Search

Background: Purpose: The combination of a mammalian target of rapamycin inhibitor and lenalidomide showed enhanced preclinical cytotoxicity. We conducted a phase 1 study in advanced solid tumour patients to assess safety, efficacy and pharmacodynamic (PD) outcomes.Methods: We employed a 3+3 dose escalation design to establish the safety and recommended phase 2 doses (RP2D) of daily everolimus and lenalidomide in patients with advanced solid tumours. The starting doses were 5 and 10 mg, respectively, with planned escalation to maximum single-agent doses of 10 and 25 mg in the absence of dose-limiting toxicity. PD endpoints of lymphocyte subsets and immune cytokines were assessed in peripheral blood using multiparameter flow cytometry and LUMINEX assay. Efficacy was evaluated by cross-sectional imaging after every two cycles of treatment.Results: The study enrolled 44 patients, median age of 58 years and 28 males (63.6%). The RP2D was established as 10 and 25 mg daily continuously for everolimus and lenalidomide. Common (>5%) grade ≥3 adverse events included rash (19%), neutropenia (19%), hypokalaemia (11%) and fatigue (9%). Best efficacy outcomes in 36 evaluable patients were partial response in 5 (13.8%), stable disease in 24 (55.8%) and progressive disease in 7 (19.4%) patients. PD assessment revealed significant association of cytokine levels (interleukin-2 (IL2), IL21 and IL17), baseline activated and total CD8+ lymphocytes and change in B cell lymphocytes and activated NK cells with clinical benefit.Conclusions: The study demonstrated the safety of everolimus and lenalidomide with promising efficacy signal in thyroid and adenoid cystic cancers.Clinical Trial Registration: NCT01218555. [ABSTRACT FROM AUTHOR]

Background: Intratumoral heterogeneity is defined by subpopulations with varying genotypes and phenotypes. Specialized, highly invasive leader cells and less invasive follower cells are phenotypically distinct subpopulations that cooperate during collective cancer invasion. Because leader cells are a rare subpopulation that would be missed by bulk sequencing, a novel image-guided genomics platform was used to precisely select this subpopulation. This study identified a novel leader cell mutation signature and tested its ability to predict prognosis in non-small cell lung cancer (NSCLC) patient cohorts.Methods: Spatiotemporal genomic and cellular analysis was used to isolate and perform RNA sequencing on leader and follower populations from the H1299 NSCLC cell line, and it revealed a leader-specific mutation cluster on chromosome 16q. Genomic data from patients with lung squamous cell carcinoma (LUSC; n = 475) and lung adenocarcinoma (LUAD; n = 501) from The Cancer Genome Atlas were stratified by 16q mutation cluster (16qMC) status (16qMC+ vs 16qMC-) and compared for overall survival (OS), progression-free survival (PFS), and gene set enrichment analysis (GSEA).Results: Poorer OS, poorer PFS, or both were found across all stages and among early-stage patients with 16qMC+ tumors within the LUSC and LUAD cohorts. GSEA revealed 16qMC+ tumors to be enriched for the expression of metastasis- and survival-associated gene sets.Conclusions: This represents the first leader cell mutation signature identified in patients and has the potential to better stratify high-risk NSCLC and ultimately improve patient outcomes. [ABSTRACT FROM AUTHOR]

Background: The major clinical obstacle that limits the long-term benefits of treatment with osimertinib (AZD9291) in patients with epidermal growth factor receptor-mutant non-small cell lung cancer is the development of acquired resistance. Therefore, effective strategies that can overcome acquired resistance to osimertinib are urgently needed. The authors' current efforts in this direction have identified LBH589 (panobinostat), a clinically used histone deacetylase inhibitor, as a potential agent in overcoming osimertinib resistance.Methods: Cell growth and apoptosis in vitro were evaluated by measuring cell numbers and colony formation and by detecting annexin V-positive cells and protein cleavage, respectively. Drug effects on tumor growth in vivo were assessed with xenografts in nude mice. Alterations of tested proteins in cells were monitored with Western blot analysis. Gene knockout was achieved using the CRISPR/Cas9 technique.Results: The combination of LBH589 and osimertinib synergistically decreased the survival of different osimertinib-resistant cell lines, including those harboring C797S mutations, with greater inhibition of cell colony formation and growth. The combination enhanced the induction of apoptosis in osimertinib-resistant cells. Importantly, the combination effectively inhibited the growth of osimertinib-resistant xenograft tumors in nude mice. Mechanistically, the combination of LBH589 and osimertinib enhanced the elevation of Bim in osimertinib-resistant cells. Knockout of Bim in osimertinib-resistant cells substantially attenuated or abolished apoptosis enhanced by the LBH589 and osimertinib combination. These results collectively support a critical role of Bim elevation in the induction of apoptosis of osimertinib-resistant cells for this combination.Conclusions: The current findings provide strong preclinical evidence in support of the potential for LBH589 to overcome osimertinib resistance in the clinic. [ABSTRACT FROM AUTHOR]

Background: Cisplatin‐based chemoradiotherapy is standard of care for locally advanced squamous cell carcinoma of the head and neck. This systemic review compared efficacy and safety of weekly vs triweekly cisplatin in locally advanced squamous cell carcinoma of the head and neck. Methods: Among 1500 prospective studies published from 1970 to 2015, 39 (18 weekly, 21 triweekly) including 3668 patients qualified for inclusion. Clinical outcomes were analyzed using weighted estimates and 2‐tailed t test for comparisons; significance level was 0.05. Results: Locoregional control was 58% (CI 53%‐63%) vs 61% (CI 56%‐65%; P = .7). The 2‐year overall survival (OS) was 74% (CI 66%‐80%) for weekly vs 67% (64%‐69%) triweekly groups (P = .67). The 2‐year progression‐free survival (PFS) was 69% (CI 59%‐77%) for weekly vs 62% (CI 58%‐65%) triweekly groups (P = .9). Grade 3 to 5 toxicities were 36% vs 40% (P = .37) in weekly vs triweekly groups. Conclusions: Weekly cisplatin was comparable in efficacy and safety to the triweekly regimen. Our analysis supports the use of weekly or triweekly cisplatin in locally advanced squamous cell carcinoma of the head and neck, with tolerability being a key factor in selection. [ABSTRACT FROM AUTHOR]

Background: Optimal prognostic and predictive biomarkers for patients with advanced-stage cancer patients who received immunotherapy (IO) are lacking. Inflammatory markers, such as the neutrophil-to-lymphocyte ratio (NLR), the monocyte-to-lymphocyte ratio (MLR), and the platelet-to-lymphocyte ratio (PLR), are readily available. The authors investigated the association between these markers and clinical outcomes of patients with advanced-stage cancer who received IO.Methods: A retrospective review was conducted of 90 patients with advanced cancer who received treatment on phase 1 clinical trials of IO-based treatment regimens. NLR, MLR, and PLR values were log-transformed and treated as continuous variables for each patient. Overall survival (OS), progression-free survival (PFS), and clinical benefit were used to measure clinical outcomes. For univariate associations and multivariable analyses, Cox proportional-hazards models or logistic regression models were used.Results: The median patient age was 63 years, and most were men (59%). The most common histologies were melanoma (33%) and gastrointestinal cancers (22%). High baseline NLR, MLR, and PLR values were associated significantly with worse OS and PFS (P < .05) and a lower chance of benefit (NLR and PLR; P < .05). Increased NLR, MLR, and PLR values 6 weeks after baseline were associated with shorter OS and PFS (P ≤ .052).Conclusions: Baseline and early changes in NLR, MLR, and PLR values were strongly associated with clinical outcomes in patients who received IO-based treatment regimens on phase 1 trials. Confirmation in a homogenous patient population treated on late-stage trials or outside of trial settings is warranted. These values may warrant consideration for inclusion when risk stratifying patients enrolled onto phase 1 clinical trials of IO agents. [ABSTRACT FROM AUTHOR]

Background: Successful implementation of non-small cell lung cancer (NSCLC) evidence-based guideline recommendations requires effective educational programs that target all clinicians from interdisciplinary teams. This study describes and evaluates the Engaging an Interdisciplinary Team for NSCLC (GAIN 3.0) experiential learning-based educational curriculum.Methods: GAIN 3.0 was designed to enhance interdisciplinary collaboration for effective NSCLC diagnosis, assessment, and treatment. The program used a flipped classroom model that included an e-learning component prior to a live 6-hour interactive program. The interactive program included hands-on simulations, small group workshops, gamification, and case discussions. Participants included academic and community members of multidisciplinary lung cancer teams. Assessments included an online baseline survey, a pretest and posttest, a program evaluation, a long-term survey (LTS), and on-site faculty evaluation of participants.Results: Of 416 attendees to 13 live GAIN 3.0 programs (nine in the United States and four in Europe), 304 (73%) completed the pretest and 187 (45%) completed the posttest. Out of a perfect score of 12 points, program participants had a mean test score of 6.3 ± 2.1 on the pretest (52%) and 7.8 ± 2.1 on the posttest (65%) (P = .03). There was an overall knowledge increase of 13% from pretest to posttest. Most LTS respondents (65%) rated the GAIN 3.0 live programs as "high impact." On the LTS, the areas with the greatest gains in participants who had very high confidence were communication across disciplines, use of a team-based approach, and personalized treatment.Conclusions: GAIN 3.0 was a highly successful interdisciplinary activity that improved participants' knowledge, competence, and likely the clinical care provided to patients with NSCLC. [ABSTRACT FROM AUTHOR]

Background: The knowledge regarding appropriate dosage of local anaesthetics for peripheral nerve blocks in children is very scarce. The main objective of the current investigation was to evaluate dosing patterns of local anaesthetics in children receiving peripheral nerve blocks across multiple paediatric hospitals in the USA. We also sought to estimate the incidence of local anaesthetic systemic toxicity.Methods: This is an observational study using the Pediatric Regional Anesthesia Network (PRAN) database. Data on every peripheral nerve block in patients aged <18 years placed from April 1, 2007 to May 31, 2015 were examined as a subset of the PRAN protocol. Data were examined for the type and dose of local anaesthetic and for the presence of local anaesthetic systemic toxicity.Results: In total, 40 121 peripheral nerve blocks in children were analysed. Individual analyses of block type demonstrated large local anaesthetic dose variability with a five- to 10-fold spread depending on the block type. Two patients developed local anaesthetic systemic toxicity, resulting in an estimated incidence (95% CI) per blocks performed of 0.005% (0.001-0.015%). None of the patients had any short- or long-term complications or sequelae.Conclusions: We detected a large variability in the local anaesthetic dosing practices for peripheral nerve blocks in children across multiple hospitals in the USA. Nonetheless, the risk of local anaesthetic systemic toxicity was very low. Due to the lack of dose findings studies, our results suggest the need to develop practice guidelines to minimize variability of regional anaesthesia practices in children. [ABSTRACT FROM AUTHOR]

Objectives: Esophageal adenosquamous carcinoma (ASC) is a rare tumor with characteristics of adenocarcinoma (AC) and squamous cell carcinoma (SCC), the two most common esophageal cancers. Its behavior is aggressive but poorly understood. Using the National Cancer Database (NCDB), the clinical features and overall survival of ASC were compared with AC and SCC. Methods: The NCDB was queried for patients with esophageal ASC, AC, and SCC. Univariate association of histology with patient characteristics and overall survival were analyzed and socioeconomic characteristics were balanced. Results: Clinical M stage was 0 in a significantly lower proportion of ASC (69.0%) than in AC (70.9%) or SCC (75.6%) (p < 0.001). Median survival was lower in patients with ASC (9.6 months) than with AC (13.5) or SCC (9.7) and 2-year OS was lower in patients with ASC (23.8%) than with AC (34.6%) or SCC (26.5%) (p < 0.001). The OS hazard ratio for ASC was 1.14 when compared to AC (95% CI = 1.016-1.267, p = 0.025) and 1.10 when compared to SCC, but the latter was not significant (95% CI = 0.980-1.222, p = 0.111). Conclusion: ASC is a rare tumor among esophageal carcinomas with a greater burden of metastatic disease than AC or SCC and worse OS than AC. [ABSTRACT FROM AUTHOR]

Introduction: Blunt trauma accounts for the majority of pediatric renal injuries. Most injuries are often minor and can be managed without surgical intervention. We have retrospectively reviewed our series of children with severe (grade IV/V) renal injuries, their management and outcome.Materials and Methods: Medical records of children less than 18 years with renal injuries were reviewed. The cause of injury, time following injury, management and outcome in these children were recorded. The outcome data were analyzed.Results: During the period between January 1996 and December 2008, 43 children with grade IV/V renal injuries were admitted with blunt abdominal trauma. Ten of these 43 children underwent exploration and 33 initially managed non-operatively. Two of these 33 children on non-operative management needed nephrectomy for vascular injury and delayed haemorrhage.Conclusions: Most children with grade IV/V renal injury following blunt trauma can be managed non-operatively. Management can be properly planned and executed based on clinical features, CT imaging and staging of renal injuries. Surgical intervention is needed for associated abdominal organ injuries and renal vascular injuries. [ABSTRACT FROM AUTHOR]

Background: Preclinical targeting of the hedgehog pathway by vismodegib and of insulin-like growth factor 1 receptor by cixutumumab enhances the efficacy of chemotherapy and also demonstrates activity against the tumor cell fraction responsible for disease recurrence in small cell lung cancer.Methods: Patients with newly diagnosed extensive-stage small cell lung cancer (SCLC-ED) were randomized to receive four 21-day cycles of cisplatin and etoposide alone (cisplatin at 75 mg/m(2) on day 1 and etoposide at 100 mg/m(2) on days 1-3; arm A) or in combination with either vismodegib (150 mg/d by mouth; arm B) or cixutumumab (6 mg/kg/wk intravenously on day 1; arm C). The primary endpoint was progression-free survival (PFS). Circulating tumor cells (CTCs) were isolated/enumerated with the Veridex CellSearch platform at the baseline.Results: One hundred fifty-two eligible patients were treated. Patient demographics and disease characteristics were well balanced between the 3 arms except for the higher rate with a performance status of 0 in arm B (P = .03). The median PFS times in arms A, B, and C were 4.4, 4.4, and 4.6 months, respectively; the median overall survival (OS) times were 8.8, 9.8, and 10.1 months, respectively; and the response rates were 48%, 56%, and 50%, respectively. None of the comparisons of these outcomes were statistically significant. The median OS was 10.5 months for those with low CTC counts (≤100/7.5 mL) at baseline and 7.2 months for those with high CTC counts (hazard ratio, 1.74; P = .006).Conclusions: There was no significant improvement in PFS or OS with the addition of either vismodegib or cixutumumab to chemotherapy in patients with SCLC-ED. A low baseline CTC count was associated with a favorable prognosis. Cancer 2016;122:2371-2378. © 2016 American Cancer Society. [ABSTRACT FROM AUTHOR]

Background: SCLC has limited treatment options and inadequate preclinical models. Promising activity of arsenic trioxide (ASO) recorded in conventional preclinical models of SCLC supported the clinical evaluation of ASO in patients. We assessed the efficacy of ASO in relapsed SCLC patients and in corresponding patient-derived xenografts (PDX).Methods: Single arm, Simon 2-stage, phase II trial to enroll patients with relapsed SCLC who have failed at least one line of therapy. ASO was administered as an intravenous infusion over 1-2 h daily for 4 days in week 1 and for 2 days in weeks 2-6 of an 8-week cycle. Treatment continued until disease progression. Pretreatment tumor biopsy was employed for PDX generation through direct implantation into subcutaneous pockets of SCID mice without in vitro manipulation and serially propagated for five generations. Ex vivo efficacy of cisplatin (3 mg/kg i.p. weekly) and ASO (3.75 mg/kg i.p. every other day) was tested in PDX representative of platinum sensitive and platinum refractory SCLC.Results: The best response in 17 evaluable patients was stable disease in 2 (12 %), progressive disease in 15 (88 %) patients and median time-to-progression of seven (range 1-7) weeks. PDX was successfully grown in 5 of 9 (56 %) transplanted biopsy samples. Serially-propagated PDXs preserved characteristic small cell histology and genomic stability confirmed by immunohistochemistry, short tandem repeat (STR) profiling and targeted sequencing. ASO showed in vitro cytotoxicity but lacked in vivo efficacy against SCLC PDX tumor growth.Conclusions: Cisplatin inhibited growth of PDX derived from platinum-sensitive SCLC but was ineffective against PDX from platinum-refractory SCLC. Strong concordance between clinical and ex vivo effects of ASO and cisplatin in SCLC supports the use of PDX models to prescreen promising anticancer agents prior to clinical testing in SCLC patients. Trial Registration The study was registered at http://www.clinicaltrials.gov (NCT01470248). [ABSTRACT FROM AUTHOR]

Background: Stereotactic body radiation therapy (SBRT) has demonstrated high rates of local control with low morbidity and has now emerged as the standard of care for medically inoperable, early stage non-small cell lung cancer (NSCLC). However, the impact of lung SBRT on survival in the elderly population is less clear given competing comorbid conditions. An analysis of the National Cancer Data Base (NCDB) was undertaken to determine whether definitive SBRT improves survival relative to observation alone patients ages 70 years and older.Methods: The NCDB, a retrospective national database that captures approximately 70% of all patients treated for cancer, was queried for patients aged 70 years or older with early stage (T1-T3N0M0) NSCLC from 2003 to 2006. Overall survival was compared between patients who received stereotactic body radiotherapy alone and those who received no treatment. An extended Cox proportional hazards model was applied to estimate the treatment effect of SBRT.Results: In total, 3147 patients met the selection criteria for this analysis. SBRT was delivered to 258 patients (8.2%), and 2889 patients (91.8%) received no treatment. There was no significant difference in the distribution of Charlson/Deyo comorbidity index scores between the 2 groups (P = .076). Multivariable analysis revealed improved overall survival with SBRT compared with observation for the entire cohort (hazard ratio, 0.64; P < .001).Conclusions: SBRT is associated with improved survival in elderly patients with early stage NSCLC who have concurrent comorbid conditions compared with observation alone. The current data support the use of SBRT for the treatment of elderly patients with early stage NSCLC who have limiting comorbid conditions. [ABSTRACT FROM AUTHOR]

Background: Preclinical evidence supports the clinical investigation of inhibitors to the insulin-like growth factor receptor (IGFR) and the epidermal growth factor receptor (EGFR) either alone or in combination as treatment for patients with non-small cell lung cancer (NSCLC).Methods: Patients with chemotherapy-naïve, advanced NSCLC who had an Eastern Cooperative Oncology Group performance status of 0 or 1 were eligible. Patients were randomized to receive carboplatin intravenously at an area under the plasma drug concentration-time curve of 6.0 plus paclitaxel 200 mg/m(2) intravenously on day 1 every 3 weeks combined with either intravenous cetuximab weekly (arm A), intravenous cixutumumab every 2 weeks (arm B), or both (arm C). Patients who had nonprogessing disease after 12 weeks of therapy were permitted to continue on maintenance antibody therapy until they developed progressive disease. The primary endpoint was progression-free survival (PFS). The study design required 180 eligible patients and had 88% power to detect a 60% increase in median PFS for either comparison (arm A vs arm C or arm B vs arm C) using the log-rank test.Results: From September 2009 to December 2010, 140 patients were accrued. The study was closed to accrual early because of an excessive number of grade 5 events reported on arms A and C. Thirteen patients died during treatment (6 patients on arm A, 2 patients on arm B, and 5 patients on arm C), including 9 within approximately 1 month of starting therapy. The estimated median PFS for arms A, B, and C were similar at 3.4 months, 4.2 months, and 4 months, respectively.Conclusions: On the basis of the apparent lack of efficacy and excessive premature deaths, the current results do not support the continued investigation of carboplatin, paclitaxel, and cixutumumab either alone or in combination with cetuximab for patients with advanced NSCLC. [ABSTRACT FROM AUTHOR]

Abstract: Hybridization of base isolation and active control is a promising alternative to suppress the seismic vibrations in civil structures. The base-isolation system introduces hysteretic/frictional nonlinearity into the structure and hence there is a need to develop a nonlinear adaptive control approach to subdue the vibrations. In this paper, the authors propose discrete direct adaptive ELM controller for active control of nonlinear base isolated building, subjected to a set of near-fault earthquakes. A single hidden layer neural controller with random selection of input weights compensates the nonlinearity and provides desired vibration suppression. The neural controller is based on the extreme learning machine algorithm with random input weight selection and output weights are updated using Lyapunov like adaptation rule. The proposed discrete adaptive control law provides necessary stability and vibration suppression in nonlinear base isolated building. Simulation studies have been carried out using the full-scale three dimensional benchmark eight-storey building comprising hysteretic lead-rubber base-isolation. One earthquake record and perturbed model is used to train the controller offline. The offline trained controller is adapted online using the actual full-scale model for a wide range of near-fault earthquakes. The results clearly show that the proposed controller suppresses the vibration significantly without increasing superstructure responses. The comprehensive performance measures are compared with existing results reported in the literature. [Copyright &y& Elsevier]

We propose a sequential Meta-Cognitive learning algorithm for Neuro-Fuzzy Inference System (McFIS) to efficiently recognize human actions from video sequence. Optical flow information between two consecutive image planes can represent actions hierarchically from local pixel level to global object level, and hence are used to describe the human action in McFIS classifier. McFIS classifier and its sequential learning algorithm is developed based on the principles of self-regulation observed in human meta-cognition. McFIS decides on what-to-learn, when-to-learn and how-to-learn based on the knowledge stored in the classifier and the information contained in the new training samples. The sequential learning algorithm of McFIS is controlled and monitored by the meta-cognitive components which uses class-specific, knowledge based criteria along with self-regulatory thresholds to decide on one of the following strategies: (i) Sample deletion (ii) Sample learning and (iii) Sample reserve. Performance of proposed McFIS based human action recognition system is evaluated using benchmark Weizmann and KTH video sequences. The simulation results are compared with well known SVM classifier and also with state-of-the-art action recognition results reported in the literature. The results clearly indicates McFIS action recognition system achieves better performances with minimal computational effort. [ABSTRACT FROM AUTHOR]

Abstract: In this paper, we present a meta-cognitive sequential learning algorithm for a neuro-fuzzy inference system, referred to as, ‘Meta-Cognitive Neuro-Fuzzy Inference System’ (McFIS). McFIS has two components, viz., a cognitive component and a meta-cognitive component. The cognitive component employed is a Takagi–Sugeno–Kang type-0 neuro-fuzzy inference system. A self-regulatory learning mechanism that controls the learning process of the cognitive component, by deciding what-to-learn, when-to-learn and how-to-learn from sequential training data, forms the meta-cognitive component. McFIS realizes the above decision by employing sample deletion, sample reserve and sample learning strategy, respectively. The meta-cognitive component use the instantaneous error of the sample and spherical potential of the rule antecedents to select the best training strategy for the current sample. Also, in sample learning strategy, when a new rule is added the rule consequent is assigned such that the localization property of Gaussian rule is fully exploited. The performance of McFIS is evaluated on four regression and eight classification problems. The performance comparison shows the superior generalization performance of McFIS compared to existing algorithms. [Copyright &y& Elsevier]

Objective: Develop the WVCR-Linked dataset by combining the West Virginia Cancer Registry (WVCR) with Medicare, Medicaid, and other data sources. Determine health care utilization, costs, and overall burden of four major cancers among the elderly in a rural and medically underserved state population, and to compare them with national estimates. Method: We extracted personal identifiers from the West Virginia Cancer Registry (WVCR) data file for individuals ≥ 65 years of age with an incident diagnosis of any cancer between January 1, 2002 and December 31, 2007. We linked the extracted data with Medicare and Medicaid administrative data using deterministic record linkage procedures. We updated missing vital status information by linking the National Death Index (NDI) data file. The updated WVCR-Linked dataset was enriched by links to the U.S. decennial census (2000) file and the Area Resource File. Results: We identified 42,333 individuals, of which 41,574 (98.2%) and 6,031 (14.3%) individuals were matched with Medicare and Medicaid administrative data files, respectively. The NDI data added or updated vital status information for 3,295 (7.8%) individuals in the WVCR-Linked dataset. Conclusion: The WVCR-Linked dataset is a comprehensive dataset offering many opportunities to understand factors related to cancer treatment patterns, costs, and outcomes in a rural and medically underserved elderly Appalachian population. Following our example, non-participant states in the Surveillance, Epidemiology and End Results (SEER) program can build a powerful dataset to identify and target cancer disparities, and to improve cancer-related outcomes for their elderly and dual-eligible citizens. [ABSTRACT FROM AUTHOR]

Abstract: A comparison of thermal characteristics of Al2O3/water and CuO/water nanofluids in transition flow through a straight circular duct fitted with helical screw tape inserts was made in this study. The helical screw tape inserts with twist ratios Y =1.78, 2.44 and 3 were used in the experimental study using 0.1% volume concentration Al2O3/water and CuO/water nanofluid. The average enhancements in Nusselt number for water with twist ratios of 1.78, 2.44 and 3 were 156.24%, 122.16% and 89.22% respectively when compared to plain tube. The average increase in Nusselt number corresponding to the twist ratios of 1.78, 2.44 and 3 were 166.84%, 128.67% and 89.22% respectively for Al2O3/water nanofluid. In the case of CuO/water nanofluid, the enhancements in Nusselt number were 179.82%, 144.29% and 105.63% for twist ratios 1.78, 2.44 and 3 respectively. Thermal performance analysis based on the constant pumping power criteria shows that helical screw tape inserts give better thermal performance when used with CuO/water nanofluid than with Al2O3/water nanofluid. [Copyright &y& Elsevier]

Abstract: This paper presents a comparison of thermal performance of helical screw tape inserts in laminar flow of Al2O3/water and CuO/water nanofluids through a straight circular duct with constant heat flux boundary condition. The helical screw tape inserts with twist ratios Y =1.78, 2.44 and 3 were used in the experimental study using 0.1% volume concentration Al2O3/water and CuO/water nanofluids. Nanofluids with required volume concentration of 0.1% were prepared by dispersing specified amounts of Al2O3 and CuO nanoparticles in deionised water. The performance analysis of helical screw tape inserts in laminar flow of Al2O3/water and CuO/water nanofluids is done by evaluating thermal performance factor for constant pumping power condition. Thermal performance factor of helical screw tape inserts using CuO/water nanofluid is found to be higher when compared with the corresponding value using Al2O3/water. Therefore, the helical screw tape inserts show better thermal performance when used with CuO/water nanofluid than with Al2O3/water nanofluid. [Copyright &y& Elsevier]

Abstract: In a fully complex-valued feed-forward network, the convergence of the Complex-valued Back Propagation (CBP) learning algorithm depends on the choice of the activation function, learning sample distribution, minimization criterion, initial weights and the learning rate. The minimization criteria used in the existing versions of CBP learning algorithm in the literature do not approximate the phase of complex-valued output well in function approximation problems. The phase of a complex-valued output is critical in telecommunication and reconstruction and source localization problems in medical imaging applications. In this paper, the issues related to the convergence of complex-valued neural networks are clearly enumerated using a systematic sensitivity study on existing complex-valued neural networks. In addition, we also compare the performance of different types of split complex-valued neural networks. From the observations in the sensitivity analysis, we propose a new CBP learning algorithm with logarithmic performance index for a complex-valued neural network with exponential activation function. The proposed CBP learning algorithm directly minimizes both the magnitude and phase errors and also provides better convergence characteristics. Performance of the proposed scheme is evaluated using two synthetic complex-valued function approximation problems, the complex XOR problem, and a non-minimum phase equalization problem. Also, a comparative analysis on the convergence of the existing fully complex and split complex networks is presented. [Copyright &y& Elsevier]

Background: Cetuximab, an immunoglobulin (Ig) G1 chimeric monoclonal antibody against the epidermal growth factor receptor, has demonstrated evidence of activity in nonsmall cell lung cancer (NSCLC). When administered in combination with carboplatin and docetaxel, a commonly used regimen for advanced NSCLC, cetuximab has exhibited synergistic interaction in preclinical studies. Therefore, a phase 2 study was conducted to evaluate the efficacy of the combination of cetuximab, carboplatin, and docetaxel for the treatment of advanced NSCLC.Methods: Chemotherapy-naïve patients aged >or=18 years with stage IIIB (with effusion) or stage IV NSCLC received cetuximab (at a dose of 400 mg/m(2) on Day 1 and 250 mg/m(2) on Days 8 and 15) plus docetaxel (at a dose of 75 mg/m(2) on Day 1) and carboplatin (area under the concentration vs time curve [AUC]=6 on Day 1) every 21 days for up to 6 cycles (graded according to the American Joint Committee on Cancer Staging System). Thereafter, patients without evidence of disease progression were continued on single-agent cetuximab for a maximum of 1 year or until disease progression. The primary endpoint was response rate.Results: Eighty patients were enrolled. The median number of cycles administered was 4 (range, 1-6 cycles). The objective response rate was 15.2%, with a median progression-free survival of 4.6 months and a median overall survival of 10.3 months. The salient grades 3 of 4 adverse events were neutropenia (30%), hypotension (3%), hypokalemia (4%), and hypomagnesemia (3%). Twenty-five patients received single-agent cetuximab (median duration, 12 weeks) and this was well tolerated.Conclusions: The results of this large, multicenter, phase 3 study indicate that the novel combination of cetuximab with docetaxel and carboplatin demonstrate modest anticancer activity for patients with advanced and metastatic NSCLC and has an acceptable toxicity profile. [ABSTRACT FROM AUTHOR]

Abstract: In this paper, a comparison of heat transfer and pressure drop characteristics of CuO/water nanofluids in a helically coiled heat exchanger held in horizontal and vertical positions is presented. Experiments were conducted in the turbulent flow regimes using water and CuO/water nanofluids of 0.1% and 0.2% volume concentrations. The experimental results show that there is no much difference between horizontal and vertical arrangements in the enhancement of convective heat transfer coefficient and friction factors of nanofluids compared to water. Irrespective of the positions of the helically coiled heat exchanger, the enhancement in internal Nusselt numbers is high for higher concentration nanofluids at turbulent flow. Also the experimental friction factors obtained are high for higher concentration nanofluids at low flow rates. Based on the experimental data, correlations are proposed for Nusselt number and friction factor. [Copyright &y& Elsevier]

Abstract: Frictional normal contact probing methods involving instrumented, depth-sensing indentation can be used to estimate the mechanical properties of small-volume structures and materials such as thin films and components of micro-electro-mechanical systems. This paper describes a new method for estimating the plastic properties, i.e. the yield strength and strain hardening exponent, of ductile materials from the topography of scratches formed by a conical tip during an instrumented, depth-sensing frictional sliding test. The proposed reverse analysis (or inverse analysis) uses dimensionless functions derived from computational simulations to extract plastic properties from an instrumented scratch response performed on a standard, commercially available instrument. Sensitivity analysis indicates that an experimental error of 5% in the scratch hardness or the pile-up height induces an error of <22% in the estimated strain hardening exponent. Laboratory experiments illustrate how two aluminum alloy tempers of the same indentation hardness have significantly different pile-up as a result of different strain hardening. Comparative results between the frictional sliding test and traditional tensile tests showed reasonable agreement for a total of 11 metallic alloys evaluated. These results confirm the potential usefulness of the proposed method as an engineering tool to probe plastic properties of small-volume materials and confined structures where it is difficult to obtain reliable estimates of mechanical properties by other means. [ABSTRACT FROM AUTHOR]

The promising therapeutic efficacy of the third generation EGFR inhibitor, osimertinib (AZD9291), for the treatment of patients with EGFR-mutant non-small cell lung cancer (NSCLC) has been demonstrated in the clinic both as first-line and second line therapy. However, inevitable acquired resistance limits its long-term benefit to patients and is thus a significant clinical challenge. The current study focuses on studying the potential role of targeting MEK5-ERK5 signaling in overcoming acquired resistance to osimertinib. Osimertinib and other third generation EGFR inhibitors exerted a rapid and sustained suppressive effect on ERK5 phosphorylation primarily in EGFR-mutant NSCLC cell lines and lost this activity in some osimertinib-resistant cell lines. Osimertinib combined with either ERK5 or MEK5 inhibitors synergistically decreased the survival of osimertinib-resistant cell lines with enhanced induction of apoptosis primarily via augmenting Bim expression. Moreover, the combination effectively inhibited the growth of osimertinib-resistant xenografts in vivo. Together, these findings suggest the potential role of MEK5-ERK5 signaling in modulating development of acquired resistance to osimertinib and value of targeting this signaling as a potential strategy in overcoming acquired resistance to osimertinib and possibly other third generation EGFR inhibitors. [ABSTRACT FROM AUTHOR]

DNA double-strand breaks (DSBs) are mainly repaired either by homologous recombination (HR) or by nonhomologous end-joining (NHEJ) pathways. Here, we showed that myeloid cell leukemia sequence 1 (Mcl-1) acts as a functional switch in selecting between HR and NHEJ pathways. Mcl-1 was cell cycle-regulated during HR, with its expression peaking in S/G2 phase. While endogenous Mcl-1 depletion reduced HR and enhanced NHEJ, Mcl-1 overexpression resulted in a net increase in HR over NHEJ. Mcl-1 directly interacted with the dimeric Ku protein complex via its Bcl-2 homology 1 and 3 (BH1 and BH3) domains, which are required for Mcl-1 to inhibit Ku-mediated NHEJ. Mcl-1 also promoted DNA resection mediated by the Mre11 complex and HR-dependent DSB repair. Using the Mcl-1 BH1 domain as a docking site, we identified a small molecule, MI-223, that directly bound to BH1 and blocked Mcl-1-stimulated HR DNA repair, leading to sensitization of cancer cells to hydroxyurea- or olaparib-induced DNA replication stress. Combined treatment with MI-223 and hydroxyurea or olaparib exhibited a strong synergy against lung cancer in vivo. This mechanism-driven combination of agents provides a highly attractive therapeutic strategy to improve lung cancer outcomes. [ABSTRACT FROM AUTHOR]