Miracle-dz/UniFAR-FTUs huggingface dataset:
Combination treatment of prostate cancer with FGF receptor and AKT kinase inhibitors

Activation of the PI3K/AKT pathway occurs in the vast majority of advanced prostate cancers (PCas). Activation of fibroblast growth factor receptor (FGFR) signaling occurs in a wide variety of malignancies, including PCa. RNA-Seq of castration resistant PCa revealed expression of multiple FGFR signaling components compatible with FGFR signaling in all cases, with multiple FGF ligands expressed in 90% of cases. Immunohistochemistry confirmed FGFR signaling in the majority of xenografts and advanced PCas. AZD5363, an AKT kinase inhibitor and AZD4547, a FGFR kinase inhibitor are under active clinical development. We therefore sought to determine if these two drugs have additive effects in PCa models. The effect of both agents, singly and in combination was evaluated in a variety of PCa cell lines in vitro and in vivo. All cell lines tested responded to both drugs with decreased invasion, soft agar colony formation and growth in vivo, with additive effects seen with combination treatment. Activation of the FGFR, AKT, ERK and STAT3 pathways was examined in treated cells. AZD5363 inhibited AKT signaling and increased FGFR1 signaling, which partially compensated for decreased AKT kinase activity. While AZD4547 could effectively block the ERK pathway, combination treatment was needed to completely block STAT3 activation. Thus combination treatment with AKT and FGFR kinase inhibitors have additive effects on malignant phenotypes in vitro and in vivo by inhibiting multiple signaling pathways and mitigating the compensatory upregulation of FGFR signaling induced by AKT kinase inhibition. Our studies suggest that co-targeting these pathways may be efficacious in advanced PCa.
Same but not alike: Structure, flexibility and energetics of domains in multi-domain proteins are influenced by the presence of other domains

The majority of the proteins encoded in the genomes of eukaryotes contain more than one domain. Reasons for high prevalence of multi-domain proteins in various organisms have been attributed to higher stability and functional and folding advantages over single-domain proteins. Despite these advantages, many proteins are composed of only one domain while their homologous domains are part of multi-domain proteins. In the study presented here, differences in the properties of protein domains in single-domain and multi-domain systems and their influence on functions are discussed. We studied 20 pairs of identical protein domains, which were crystallized in two forms (a) tethered to other proteins domains and (b) tethered to fewer protein domains than (a) or not tethered to any protein domain. Results suggest that tethering of domains in multi-domain proteins influences the structural, dynamic and energetic properties of the constituent protein domains. 50% of the protein domain pairs show significant structural deviations while 90% of the protein domain pairs show differences in dynamics and 12% of the residues show differences in the energetics. To gain further insights on the influence of tethering on the function of the domains, 4 pairs of homologous protein domains, where one of them is a full-length single-domain protein and the other protein domain is a part of a multi-domain protein, were studied. Analyses showed that identical and structurally equivalent functional residues show differential dynamics in homologous protein domains; though comparable dynamics between in-silico generated chimera protein and multi-domain proteins were observed. From these observations, the differences observed in the functions of homologous proteins could be attributed to the presence of tethered domain. Overall, we conclude that tethered domains in multi-domain proteins not only provide stability or folding advantages but also influence pathways resulting in differences in function or regulatory properties.
Outcomes of Anatomic Anterior Cruciate Ligament Reconstruction

Background: The choice of graft type is an important factor to the outcome of anterior cruciate ligament (ACL) reconstruction. Purpose: To compare knee joint stability and functional outcomes of anatomic ACL reconstruction with double-bundle hamstring tendon (DBHT) and bone–quadriceps tendon (BQT) autografts. Study Design: Cohort study; Level of evidence, 3. Methods: Ninety-six patients underwent ACL reconstruction with either DBHT (hamstring group) or BQT autograft (quadriceps group). Each group included 48 patients who were retrospectively matched on the basis of age, sex, and body mass index; there were no statistically significant differences between the 2 groups (all P > .05). All patients had a minimum follow-up of 2 years. Outcome evaluations included the manual laxity test, International Knee Documentation Committee subjective evaluation, Tegner activity score, modified Lysholm score, anterior knee pain questionnaire, KT-2000 arthrometer side-to-side difference, Cybex II isokinetic testing, and tunnel position evaluation by quadrant method. Results: Manual laxity test results were significantly improved in both groups after surgery (all P < .05). The maximum KT-2000 arthrometer side-to-side difference improved from 4.0 to 1.9 mm in the hamstring group and 3.9 to 2.1 mm in the quadriceps group (P = .65). Modified Lysholm scores in the hamstring and quadriceps groups improved from 69.4 and 70.2 to 88.4 and 92.1 (P = .30), and International Knee Documentation Committee subjective evaluation scores improved from 56.0 and 60.3 to 77.9 and 80.2 (P = .37), respectively. Tegner activity scores for the hamstring and quadriceps groups were 4.7 and 4.6 preoperatively and 4.6 and 4.7 (P = .80) at final follow-up, respectively. There were no between-group differences on postoperative anterior knee pain (P > .05 for all questionnaire categories), nor were there differences in recovered extensor muscle strength during isokinetic testing (82.9% vs 81.0% at 60 deg/s, P = .71; 85.1% vs 83.8% at 180 deg/s, P = .81). However, flexor muscle strength recovery was better in the quadriceps group (86.6% vs 92.2% at 60 deg/s, P = .22; 87.1% vs 99.6% at 180 deg/s, P = .01). There were no significant differences in tunnel positioning between the 2 groups (all P > .05). Conclusion: Anatomic ACL reconstruction with the BQT autograft showed similar knee stability and functional outcome scores when compared with the DBHT autograft. Additionally, better flexor muscle strength recovery was found in the quadriceps group, indicating a potential advantage of the BQT autograft in ACL reconstruction.
Better outcomes of modified myeloablative conditioning without antithymocyte globulin versus myeloablative conditioning in cord blood transplantation for hematological malignancies: A retrospective (development) and a prospective (validation) study

Cord blood transplantation (CBT) is an effective option for treating hematological malignancies, but graft failure (GF) remains the primary cause of therapy failure. Thus, based on myeloablative conditioning (MAC) of busulfan with cyclophosphamide (Bu/Cy) or total body irradiation with Cy (TBI/Cy), fludarabine (Flu) was added to Bu/Cy and cytarabine (CA) to TBI/Cy for a modified myeloablative conditioning (MMAC). To compare the prognosis of MMAC with MAC, we conducted a retrospective study including 58 patients who underwent CBT with MAC or MMAC from 2000 to 2011. Neutrophil and platelet engraftment rate, overall survival (OS) and disease free survival (DFS) were significantly higher in the MMAC group (adjusted hazard ratio [HR], 2.58, 2.43, 0.36 and 0.37; p < 0.01, p = 0.01, p = 0.02 and p = 0.02, separately). Nonrelapse mortality (NRM) was comparable (p = 0.183). To validate the outcomes noted in the MMAC group, we conducted a prospective single‐arm clinical trial including 188 patients who underwent CBT with MMAC from 2011 to 2015. Engraftment rate, survival and NRM of the MMAC group in the prospective trail (MMAC‐P) were similar to the MMAC group in the retrospective study (MMAC‐R). This study is the first to demonstrate the superiority of MMAC to MAC in CBT for hematological malignancies.
Full duplex spectrum sensing in non-time-slotted cognitive radio networks

In cognitive radio networks, previous works almost assume that the primary (licensed) traffic is time-slotted. In time-slotted cognitive radio networks, the secondary (unlicensed) users only need to spend a short time to sense the spectrum because the primary users' states (active or not active) are not changed during the whole secondary frame. However, in realistic cases, the primary traffic is non-time-slotted, which means the primary users can become to be active or not active at any time during the whole secondary frame. Obviously, using the traditional half duplex spectrum sensing scheme, it is impossible for the secondary users to detect the state change in their transmission periods. In this paper, we derive the probability of detection and the probability of false alarm for non-time-slotted cognitive radio networks. We propose the continuous-time Markov chain model to analyze the achievable throughput of primary users and secondary users. To achieve the required primary users' throughput, we develop the full duplex spectrum sensing scheme for non-time-slotted cognitive radio networks. Analyses and numerical results show that using our proposed full duplex spectrum sensing scheme, the primary users can achieve their required throughput and the secondary users' achievable throughput can be increased compared with that of using the half duplex spectrum sensing scheme in non-time-slotted cognitive radio networks.
Porous Apatite Coating on Various Titanium Metallic Materials via Low Temperature Processing

Nowadays, hydorxyapatite (HA) is widely used as bioceramics in reconstructive surgery, in dentistry and as drug delivery materials due to the good biocompatibility and osteoconductivity [Hench, 1998]. One of the limitations for the usage of these materials is their low mechanical strength. Thus, many researchers focuses on the development of new biomaterials, that combine the osteoconductive characteristics of bioactive ceramics with sufficient strength and toughness for load-bearing applications. The combination of high strength of the metals with osteoconductive properties of bioactive ceramics makes HA coated metallic implants, which titanium (Ti) or its alloys was mainly used, very attractive for the loaded-bearing applications in orthopedic and dental surgery[Long & Rack, 1998]. A plasma spraying method has been conventionally employed for the HA coating. However, this method has some problems (e.g. a poor coating-substrate adherence, lack of HA crystallinity) for the long-term performance and lifetime of the implants [Aoki, 1994]. Therefore, new HA coating methods hava attracted great interests in recent years for replacing the high temperature techniques like plasma spraying. Hydrothermal hot-pressing (HHP) method is a possible processing route for producing a ceramic body at relatively low temperatures (under 300 C) [Yamasaki et al., 1986]. The compression of samples under hydrothermal conditions accelerates densification of inorganic materials. It is known that the water of crystallization in calcium hydrogen phosphate dihydrate (CaHPO4・2H2O; DCPD) is slowly lost below 100 C [Peelen et al., 1991]. If the released water can be utilized as a reaction solvent during the HHP treatment, it is to be expected that the joining HA to metal can be achieved simultaneously under the hydrothermal condition, in addition to the synthesis and solidification of HA through the chemical reaction as follows [Hosoi et al., 1996]:
&bgr;-Catenin Directs Long-Chain Fatty Acid Catabolism in the Osteoblasts of Male Mice

Wnt-initiated signaling through a frizzled receptor and the low-density lipoprotein-related receptor-5 coreceptor instructs key anabolic events during skeletal development, homeostasis, and repair. Recent studies indicate that Wnt signaling also regulates the intermediary metabolism of osteoblastic cells, inducing glucose consumption in osteoprogenitors and fatty acid utilization in mature osteoblasts. In this study, we examined the role of the canonical Wnt-signaling target, β-catenin, in the control of osteoblast metabolism. In vitro, Wnt ligands and agonists that stimulated β-catenin activation in osteoblasts enhanced fatty acid catabolism, whereas genetic ablation of β-catenin dramatically reduced oleate oxidation concomitant with reduced osteoblast maturation and increased glycolytic metabolism. Temporal ablation of β-catenin expression in osteoblasts in vivo produced the expected low-bone-mass phenotype and also led to an increase in white adipose tissue mass, dyslipidemia, and impaired insulin sensitivity. Because the expression levels of enzymatic mediators of fatty acid β-oxidation are reduced in the skeleton of β-catenin mutants, these results further confirm the role of the osteoblast in lipid metabolism and indicate that the influence of Wnt signaling on fatty acid utilization proceeds via its canonical signaling pathway.
Flip-chip routing with IO planning considering practical pad assignment constraints

In order to support the pad-limited Application-Specific Integrated Circuit (ASIC) designs, the flip chip package is used and provides the highest chip density compared to other packaging technologies. In this paper, we propose the first work of free-assignment flip-chip routing considering practical bump/IO pad constraints and flexibilities. Unlike previous studies regarding all nets as the same, we differentiate signal and power/ground nets and set different bump pad assignment constraints for substrate layout optimization. In our flow, a global routing-based IO-bump assignment algorithm is proposed with a multi-commodity flow network model. After that, a detailed routing algorithm minimizing total wirelength is presented, which determines optimal relay points with a linear programming (LP) formulation. Finally, a dynamic programming (DP)-based IO pad planning technique is applied to further reduce the number of wire bends. Experimental results based on modified industrial cases show that our algorithm flow not only achieves 100% routability of all testcases but also minimizes total wirelength and bump utilization.
Clinical impact of tumor location on the colon cancer survival and recurrence: analyses of pooled data from three large phase III randomized clinical trials

The aim of the present study was to determine whether or not the overall survival (OS) and disease‐free survival (DFS) were affected by the tumor location in patients who underwent curative resection for colon cancer in a pooled analysis of three large phase III studies performed in Japan. In total, 4029 patients were included in the present study. Patients were classified as having right‐side colon cancer (RC) if the primary tumor was located in the cecum, ascending colon, hepatic flexure or transverse colon, and left‐side colon cancer (LCC) if the tumor site was within the splenic flexure, descending colon, sigmoid colon or recto sigmoid junction. The risk factors for the OS and DFS were analyzed. In the present study, 1449 patients were RC, and 2580 were LCC. The OS rates at 3 and 5 years after surgery were 87.6% and 81.6% in the RC group and 91.5% and 84.5% in the LCC group, respectively. Uni‐ and multivariate analyses showed that RRC increased the risk of death by 19.7% (adjusted hazard ratio = 1.197; 95% confidence interval, 1.020–1.408; P = 0.0272). In contrast, the DFS was similar between the two locations. The present study confirmed that the tumor location was a risk factor for the OS in patients who underwent curative treatment for colon cancer. Tumor location may, therefore, need to be considered a stratification factor in future phase III trials of colon cancer.
Experiences and needs of relatives of people with dementia in acute hospitals—A meta‐synthesis of qualitative studies

AIMS AND OBJECTIVES To present an in-depth analysis of existing qualitative literature concerning experiences and needs of the relatives of patients with dementia in hospitals. BACKGROUND Relatives are an important resource for the care of patients with dementia in hospitals. They provide necessary information about the patient and can support the patient's care. Simultaneously, they are themselves vulnerable, having specific needs and experiences. A number of studies have been conducted that focus on the perspectives of the relatives. The synthesis of qualitative studies contributes to a more comprehensive understanding of recent study findings. DESIGN A meta-ethnographic synthesis of qualitative research findings was used. METHODS The synthesis process followed six defined steps. We located relevant studies through searching the CINAHL, PubMed and PsycInfo databases and through searching journals and reference lists by hand. A list of metaphors was created and translated into one another. Identified metaphors were synthesised and interpreted as a new whole. RESULTS Relatives of patients with dementia frequently experience a negative cycle of specific worries, negative feelings and resulting roles and functions in hospital due to negative care experiences. CONCLUSIONS Experiences of relatives are strongly influenced by the attitudes, expertise and communication that they receive from health professionals working in the hospital. The results clearly show how health professionals have the potential to break through the negative cycle and contribute to a more positive feeling about a patient's hospital stay. RELEVANCE TO CLINICAL PRACTICE Structured and individually planned involvement of the relatives during the hospital care seems to be a key aspect for improving the experiences for the relatives and the patients with dementia. Collaboration with the relatives needs to be valued and supported by the organisation. Also a professional and defined frame for this area of responsibility needs to be provided.
Approximate Hybrid High Radix Encoding for Energy-Efficient Inexact Multipliers

Approximate computing forms a design alternative that exploits the intrinsic error resilience of various applications and produces energy-efficient circuits with small accuracy loss. In this paper, we propose an approximate hybrid high radix encoding for generating the partial products in signed multiplications that encodes the most significant bits with the accurate radix-4 encoding and the least significant bits with an approximate higher radix encoding. The approximations are performed by rounding the high radix values to their nearest power of two. The proposed technique can be configured to achieve the desired energy-accuracy tradeoffs. Compared with the accurate radix-4 multiplier, the proposed multipliers deliver up to 56% energy and 55% area savings, when operating at the same frequency, while the imposed error is bounded by a Gaussian distribution with near-zero average. Moreover, the proposed multipliers are compared with state-of-the-art inexact multipliers, outperforming them by up to 40% in energy consumption, for similar error values. Finally, we demonstrate the scalability of our technique.
T but not N stage predicts survival for patients with tonsillar carcinoma treated with external radiotherapy and brachytherapy

Abstract Background. Our aim was to determine the efficacy of a therapeutic schedule including external radiation and brachytherapy in a consecutive and retrospective series of tonsillar carcinoma patients. Patients and methods. Ninety-six patients with tonsillar carcinoma were treated between 1988 and 2000 and were followed up for at least for three years. All patients were treated with accelerated hyperfractionated external radiotherapy, 68 patients had additional brachytherapy and 69 patients with advanced stages also received chemotherapy. There was no planned surgery even though 73% had N+ disease. Eleven patients with persistent neck nodes underwent ultimate salvage surgery. Results. The overall three-year survival (OS) was 70%. OS for the T stage was T1 90%, T2 89%, T3 54% and T4 60%. The corresponding numbers for the N stage were N0 61.5%, N1 73%, N2 78% and N3 66%. Accordingly OS was influenced by the T stage (p>0.001) rather than by N stage. Only four patients with salvage surgery had viable tumour cells in the specimen, their survival was not inferior. Discussion. The primary tumour stage is an essential determinant for survival in patients with irradiated tonsillar carcinoma. Neck dissection should be confined only as a salvage procedure.
Comprehensible Predictive Models for Business Processes

Predictive modeling approaches in business process management provide a way to streamline operational business processes. For instance, they can warn decision makers about undesirable events that are likely to happen in the future, giving the decision maker an opportunity to intervene. The topic is gaining momentum in process mining, a field of research that has traditionally developed tools to discover business process models from data sets of past process behavior. Predictive modeling techniques are built on top of process-discovery algorithms. As these algorithms describe business process behavior using models of formal languages (e.g., Petri nets), strong language biases are necessary in order to generate models with the limited amounts of data included in the data set. Naturally, corresponding predictive modeling techniques reflect these biases. Based on theory from grammatical inference, a field of research that is concerned with inducing language models, we design a new predictive modeling technique based on weaker biases. Fitting a probabilistic model to a data set of past behavior makes it possible to predict how currently running process instances will behave in the future. To clarify how this technique works and to facilitate its adoption, we also design a way to visualize the probabilistic models. We assess the effectiveness of the technique in an experimental evaluation with synthetic and real-world data.
Human liver epigenetic alterations in non-alcoholic steatohepatitis are related to insulin action

ABSTRACT Both genetic and lifestyle factors contribute to the risk of non-alcoholic steatohepatitis (NASH). Additionally, epigenetic modifications may also play a key role in the pathogenesis of NASH. We therefore investigated liver DNA methylation, as a marker for epigenetic alterations, in individuals with simple steatosis and NASH, and further tested if these alterations were associated with clinical phenotypes. Liver biopsies obtained from 95 obese individuals (age: 49.5 ± 7.7 years, BMI: 43 ± 5.7 kg/m2, type 2 diabetes [T2D]: 35) as a wedge biopsy during a Roux-en-Y gastric bypass operation were investigated. Thirty-four individuals had a normal liver phenotype, 35 had simple steatosis, and 26 had NASH. Genome-wide DNA methylation pattern was analyzed using the Infinium HumanMethylation450 BeadChip. mRNA expression was analyzed from 42 individuals using the HumanHT-12 Expression BeadChip. We identified 1,292 CpG sites representing 677 unique genes differentially methylated in liver of individuals with NASH (q < 0.001), independently of T2D, age, sex, and BMI. Focusing on the top-ranking 30 and another 37 CpG sites mapped to genes enriched in pathways of metabolism (q = 0.0036) and cancer (q = 0.0001) all together, 59 NASH-associated CpG sites correlated with fasting insulin levels independently of age, fasting glucose, or T2D. From these, we identified 30 correlations between DNA methylation and mRNA expression, for example LDHB (r = −0.45, P = 0.003). We demonstrated that NASH, more than simple steatosis, associates with differential DNA methylation in the human liver. These epigenetic alterations in NASH are linked with insulin metabolism.