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Immune checkpoint inhibitors improve overall survival in advanced urothelial carcinoma, but response rates remain modest. We performed a multi-institutional retrospective cohort study comparing outcomes (observed response rate, progression-free, and overall survival) between patients based on time from initiation of first line platinum-based chemotherapy to second line immune checkpoint inhibitor. This study provides preliminary data that earlier resistance to platinum-based chemotherapy may be associated with shorter survival in those who receive subsequent ICI. BACKGROUND: Early progression on first-line (1L) platinum-based therapy or between therapy lines may be a surrogate of more aggressive disease and poor outcomes in advanced urothelial carcinoma (aUC), but its prognostic role regarding immune checkpoint inhibitor (ICI) response and survival is unclear. We hypothesized that shorter time until start of second-line (2L) ICI would be associated with worse outcomes in aUC. PATIENTS AND METHODS: We performed a retrospective multi-institution cohort study in patients with aUC treated with 1L platinum-based chemotherapy, who received 2L ICI. Patients receiving switch maintenance ICI were excluded. We defined time to 2L ICI therapy as the time between the start of 1L platinum-based chemotherapy to the start of 2L ICI and categorized patients a priori into 1 of 3 groups: less than 3 months versus 3–6 months versus more than 6 months. We calculated overall response rate (ORR) with 2L ICI, progression-free survival (PFS) and overall survival (OS) from the start of 2L ICI. ORR was compared among the 3 groups using multivariable logistic regression, and PFS, OS using cox regression. Multivariable models were adjusted for known prognostic factors. RESULTS: We included 215, 215, and 219 patients in the ORR, PFS, and OS analyses, respectively, after exclusions. ORR difference did not reach statistical significance between patients with less than 3 months versus 3–6 months versus more than 6 months to 2L ICI. However, PFS (HR 1.64; 95% CI 1.02–2.63) and OS (HR 1.77; 95% CI 1.10–2.84) was shorter among those with time to 2L ICI less than 3 months compared to those who initiated 2L ICI more than 6 months. CONCLUSION: Among patients with aUC treated with 2L ICI, time to 2L ICI less than 3 months was associated with lower, but not significantly different ORR, but shorter PFS and OS compared to 2L ICI more than 6 months. This highlights potential cross resistance mechanisms between ICI and platinum-based chemotherapy.

Drug reaction with eosinophilia and systemic symptoms syndrome is a severe type IV (delayed T-cell-dependent reaction) hypersensitivity reaction, characterized by fever, mucocutaneous eruptions, eosinophilia, and systemic inflammatory involvement. It usually begins a few weeks after the exposure to offending drug. Commonly implicated drugs are aromatic anticonvulsants (phenytoin, phenobarbitone, and carbamazepine) and sulfa drugs (sulfonamides, sulfasalazine, and dapsone). It is a potentially life-threatening hypersensitivity reaction. Here we report a case of drug reaction with eosinophilia and systemic symptoms syndrome associated with carbamazepine, which was successfully treated with intravenous methylprednisolone.

Background Erdafitinib, a pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor, was shown to be clinically active and tolerable in patients with advanced urothelial carcinoma and prespecified FGFR alterations in the primary analysis of the BLC2001 study at median 11 months of follow-up. We aimed to assess the long-term efficacy and safety of the selected regimen of erdafitinib determined in the initial part of the study. Methods The open-label, non-comparator, phase 2, BLC2001 study was done at 126 medical centres in 14 countries across Asia, Europe, and North America. Eligible patients were aged 18 years or older with locally advanced and unresectable or metastatic urothelial carcinoma, at least one prespecified FGFR alteration, an Eastern Cooperative Oncology Group performance status of 0–2, and progressive disease after receiving at least one systemic chemotherapy or within 12 months of neoadjuvant or adjuvant chemotherapy or were ineligible for cisplatin. The selected regimen determined in the initial part of the study was continuous once daily 8 mg/day oral erdafitinib in 28-day cycles, with provision for pharmacodynamically guided uptitration to 9 mg/day (8 mg/day UpT). The primary endpoint was investigator-assessed confirmed objective response rate according to Response Evaluation Criteria In Solid Tumors version 1.1. Efficacy and safety were analysed in all treated patients who received at least one dose of erdafitinib. This is the final analysis of this study. This study is registered with ClinicalTrials.gov, NCT02365597. Findings Between May 25, 2015, and Aug 9, 2018, 2328 patients were screened, of whom 212 were enrolled and 101 were treated with the selected erdafitinib 8 mg/day UpT regimen. The data cutoff date for this analysis was Aug 9, 2019. Median efficacy follow-up was 24·0 months (IQR 22·7–26·6). The investigator-assessed objective response rate for patients treated with the selected erdafitinib regimen was 40 (40%; 95% CI 30–49) of 101 patients. The safety profile remained similar to that in the primary analysis, with no new safety signals reported with longer follow-up. Grade 3–4 treatment-emergent adverse events of any causality occurred in 72 (71%) of 101 patients. The most common grade 3–4 treatment-emergent adverse events of any cause were stomatitis (in 14 [14%] of 101 patients) and hyponatraemia (in 11 [11%]). There were no treatment-related deaths. Interpretation With longer follow-up, treatment with the selected regimen of erdafitinib showed consistent activity and a manageable safety profile in patients with locally advanced or metastatic urothelial carcinoma and prespecified FGFR alterations.

445 Background: Different metastatic sites have variable prognostic implications in aUC. However, details on response and outcomes with ICI for particular mets is still unknown. We hypothesized that bone and liver mets would have poor response and outcomes with ICIs. Methods: We performed a retrospective cohort study in patients (pts) with aUC who received ICI. We compared overall response rate (ORR) and overall survival (OS) between pts with different mets at ICI initiation. We developed 4 different models: 1) lymph node (LN) only vs other; 2) visceral mets (bone, lung, liver) vs other; 3) bone + liver mets vs bone without liver vs liver without bone vs neither and 4) 6 factor model: a. LN +/- soft tissue/locoregional recurrence b. lung +/- (a) c. bone +/- (b) d. liver +/- (c) e. central nervous system (CNS) +/- (d) and f. other. ORR and OS were compared among groups using multivariable (adjusting for ECOG PS and hemoglobin

When the COVID-19 pandemic began, formal frameworks to collect data about affected patients were lacking. The COVID-19 and Cancer Consortium (CCC19) was formed to collect granular data on patients with cancer and COVID-19 at scale and as rapidly as possible. CCC19 has grown from five initial institutions to 125 institutions with >400 collaborators. More than 5,000 cases with complete baseline data have been accrued. Future directions include increased electronic health record integration for direct data ingestion, expansion to additional domestic and international sites, more intentional patient involvement, and granular analyses of still-unanswered questions related to cancer subtypes and treatments.

We report a facile and economic hydrothermal process for multifunctionally engineered copper oxide/zinc oxide-tetrapods (CuO/ZnO-T) nanocomposite for wastewater treatment. The resultant CuO/ZnO-T nanocomposite possesses high porosity, large surface area, and low band gap. All these properties are advantageous for photocatalyst and adsorbent for dyes and heavy metal ions removal. The morphology of synthesized nanocomposite was characterized using X-ray diffraction, scanning electron microscopy, Brunauer–Emmett–Teller, Fourier-transform infrared spectroscopy, and UV–Visible absorption spectroscopy. The results confirmed the attachment of CuO on the ZnO-T surface, forming a hybrid nanocomposite. The concentration of heavy metal ions was monitored using the atomic absorption spectroscopy technique. The synthesized CuO/ZnO-T nanocomposite was investigated for the decontamination of anionic and cationic dyes, Reactive yellow-145 (RY-145) and Basic violet-3 (BV-3) and heavy metal ions (Chromium (VI) and Lead (II)). The CuO/ZnO-T nanocomposite exhibited superior photocatalytic efficiency (80% RY-145 dye removal and 86% BV-3 dye removal) and adsorption capacity (99% Chromium (VI) removal and 97% Lead (II) removal) as compared to pristine ZnO-T. The mechanism for the reduction of dyes and heavy metal ions was discussed by different kinetics and isotherm models. The current study inferred that CuO/ZnO-T nanocomposite is a potential candidate as a proficient photocatalyst/adsorbent for the removal of various wastewater contaminants.

Background DNA damage response (DDR) genomic alterations may play an important role in clinical outcomes of patients with urothelial cancer (UC). However, data on the prognostic role of DDR gene alterations in patients with advanced UC remain unclear. Materials and Methods We retrospectively collected data of three independent patient cohorts with relapsed or advanced UC including 81 and 91 patients from four institutions who underwent FoundationOne genomic sequencing as well as 129 patients selected from The Cancer Genome Atlas bladder cohort. Fisher's exact test was used to determine differences of mutation frequency among the three cohorts. Logistic regression analysis was performed to calculate odds ratio (OR) and 95% confidence interval (CI). Overall survival (OS) was measured from time of initial diagnosis and Cox proportional hazard regression analysis was performed to calculate the hazard ratio (HR) and 95% CI. Results DDR genomic alterations were present in 76.5% (62/81), 40.7% (37/91), and 51.2% (66/129) of the three cohorts. ATM alterations consistently correlated with significantly shorter OS, whereas other DDR alterations (excluding ATM) were associated with better prognosis. In 152 patients treated with platinum pooled from the three cohorts, the prognostic value of alterations in ATM as compared with other predefined DDR genes was substantially different (ATM: adjusted HR [HR], 2.03; 95% CI, 1.03–4; p = .04; other DDR: adjusted HR, 0.49; 95% CI, 0.31–0.8; p = .003). Conclusions Genomic alterations in ATM and other DDR genes may have opposite prognostic value in relapsed and/or advanced UC. ATM may have a complex role in UC progression. Implications for Practice Somatic mutations of DNA damage response (DDR) genes are frequently found in urothelial cancer and appear to play an important role in tumorigenesis, progression, treatment response, and outcomes. In a set of DDR genes, ATM alterations were associated with worse survival, while other alterations were associated with better survival in advanced urothelial cancer. The results of this study suggest a complex role of ATM in tumor progression and call for further studies to determine the underlying mechanisms and biomarker clinical utility.

Background: Characterization of the different genomic alterations (GAs) in urothelial carcinoma (UC), by site of origin, may identify contrasting therapeutic opportunities and inform distinct putative pathogenetic mechanisms. Objective: To describe the genomic landscape of UC based on the anatomic site of the primary tumor. Design, setting, and participants: In total, 479 upper tract UC (UTUC) and 1984 bladder UC (BUC) patients underwent comprehensive genomic profiling (CGP) to evaluate all classes of GAs, tumor mutational burden (TMB), and microsatellite instability (MSI) status. Targetable GAs and signatures were assessed according to the European Society for Medical Oncology Scale for Clinical Actionability of molecular Targets (ESCAT). Intervention: Hybrid-capture–based CGP. Outcome measurements and statistical analysis: Descriptive analyses and differences between anatomic subgroups were reported. Results and limitations: In total, 39% of patients with UC harbored one or more tier 1–2 GAs, suggesting potential benefit from approved or investigational therapies. UTUC cases were enriched in FGFR3 short variant (SV) GA (20% vs 13%) and HRAS SV GA (7.3% vs 3%), the latter attributed specifically to enrichment in renal pelvis UC (9.5%) versus ureteral UC (1.8%, p = 0.002). RB1 GAs were more frequent in BUC than in UTUC (21% vs 7.8% p < 0.001). Non-FGFR3 kinase fusions were observed in 1% of patients, including BRAF/RAF1 fusions in 0.5%. BRAF mutations/fusions were observed in 2% of cases and were mutually exclusive with FGFR3 GA (p = 0.002). There were no differences of TMB high/MSI high for primary tumor and metastatic sites, but UTUC was enriched for MSI high (3.4%) relative to BUC (0.8%, p < 0.001). Conclusions: Differences in the genomic landscapes of UTUC and BUC were modest; however, patients with UTUC were enriched for FGFR3 and HRAS SV relative to BUC. Further investigation on UC, stratified by the site of origin, is warranted. In addition, these results suggest an opportunity for the routine incorporation of CGP prior to systemic therapy initiation in metastatic UC. Patient summary: Genomic profiling of advanced urothelial carcinoma can inform several therapeutic opportunities for patients, particularly those with upper tract urothelial carcinoma, an infrequent and generally aggressive tumor entity with nonoverlapping clinical features compared with its bladder counterpart, which is often treated based on the data extrapolated from bladder cancer.

BACKGROUND Immune checkpoint inhibitors (ICIs) represent an appealing treatment for patients with advanced urothelial cancer (aUC) and a poor performance status (PS). However, the benefit of ICIs for patients with a poor PS remains unknown. It was hypothesized that a poor Eastern Cooperative Oncology Group (ECOG) PS (≥2 vs 0-1) would correlate with shorter overall survival (OS) in patients receiving ICIs. METHODS In this retrospective cohort study, clinicopathologic, treatment, and outcome data were collected for patients with aUC who were treated with ICIs at 18 institutions (2013-2019). The overall response rate (ORR) and OS were compared for patients with an ECOG PS of 0 to 1 and patients with an ECOG PS ≥ 2 at ICI initiation. The association between a new ICI in the last 30 and 90 days of life (DOL) and death location was also tested. RESULTS Of the 519 patients treated with ICIs, 395 and 384 were included in OS and ORR analyses, respectively, with 26% and 24% having a PS ≥ 2. OS was higher in those with a PS of 0 to 1 than those with a PS ≥ 2 who were treated in the first line (median, 15.2 vs 7.2 months; hazard ratio [HR], 0.62; P = .01) but not in subsequent lines (median, 9.8 vs 8.2 months; HR, 0.78; P = .27). ORRs were similar for patients with a PS of 0 to 1 and patients with a PS ≥ 2 in both lines. Of the 288 patients who died, 10% and 32% started ICIs in the last 30 and 90 DOL, respectively. ICI initiation in the last 30 DOL was associated with increased odds of death in a hospital (odds ratio, 2.89; P = .04). CONCLUSIONS Despite comparable ORRs, ICIs may not overcome the negative prognostic role of a poor PS, particularly in the first-line setting, and the initiation of ICIs in the last 30 DOL was associated with hospital death location.

// Ming Yin 1, 6 , Petros Grivas 2, 7 , Hamid Emamekhoo 3 , Prateek Mendiratta 2 , Siraj Ali 4 , JoAnn Hsu 5 , Monali Vasekar 1 , Joseph J. Drabick 1 , Sumanta Pal 5 and Monika Joshi 1 1 Department of Medicine, Division of Hematology-Oncology, Penn State Cancer Institute, Hershey, PA, USA 2 Department of Hematology and Medical Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA 3 Department of Medicine, Division of Hematology-Oncology, University of Wisconsin Carbone Cancer Center, WI, USA 4 Foundation Medicine, Cambridge, MA, USA 5 Department of Medical Oncology, City of Hope Comprehensive Cancer Center, Duarte, CA, USA 6 Department of Medicine, Division of Oncology, Ohio State University Comprehensive Cancer Center, Columbus, OH, USA 7 Department of Medicine, Division of Oncology, University of Washington, Seattle, WA, USA Correspondence to: Monika Joshi, email: mjoshi@pennstatehealth.psu.edu Keywords: biomarkers; prognosis; bladder cancer; genomic alterations; next generation sequencing Received: November 30, 2017 Accepted: March 02, 2018 Published: March 30, 2018 ABSTRACT Background: Mutations of DNA repair genes, e.g. ATM/RB1 , are frequently found in urothelial cancer (UC) and have been associated with better response to cisplatin-based chemotherapy. Further external validation of the prognostic value of ATM/RB1 mutations in UC can inform clinical decision making and trial designs. Results: In the discovery dataset, ATM/RB1 mutations were present in 24% of patients and were associated with shorter OS (adjusted HR 2.67, 95% CI, 1.45–4.92, p = 0.002). There was a higher mutation load in patients carrying ATM/RB1 mutations (median mutation load: 6.7 versus 5.5 per Mb, p = 0.072). In the validation dataset, ATM/RB1 mutations were present in 22.2% of patients and were non-significantly associated with shorter OS (adjusted HR 1.87, 95% CI, 0.97–3.59, p = 0.06) and higher mutation load (median mutation load: 8.1 versus 7.2 per Mb, p = 0.126). Materials and Methods: Exome sequencing data of 130 bladder UC patients from The Cancer Genome Atlas (TCGA) dataset were analyzed as a discovery cohort to determine the prognostic value of ATM/RB1 mutations. Results were validated in an independent cohort of 81 advanced UC patients. Cox proportional hazard regression analysis was performed to calculate the hazard ratio (HR) and 95% confidence interval (CI) to compare overall survival (OS). Conclusions: ATM/RB1 mutations may be a biomarker of poor prognosis in unselected UC patients and may correlate with higher mutational load. Further studies are required to determine factors that can further stratify prognosis and evaluate predictive role of ATM/RB1 mutation status to immunotherapy and platinum-based chemotherapy.

BACKGROUND In a prior open-label study, the combination of dalantercept, a novel antiangiogenic targeting activin receptor-like kinase 1 (ALK1), plus axitinib was deemed safe and tolerable with a promising efficacy signal in patients with advanced renal cell carcinoma (RCC). METHODS In the current phase 2, randomized, double-blind, placebo-controlled study, patients with clear cell RCC previously treated with 1 prior angiogenesis inhibitor were randomized 1:1 to receive axitinib plus dalantercept versus axitinib plus placebo. Randomization was stratified by the type of prior therapy. The primary endpoint was progression-free survival (PFS). Secondary endpoints were PFS in patients with ≥2 prior lines of anticancer therapy, overall survival, and the objective response rate. RESULTS Between June 10, 2014, and February 23, 2017, a total of 124 patients were randomly assigned to receive axitinib plus dalantercept (59 patients) or placebo (65 patients). The median PFS was not found to be significantly different between the treatment groups (median, 6.8 months vs 5.6 months; hazard ratio, 1.11 [95% CI, 0.71-1.73; P = .670]). Neither group reached the median overall survival (hazard ratio, 1.39 [95% CI, 0.70-2.77; P = .349]). The objective response rate was 19.0% (11 of 58 patients; 95% CI, 9.9%-31.4%) in the dalantercept plus axitinib group and 24.6% (15 of 61 patients; 95% CI, 14.5%-37.3%) in the placebo plus axitinib group. At least 1 treatment-emergent adverse event of ≥grade 3 was observed in 59% of patients (34 of 58 patients) in the dalantercept group and 64% of patients (39 of 61 patients) in the placebo group. One treatment-related death occurred in the placebo plus axitinib group. CONCLUSIONS Although well tolerated, the addition of dalantercept to axitinib did not appear to improve treatment-related outcomes in previously treated patients with advanced RCC.

The present investigation was focused to formulate semi-solid capsules (SSCs) of hydrophobic drug telmisartan (TLMS) by encapsulating semi-solid matrix of its solid dispersion (SD) in HPMC capsules. The combinational approach was used to reduce the lag time in drug release and improvise its dissolution. SDs of TLMS was prepared using hot fusion method by varying the combinations of Pluronic-F68, Gelucire 50/13 and Plasdone S630. A total of nine batches (SD1-SD9) were characterized for micromeritic properties, in vitro dissolution behavior and surface characterization. SD4 with 52.43% cumulative drug release (CDR) in phosphate buffer, pH 7.4, in 120 min, t50% 44.2 min and DE30min 96.76% was selected for the development of semi-solid capsules. Differential scanning calorimetry of SD4 revealed molecular dispersion of TLMS in Pluronic-F68. SD4 was formulated into SSCs using Gelucire 44/14 and PEG 400 as semi-solid components and PEG 6000 as a suspending agent to achieve reduction in lag time for effective drug dissolution. SSC6 showed maximum in vitro drug dissolution 97.49 % in phosphate buffer, pH 7.4 with in 20 min that was almost a three folds reduction in the time required to achieve similar dissolution by SD. Thus, SSCs present an excellent approach to enhance in vitro dissolution as well as to reduce the lag time of dissolution for poorly water soluble drugs especially to those therapeutic classes that are intended for faster onset of action. Developed approach based on HPMC capsules provided a better alternative to target delivery of telmisartan to the vegetarian population.

Targeting the epidermal growth factor receptor (EGFR) in patients with non-small cell lung cancer (NSCLC) harboring sensitizing mutations in the tyrosine kinase (TKI) domain has led to a significant change in the management of this disease. The classic or sensitizing mutations are G719X mutation in exon 18, in-frame deletions or insertion of exon 19, L858R or L861Q mutation in exon 21. Approximately 90% of these mutations are exon 19 deletion or exon 21 L858R point mutation. Gefitinib and erlotinib are reversible first-generation inhibitors of mutant EGFR, and treatment with these agents in the first-line setting has demonstrated a progression-free survival of 9.5–13.7 months. However, the majority of these patients ultimately develop resistance to these drugs. Afatinib is an irreversible pan-ErbB inhibitor that was developed to circumvent the problem of resistance to first-generation TKIs. The LUX-Lung studies have evaluated the efficacy and toxicities of afatinib in treatment-naïve and refractory NSCLC patients. The promising results of some of these trials led to approval of afatinib by the US Food and Drug Administration for patients with advanced NSCLC and EGFR exon 19 deletions or exon 21 (L858R) substitution mutations. Afatinib causes toxicities similar to those of the first-generation EGFR TKIs, such as diarrhea, rash, acne, and stomatitis, and overall is well tolerated. This article focuses on the clinical studies of afatinib in patients with NSCLC., Video abstract

The cycle process of the tidal force of celestial body for Lushan M7.0 earthquake, occurred in Lushan county of Sichuan, China on April 20, 2013 was calculated. The earthquake occurred at the lowest point phase. It indicated that the type of seismogenic fault that the tide force acted on belonged to the thrust fault. According to the tidal cycle, the abnormal air temperature change was analyzed based on NCEP satellite data around the whole China before and after the earthquake. The result showed that the air temperature changed evidently with the tide force changing. In temporal, the change went through: initial air temperature rise → strength→ reaching abnormal peak→ gradually decline; in spatial, the abnormal area winded its way along the margin of the southern Qinghai-Tibet Plateau and went through: scattered→ conversion→ scattered procession. The procession was similar to the change procession of a rock breaking under the stress loading. This shows that the stress change of rock may cause the air temperature change in the atmosphere before and after earthquake. It indicated that the tidal force of celestial body could trigger the earthquake, when the tectonic stress reaches its critical broken point and the air temperature anomaly was proportional to the seismic tectonic stress change. It was useful to combine air temperature and tidal force in earthquake precursory.

Gas sensors of different types are being used for environmental monitoring. Among all the gas sensors CNT based gas sensors are widely used .The gas sensors consist of polymer- CNT as an active layer, where the adsorption of gas molecules leads to a large change in its electrical resistivity. They have merits of being low cost, good sensitivity, and convenient to measure response (a simple change in resistance). In the present investigation purified multi wall carbon nanotubes (MWNT) have been used as a sensing material for detecting ammonia gas. In this work, a thick film of Carbon nanotube -polymer was prepared and painted over ring types of electrodes. Carbon nanotubes are highly efficient gas adsorption agents due to their high surface-to-volume ratio. In order to improve the efficiency of the sensor CNT-polyvinyl pyroiodine composite film was prepared. The gas sensing properties of the composite film for ammonia vapor were tested by measuring the resistance during a span of 720 seconds at an interval of 10 seconds each. A composite polymer CNT film showed a high response and rapid sensing to the test gas. The observations were taken by varying the concentration of ammonia at room temperature. An increase in resistance has been observed with the increase in time. The sensing mechanism of the composite has been explained on the basis of volume expansion and polar interaction of various vapors on the carbon nanotubes surface.

Laser has been used efficiently for treatment of oral lichen planus, leukoplakia, aphthous ulcers and oral manifestations of HIV. Two cases of recalcitrant oral pemphigus vulgaris that were successfully treated with CO 2 laser are described. The patients had been treated by a dermatologist with pulse therapy of methyl prednisolone and cyclophosphamide over a period of 6 to 8 months, but the clinical course was characterized by episodes of painful flare-ups and nonresponsiveness. The patients were extremely uncomfortable with recurrent oral lesions. CO 2 laser at low power was used to irradiate the lesions. It was shown to be effective in relieving pain and healing of lesions, with nonrecurrence. To the best of our knowledge, this is the first case report of such a treatment of oral pemphigus vulgaris. Further clinical studies are warranted to confirm efficacy and to optimize the treatment protocol.

Humidity Sensors of different types are being used for various applications. Resistive Humidity Sensor has advantage over others for being small, low cost, interchangeable and long term stable. This makes them suitable for industrial, commercial and residential applications. In the present investigation humidity sensing behavior of various composite films made of Polyvinyl Alcohol (PVA), Polyethylene glycol (PEG), alkalies and oxide nanoparticles has been studied. It was found that relationship of resistance v/s relative humidity (RH) was linear from 40 RH to 60 RH for a composite film made of PVA + PEG+ alkalies .The film can work with reliable efficiency for more than 100 days for the above range of humidity at room temperature. In order to improve the efficiency of composite polymer film TiO2 nanoparticles were added in the film and studied for resistance vs. RH responses. It was found that humidity range expands from 30 RH to 65 RH indicating the proportional decrease in resistance with increase in humidity at both ends as a result of the presence of TiO2 nanoparticles. The composite film with TiO2 nanoparticles can thus be used for wider range of humidity with reasonable stability and consistency. The observed behavior of the film has been attributed to the transportation of charge through TiO2 nanoparticles enhancing the conduction with the cross linked polymers.

V-Raf Murine Sarcoma Viral Oncogene Homolog B (BRAF) mutated lung cancer is relatively aggressive and is resistant to currently available therapies. In a recent phase II study for patients with BRAF-V600E non-small cell lung cancer (NSCLC), BRAF V600E inhibitor demonstrated evidence of activity, but 30% of this selected group progressed while on treatment, suggesting a need for developing alternative strategies. We tested two different options to enhance the efficacy of vemurafenib (BRAF V600E inhibitor) in BRAF mutated NSCLC. The first option was the addition of erlotinib to vemurafenib to see whether the combination provided synergy. The second was to induce MEK inhibition (downstream of RAF) with trametinib (MEK inhibitor). We found that the combination of vemurafenib and erlotinib was not synergistic to the inhibition of p-ERK signaling in BRAF-V600E cells. Vemurafenib caused significant apoptosis, G1 arrest and upregulation of BIM in BRAF-V600 cells. Trametinib was effective as a single agent in BRAF mutated cells, either V600E or non-V600E. Finally, the combination of vemurafenib and trametinib caused a small but significant increase in apoptosis as well as a significant upregulation of BIM when compared to either single agent. Thus, hinting at the possibility of utilizing a combinational approach for the management of this group of patients. Importantly, trametinib alone caused upregulation of p-AKT in BRAF non-V600 mutated cells, while this effect was nullified with the combination. This finding suggests that, the combination of a MEK inhibitor with a BRAF inhibitor will be more efficacious in the clinical setting for patients with BRAF mutated NSCLC.

The T-lymphoma and metastasis gene 1 (TIAM1) encodes a guanine nucleotide-exchange factor protein (Tiam1) that is specific for the Rho-family GTPase Rac1 and is important for cell polarity, migration and adhesion. Tiam1 is a large multi-domain protein that contains several protein-protein binding domains that are important for regulating cellular function. The PHn-CC-Ex domain is critical for plasma-membrane association and interactions with protein-scaffold proteins (e.g. Par3b, spinophilin, IRSp53 and JIP2) that direct Tiam1-Rac1 signaling specificity. It was determined that the coiled-coil domain of Par3b binds the PHn-CC-Ex domain with a dissociation constant of ≈ 30 µM. Moreover, the structures of two variants of the Tiam1 PHn-CC-Ex domain were solved at resolutions of 1.98 and 2.15 Å, respectively. The structures indicate that the PHn, CC and Ex regions form independent subdomains that together provide an integrated platform for binding partner proteins. Small-angle X-ray scattering (SAXS) data indicate that the Tiam1 PHn-CC-Ex domain is monomeric in solution and that the solution and crystal structures are very similar. Together, these data provide the foundation necessary to elucidate the structural mechanism of the PHn-CC-Ex/scaffold interactions that are critical for Tiam1-Rac1 signaling specificity.

Background Pesticides are widely used in households to control insects and weeds. Several studies, over the past decades, have examined the possible relationship of serum concentration of organochlorine pesticides and the development of breast cancer. However, little data exists regarding an association between self-reported, residential exposure to pesticides and breast cancer risk. We, therefore, present a case-control study examining self-reported exposure to household pesticides with regard to associated risk of breast cancer. Methods This study was conducted in the area in and around New York City, NY and included 1205 patients (447 cases and 758 controls). Cases were defined as women with newly diagnosed breast cancer or carcinoma in-situ, while controls included women with benign breast diseases or those undergoing non-breast related surgery. All patients were asked a series of questions to determine their pesticide exposure, including the type of pesticide, location of exposure (inside vs. outside the home), who applied the pesticide (self vs. a professional) and duration of pesticide use. Logistic regression models were used to estimate unadjusted and adjusted odds ratios (OR) and corresponding 95% confidence intervals (CI). Results The most common pests encountered in participants' homes were ants, carpenter ants, and cockroaches. The calculated adjusted odds ratios for both self and professionally applied pesticides, specifically against the above mentioned insects, with regard to breast cancer risk were 1.25 (95% CI: 0.79-1.98) and 1.06 (95% CI: 0.65-1.73), respectively. Similarly, odds ratios and confidence intervals were calculated for other types of pesticides. Conclusions Overall, the results of our study did not show an association between self-reported exposure to pesticides and breast cancer risk. Future studies, utilizing a larger sample size and more specific detail on time frame of pesticide exposure, are needed to further explore this question.

The mitotic kinesin motor protein KIF14 is essential for cytokinesis during cell division and has been implicated in cerebral development and a variety of human cancers. Here we show that the mouse KIF14 motor domain binds tightly to microtubules and does not display typical nucleotide-dependent changes in this affinity. It also has robust ATPase activity but very slow motility. A crystal structure of the ADP-bound form of the KIF14 motor domain reveals a dramatically opened ATP-binding pocket, as if ready to exchange its bound ADP for Mg·ATP. In this state, the central β-sheet is twisted ~ 10° beyond the maximal amount observed in other kinesins. This configuration has only been seen in the nucleotide-free states of myosins—known as the “rigor-like” state. Fitting of this atomic model to electron density maps from cryo-electron microscopy indicates a distinct binding configuration of the motor domain to microtubules. We postulate that these properties of KIF14 are well suited for stabilizing midbody microtubules during cytokinesis.