies are introduced which allow flexible and high bandwidth connection. The access network evolution is obvious in Europe with the rapid growth of xDSL technologies (DSL: Digital Subscriber Loop). They enable a broadband connection over a copper cable and allow maintaining the telephone service for that user. In 2000, the maximum bit rate was around 512 kbit/s while today it is around 12 Mbit/s. However since 2005, new applications as video-on-demand need even more bandwidth and the xDSL technologies have reached their limits. The introduction of broadband access network based on FTTx (Fiber To The x) technology is necessary to answer to the recent explosive growth of the internet. Today, Internet service providers propose 100 Mbit/s using optical fibre. The experience from the core network evolution is a great benefit to access network. The use of WDM mature technology in access and
Alteration of Internal Circadian Phase Relationships after Morning versus Evening Carbohydrate-Rich Meals in Humans

The effects of a single morning and evening carbohydrate-rich meal for 3 consecutive days on circadian phase of core body temperature (CBT), heart rate, and salivary melatonin rhythms were compared under controlled constant routine conditions. In 10 healthy young men entrained to a natural light-dark cycle with regular sleep timing, CBT and heart rate were significantly elevated for approximately 8 h after the last evening carbohydrate-rich meal (EM), and nocturnal melatonin secretion (as measured by salivary melatonin and urinary 6-sulphatoxymelatonin levels) was reduced, compared to the morning carbohydraterich meal (MM) condition. Thus, circadian phase could not be measured until the following day due to this acute masking effect. The day after the last meal intervention, MM showed a significant advanced circadian phase position in CBT (+59 ± 12 min) and heart rate (+43 ± 18 min) compared to EM. However, dim-light melatonin onset was not significantly changed (+15 ± 13 min). The results are discussed with respect to central (light-entrainable) and peripheral (foodentrainable) oscillators. Food may be a zeitgeber in humans for the food-entrainable peripheral oscillators, but melatonin data do not support such a conclusion for the light-entrainable oscillator in the suprachiasmatic nucleus.
MRI Study on Reversible and Irreversible Electroporation Induced Blood Brain Barrier Disruption

Electroporation, is known to induce cell membrane permeabilization in the reversible (RE) mode and cell death in the irreversible (IRE) mode. Using an experimental system designed to produce a continuum of IRE followed by RE around a single electrode we used MRI to study the effects of electroporation on the brain. Fifty-four rats were injected with Gd-DOTA and treated with a G25 electrode implanted 5.5 mm deep into the striata. MRI was acquired immediately after treatment, 10 min, 20 min, 30 min, and up to three weeks following the treatment using: T1W, T2W, Gradient echo (GE), serial SPGR (DCE-MRI) with flip angles ranging over 5–25°, and diffusion-weighted MRI (DWMRI). Blood brain barrier (BBB) disruption was depicted as clear enhancement on T1W images. The average signal intensity in the regions of T1-enhancement, representing BBB disruption, increased from 1887±83 (arbitrary units) immediately post treatment to 2246±94 20 min post treatment, then reached a plateau towards the 30 min scan where it reached 2289±87. DWMRI at 30 min showed no significant effects. Early treatment effects and late irreversible damage were clearly depicted on T2W. The enhancing volume on T2W has increased by an average of 2.27±0.27 in the first 24–48 hours post treatment, suggesting an inflammatory tissue response. The permanent tissue damage, depicted as an enhancing region on T2W, 3 weeks post treatment, decreased to an average of 50±10% of the T2W enhancing volumes on the day of the treatment which was 33±5% of the BBB disruption volume. Permanent tissue damage was significantly smaller than the volume of BBB disruption, suggesting, that BBB disruption is associated with RE while tissue damage with IRE. These results demonstrate the feasibility of applying reversible and irreversible electroporation for transient BBB disruption or permanent damage, respectively, and applying MRI for planning/monitoring disruption volume/shape by optimizing electrode positions and treatment parameters.
Potentiometric determination of chloride in biological fluids.

Potentiometric titration of chloride with silver nitrate has been a standard procedure for many years, and the theoretical considerations involved have been clearly set forth by Kolthoff & Furman (1931). However, methods based on this principle have been little used in biological work, in spite of theirattractivepossibilities. Lehmann(1939)seems to have been the first to describe a method suitable for clinical work; more recently, Norberg (1949) has