Everolimus synergistically enhances taxane-induced cytotoxicity in breast cancer cells in vitro and in vivo in addition to demonstrating a direct antiproliferative activity. We aim to determine ...pharmacodynamics changes and response of adding everolimus to standard neoadjuvant chemotherapy in triple-negative breast cancer (TNBC).
Phase II study in patients with primary TNBC randomized to T-FEC (paclitaxel 80mg/m2 i.v. weekly for 12 weeks, followed by 5-fluorouracil 500mg/m2, epirubicin 100mg/m2, and cyclophosphamide 500mg/m2 every 3 weeks for four cycles) versus TR-FEC (paclitaxel 80mg/m2 i.v. and everolimus 30mg PO weekly for 12 weeks, followed by FEC). Tumor samples were collected to assess molecular changes in the PI3K/AKT/mTOR pathway, at baseline, 48h, 12 weeks, and at surgery by reverse phase protein arrays (RPPA). Clinical end points included 12-week clinical response rate (12-week RR), pathological complete response (pCR), and toxicity.
Sixty-two patients were registered, and 50 were randomized, 27 received T-FEC, and 23 received TR-FEC. Median age was 48 (range 31–75). There was downregulation of the mTOR pathway at 48h in the TR-FEC arm. Twelve-week RR by ultrasound were 29.6% versus 47.8%, (P = 0.075), and pCR were 25.9% versus 30.4% (P = 0.76) for T-FEC and TR-FEC, respectively. mTOR downregulation at 48h did not correlate with 12-week RR in the TR-FEC group (P = 0.58). Main NCI grade 3/4 toxicities included anemia, neutropenia, rash/desquamation, and vomiting in both arms. There was one case of grade 3 pneumonitis in the TR-FEC arm. No grade 3/4 stomatitis occurred.
The addition of everolimus to paclitaxel was well tolerated. Everolimus downregulated mTOR signaling but downregulation of mTOR at 48h did not correlate with 12-week RR in the TR-FEC group.
NCT00499603.
The purpose of this retrospective study was to determine, in a cohort of patients with breast cancer and central nervous system (CNS) metastases, the effect of trastuzumab in patients with human ...epidermal growth factor receptor 2 (HER2)-positive disease and to compare this with that of patients with HER2-negative disease.
Five hundred and ninety-eight patients with invasive breast cancer, CNS metastases and known HER2 status were identified. Time to CNS metastases and survival after CNS metastases were estimated by the Kaplan–Meier method, and Cox models were fitted to determine the association between HER2 status, trastuzumab treatment and outcomes after adjustment for other patient characteristics.
In the multivariable model, patients with HER2-negative disease Hazard ratio (HR) 1.50, 95% confidence interval (CI) 1.15–1.95, P=0.003 and patients with HER2-positive disease who did not receive trastuzumab (HR 2.13, 95% CI 1.51–3.00, P < 0.0001) had shorter times to CNS metastases compared with patients with HER2-positive disease who had received trastuzumab as first-line therapy for metastases. Furthermore, patients with HER2-negative disease (HR 1.66, 95% CI 1.31–2.12, P < 0.0001) and patients with HER2-positive disease who had never received trastuzumab (HR 1.34, 95% CI 0.78–2.30, P = 0.28) had an increased hazard of death compared with patients with HER2-positive disease who had received trastuzumab before or at the time of CNS metastases diagnosis.
In our cohort of patients with breast cancer and CNS metastases, patients with HER2-positive disease treated with trastuzumab had longer times to development of and better survival from CNS metastases compared with patients with HER2-positive disease who had never received trastuzumab and patients with HER2-negative breast cancer.
The importance of pollination services by honey bees (
Apis mellifera
L.) and their products is well-known. However, honey bee colonies currently face many challenges. These challenges include both ...biotic and abiotic factors. In this article, the impacts of abiotic factors (mainly temperature and relative humidity) on honey bee activities are reviewed. The suitable ranges of these two factors and the potential impacts of atypical minimal or maximal limits are presented. Social homeostasis of honey bees, and activities inside and outside the colony that are influenced by these two factors are included, followed by a suggestion of additional studies.
Multimedia content delivery, such as video transmission over wireless networks, imposes significant challenges include spectrum capacity and packet losses. The cognitive radio (CR) technology is ...developed to solve the spectrum issue, while multiple description coding (MDC) is one of the promising source coding techniques to alleviate packet loss problems and exploit the benefit of path diversity. The source information was split into several descriptions in MDC, then transmitted over a network with multiple paths. The quality of the received data increases with the number of descriptions received at the receiver. In this paper, the proposed system comprises of relay-assisted cognitive radio network using the MDC technique for video transmission. In the simulations, the outage performance of the MDC scheme over two networks, which were relay-assisted network and non-relay network, were compared. Then, the outage probability was used to estimate the video quality, peak signal to noise ratio (PSNR) of the received video. The results obtained show the benefits of the relay assisted networks by 9% improvement on average outage performance over the non-relay network. Furthermore, the video performance improved by an average of 9% in PSNR compared to the non-relay system.
Although well recognized in breast oncology literature, histologic subtypes have not been previously described in inflammatory breast cancer (IBC). The purpose of this study was to describe lobular ...subtype in IBC and assess the impact of histology on patient outcomes.
We performed a retrospective analysis of 659 IBC patients at MD Anderson Cancer Center between January 1984 and December 2009. Patients with Invasive Lobular, Mixed Invasive Ductal and Lobular, or Invasive Ducal Carcinomas (ILC, MIC, IDC, respectively) comprise the subject of this report. Patient characteristics and survival estimates were compared by using chi-square test and Kaplan-Meier method with log-rank statistic. Cox proportional hazards models were fit to determine association of histology with outcomes after adjustment for other characteristics.
A total of 30, 37, and 592 patients were seen to have invasive lobular, mixed, or ductal histology, respectively. Grade 3 tumors were more common in the ductal group (78%) than in the lobular (60%) or mixed (61%) group (P = 0.01). The 3-year overall survival rates were 68%, 64%, and 62% in the lobular, mixed, and ductal groups, respectively (P = 0.68). After adjustment, histology did not have a significant effect on death in the lobular group (HR = 0.70, 95% confidence interval CI: 0.26-1.94; P = 0.50) or mixed group (HR = 0.53, 95% CI: 0.25-1.13; P = 0.10) compared with the ductal group.
In this cohort of IBC patients, lobular histology was seen in 4.5% cases. Histology does not appear to have a significant effect on survival outcomes in IBC patients, unlike in patients with non-inflammatory breast cancer (n-IBC), indicating the distinct biological behavior of the IBC phenotype.
We investigate the impact of shell growth on the carrier dynamics and exciton–phonon coupling in CdSe–CdS core–shell nanoplatelets with varying shell thickness. We observe that the recombination ...dynamics can be prolonged by more than one order of magnitude, and analyze the results in a global rate model as well as with simulations including strain and excitonic effects. We reveal that type I band alignment in the hetero platelets is maintained at least up to three monolayers of CdS, resulting in approximately constant radiative rates. Hence, observed changes of decay dynamics are not the result of an increasingly different electron and hole exciton wave function delocalization as often assumed, but an increasingly better passivation of nonradiative surface defects by the shell. Based on a global analysis of time-resolved and time-integrated data, we recover and model the temperature dependent quantum yield of these nanostructures and show that CdS shell growth leads to a strong enhancement of the photoluminescence quantum yield. Our results explain, for example, the very high lasing gain observed in CdSe–CdS nanoplatelets due to the type I band alignment that also makes them interesting as solar energy concentrators. Further, we reveal that the exciton-LO-phonon coupling is strongly tunable by the CdS shell thickness, enabling emission line width and coherence length control.
The optimisation of blood pressure management is critical in managing hypotensive episodes in patients with spinal cord injury. Improper handling of this preventable factor will negatively impact the ...patient recovery prognosis. A 42-year-old man was admitted for a complete spinal cord injury after fell from height. He developed subacute neurological deterioration unrelated to the mechanical instability but due to multiple episodes of hypotension occurring one month after the initial injury. After proper management of blood pressure, his deterioration was halted and no further progression. Spinal cord haemodynamics play an important role in mediating the onset of subacute post-traumatic ascending myelopathy. Better education and awareness on Subacute Post-traumatic Ascending Myelopathy (SPAM) especially to the junior healthcare providers are important to hinder this rare but avoidable condition.
This study proposes an evaluation and benchmarking decision matrix (DM) on the basis of multi-criteria decision making (MCDM) for young learners' English mobile applications (E-apps) in terms of ...listening, speaking, reading and writing (LSRW) skills. Benchmarking E-apps for young learners is challenging due to (a) multiple criteria, (b) criteria importance and (c) data variation. The DM was constructed on the basis of the intersection amongst evaluation criteria in terms of LSRW and E-apps for young learners. The criteria were adopted from a preschool education curriculum standard. The DM data included six E-apps as alternatives and 17 skills as criteria. Thereafter, the six E-apps were evaluated by distributing a checklist form amongst six English learning experts. These apps were subsequently benchmarked by utilising MCDM methods, namely, best-worst method (BWM) and technique for order of preference by similarity to ideal solution (TOPSIS). BWM was used for criterion weighting, whereas TOPSIS was employed to benchmark and rank the apps. TOPSIS was utilised in two contexts, namely, individual and group. In the group context, internal and external aggregations are applied. Mean was computed to ensure that the E-apps undergo a systematic ranking for objective validation. This study provides scenarios and a benchmarking checklist to evaluate and compare the proposed work with six relative studies. Results indicated that (1) BWM is suitable for criteria weighting. (2) TOPSIS is suitable for benchmarking and ranking E-apps. Moreover, the internal and external TOPSIS group decision making exhibited similar findings, with the best app being `Montessori' and the worst app being `FunWithFlupe.' (3) For objective validation, remarkable differences were observed amongst the group scores, which indicate that the internal and external ranking results are identical. (4) In the evaluation, the proposed DM revealed advantages over the six relative studies by 40.00%, 53.33%, 40.00%, 46.67%, 46.67% and 46.67%.
The distinctive anatomical assemble and functionally discrete multicellular cerebrovasculature dynamics confer varying rheological and blood-brain barrier permeabilities to preserve the integrity of ...cerebral white matter and its neural microenvironment. This homeostasis intricately involves the glymphatic system that manages the flow of interstitial solutes, metabolic waste, and clearance through the venous circulation. As a physiologically integrated neurogliovascular unit (NGVU) serving a particularly vulnerable cerebral white matter (from hypoxia, metabolic insults, infection, and inflammation), a likely insidious process over a lifetime could inflict microenvironment damages that may lead to pathological conditions. Two such conditions, cerebral small vessel disease (CSVD) and vascular parkinsonism (VaP), with poorly understood pathomechanisms, are frequently linked to this brain-wide NGVU. VaP is widely regarded as an atypical parkinsonism, described by cardinal motor manifestations and the presence of cerebrovascular disease, particularly white matter hyperintensities (WMHs) in the basal ganglia and subcortical region. WMHs, in turn, are a recognised imaging spectrum of CSVD manifestations, and in relation to disrupted NGVU, also include enlarged perivascular spaces. Here, in this narrative review, we present and discuss on recent findings that argue for plausible clues between CSVD and VaP by focusing on aberrant multicellular dynamics of a unique integrated NGVU-a crossroad of the immune-vascular-nervous system-which may also extend fresher insights into the elusive interplay between cerebral microvasculature and neurodegeneration, and the potential therapeutic targets.
Abstract
Favipiravir is a modern antiviral drug that can be used in developing viral pandemics, such as the Ebola virus, H1N1 flu, Lassa fever, and haemorrhagic fever outbreaks in Argentina in 2009. ...A. Chain conclusion Favipiravir is transformed to favipiravir-RTP and inserted into the RNA strand that is elongating. Then, since favipiravir acts as a chain terminator, chain elongation slows down at incorporation site of favipiravir and does not continue. The proofreading enzyme cannot repair this complex of RNA-favipiravir and it will be discarded as excessive RNA, which causes the extinction of the viral genome. Mutagenesis with lethal consequences Ribavirin is used in the RNA elongating process until completion. The single strand of RNA with several ribavirin incorporation sites incorporates ribavirin or acts as mRNA for the production of viral proteins. Due to incorporation of ribavirin onto viral RNA, a mismatching of the base pairs (transition mutation) will occur. Translation of this mutated RNA will then cause mutations in the sequence of amino acid residues of the protein, result in impaired of protein function. Viral proteins that have lost their function are unable to replicate or generate infectious viral particles, and the virus is no longer infectious. As a result, lethal mutagenesis ends viral infection in a different way than chain termination. Favipiravir’s clinical trial against Ebola virus-infected patients has not yet been formally approved, and further research is required. Favipiravir, on the other hand, poses a risk of embryo toxicity and teratogenicity. As a result, the Japanese Ministry of Health, Welfare and Labor have been approved this medication with recommendations for more clinical use until August 15, 2014, when they approved the use of favipiravir due to the Ebola virus epidemic in West Africa. The aim of this review is to investigate the potential impact of favipiravir on infections espectially RNA-virus infections, according to previous published investigations, and thus to encourage rapid approval of this interesting antivirus in emergencies.
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