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Carbon dots (CDs) are a versatile nanomaterial with attractive photoluminescent and photocatalytic properties. Here we show that these two functionalities can be easily tuned through a simple synthetic means, using a microwave irradiation, with citric acid and varying concentrations of nitrogen-containing branched polyethyleneimine (BPEI) as precursors. The amount of BPEI determines the degree of nitrogen incorporation and the different inclusion modes within the CDs. At intermediate levels of BPEI, domains grow containing mainly graphitic nitrogen, producing a high photoluminescence yield. For very high (and very low) BPEI content, the nitrogen atoms are located primarily at the edge sites of the aromatic domains. Accordingly, they attract photogenerated electrons, enabling efficient charge separation and enhanced photocatalytic hydrogen generation from water. The ensuing ability to switch between emissive and photocatalytic behavior of CDs is expected to bring substantial improvements on their efficiency for on-demand light emission or energy conversion applications. Carbon dots are an emergent class of nanomaterials that hold promise for innovations in imaging, sensing, and catalytic technologies. Here, Stolarczyk and colleagues control the nitrogen-atom content and location within carbon dots, reporting the resulting impact on emissivity and photocatalytic behaviour.

Ceritinib is a next-generation anaplastic lymphoma kinase (ALK) inhibitor, which has shown robust anti-tumour efficacy, along with intracranial activity, in patients with ALK-rearranged non-small-cell lung cancer. In phase 1 and 2 studies, ceritinib has been shown to be highly active in both ALK inhibitor-naive and ALK inhibitor-pretreated patients who had progressed after chemotherapy (mostly multiple lines). In this study, we compared the efficacy and safety of ceritinib versus single-agent chemotherapy in patients with advanced ALK-rearranged non-small-cell lung cancer who had previously progressed following crizotinib and platinum-based doublet chemotherapy. In this randomised, controlled, open-label, phase 3 trial, we recruited patients aged at least 18 years with ALK-rearranged stage IIIB or IV non-small-cell lung cancer (with at least one measurable lesion) who had received previous chemotherapy (one or two lines, including a platinum doublet) and crizotinib and had subsequent disease progression, from 99 centres across 20 countries. Other inclusion criteria were a WHO performance status of 0–2, adequate organ function and laboratory test results, a life expectancy of at least 12 weeks, and having recovered from previous anticancer treatment-related toxicities. We randomly allocated patients (1:1; with blocking [block size of four]; stratified by WHO performance status [0 vs 1–2] and presence or absence of brain metastases) to oral ceritinib 750 mg per day fasted (in 21 day treatment cycles) or chemotherapy (intravenous pemetrexed 500 mg/m2 or docetaxel 75 mg/m2 [investigator choice], every 21 days). Patients who discontinued chemotherapy because of progressive disease could cross over to the ceritinib group. The primary endpoint was progression-free survival, assessed by a masked independent review committee using Response Evaluation Criteria in Solid Tumors 1.1 in the intention-to-treat population, assessed every 6 weeks until month 18 and every 9 weeks thereafter. This trial is registered with ClinicalTrials.gov, number NCT01828112, and is ongoing but no longer recruiting patients. Between June 28, 2013, and Nov 2, 2015, we randomly allocated 231 patients; 115 (50%) to ceritinib and 116 (50%) to chemotherapy (40 [34%] to pemetrexed, 73 [63%] to docetaxel, and three [3%] discontinued before receiving treatment). Median follow-up was 16·5 months (IQR 11·5–21·4). Ceritinib showed a significant improvement in median progression-free survival compared with chemotherapy (5·4 months [95% CI 4·1–6·9] for ceritinib vs 1·6 months [1·4–2·8] for chemotherapy; hazard ratio 0·49 [0·36–0·67]; p<0·0001). Serious adverse events were reported in 49 (43%) of 115 patients in the ceritinib group and 36 (32%) of 113 in the chemotherapy group. Treatment-related serious adverse events were similar between groups (13 [11%] in the ceritinib group vs 12 [11%] in the chemotherapy group). The most frequent grade 3–4 adverse events in the ceritinib group were increased alanine aminotransferase concentration (24 [21%] of 115 vs two [2%] of 113 in the chemotherapy group), increased γ glutamyltransferase concentration (24 [21%] vs one [1%]), and increased aspartate aminotransferase concentration (16 [14%] vs one [1%] in the chemotherapy group). Six (5%) of 115 patients in the ceritinib group discontinued because of adverse events compared with eight (7%) of 116 in the chemotherapy group. 15 (13%) of 115 patients in the ceritinib group and five (4%) of 113 in the chemotherapy group died during the treatment period (from the day of the first dose of study treatment to 30 days after the final dose). 13 (87%) of the 15 patients who died in the ceritinib group died because of disease progression and two (13%) died because of an adverse event (one [7%] cerebrovascular accident and one [7%] respiratory failure); neither of these deaths were considered by the investigator to be treatment related. The five (4%) deaths in the chemotherapy group were all due to disease progression. These findings show that patients derive significant clinical benefit from a more potent ALK inhibitor after failure of crizotinib, and establish ceritinib as a more efficacious treatment option compared with chemotherapy in this patient population. Novartis Pharmaceuticals Corporation.

The PI3K-AKT-mTOR pathway is frequently activated in cancer. PI3K inhibitors, including the pan-PI3K inhibitor buparlisib (BKM120) and the PI3Kα-selective inhibitor alpelisib (BYL719), currently in clinical development by Novartis Oncology, may therefore be effective as anticancer agents. Early clinical studies with PI3K inhibitors have demonstrated preliminary antitumor activity and acceptable safety profiles. However, a number of unanswered questions regarding PI3K inhibition in cancer remain, including: what is the best approach for different tumor types, and which biomarkers will accurately identify the patient populations most likely to benefit from specific PI3K inhibitors? This review summarizes the strategies being employed by Novartis Oncology to help maximize the benefits of clinical studies with buparlisib and alpelisib, including stratification according to PI3K pathway activation status, selective enrollment/target enrichment (where patients with PI3K pathway-activated tumors are specifically recruited), nonselective enrollment with mandatory tissue collection, and enrollment of patients who have progressed on previous targeted agents, such as mTOR inhibitors or endocrine therapy. An overview of Novartis-sponsored and Novartis-supported trials that are utilizing these approaches in a range of cancer types, including breast cancer, head and neck squamous cell carcinoma, non-small cell lung carcinoma, lymphoma, and glioblastoma multiforme, is also described.

Lipid membranes are almost impermeable for charged molecules and ions that can pass the membrane barrier only with the help of specialized transport proteins. Here, we report how temperature manipulation at the nanoscale can be employed to reversibly control the electrical resistance and the amount of current that flows through a bilayer membrane with pA resolution. For this experiment, heating is achieved by irradiating gold nanoparticles that are attached to the bilayer membrane with laser light at their plasmon resonance frequency. We found that controlling the temperature on the nanoscale renders it possible to reproducibly regulate the current across a phospholipid membrane and the membrane of living cells in absence of any ion channels.

Phosphatidylinositol 3-kinase (PI3K) pathway activation is a hallmark of endocrine therapy-resistant, hormone receptor-positive breast cancer. This phase 3 study assessed the efficacy of the pan-PI3K inhibitor buparlisib plus fulvestrant in patients with advanced breast cancer, including an evaluation of the PI3K pathway activation status as a biomarker for clinical benefit. The BELLE-2 trial was a randomised, double-blind, placebo-controlled, multicentre study. Postmenopausal women aged 18 years or older with histologically confirmed, hormone receptor-positive and human epidermal growth factor (HER2)-negative inoperable locally advanced or metastatic breast cancer whose disease had progressed on or after aromatase inhibitor treatment and had received up to one previous line of chemotherapy for advanced disease were included. Eligible patients were randomly assigned (1:1) using interactive voice response technology (block size of 6) on day 15 of cycle 1 to receive oral buparlisib (100 mg/day) or matching placebo, starting on day 15 of cycle 1, plus intramuscular fulvestrant (500 mg) on days 1 and 15 of cycle 1, and on day 1 of subsequent 28-day cycles. Patients were assigned randomisation numbers with a validated interactive response technology; these numbers were linked to different treatment groups which in turn were linked to treatment numbers. PI3K status in tumour tissue was determined via central laboratory during a 14-day run-in phase. Randomisation was stratified by PI3K pathway activation status (activated vs non-activated vs and unknown) and visceral disease status (present vs absent). Patients, investigators, local radiologists, study team, and anyone involved in the study were masked to the identity of the treatment until unblinding. The primary endpoints were progression-free survival by local investigator assessment per Response Evaluation Criteria In Solid Tumors (version 1.1) in the total population, in patients with known (activated or non-activated) PI3K pathway status, and in PI3K pathway-activated patients. Efficacy analyses were done in the intention-to-treat population. Safety was analysed in all patients who received at least one dose of study drug and had at least one post-baseline safety assessment according to the treatment they received. This trial is registered with ClinicalTrials.gov, number NCT01610284, and is currently ongoing but not recruiting participants. Between Sept 7, 2012, and Sept 10, 2014, 1147 patients from 267 centres in 29 countries were randomly assigned to receive buparlisib (n=576) or placebo plus fulvestrant (n=571). In the total patient population (n=1147), median progression-free survival was 6·9 months (95% CI 6·8–7·8) in the buparlisib group versus 5·0 months (4·0–5·2) in the placebo group (hazard ratio [HR] 0·78 [95% CI 0·67–0·89]; one-sided p=0·00021). In patients with known PI3K status (n=851), median progression-free survival was 6·8 months (95% CI 5·0–7·0) in the buparlisib group vs 4·5 months (3·3–5·0) in the placebo group (HR 0·80 [95% CI 0·68–0·94]; one-sided p=0·0033). In PI3K pathway-activated patients (n=372), median progression-free survival was 6·8 months (95% CI 4·9–7·1) in the buparlisib group versus 4·0 months (3·1–5·2) in the placebo group (HR 0·76 [0·60–0·97], one-sided p=0·014). The most common grade 3–4 adverse events in the buparlisib group versus the placebo group were increased alanine aminotransferase (146 [25%] of 573 patients vs six [1%] of 570), increased aspartate aminotransferase (103 [18%] vs 16 [3%]), hyperglycaemia (88 [15%] vs one [<1%]), and rash (45 [8%] vs none). Serious adverse events were reported in 134 (23%) of 573 patients in the buparlisib group compared with 90 [16%] of 570 patients in the placebo group; the most common serious adverse events (affecting ≥2% of patients) were increased alanine aminotransferase (17 [3%] of 573 vs one [<1%] of 570) and increased aspartate aminotransferase (14 [2%] vs one [<1%]). No treatment-related deaths occurred. The results from this study show that PI3K inhibition combined with endocrine therapy is effective in postmenopausal women with endocrine-resistant, hormone receptor-positive and HER2-negative advanced breast cancer. Use of more selective PI3K inhibitors, such as α-specific PI3K inhibitor, is warranted to further improve safety and benefit in this setting. No further studies are being pursued because of the toxicity associated with this combination. Novartis Pharmaceuticals Corporation.

PurposeCeritinib 750 mg/day was approved for the treatment of patients with untreated anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC) based on ASCEND-4 study. The objective of this article is to introduce the use of time-dependent modeling approach in the updated exposure–efficacy analysis of ceritinib for the first-line indication.MethodsExposure–efficacy analyses, including data from 156 patients, were first conducted using time-independent logistic regression model for response of complete or partial response and Cox regression model for progression-free survival (PFS). The exposure measure used was average Ctrough, which is defined as the geometric mean of all evaluable Ctrough for each patient. To further investigate the impact of exposure measure on exposure–efficacy analyses, a time-dependent modeling approach was used, where exposure at different time intervals was associated with the corresponding response endpoints in a longitudinal manner.ResultsWith exposure measure being average Ctrough, it was observed that higher exposure was associated with reduced efficacy in terms of response (odds ratio = 0.77) and PFS [hazard ratio (HR) = 1.12]. These time-independent models do not account for the impact of time-varying concentration due to dose modifications. Subsequently, a new time-dependent modeling approach was used, where exposure and efficacy were associated longitudinally in the analyses. The results showed that the odds ratio of response became 1.07, and the HR of PFS became 1.04, indicating no apparent reverse relationship between exposure and efficacy across the exposure range studied.ConclusionThe drug effect on efficacy in clinical trials could be better characterized using time-dependent exposure–response models.

Background: New agents that are active in patients with metastatic colorectal cancer are needed. Patupilone (EPO906; epothilone B) is a novel microtubule-stabilising agent. Methods: Patients with advanced colon cancer who progressed after prior treatment regimens received intravenous patupilone (6.5–10.0 mg m –2 ) once every 3 weeks by a 20-min infusion (20MI), 24-h continuous infusion (CI-1D) or 5-day intermittent 16-h infusion (16HI-5D). Adverse events (AEs), dose-limiting toxicities (DLTs), pharmacokinetics and anti-tumour activity were assessed. Results: Sixty patients were enrolled. The maximum tolerated dose (MTD) was not reached in the 20MI arm ( n =31), as no DLTs were observed. Three patients in the CI-1D arm ( n =26) experienced 1 DLT each at 7.5, 8.0 and 9.0 mg m –2 , but MTD was not reached. However, the prolonged 16HI-5D arm was terminated at 6.5 mg m –2 after two of the three patients developed a DLT. Diarrhoea was the most common AE and DLT, with increased severity at the higher doses (9.0 and 10.0 mg m –2 ). Grade 3 or 4 diarrhoea was observed in 11 (35%) of the patients in the 20MI arm, 4 (15%) of the patients in the CI-1D arm and 2 (67%) of the patients in the 16HI-5D arm. Patupilone activity was observed in the 20MI arm with a disease control rate of 58%, including four confirmed partial responses. The disease control rate in CI-1D arm was 39%. Conclusion: Patupilone given once every 3 weeks as a 20-min infusion had promising anti-tumour activity and manageable safety profile at doses that demonstrated therapeutic efficacy.

Summary A phase 1, open-label, non-randomized, single center study was conducted to determine the pharmacokinetics, distribution, metabolism, elimination, and mass balance of patupilone in patients with advanced solid tumors. Five patients with advanced solid tumors received 10 mg/m 2 (1.1 MBq) of 14  C–radiolabeled patupilone at cycle 1 as a 20-minute intravenous infusion every 3 weeks until disease progression. Sequential samples of blood/plasma were taken for 3 weeks and urine and fecal samples were collected for seven days after the first dose of patupilone. Patupilone blood levels decreased rapidly after the infusion. The compound showed a large volume of distribution (V ss : 2242 L). The main radiolabeled component in blood was patupilone itself, accompanied by the lactone hydrolysis products that are unlikely to contribute to the pharmacological effect of patupilone. The blood clearance of patupilone was relatively low at 14 L/h. The administered radioactivity dose was excreted slowly (46 % of dose up to 168 h) but ultimately accounted for 91 % of the dose by extrapolation. The fecal excretion of radioactivity was 2–3 times higher than the urinary excretion consistent with hepato-biliary elimination. Three patients had progressive disease and two patients had stable disease as their best response. Patupilone was generally well tolerated in patients with advanced solid tumors with no newly occurring safety events compared to previous clinical studies. In adult solid tumor patients, intravenous radiolabeled patupilone undergoes extensive metabolism with fecal excretion of radioactive metabolites predominating over renal excretion.

Purpose Patupilone is a novel microtubule-targeting cytotoxic agent with potential interaction with CYP3A4/CYP2C19 enzymes. Midazolam and omeprazole are primarily metabolized by CYP3A4 and CYP2C19, respectively. We evaluated the inhibitory effects of patupilone on the CYP3A4/CYP2C19 pathways. Methods This study had 2 parts: in an initial core phase, patients were randomly assigned to receive midazolam 4 mg or omeprazole 40 mg PO (days 1 and 29) and patupilone 10 mg/m 2 IV (days 8 and 29). Patients without progression continued patupilone every 3 weeks until disease progression or unacceptable toxicity (extension phase). Results Forty-six patients were treated. The areas under the concentration–time curves (AUC)s of midazolam with or without patupilone co-administration were similar. The C max of midazolam when co-administered with patupilone was highly variable and was lower compared with midazolam alone; however, the oral clearance and terminal half-lives were similar. Both the C max and AUC of omeprazole when co-administered with patupilone were highly variable and lower than with omeprazole alone. However, the oral clearance and terminal half-lives were similar. The latter data suggest that patupilone decreased the absorption of omeprazole (by ~20%). The overall safety profile was consistent with that of previous single-agent patupilone studies; 2 partial responses (ovarian and pancreatic cancer) and 1 complete response (serous ovarian adenocarcinoma) were observed. Conclusions Patupilone was not a potent CYP3A4 or CYP2C19 inhibitor. No dose adjustment is required when omeprazole or midazolam is used in patients treated with patupilone. Patupilone exhibited promising antitumor activity in heavily pretreated patients with ovarian and pancreatic cancer.

Der Artikel skizziert die Grundlagen einer neuen Subdisziplin innerhalb der Religionswissenschaft, der Religionsethologie. Religionsethologie lässt sich letztlich auf Charles Darwin selbst zurückführen, der bereits in seinem Buch (1872) belegen konnte, dass jede Form von Verhalten (also auch religiöses Verhalten) für das Überleben der Art genau so wichtig ist wie die Adaptation des Phänotypus. In den Geisteswissenschaften wurde der Darwinsche Ansatz sofort aufgegriffen und von bedeutenden Forschern wie Karl Meuli (1891–1968), Aby Warburg (1866–1929) und in jüngerer Zeit von Roy Rappaport (1926–1997), Marvin Harris (1927–2001) und anderen aufgegriffen und fruchtbar gemacht, indem sie einerseits religiöse Universalien herausarbeiten, andererseits aber auch die Grundzüge einer religiösen Evolution darstellen konnten. Religion ist demnach tief in der Biologie des Menschen verwurzelt und kann demzufolge auch unter biologischen Gesichtspunkten erforscht werden.