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Sleep problems in children with epilepsy (CWE) are common. However, little is known about parental experiences and feelings about managing sleep in their CWE. To provide the most appropriate services' provision, it is essential that the lived experience of parents of this patient group and the issues and problems that they face in managing their child's sleep is understood.In 2018, nine mothers of CWE (aged 5-15 years) were interviewed about their perceptions and experiences around their child's sleep, sleep problems and their management, the impact of sleep difficulties on the child and their family and available support.Four themes were identified that represented the nature of the child's sleep problems, including settling and night-waking issues, parasomnias and child anxiety around sleep. Seven themes represented mothers' experiences of managing their child's sleep and any associated problems, including the longstanding challenging nature of child sleep issues, management strategies adopted, challenges related to managing sleep over time, the link between sleep and seizures, the negative impact of poor sleep on daytime functioning, role of antiseizure medication and maternal concerns about child sleep. One theme represented the perceived lack of information, help and support available.Findings suggest there are unmet needs in supporting parents to deal with sleep, sleep problems and their management in CWE.This individual study was conducted under the umbrella of the CASTLE research programme (see https://castlestudy.org.uk/). Parents who have lived experience of parenting a child with epilepsy were co-applicants for the programme and were involved in the original conception, aims, design and funding application for the research programme (including the project reported in this paper) and advised on project design. Mothers of CWE who have lived experience of managing sleep and sleep problems in their child were participants who shared their experiences through the interviews, which formed the data of the current study.

OBJECTIVE Emotional problem-related distress is a common issue faced by patients with cancer. However, patients suffering with this emotional burden do not typically seek assistance. This study sought to determine the prevalence of emotional problem-related distress by cancer type, and identify factors correlated with the level of assistance requested. METHODS Using the SupportScreen®, patients were screened for emotional problem-related distress at their first or second visit to an NCI designated Comprehensive Cancer Center. General Linear Model was used to test the association between emotional problem-related distress and type of cancer, and the relationship between level of assistance requested and patients' characteristics. RESULTS A total of 2,421 patients were included in this analysis. Patients were mostly female (62%), diagnosed with breast (24%), gynecological (16%) or gastrointestinal (15%) cancers. Highest levels of emotional problem-related distress were reported by patients diagnosed with lung, gynecological, breast and gastrointestinal cancers. Level of assistance requested were significantly associated with problem-related distress scores (p

Background Systemic therapy (ST) can be deferred in patients who have metastatic renal cell carcinoma (mRCC) and slow-growing metastases. Currently, this subset of patients managed with active surveillance (AS) is not well described in the literature. Methods This was a prospective observational study of patients with mRCC across 46 US community and academic centers. The objective was to describe baseline characteristics and demographics of patients with mRCC initially managed by AS, reasons for AS, and patient outcomes. Descriptive statistics were used to characterize demographics, baseline characteristics, and patient-related outcomes. Wilcoxon 2-sample rank-sum tests and χ2 tests were used to assess differences between ST and AS cohorts in continuous and categorical variables, respectively. Kaplan-Meier survival curves were used to assess survival. Results Of 504 patients, mRCC was initially managed by AS (n = 143) or ST (n = 305); 56 patients were excluded from the analysis. Disease was present in 69% of patients who received AS, whereas the remaining 31% had no evidence of disease. At data cutoff, 72 of 143 patients (50%) in the AS cohort had not received ST. The median overall survival was not reached (95% CI, 122 months to not estimable) in patients who received AS versus 30 months (95% CI, 25-44 months) in those who received ST. Quality of life at baseline was significantly better in patients who were managed with AS versus ST. Conclusions AS occurs frequently (32%) in real-world clinical practice and appears to be a safe and appropriate alternative to immediate ST in selected patients.

Objective Recent neuroimaging studies have revealed differences in cortical and white matter brain structure in children with self‐limiting rolandic epilepsy (RE). Despite this, reproducibility of the findings has been difficult, and there is no consensus about where and when structural differences are most apparent. We performed a systematic review of quantitative neuroimaging studies in children with RE to explore these questions. Methods Using PRISMA guidelines, we used a multilayered search strategy to identify neuroimaging studies in RE. Publications were included if they were quantitative and derived from controlled group studies and passed a quality assessment. Findings of the studies were presented and stratified by duration of epilepsy and age of participants. Results We identified six gray matter studies and five white matter studies. Consistent findings were found inside and outside the central sulcus, predominantly within the bilateral frontal and parietal lobes, striatal structures, such as the putamen and white matter, mainly involving the left superior longitudinal fasciculus and connections between the left pre‐ and postcentral gyrus. Stratification of the T1 studies by age found that cortical thickness differences varied between the under and over 10 year olds. Furthermore, the longer the duration of epilepsy, the less likely differences were detected. In white matter studies, there was a reduction in differences with increased age and duration of epilepsy. Significance These findings would suggest that the development of regions of the cortex in children with RE is abnormal. These regions are more widespread than the suspected seizure onset zone. Moreover, the findings would suggest that these differences are evidence of neurodevelopmental delay rather than apparent “damage” from the epilepsy.

BACKGROUND Patient-reported outcomes have been used to assess treatment effectiveness and actively engage patients in their disease management. This study was designed to describe the patient-reported performance status (PS) and the provider-reported PS. METHODS Patients with metastatic genitourinary cancers were recruited from a single cancer center before the initiation of a new line of treatment. PS (Eastern Cooperative Oncology Group [ECOG]), quality of life (Functional Assessment of Chronic Illness Therapy-General), and distress (Patient-Reported Outcomes Measurement Information System Anxiety and Depression) were self-reported by patients. Clinical data (eg, age, sex, diagnosis, and physician-reported ECOG PS) were extracted from medical records. Multivariate analysis was used to determine the association between PS, quality of life, and psychological symptoms. RESULTS One hundred forty-five patients were enrolled (76.6% male, 70.3% White, 81.4% married, and 76.6% well educated). The median age was 67 years; 66.9% were diagnosed with renal cell carcinoma, 20.0% were diagnosed with urothelial carcinoma, and 13.1% were diagnosed with prostate cancer. Clinicians more frequently classified patients' ECOG PS as 0 in comparison with the patients themselves (92.4% vs 64.1%; P = .001). Higher clinician-reported ECOG PS was associated with poorer physical and functional well-being and higher rates of depression (P < .01), whereas higher patient-reported ECOG PS was associated with worse psychosocial outcomes (P < .01). CONCLUSIONS Discrepancies were noted between the patient- and provider-reported ECOG PS, with clinicians overestimating the ECOG PS in comparison with the patients themselves. This study's findings suggest that patients incorporate their social and emotional well-being into their PS score in addition to their physical well-being. This information is not immediately accessible to most clinicians from just a standard patient interview and likely accounts for the overestimation of the patients' ECOG PS by the clinicians.

LAY SUMMARY Despite longer survival with immune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1)/programmed cell death-ligand 1 (PD-L1), metastatic urothelial carcinoma remains lethal. There is an unmet need to further improve the efficacy of these agents. In their phase 2 trial, Zhang et al. evaluated the combination of pembrolizumab (a PD-1 inhibitor) plus acalabrutinib (a novel agent inhibiting an enzyme considered relevant to immunotherapy resistance) based on strong rationale but did not demonstrate clinical benefit compared with pembrolizumab alone. Future trials that examine such promising rational combinations may be able to evaluate selected patients based on validated biomarkers to optimize benefit in an endless pursuit of personalizing therapies.

Objective To evaluate patient-reported outcome (PRO) data from the IMmotion150 study. The phase 2 IMmotion150 study showed improved progression-free survival with atezolizumab plus bevacizumab vs sunitinib in patients with programmed death-ligand 1 (PD-L1)+ tumours and suggested activity of atezolizumab monotherapy in previously untreated metastatic renal cell carcinoma (mRCC). Patients and methods Patients with previously untreated mRCC were randomised to atezolizumab 1200 mg intravenously (i.v.) every 3 weeks (n = 103), the atezolizumab regimen plus bevacizumab 15 mg/kg i.v. every 3 weeks (n = 101), or sunitinib 50 mg orally daily (4 weeks on, 2 weeks off; n = 101). The MD Anderson Symptom Inventory (MDASI) and Brief Fatigue Inventory (BFI) were administered on days 1 and 22 of each 6-week cycle. Time to deterioration (TTD), change from baseline in MDASI core and RCC symptom severity, interference with daily life, and BFI fatigue severity and interference scores were reported for all comers. The TTD was the first ≥2-point score increase over baseline. Absolute effect size ≥0.2 suggested a clinically important difference with checkpoint inhibitor therapy vs sunitinib. Results Completion rates were >90% at baseline and ≥80% at most visits. Delayed TTD in core and RCC symptoms, symptom interference, fatigue, and fatigue-related interference was observed with atezolizumab (both alone and in combination) vs sunitinib. Improved TTD (hazard ratio [HR], 95% confidence interval [CI]) was more pronounced with atezolizumab monotherapy: core symptoms, 0.39 (0.22-0.71); RCC symptoms, 0.22 (0.12-0.41); and symptom interference, 0.36 (0.22-0.58). Change from baseline by visit, evaluated by the MDASI, also showed a trend favouring atezolizumab monotherapy vs sunitinib. Small sample sizes may have limited the ability to draw definitive conclusions. Conclusion PROs suggested that atezolizumab alone or with bevacizumab maintained daily function compared with sunitinib. Notably, symptoms were least severe with atezolizumab alone vs sunitinib (IMmotion150; ClinicalTrials.gov Identifier: NCT01984242).

Objective To review the genomic landscape of advanced urothelial carcinoma (UC) to assess the frequencies of EGFR and ERBB2 (HER2) alterations. Materials and methods Tumour specimens from 3753 patients with advanced UC were assayed with hybrid capture-based comprehensive genomic profiling of 180-395 genes. Tumour mutational burden (TMB) was assessed on 0.8 or 1.1 Mb of DNA, and is reported as mutations per megabase. Results In 3753 cases of UC, EGFR alterations were detected in 4.1% (154) and were most commonly amplifications (64%; 99/154), while exon 20 insertions (EGFRexon20ins ) were the second most common alteration (18%; 27/154). Alterations in ERBB2 were observed in 15% (552/3753) of cases and, similarly, ERBB2 amplification was the most commonly observed alteration (278/552; 50%); ERBB2exon20ins occurred in 3.6% (20/552) of cases. EGFRexon20ins and ERBB2exon20ins occurred in younger patients (median age 62 vs 69 years, P = 2.6E-2 and 60 vs 68 years, P = 7.8E-4), and these cases had significantly lower TMB (median 3.6 vs 7.2, P = 2.7E-4 and 2.5 vs 10, P = 1.2E-7) and less frequent TP53 alterations (3.7% vs 83%, P = 4.3E-14 and 20% vs 68%, P = 9.8E-4) compared to cases with other EGFR or ERBB2 alterations. Conclusion EGFR and ERBB2 alterations occur in 4% and 15% of UC, respectively. EGFRexon20ins and ERBB2exon20ins were present in 0.7% and 0.5% of UC overall and collectively define a small, but distinct, subset of UC with infrequent co-occurrence of other drivers and low TMB. Given recent promising clinical studies of inhibitors with activity against exon 20 insertions in non-small cell lung cancer, consideration should be given to developing a trial inclusive of patients with UC harbouring these alterations.

Anoxic-epileptic seizures (AES) are rare outcomes of common childhood reflex anoxic syncope that trigger a true epileptic seizure. The term AES was coined by Stephenson in 1983, to differentiate these events from convulsive syncopes and the more common reflex anoxic syncopes. A genetic susceptibility for AES has been postulated; but, its molecular basis has up to now been elusive. We report here two illustrative cases and show the association of de novo SCN8A variants and AES. One of them had focal or generalized seizures and autonomic symptoms triggered by orthostatism; the second had breath-holding spells triggered by pain or exercise leading to tonic-clonic seizures; both had repeatedly normal EEGs and a family history of reflex syncope. The data of three additional AES patients further suggest, for the first time, a link between SCN8A pathogenic variants and AES. The neurodevelopment of four patients was abnormal. Four of the five SCN8A mutations observed here were previously described in patients with seizure disorders. Seizures responded particularly well to sodium channel blockers. Our observation enriches the spectrum of seizures linked with SCN8A pathogenic variants.

BACKGROUND Achieving a pathologic complete response (pCR) with neoadjuvant chemotherapy (NAC) in patients with muscle-invasive bladder cancer (MIBC) has been associated with improved overall survival (OS). This study was aimed at evaluating the impact of pathologic downstaging (pDS; ie, a pT stage at least 1 stage lower than the pre-NAC cT stage) on the OS of patients with MIBC treated with NAC. METHODS The Retrospective International Study of Cancers of the Urothelial Tract (RISC) and the National Cancer Database (NCDB) were queried for cT2-4N0M0 patients treated with NAC. A multivariable Cox model including either pDS or pCR was generated. A nested model was built to evaluate the added value of pDS (excluding patients achieving a pCR) to a model including pCR alone. C indices were computed to assess discrimination. NCDB was used for validation. The treatment effect of NAC versus cystectomy alone in achieving pDS was estimated through an inverse probability-weighted regression adjustment. RESULTS Overall, 189 and 2010 patients from the RISC and NCDB cohorts, respectively, were included; pDS and pCR were achieved by 33% and 35% and by 20% and 15% in RISC and NCDB, respectively. In both data sets, pDS and pCR were associated with better OS and C indices. Adding pDS excluding pCR to the model with pCR fit the data better (likelihood ratio, P = .019 for RISC and P

Porous solids that can be switched between different forms with distinct physical properties are appealing candidates for separation, catalysis, and host-guest chemistry. In this regard, porous organic cages (POCs) are of profound interest because of their solution-state accessibility. However, the application of POCs is limited by poor chemical stability. Synthesis of an exceptionally stable imine-linked (4+6) porous organic cage (TpOMe-CDA) is reported using 2,4,6-trimethoxy-1,3,5-triformyl benzene (TpOMe) as a precursor aldehyde. Introduction of the -OMe functional group to the aldehyde creates significant steric and hydrophobic characteristics in the environment around the imine bonds that protects the cage molecules from hydrolysis in the presence of acids or bases. The electronic effect of the -OMe group also plays an important role in enhancing the stability of the reported POCs. As a consequence, TpOMe-CDA reveals exceptional chemical stability in neutral, acidic and basic conditions, even in 12 m NaOH. Interestingly, TpOMe-CDA exists in three different porous and non-porous polymorphic forms (α, β, and γ) with respect to differences in crystallographic packing and the orientation of the flexible methoxy groups. All of the polymorphs retain their crystallinity even after treatment with acids and bases. All the polymorphs of TpOMe-CDA differ significantly in their properties as well as morphology and could be reversibly switched in the presence of an external stimulus.

Background Because cell-free DNA (cfDNA) analysis facilitates the noninvasive genomic profiling of metastatic castration-resistant prostate cancer (mCRPC), the authors evaluated the association between cfDNA alterations and outcomes and evolution with therapy. Methods Patients with mCRPC underwent cfDNA genomic profiling using Guardant360, which examines major cancer-associated genes. Clinical factors, therapy information, failure-free survival, and overall survival (OS) were obtained for select patients. The association between genomic alterations and outcomes was investigated. Results Of 514 men with mCRPC, 482 (94%) had ≥1 circulating tumor DNA (ctDNA) alteration. The most common recurrent somatic mutations were in TP53 (36%), androgen receptor (AR) (22%), adenomatous polyposis coli (APC) (10%), neurofibromin 1 (NF1) (9%), epidermal growth factor receptor (EGFR), catenin beta-1 (CTNNB1), and AT-rich interactive domain-containing protein 1A (ARID1A) (6% each); and BRCA1, BRCA2, and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) (5% each) The most common genes with increased copy numbers were AR (30%), MYC (20%), and BRAF (18%). Clinical outcomes were available for 163 patients, 46 of whom (28.8%) were untreated for mCRPC. A higher number of ctDNA alterations, AR alterations, and amplifications of MYC and BRAF were associated with worse failure-free survival and/or OS. On multivariable analysis, MYC amplification remained significantly associated with OS. Prior therapy and serial profiling demonstrated the evolution of alterations in AR and other genes. Conclusions ctDNA frequently was detected in this large cohort of "real-world" patients with mCRPC, and the alterations appeared to be similar to previously reported tumor tissue alterations. A higher number of alterations, and AR and MYC alterations, appear to compromise clinical outcomes, suggesting a role for immune checkpoint inhibitors and novel AR and BET inhibitors in selected patients.

Background The authors evaluated mocetinostat (a class I/IV histone deacetylase inhibitor) in patients with urothelial carcinoma harboring inactivating mutations or deletions in CREB binding protein [CREBBP] and/or E1A binding protein p300 [EP300] histone acetyltransferase genes in a single‐arm, open‐label phase 2 study. Methods Eligible patients with platinum‐treated, advanced/metastatic disease received oral mocetinostat (at a dose of 70 mg 3 times per week [TIW] escalating to 90 mg TIW) in 28‐day cycles in a 3‐stage study (ClinicalTrials.gov identifier NCT02236195). The primary endpoint was the objective response rate. Results Genomic testing was feasible in 155 of 175 patients (89%). Qualifying tumor mutations were CREBBP (15%), EP300 (8%), and both CREBBP and EP300 (1%). A total of 17 patients were enrolled into stage 1 (the intent‐to‐treat population); no patients were enrolled in subsequent stages. One partial response was observed (11% [1 of 9 patients; the population that was evaluable for efficacy comprised 9 of the 15 planned patients]); activity was deemed insufficient to progress to stage 2 (null hypothesis: objective response rate of ≤15%). All patients experienced ≥1 adverse event, most commonly nausea (13 of 17 patients; 77%) and fatigue (12 of 17 patients; 71%). The median duration of treatment was 46 days; treatment interruptions (14 of 17 patients; 82%) and dose reductions (5 of 17 patients; 29%) were common. Mocetinostat exposure was lower than anticipated (dose‐normalized maximum serum concentration [Cmax] after TIW dosing of 0.2 ng/mL/mg). Conclusions To the authors’ knowledge, the current study represents the first clinical trial using genomic‐based selection to identify patients with urothelial cancer who are likely to benefit from selective histone deacetylase inhibition. Mocetinostat was associated with significant toxicities that impacted drug exposure and may have contributed to modest clinical activity in these pretreated patients. The efficacy observed was considered insufficient to warrant further investigation of mocetinostat as a single agent in this setting., After the genomic‐based selection of patients with urothelial cancer with inactivating mutations/deletions in the histone acetyltransferase genes CREBBP and/or EP300, single‐agent mocetinostat appears to be associated with significant toxicities that limit drug exposure. This may have contributed to the limited activity noted in the current phase 2 study (response rate of 11%) among heavily pretreated patients with platinum‐refractory disease.

OBJECTIVE Rare cancers are a heterogeneous group of conditions that can be associated with emotional and physical impairments. In view of the dearth of research in this area, we investigated the quality of life and prevalence of distress in a cohort of patients diagnosed with a rare cancer, classified by the RARECARE definition. METHODS A cohort of rare cancer patients, treated in a Brazilian public cancer center, was assessed for distress (Distress Thermometer), anxiety/depression (Hospital Anxiety and Depression Scale), and quality of life (Functional Assessment of Cancer Therapy-General Version). Descriptive statistics were generated, and multivariate analyses were used to identify factors associated with distress, anxiety/depression, and quality of life. RESULTS A total of 137 patients (52.6% male, mean age of 50 years; range 18-90) were identified. Nearly half (49.6%) of patients reported high levels of distress, with 19.7% endorsing anxiety and 15.3% depression. In multivariate analysis, demographic and clinical variables associated with worse psychosocial outcomes included younger age (P

Background Androgens and the androgen receptor (AR) are necessary for the development, function, and homeostatic growth regulation of the prostate gland. However, once prostate cells are transformed, the AR is necessary for the proliferation and survival of the malignant cells. This change in AR function appears to occur in nearly every prostate cancer. We have termed this the AR malignancy shift. Methods In this review, we summarize the current knowledge of the AR malignancy shift, including the DNA-binding patterns that define the shift, the transcriptome changes associated with the shift, the putative drivers of the shift, and its clinical implications. Results In benign prostate epithelial cells, the AR primarily binds consensus AR binding sites. In carcinoma cells, the AR cistrome is dramatically altered, as the AR associates with FOXA1 and HOXB13 motifs, among others. This shift leads to the transcription of genes associated with a malignant phenotype. In model systems, some mutations commonly found in localized prostate cancer can alter the AR cistrome, consistent with the AR malignancy shift. Current evidence suggests that the AR malignancy shift is necessary but not sufficient for transformation of prostate epithelial cells. Conclusions Reinterpretation of prostate cancer genomic classification systems in light of the AR malignancy shift may improve our ability to predict clinical outcomes and treat patients appropriately. Identifying and targeting the molecular factors that contribute to the AR malignancy shift is not trivial but by doing so, we may be able to develop new strategies for the treatment or prevention of prostate cancer.

Background Two androgen receptor (AR)-targeted therapies, enzalutamide and abiraterone acetate plus prednisone (abiraterone), have been approved for the treatment of metastatic castration-resistant prostate cancer (CRPC). Many patients respond to these agents, but both de novo and acquired resistance are common. The authors characterized resistant phenotypes that emerge after treatment with abiraterone or enzalutamide. Methods Patients who received abiraterone or enzalutamide in the course of routine clinical care were consented for serial blood collection. A proprietary system (CellSearch) was used to enumerate and enrich circulating tumor cells (CTCs). RNA-sequencing (RNA-seq) was performed on pools of up to 10 epithelial cell adhesion molecule (EpCAM)-positive/CD45-negative CTCs. The impact of gene expression changes observed in CTCs between patients who responded or were resistant to abiraterone/enzalutamide therapies was further explored in a model cell line system. Results RNA-seq data from CTCs identified mutations commonly associated with CRPC as well as novel mutations, including several in the ligand-binding domain of AR that could facilitate escape from AR-targeted agents. Ingenuity pathway analysis of differentially regulated genes identified the transforming growth factor β (TGFβ) and cyclin D1 (CCND1) signaling pathways as significantly upregulated in drug-resistant CTCs. Transfection experiments using enzalutamide-sensitive and enzalutamide-resistant LNCaP cells confirmed the involvement of SMAD family member 3, a key mediator of the TGFβ pathway, and of CCND1 in resistance to enzalutamide treatment. Conclusions The current results indicate that RNA-seq of CTCs representing abiraterone and enzalutamide sensitive and resistant states can identify potential mechanisms of resistance. Therapies targeting the downstream signaling mediated by SMAD family member 3 (SMAD3) and CCND1, such as cyclin-dependent kinase 4/cyclin-dependent kinase 6 inhibitors, could provide new therapeutic options for the treatment of antiandrogen-resistant disease. Cancer 2018;124:1216-24. © 2017 American Cancer Society.

Trend analysis is an ideal way of investigating first-hand information about climate change; climate variables exhibit trends on variety of scales, and an understanding of these trends can be used to make estimates about the future of the climate. The objective of this paper is to examine temporal variations in climate by analysing climatic variables. Angul is one of the hottest districts in India, with a maximum summer temperature of 50°C recorded in 2005. Climate data for the period 1901 to 2015 have been statistically analysed to investigate variations in climate in the region. The nonparametric Mann–Kendall rank test, Pearson's correlation, Kendall's rank correlation, analysis of variance (ANOVA) and the autoregressive integrated moving average (ARIMA) model were used to identify diurnal, monthly, seasonal, and annual changes in temperature, precipitation, vapour pressure, potential evapotranspiration and crop evapotranspiration. The results of these analyses reveal the presence of both increasing and decreasing trends for a number of climate variables. Temperature has increased drastically over the last three decades. The average minimum and maximum temperatures for 1901 were 20 and 31°C, respectively; these values increased to 23 and 33°C in 2015. The Auto-Regressive Integrated Moving Average model projected a significant rise in seasonal temperature and a decreasing trend in rainfall; these results are considered to be an early warning sign for future extreme climate events.

A photosensitizer based on a ruthenium complex of a bisamide-polypyridyl ligand gives rise to a large improvement in photocatalytic stability, rate of activity, and efficiency in photocatalytic H2 production compared to [Ru(bpy)3 ]2+ (bpy=2,2'-bpyridine). The bisamide ruthenium polypyridyl complex combined with a cobaltoxime-based photocatalyst was found to be highly efficient under blue-light (turnover number (TON)=7800) and green-light irradiation (TON=7200) whereas [Ru(bpy)3 ]2+ was significantly less effective with a TON of 2600 and 1100, respectively. The greatest improvement was under red-light-emitting diodes, with bisamide ruthenium polypyridyl complex and cobaltoxime exhibiting a TON of 4200 compared to [Ru(bpy)3 ]2+ and cobaltoxime at a TON of only 71.

BACKGROUND Targeting the vascular endothelial growth factor (VEGF) pathway has improved outcomes in metastatic renal cell carcinoma (RCC); however, resistance inevitably occurs. CD105 (endoglin) is an angiogenic pathway that is strongly upregulated after VEGF inhibition, potentially contributing to resistance. The authors tested whether TRC105, a monoclonal antibody against endoglin, impacted disease control in patients with previously treated RCC who were receiving bevacizumab. METHODS Eligible patients with metastatic RCC who had previously received 1 to 4 prior lines of therapy, including VEGF-targeted agents, were randomized 1:1 to receive bevacizumab 10 mg/kg intravenously every 2 weeks (arm A) or the same plus TRC105 10 mg/kg intravenously every 2 weeks (arm B). The primary endpoint was progression-free survival (PFS) at 12 and 24 weeks. Correlative studies included serum transforming growth factor β (TGFβ) and CD105 levels as well as tissue immunostaining for TGFβ receptors. RESULTS Fifty-nine patients were enrolled (28 on arm A and 31 on arm B), and 1 patient on each arm had a confirmed partial response. The median PFS for bevacizumab alone was 4.6 months compared with 2.8 for bevacizumab plus TRC105 (P = .09). Grade ≥ 3 toxicities occurred in 16 patients (57%) who received bevacizumab compared with 19 (61%) who received bevacizumab plus TRC105 (P = .9). Baseline serum TGFβ levels below the median (

Cancer stem cells (CSCs) are found in many cancer types, including breast carcinoma. Breast cancer stem cells (BCSCs) are considered as seed of cancer formation and they are associated with metastasis and genotoxic drug resistance. Several studies highlighted the presence of BCSCs in tumor microenvironment and they are accentuated with several carcinoma events including metastasis and resistance to genotoxic drugs and they also rebound after genotoxic burn. Stemness properties of a small population of cells in carcinoma have provided clues regarding the role of tumor microenvironment in tumor pathophysiology. Hence, insights in cancer stem cell biology with respect to molecular signaling, genetics and epigenetic behavior of CSCs have been used to modulate tumor drug resistance due to genotoxic drugs and signaling protein inhibitors. This review summarizes major scientific breakthroughs in understanding the contribution of BCSCs towards tumor's capability to endure destruction inflicted by molecular as well as genotoxic drugs.

We examined the effect of optimum (32%) and suboptimum (27%) levels of dietary protein on the hemolymph and oxidative physiology of giant freshwater prawn Macrobrachium rosenbergii juveniles. Wild juveniles of different stocks were collected from the west coast (Gujarat [G-stock] and Maharashtra [M-stock]) and east coast (Andhra Pradesh [A-stock]) of India. Prawns were raised in 200-m2 culture ponds, with individual animals tracked by using stock-specific, colored elastomer tags. Hemolymph glucose, plasma total protein, albumin-to-globulin (A:G) ratio, plasma calcium, and activity of five key metabolic enzymes in plasma (plasma cholinesterase, aspartate aminotransferase, alkaline phosphatase, lactate dehydrogenase, and amylase) were examined to compare the hemolymph physiology due to dietary protein variations fed to the different stocks. Plasma fatty acid profile was also monitored. Effect of feeding on oxidative physiology of prawns was analyzed by measuring the catalase and acetylcholinesterase...

OBJECTIVES To assess real-world treatment patterns of targeted therapies after failure of first-line tyrosine kinase inhibitors in patients with advanced renal cell carcinoma. METHODS A large, retrospective review of medical charts of patients with advanced renal cell carcinoma in the USA was carried out. Descriptive statistics were used to summarize physicians' and patients' characteristics, treatment sequences, and reasons for treatment choices. P-values were calculated using χ2 -tests for categorical variables and Wilcoxon rank-sum tests for continuous variables. A descriptive comparison was carried out between current results and those of a previous treatment pattern study conducted in 2012 to identify changes in treatment patterns over time. RESULTS Sunitinib and everolimus remained the most commonly-used first and second targeted therapies, respectively. Among patients who continued to a third targeted therapy, everolimus and axitinib were the most commonly-used treatments after second targeted therapy with a tyrosine kinase inhibitor and a mammalian target of rapamycin inhibitor, respectively. The use of pazopanib as first targeted therapy, and of axitinib and sorafenib as second targeted therapies, increased over time. Efficacy, treatment guidelines and a different mechanism of action were the main reasons given by physicians for choosing among second targeted therapies after failure of a first tyrosine kinase inhibitor. CONCLUSIONS The results of the present study document patterns of care during a period of rapid and ongoing therapeutic advancement in advanced renal cell carcinoma. Sequencing of therapies warrants ongoing analysis in light of new agents entering the advanced renal cell carcinoma treatment landscape.

Dominant-negative mutation of LdeK1 gene, an eIF2α kinase from Leishmania donovani, revealed its role in translation regulation in response to nutrient starvation earlier. However, whether the kinase influences the infectivity of the parasites which naturally encounters nutrient deprivation during its life cycle was interesting to investigate. Both in vitro and in vivo experiments resulted in decrease of the parasite burden in peritoneal macrophages and in splenic/ hepatic load, respectively. An insight into the immune response of mice infected with mutant parasite showed enhanced pro-inflammatory cytokines and nitric oxide levels but reduced TH 2 and Treg population. The significantly reduced loss of infectivity of the parasites lacking a functional LdeK1 by modulating the immune response towards host protection makes it a potential vaccine candidate against Leishmaniasis.

The 5′ untranslated region (5′-UTR) of a messenger ribonucleic acid (mRNA) plays a critical role in translation regulation by influencing mRNA stability and translation efficiency. Functional elements in the 5′-UTR such as internal ribosome entry site (IRES), upstream open reading frames (uORFs) and iron responsive element (IRE) serve to fine tune protein expression in response to cellular requirement. Genetic variations such as mutations and single nucleotide polymorphisms (SNPs) in the 5′-UTR are associated with a number of human diseases and increased susceptibility to diseases. Such pathological variations disrupt the motifs at the 5′-UTR and cause diseases such as X-linked Charcot-Marie-Tooth (CMTX) disease, multiple myeloma, hereditary hyperferritinaemia/cataract syndrome (HHCS), familial predisposition to melanoma, Marie Unna hereditary hypotrichosis (MUHH), oesophageal cancer and many others. Genetic and molecular profiling of many diseases has shown that a holistic approach of including the UTRs in regular diagnostic deoxyribonucleic acid (DNA) screening would aid in better disease profiling and disease management. Key Concepts: 5′ Untranslated regions (UTRs) are noncoding regions of messenger RNAs (mRNAs). The 5′-UTR is delimited by transcription initiation site at 5′ end and the physiological start codon (AUG) at the 3′ end. Motifs such as internal ribosome entry site (IRES), upstream open reading frames (uORFs), iron responsive element (IRE) and others are involved in mRNA stability and translation control. mRNAs encoding regulatory proteins need to be strongly and precisely regulated. These mRNAs are often endowed with longer than average 5′-UTR, uORFs and stable secondary structures that regulate their translation efficiency. Mutations are changes in the DNA/genes of an organism which are heritable. Mutations that disrupt the functional elements of the 5′-UTR are often associated with diseases. Single nucleotide polymorphisms (SNPs) in the 5′-UTR are associated with individual's drug response and disease risk. Keywords: 5′ untranslated regions of mRNA; human diseases; truncations; upstream open reading frames (uORFs); internal ribosome entry site (IRES); iron responsive element (IRE)

Background Upregulation of sphingosine-1-phosphate (S1P) may mediate resistance to vascular endothelial growth factor (VEGF)-directed therapies and inhibit antitumor immunity. Antagonism of S1P in preclinical models appears to overcome this resistance. In this phase 2 study, the authors assessed the activity of sonepcizumab, a first-in-class inhibitor of S1P, in patients with metastatic renal cell carcinoma (mRCC) with a history of prior VEGF-directed therapy. Methods Patients were required to have clear cell mRCC and to have received treatment with at least 1 prior VEGF-directed agent. Prior treatment with immunotherapeutic agents and ≤1 mammalian target of rapamycin inhibitors was permitted. The primary endpoint of the study was progression-free survival. Additional endpoints included response rate and safety, and overall survival (OS) performed post hoc. Results A total of 40 patients were enrolled with a median of 3 prior therapies (range, 1-5 prior therapies), 78% of whom had intermediate-risk disease by second-line International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria. Although the current study did not achieve its primary endpoint based on the 2-month progression-free survival, a median OS of 21.7 months was observed. Four patients (10%) demonstrated a partial response, with a median duration of response of 5.9 months. No grade 3/4 treatment-related adverse events were observed in >5% of patients (adverse events were graded and recorded for each patient using Common Terminology Criteria for Adverse Events [version 4.0]); the most frequent grade 1/2 treatment-related adverse events were fatigue (30%), weight gain (18%), constipation (15%), and nausea (15%). Biomarker studies demonstrated an increase in S1P concentrations with therapy. Comprehensive genomic profiling of 3 patients with a clinical benefit of >24 months indicated von Hippel-Lindau (VHL) and polybromo-1 (PBRM1) alterations. Conclusions The encouraging OS and favorable safety profile observed with sonepcizumab should prompt further investigation of the agent in combination with VEGF-directed agents or checkpoint inhibitors. Cancer 2017;123:576-582. © 2016 American Cancer Society.

Bis(pyridin-3-ylmethyl) pyridine-3,5-dicarboxylate (L) possessing one internal and two terminal pyridine moieties displayed differential coordination ability when combined with suitable PdII components. The compound L acted as a bidentate chelating ligand to form mononuclear complexes when combined with cis-[Pd(tmeda)(NO3)2] or Pd(NO3)2 in calculated ratios. The combination of Pd(NO3)2 with L in a ratio of 3:4, however, afforded the trinuclear “double-decker” cage [(NO3)2⊂Pd3(L)4](NO3)4, in which L acts as a nonchelating tridentate ligand and the counter anion (i.e., NO3–) acts as template. The encapsulated NO3– can be replaced by F–, Cl–, or Br– but not by I–. The F–-encapsulated cage could not be isolated due to its reactivity, whereas the Cl– or Br– encapsulated cages could be isolated. Although anionic guests such as NO3–, Cl–, or Br– stabilized the cages, the presence of excess Cl– or Br– (not NO3–) facilitated decomplexation reactions releasing the ligand. The complexation of Pd(Y)2 (Y = BF4–, PF6–, CF3SO3–, or ClO4–) with L afforded the corresponding mononuclear complexes under appropriate conditions. However, these counter anions could not act as templates for the construction of double-decker cages.

A linear tetracarboxylic acid ligand, H4 L, with a pendent amine moiety solvothermally forms two isostructural metal-organic frameworks (MOFs) LM (M=ZnII , CuII ). Framework LCu can also be obtained from LZn by post- synthetic metathesis without losing crystallinity. Compared with LZn , the LCu framework exhibits high thermal stability and allows removal of guest solvent and metal-bound water molecules to afford the highly porous, LCu '. At 77 K, LCu ' absorbs 2.57 wt % of H2 at 1 bar, which increases significantly to 4.67 wt % at 36 bar. The framework absorbs substantially high amounts of methane (238.38 cm3 g-1 , 17.03 wt %) at 303 K and 60 bar. The CH4 absorption at 303 K gives a total volumetric capacity of 166 cm3 (STP) cm-3 at 35 bar (223.25 cm3 g-1 , 15.95 wt %). Interestingly, the NH2 groups in the linker, which decorate the channel surface, allow a remarkable 39.0 wt % of CO2 to be absorbed at 1 bar and 273 K, which comes within the dominion of the most famous MOFs for CO2 absorption. Also, LCu ' shows pronounced selectivity for CO2 absorption over CH4 , N2 , and H2 at 273 K. The absorbed CO2 can be converted to value-added cyclic carbonates under relatively mild reaction conditions (20 bar, 120 °C). Finally, LCu ' is found to be an excellent heterogeneous catalyst in regioselective 1,3-dipolar cycloaddition reactions ("click" reactions) and provides an efficient, economic route for the one-pot synthesis of structurally divergent propargylamines through three-component coupling of alkynes, amines, and aldehydes.

BACKGROUND In the current study, the authors present a comprehensive genomic profile (CGP)-based study of advanced urothelial carcinoma (UC) designed to detect clinically relevant genomic alterations (CRGAs). METHODS DNA was extracted from 40 µm of formalin-fixed, paraffin-embedded sections from 295 consecutive cases of recurrent/metastatic UC. CGP was performed on hybridization-captured, adaptor ligation-based libraries to a mean coverage depth of 688X for all coding exons of 236 cancer-related genes plus 47 introns from 19 genes frequently rearranged in cancer, using process-matched normal control samples as a reference. CRGAs were defined as GAs linked to drugs on the market or currently under evaluation in mechanism-driven clinical trials. RESULTS All 295 patients assessed were classified with high-grade (International Society of Urological Pathology classification) and advanced stage (stage III/IV American Joint Committee on Cancer) disease, and 294 of 295 patients (99.7%) had at least 1 GA on CGP with a mean of 6.4 GAs per UC (61% substitutions/insertions/deletions, 37% copy number alterations, and 2% fusions). Furthermore, 275 patients (93%) had at least 1 CRGA involving 75 individual genes with a mean of 2.6 CRGAs per UC. The most common CRGAs involved cyclin-dependent kinase inhibitor 2A (CDKN2A) (34%), fibroblast growth factor receptor 3 (FGFR3) (21%), phosphatidylinositol 3-kinase catalytic subunit alpha (PIK3CA) (20%), and ERBB2 (17%). FGFR3 GAs were diverse types and included 10% fusions. ERBB2 GAs were equally divided between amplifications and substitutions. ERBB2 substitutions were predominantly within the extracellular domain and were highly enriched in patients with micropapillary UC (38% of 32 cases vs 5% of 263 nonmicropapillary UC cases; P

UNLABELLED High-resolution micropatterning of a PEDOT PSS conducting-polymer-silksericin composite is presented using a water-based, benchtop photolithographic process. Conducting microstructures formed on a flexible silk fibroin sheet allow a fully organic, flexible bioelectronic device. Large-area microfabricated devices such as biosensors that are biocompatible and degradable over a controlled period of time can be formed.