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Recently, extensive efforts have been devoted to the development of the second near-infrared bio-window (NIR-II, 1000-1700 nm) theranostic agents owing to the excellent tissue-penetration capability of NIR-II light. The exploration of organic NIR-II photothermal therapy materials, especially those with absorption peak over 1000 nm, is an appealing yet significantly challenging task. Herein, we have designed conjugated polymer nanoparticles (PIS NPs) with NIR-II absorption peak at 1026 nm through a combined strategy of introducing quinoid donor-acceptor (D-A) structures, constructing intramolecular "conformational locks" and extending the conjugation area to narrow the band gap. Irradiated at 1064 nm, PIS NPs showed remarkable photothermal conversion performance for efficient photothermal ablation of tumor cells in vitro and in vivo. This study provides useful insights into the rational design of organic NIR-II photothermal agents based on multiple strategies.

Though the concept of green dynamic capability has been increasingly gaining traction among academics, practitioners, and policymakers, its association with green innovation adoption remains unclear. The present study addresses this gap and aims to provide clarity by distinguishing green innovation adoption in the context of developing countries. Drawing on dynamic capability and stakeholder theory, this research shed light on the significance of green dynamic capability for green innovation adoption. Additionally, this study examines the moderating role of environmental dynamism and big data analytics capability in the link between green dynamic capability and green innovation adoption. Adopting a two-wave research design, the sample for this study contained SMEs from Pakistan and Malaysia. Data was obtained from 220 SMEs (105 from Pakistan, 115 from Malaysia). To test the hypotheses, covariance-based structural equation modelling was performed to analyze causal relationships in the model, by using AMOS 23 software. The results showed that green dynamic capability positively impacts green innovation adoption, but environmental dynamism does not positively moderate between green dynamic capability and green innovation adoption. In addition, big data analytics capability positively moderates between green dynamic capability and green innovation adoption. We believe that this study opens a new avenue in the environmental literature under which green innovation adoption is useful for SMEs.

Notch signaling plays an important role in development and tissue homeostasis. Deregulation of Notch signaling has been implicated in multiple malignancies. Crenigacestat (LY3039478), a potent Notch inhibitor, decreases Notch signaling and its downstream biologic effects. I6F-MC-JJCD was a multicenter, nonrandomized, open-label, Phase 1b study with 5 separate, parallel dose-escalations in patients with advanced or metastatic cancer from a variety of solid tumors, followed by a dose-confirmation phase in prespecified tumor types. This manuscript reports on 3 of 5 groups. The primary objective was to determine the recommended Phase 2 dose of crenigacestat in combination with other anticancer agents (taladegib, LY3023414 [dual inhibitor of phosphoinositide 3-kinase; mechanistic target of rapamycin], or abemaciclib). Secondary objectives included evaluation of safety, tolerability, efficacy, and pharmacokinetics. Patients (N = 63) received treatment between November 2016 and July 2019. Dose-limiting toxicities occurred in 12 patients, mostly gastrointestinal (diarrhea, nausea, vomiting). The maximum-tolerated dose of crenigacestat was 25 mg in Part B (LY3023414), 50 mg in Part C (abemaciclib), and not established in Part A (taladegib) due to toxicities. Patients had at least 1 adverse event (AE) and 75.0–82.6% were ≥ Grade 3 all-causality AEs. No patient had complete or partial response. Disease control rates were 18.8% (Part B) and 26.1% (Part C). The study was terminated before dose confirmation cohorts were triggered. This study demonstrated that crenigacestat combined with different anticancer agents (taladegib, LY3023414, or abemaciclib) was poorly tolerated, leading to lowered dosing and disappointing clinical activity in patients with advanced or metastatic solid tumors. NCT02784795 and date of registration: May 27, 2016.

Background Tumor-associated macrophages (TAMs) promote tumor growth, metastasis, and therapeutic resistance via colony-stimulating factor-1 (CSF-1), acting through CSF-1 receptor (CSF-1R) signaling. This phase 1 study determined the safety, tolerability, pharmacokinetics-pharmacodynamics, immunogenicity, and efficacy of the anti–CSF-1R antibody LY3022855 in solid tumors. Methods Patients with advanced solid tumors refractory to standard therapy were enrolled and treated in 2 dosing cohorts: weight-based (part A) and non–weight-based (part B). Part A patients were assigned to intravenous (IV) dose-escalation cohorts: 2.5 mg/kg once per week (QW), 0.3 mg/kg QW, 0.6 mg/kg QW, 1.25 mg/kg once every 2 weeks (Q2W) and 1.25 mg/kg QW doses of LY3022855. Non–weight-based doses in part B were 100 mg and 150 mg IV QW. Results Fifty-two patients (mean age 58.6 ± 10.4 years) were treated with ≥1 dose of LY3022855 (range: 4–6). Five dose-limiting toxicities (left ventricular dysfunction, anemia, pancreatitis, rhabdomyolysis, and acute kidney injury) occurred in 4 patients. The non–weight-based 100 mg QW dose was established as the RP2D. The most common treatment-emergent adverse events were increase in liver function variables, fatigue, nausea, vomiting, diarrhea, anorexia, pyrexia, increased lipase, amylase, and lactate dehydrogenase. Clearance decreased with increasing dose and weight-based dosing had minimal effect on pharmacokinetics. Serum CSF-1, and IL-34 levels increased at higher doses and more frequent dosing, whereas TAMs and CD14dimCD16bright levels decreased. Three patients achieved stable disease. No responses were seen. Conclusions LY3022855 was well tolerated and showed dose-dependent pharmacokinetics-pharmacodynamics and limited clinical activity in a heterogenous solid tumor population. ClinicalTrials.gov ID NCT01346358 (Registration Date: May 3, 2011).

Purpose: Tumor-associated macrophages correlate with increased invasiveness, growth, and immunosuppression. Activation of the colony-stimulating factor-1 receptor (CSF-1R) results in proliferation, differentiation, and migration of monocytes/macrophages. This phase I study evaluated the immunologic and clinical activity, and safety profile of CSF-1R inhibition with the mAb LY3022855. Patients and Methods: Patients with advanced refractory metastatic breast cancer (MBC) or metastatic castration-resistant prostate cancer (mCRPC) were treated with LY3022855 intravenously in 6-week cycles in cohorts: (A) 1.25 mg/kg every 2 weeks (Q2W); (B) 1.0 mg/kg on weeks 1, 2, 4, and 5; (C) 100 mg once weekly; (D)100 mg Q2W. mCRPC patients were enrolled in cohorts A and B; patients with MBC were enrolled in all cohorts. Efficacy was assessed by RECIST and Prostate Cancer Clinical Trials Working Group 2 criteria. Results: Thirty-four patients (22 MBC; 12 mCRPC) received ≥1 dose of LY3022855. At day 8, circulating CSF-1 levels increased and proinflammatory monocytes CD14DIMCD16BRIGHT decreased. Best RECIST response was stable disease in five patients with MBC (23%; duration, 82–302 days) and three patients with mCRPC (25%; duration, 50–124 days). Two patients with MBC (cohort A) had durable stable disease >9 months and a third patient with MBC had palpable reduction in a nontarget neck mass. Immune-related gene activation in tumor biopsies posttreatment was observed. Common any grade treatment-related adverse events were fatigue, decreased appetite, nausea, asymptomatic increased lipase, and creatine phosphokinase. Conclusions: LY3022855 was well tolerated and showed evidence of immune modulation. Clinically meaningful stable disease >9 months was observed in two patients with MBC.

Narrow-bandgap tin-lead (Sn-Pb) mixed perovskite solar cells (PSCs) play a key role in constructing perovskite tandem solar cells that are potential to overpass Shockley-Queisser limit. A robust, chemically stable and low-temperature-processed hole transporting layer (HTL) is essential for building high-efficiency Sn-Pb solar cells and perovskite tandem solar cells. Here, we explore a room-temperature-processed NiO x (L-NiO x ) HTL based on nanocrystals (NCs) for Sn-Pb PSCs. In comparison with high-temperature-annealed NiO x (H-NiO x ) film, the L-NiO x film shows deeper valence band and lower trap density, which increases the built-in potential and reduces carrier recombination, leading to a power conversion efficiency of 18.77%, the record for NiO x -based narrow-bandgap PSCs. Furthermore, the device maintains about 96% of its original efficiency after 50 days. This work provides a robust and room-temperature-processed HTL for highly efficient and stable narrow-bandgap PSCs.

Background: Environmental reporting is an indispensable part of the corporate social responsibility (CSR) report, which has become a main genre of nonfinancial disclosure for corporations. The present study explores how companies use metaphors to construct their role in the relationship with the environment. Literature review: Previous studies tend to focus on environmental metaphors in genres such as newspapers, blogs, and scientific discourse, but rarely attend to the genre of corporate environmental reporting. Research questions: 1. What metaphors are used by banking and energy companies to represent their role in the relationship with the environment? Are there similarities or differences across cultures? 2. What are their representations in terms of the corporate role, and what impacts do they have on the environment from an ecolinguistic perspective? 3. Why are these metaphors used for environmental communication? Research methodology: The study investigates a corpus of 180 CSR reports published by Chinese, US, and Italian companies with the framework of critical metaphor analysis combined with genre analysis, so as to approach metaphor use from a cross-cultural perspective. Results and conclusions: The study highlights both universal metaphors (manager, protector, and traveler) and culture-specific metaphors (the bee metaphor in Chinese, the steward metaphor in English, and the fighter metaphor in Italian) across three languages, which are used to represent the company's good intentions, caring attitude, and responsible behavior, contributing to building an environmentally responsible corporate image. Some of the metaphors seem useful in inspiring eco-constructive behavior, while others may bear eco-destructive connotations.

BackgroundImmune checkpoint inhibitor-based combinations have expanded the treatment options for patients with renal cell carcinoma (RCC); however, tolerability remains challenging. The aim of this study was to evaluate the safety and efficacy of the immunostimulatory interleukin-2 cytokine prodrug bempegaldesleukin (BEMPEG) plus nivolumab (NIVO) as first-line therapy in patients with advanced clear-cell RCC.MethodsThis was an open-label multicohort, multicenter, single-arm phase 1/2 study; here, we report results from the phase 1/2 first-line RCC cohort (N=49). Patients received BEMPEG 0.006 mg/kg plus NIVO 360 mg intravenously every 3 weeks. The primary objectives were safety and objective response rate (ORR; patients with measurable disease at baseline and at least one postbaseline tumor response assessment). Secondary objectives included overall survival (OS) and progression-free survival (PFS). Exploratory biomarker analyses: association between baseline biomarkers and ORR.ResultsAt a median follow-up of 32.7 months, the ORR was 34.7% (17/49 patients); 3/49 patients (6.1%) had a complete response. Of the 17 patients with response, 14 remained in response for >6 months, and 6 remained in response for >24 months. Median PFS was 7.7 months (95% CI 3.8 to 13.9), and median OS was not reached (95% CI 37.3 to not reached). Ninety-eight per cent (48/49) of patients experienced ≥1 treatment-related adverse event (TRAE) and 38.8% (19/49) had grade 3/4 TRAEs, most commonly syncope (8.2%; 4/49) and increased lipase (6.1%; 3/49). No association between exploratory biomarkers and ORR was observed. Limitations include the small sample size and single-arm design.ConclusionsBEMPEG plus NIVO showed preliminary antitumor activity as first-line therapy in patients with advanced clear-cell RCC and was well tolerated. These findings warrant further investigation.

The combination of comprehensive surface passivation and effective interface carriers transfer plays a critical role in high-performance perovskite solar cells. A 2D structure is an important approach for surface passivation of perovskite film, however, its large band gap could compromise carrier transfer. Herein, we synthesize a new molecule 2-thiopheneethylamine thiocyanate (TEASCN) for the construction of bilayer quasi-2D structure precisely on a tin-lead mixed perovskite surface. This bilayer structure can passivate the perovskite surface and ensure effective carriers transfer simultaneously. As a result, the open-circuit voltage (V

The development of methodologies for synthesizing carrier-transporting materials is critical for optoelectronic device fabrication. Amorphous metal oxides have emerged as potential carrier transport materials for perovskite tandem solar cells and flexible electronics due to their ease of fabrication and excellent electronic properties. However, perovskite solar cells employing amorphous metal oxides as the electron-transporting layers (ETLs) remain inefficient. This research describes a moderate dehydration reaction for the low-temperature synthesis of amorphous SnO

Combination antiretroviral therapy (cART) given orally has transformed HIV from a terminal illness to a manageable chronic disease. Yet despite the recent development of newer and more potent drugs for cART and suppression of virus in blood to undetectable levels, residual virus remains in tissues. Upon stopping cART, virus rebounds and progresses to AIDS. Current oral cART regimens have several drawbacks including (1) challenges in patient adherence due to pill fatigue or side-effects, (2) the requirement of life-long daily drug intake, and (3) limited penetration and retention in cells within lymph nodes. Appropriately designed injectable nano-drug combinations that are long-acting and retained in HIV susceptible cells within lymph nodes may address these challenges. While a number of nanomaterials have been investigated for delivery of HIV drugs and drug combinations, key challenges involve developing and scaling delivery systems that provide a drug combination targeted to HIV host cells and tissues where residual virus persists. With validation of the drug-insufficiency hypothesis in lymph nodes, progress has been made in the development of drug combination nanoparticles that are long-acting and targeted to lymph nodes and cells. Unique drug combination nanoparticles (DcNPs) composed of three HIV drugs-lopinavir, ritonavir, and tenofovir-have been shown to provide enhanced drug levels in lymph nodes; and elevated drug-combination levels in HIV-host cells in the blood and plasma for two weeks. This review summarizes the progress in the development of nanoparticle-based drug delivery systems for HIV therapy. It discusses how injectable nanocarriers may be designed to enable delivery of drug combinations that are long-lasting and target-selective in physiological contexts (in vivo) to provide safe and effective use. Consistent drug combination exposure in the sites of residual HIV in tissues and cells may overcome drug insufficiency observed in patients on oral cART.

With efficiency of perovskite solar cells (PSCs) overpassing 23%, to realize their commercialization, the biggest challenge now is to boost the stability to the same level as conventional solar cells. Thus, tremendous effort has been directed over the past few years toward improving the stability of these cells. Various methods were used to improve the stability of bulk perovskites, including compositional engineering, interface adjustment, dimensional manipulation, crystal engineering, and grain boundary decoration. Diverse device configurations, carrier transporting layers, and counter electrodes are investigated. To compare the stability of PSCs and clarify the degradation mechanism, diverse characterization methods were developed. Overall stability of PSCs has become one central topic for the development of PSCs. In this review, we summarize the state-of-the-art progress on the improvement of device stability and discuss the directions for future research, hoping it provides an overview of the current status of the research on the stability of PSCs and guidelines for future research.

Aqueous Fe(II)-catalyzed activation commonly deteriorates the oxidation performance of persulfate (PS) to the treatment of organic contaminants. In this study, a PS-doped layered bimetallic hydroxide (Fe-Mn hydroxide) was synthesized to construct a heterogeneously catalytic system to solve the issue brought by homogeneity. The molar ratio of Fe(II) to Mn(II) and the mass ratio of PS to Fe-Mn hydroxide both had a significant impact on the catalytic degradation of p-CP. Reaction temperatures engaged in the most essential role in influencing the degradation and removal of p-chlorophenol (p-CP). The optimal combination of factors for the preparation of PS-hydroxide and the treatment of p-CP was finally determined by significance analysis. The degradation process was appropriately fitted by the pseudo-first-order kinetic model. the benzene ring in p-CP was broken by PS-hydroxide during the adsorption. The surface modification of PS-hydroxide caused by the valence transition of Mn was beneficial to the adsorption and catalytic degradation of p-CP.CapsuleA persulfate-doped layered bimetallic hydroxide was synthesized to construct a heterogeneously catalytic system to solve the drawback of homogeneity for the effective treatment of p-chlorophenol.

Purpose: Immune checkpoint inhibitors show high response rates and durable clinical benefit in microsatellite instability–high/mismatch repair–deficient (MSI-H/dMMR) tumors. However, 50%–60% do not respond to single-agent anti–programmed death-1/programmed death ligand 1 (PD-1/PD-L1) antibodies, and approximately 50% of responders relapse within 6–12 months. This phase Ib trial evaluated safety and antitumor activity of anti–PD-L1 antibody LY3300054 monotherapy or in combination with anti–TIM-3 antibody LY3321367 in patients with MSI-H/dMMR advanced solid tumors. Patients and Methods: Eligible patients ≥18 years without prior anti–PD-1/PD-L1 therapy received LY3300054 monotherapy (N = 40) or combination (N = 20); patients with PD-1/PD-L1 inhibitor–resistant/refractory tumors received the combination (N = 22). LY3300054 (700 mg) and anti–TIM-3 antibody (cycles 1–2: 1,200 mg, cycle 3 onward: 600 mg) were administered intravenously every 2 weeks. Primary endpoints were safety and tolerability. Results: Eighty-two patients were enrolled. Most had colorectal (n = 39, 47.6%) or endometrial (n = 14, 17.1%) tumors. More than 70% of patients in the PD-1/PD-L1 inhibitor–resistant/refractory combination cohort had received ≥3 treatment lines. Treatment-related adverse events (TRAE) occurred in 22 patients (55.0%) receiving monotherapy, 13 (65.0%) in the PD-1/PD-L1 inhibitor–naïve combination cohort, and 6 (27.3%) in the PD-1/PD-L1 inhibitor–resistant/refractory combination cohort. A total of 2 patients (5.0%) receiving monotherapy and 3 (7.1%) receiving the combination experienced grade ≥3 TRAEs. Objective responses occurred in 13 patients (32.5%) with monotherapy, 9 (45.0%) in the PD-1/PD-L1 inhibitor–naïve combination cohort, and 1 patient (4.5%) in the PD-1/PD-L1 inhibitor–resistant/refractory combination cohort. Conclusions: LY3300054 monotherapy and combined LY3300054/anti–TIM-3 had manageable safety profiles. Both regimens showed promising clinical activity against PD-1/PD-L1 inhibitor–naïve MSI-H/dMMR tumors. The combination had limited clinical benefit in patients with PD-1/PD-L1 inhibitor–resistant/refractory MSI-H/dMMR tumors.

Notch signaling plays an important role in development and tissue homeostasis. Deregulation of Notch signaling has been implicated in multiple malignancies. Crenigacestat (LY3039478), a potent Notch inhibitor, decreases Notch signaling and its downstream biologic effects. I6F-MC-JJCD was a multicenter, nonrandomized, open-label, Phase 1b study with 5 separate, parallel dose-escalations in patients with advanced or metastatic cancer from a variety of solid tumors, followed by a dose-confirmation phase in prespecified tumor types. This manuscript reports on 3 of 5 groups. The primary objective was to determine the recommended Phase 2 dose of crenigacestat in combination with other anticancer agents (taladegib, LY3023414 [dual inhibitor of phosphoinositide 3-kinase; mechanistic target of rapamycin], or abemaciclib). Secondary objectives included evaluation of safety, tolerability, efficacy, and pharmacokinetics. Patients (N = 63) received treatment between November 2016 and July 2019. Dose-limiting toxicities occurred in 12 patients, mostly gastrointestinal (diarrhea, nausea, vomiting). The maximum-tolerated dose of crenigacestat was 25 mg in Part B (LY3023414), 50 mg in Part C (abemaciclib), and not established in Part A (taladegib) due to toxicities. Patients had at least 1 adverse event (AE) and 75.0-82.6% were ≥ Grade 3 all-causality AEs. No patient had complete or partial response. Disease control rates were 18.8% (Part B) and 26.1% (Part C). The study was terminated before dose confirmation cohorts were triggered. This study demonstrated that crenigacestat combined with different anticancer agents (taladegib, LY3023414, or abemaciclib) was poorly tolerated, leading to lowered dosing and disappointing clinical activity in patients with advanced or metastatic solid tumors. NCT02784795 and date of registration: May 27, 2016.

Purpose: T-cell immunoglobulin and mucin-domain–containing molecule-3 (TIM-3) blunts anticancer immunity and mediates resistance to programmed death 1 (PD-1) and PD ligand 1 (PD-L1) inhibitors. We assessed a novel, first-in-class, TIM-3 mAb, LY3321367, alone or in combination with the anti-PD-L1 antibody, LY300054 in patients with advanced solid tumor. Patients and Methods: This open-label, multicenter, phase Ia/b study aimed to define the safety/tolerability and recommended phase II dose (RP2D) of LY3321367 with or without LY300054. Secondary objectives included pharmacokinetics/pharmacodynamics, immunogenicity, and efficacy. Biomarkers were assessed in exploratory analysis. Results: No dose-limiting toxicities were observed in the monotherapy (N = 30) or combination (N = 28) dose escalation. LY3321367 treatment-related adverse events (≥2 patients) included pruritus, rash, fatigue, anorexia, and infusion-related reactions. Dose-proportional increase in LY3321367 concentrations was not affected by either LY300054 or antidrug antibodies (observed in 50%–70% of patients). Pharmacokinetic/pharmacodynamic modeling indicated 100% target engagement at doses ≥600 mg. LY3321367 RP2D was 1,200 mg biweekly for four doses followed by 600 mg every 2 weeks thereafter. In the non–small cell lung cancer monotherapy expansion cohort, outcomes varied by prior anti-PD-1 therapy response status: anti-PD-1/L1 refractory patients [N = 23, objective response rate (ORR) 0%, disease control rate (DCR) 35%, progression-free survival (PFS) 1.9 months] versus anti-PD-1/L1 responders (N = 14, ORR 7%, DCR 50%, PFS 7.3 months). In combination expansion cohorts (N = 91), ORR and DCR were 4% and 42%; CD8 infiltration in paired biopsies increased in approximately half these patients. Conclusions: LY3321367 exhibited acceptable safety profile with favorable pharmacokinetics/pharmacodynamics but only modest antitumor activity. The therapeutic relevance of TIM-3 blockade requires further investigation.

Background Tumor-associated macrophages (TAMs) promote tumor growth, metastasis, and therapeutic resistance via colony-stimulating factor-1 (CSF-1), acting through CSF-1 receptor (CSF-1R) signaling. This phase 1 study determined the safety, tolerability, pharmacokinetics-pharmacodynamics, immunogenicity, and efficacy of the anti-CSF-1R antibody LY3022855 in solid tumors. Methods Patients with advanced solid tumors refractory to standard therapy were enrolled and treated in 2 dosing cohorts: weight-based (part A) and non-weight-based (part B). Part A patients were assigned to intravenous (IV) dose-escalation cohorts: 2.5 mg/kg once per week (QW), 0.3 mg/kg QW, 0.6 mg/kg QW, 1.25 mg/kg once every 2 weeks (Q2W) and 1.25 mg/kg QW doses of LY3022855. Non-weight-based doses in part B were 100 mg and 150 mg IV QW. Results Fifty-two patients (mean age 58.6 ± 10.4 years) were treated with ≥1 dose of LY3022855 (range: 4-6). Five dose-limiting toxicities (left ventricular dysfunction, anemia, pancreatitis, rhabdomyolysis, and acute kidney injury) occurred in 4 patients. The non-weight-based 100 mg QW dose was established as the RP2D. The most common treatment-emergent adverse events were increase in liver function variables, fatigue, nausea, vomiting, diarrhea, anorexia, pyrexia, increased lipase, amylase, and lactate dehydrogenase. Clearance decreased with increasing dose and weight-based dosing had minimal effect on pharmacokinetics. Serum CSF-1, and IL-34 levels increased at higher doses and more frequent dosing, whereas TAMs and CD14dimCD16bright levels decreased. Three patients achieved stable disease. No responses were seen. Conclusions LY3022855 was well tolerated and showed dose-dependent pharmacokinetics-pharmacodynamics and limited clinical activity in a heterogenous solid tumor population. ClinicalTrials.gov ID NCT01346358 (Registration Date: May 3, 2011).

As a BCS IV drug, ursolic acid (UA) has low oral bioavailability mainly because of its poor aqueous solubility/dissolution, poor permeability, and metabolism by cytochrome P450 (CYP) isozymes, such as CYP3A4. Most UA preparations demonstrated a much higher dissolution than that of its crystalline form yet a low drug concentration in plasma due to their lower consideration or evaluation for the permeability and metabolism issues. In the current study, a supramolecular coamorphous system of UA with piperine (PIP) was prepared and characterized by powder X-ray diffraction, differential scanning calorimetry, and scanning electron microscopy. In comparison to crystalline UA and UA in physical mixture, such coamorphous system enhanced solubility (5.3-7-fold in the physiological solution) and dissolution (7-8-fold in the physiological solution within 2 h) of UA and exhibited excellent physical stability under 90-day storage conditions. More importantly, the pharmacokinetic study of coamorphous UA in rats exhibited 5.8-fold and 2.47-fold improvement in AUC0-∞ value, respectively, compared with its free and mixed crystalline counterparts. In order to further explore the mechanism of such improvement, the molecular interactions of a coamorphous system in the solid state were investigated. Fourier transform infrared spectroscopy, solid-state 13C nuclear magnetic resonance spectroscopy, and density functional theory modeling suggested that intermolecular hydrogen bonds with strong interactions newly formed between UA and PIP after coamorphization. The in vitro permeability studies across Caco-2 cell monolayer and metabolism studies by rat hepatic microsomes indicated that free PIP significantly increased the permeability of UA and inhibited the enzymatic metabolism of UA by CYP3A4. However, PIP in the coamorphous combination exhibited a much lower level in the bioenhancing than its free form arising from the synchronized dissolution characteristic of the preparation (only 60% of PIP released in comparison to its free counterpart in 2 h). The in situ loop study in rats proposed that the acid-sensitive dissolution in the stomach of the coamorphous preparation helped to improve the effective free drug concentration, thereby facilitating PIP to play its role in bioenhancing. The current study offers an exploratory strategy to overcome poor solubility/dissolution, poor permeability, and metabolism by cytochrome P450 isozymes of the BCS IV drug to improve its oral bioavailability.

Diverging physicochemical properties of HIV drug combinations are challenging to formulate as a single dosage form. We have found that 2-to-4 hydrophilic and hydrophobic HIV drugs in combination can be stabilized with lipid excipients under a controlled solvent removal process to form a novel pharmaceutical powder distinct from typical amorphous material. This discovery has enabled production of a drug combination nanoparticle (DcNP) powder composed of 3 HIV drugs—water-insoluble lopinavir (LogP = 4.7) and ritonavir (LogP = 5.6) and water-soluble tenofovir (LogP = −1.6). DcNP powder, exhibiting repeating units of multi-drug-motifs (referred to as MDM), is made by dissolving all constituents in ethanolic solution, followed by controlled solvent removal. The DcNP powder intersperses chemically diverse drug molecules with lipid excipients to form repeating MDM units. The proposed MDM structure is consistent with data collected with X-ray diffraction, differential calorimetry, and time-of-flight secondary ion mass spectrometry. The successful assembly of chemically diverse drugs in MDM structure is likely due to a novel process of making drug combination powders. The method described here has successfully extended to formulating other clinically prescribed antiviral drug combinations, and thus may serve as a platform technology for developing drug combination nanoparticles for treating a wide range of chronic diseases.

Purpose: This phase Ia/Ib PACT study evaluated the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of a new programmed cell death ligand 1 (PD-L1) inhibitor, LY3300054, as monotherapy or in combination with ramucirumab, abemaciclib, or merestinib (a type II MET kinase inhibitor) in patients with advanced, refractory solid tumors (NCT02791334). Patients and Methods: Patients were enrolled into cohorts of escalating LY3300054 dose (phase Ia) as monotherapy (N = 15) or combined with ramucirumab (N = 10), abemaciclib (N = 24), or merestinib (N = 12). The phase Ib dose expansion enrolled 8 patients with melanoma in the monotherapy arm and 12 patients with pancreatic cancer in the merestinib combination arm. Combination treatments were administered concurrently from day 1 of each cycle. A 14-day lead-in abemaciclib arm was also explored. Primary endpoints were dose-limiting toxicity (DLT) and safety. Results: Treatment-related adverse events included fatigue and nausea in the monotherapy arm (13% for each), hypothyroidism (30%) in the ramucirumab arm, diarrhea (54%) in the abemaciclib arm, and nausea (25%) in the merestinib arm. DLTs associated with hepatoxicity were observed in 3 of 4 patients in the abemaciclib lead-in cohorts. No DLTs or grade 3 or 4 hepatoxicity were reported in the concurrent abemaciclib arm. Pharmacokinetic characteristics were comparable with other PD-L1 inhibitors. One patient in each arm experienced a partial response per RECIST v1.1 lasting ≥7 months. Conclusions: LY3300054 was well tolerated without unexpected safety concerns when administered alone or concurrently with ramucirumab, abemaciclib, or merestinib. Lead-in abemaciclib before combining with LY3300054 was not feasible due to hepatotoxicity. Durable clinical benefits were seen in all regimens.

BackgroundHigh-dose IL2 therapy has shown clinical benefit in metastatic melanoma and renal cell carcinoma, however only in a select subset of patients. Bempegaldesleukin (BEMPEG), a novel CD122-preferential IL2 pathway agonist, preferentially binds the heterodimeric IL2βγR predominantly expressed on NK and CD8 T cells and minimizes binding to the IL2αR expressed on immunosuppressive Tregs. BEMPEG monotherapy in Phase I clinical trials induced proliferation and activation of NK cells in the blood and tumor microenvironment.1 NK activation is dependent on the balance of inhibitory and excitatory signals transmitted by NK receptors, including Fc-gamma receptors (FCγRs) and killer immunoglobulin-like receptors (KIRs) along with their KIR-ligands. The repertoire of KIRs/KIR-ligands an individual inherits and the single-nucleotide polymorphisms (SNPs) of FCγRs can influence NK cell function and affect responses to immunotherapies.2–4 Thus, we sought to investigate whether distinct immunogenotypes are associated with clinical response of patients enrolled in PIVOT-02, a Phase II study of BEMPEG plus nivolumab.Methods200 patients with advanced solid tumors enrolled in PIVOT-02 who were not previously treated with immunotherapy (immunotherapy-naïve, ‘IO’) had DNA available for genotyping and clinical data for correlative analyses. All patients received 0.006mg/kg BEMPEG plus 360mg nivolumab every 3 weeks.5 KIR/KIR-ligand gene status was assessed by real-time SYBR green PCR melt-curve analyses and PCR-SSP. FCγR SNP status was determined using Taqman primers/probes for FCγR2A, and FCγR3A and FCγR2C were determined using RNaseH primers/probes.6 Clinical outcome parameters included objective response rate (ORR), progression-free survival (PFS), and tumor shrinkage (TS, defined as best objective response ResultsKIR2DL2+/C1+ IO patients observed significantly greater TS (p=0.015) and a trend towards improved ORR (p=0.060) and increased PFS (p=0.058) compared to IO patients who were not KIR2DL2+/C1+. IO patients who were KIR2DL2+/C1+/KIR3DL1+/Bw4+ showed significantly improved ORR (p=0.014) and greater TS (p=0.044) compared to IO patients who were not KIR2DL2+/C1+/KIR3DL1+/Bw4+, with no significance found for PFS in these patients. FCγR polymorphisms did not influence ORR/PFS/TS.ConclusionsNK cells may play an important role in the anti-tumor efficacy of BEMPEG plus nivolumab, and NK activation is influenced by certain immunogenotypes. Similar to previous findings,2–4 the status of KIR2DL2+/C1+ and KIR2DL2+/C1+/KIR3DL1+/Bw4+ was associated with the response to BEMPEG plus nivolumab treatment in the PIVOT-02 trial. The potential to utilize these genotypes in clinical decision-making for immunotherapy treatment requires further investigation.Trial RegistrationClinicalTrialsgov NCT02983045ReferencesBentebibel S-E, et al. A first-in-human study and biomarker analysis of NKTR-214, a Novel IL2βγ-Biased cytokine, in patients with advanced or metastatic solid tumors. Cancer Discov 2019;9:711–21.Erbe AK, et al. Follicular lymphoma patients with KIR2DL2 and KIR3DL1 and their ligands (HLA-C1 and HLA-Bw4) show improved outcome when receiving rituximab. J Immunother Cancer 2019;7(1):70.Erbe AK, et al. Neuroblastoma patients’ KIR and KIR-Ligand genotypes influence clinical outcome for dinutuximab-based immunotherapy: A report from the Children’s Oncology Group. Clin Cancer Res 2018;24(1):189–96.Erbe AK, et al. FCGR polymorphisms influence response to IL2 in metastatic renal cell carcinoma. Clin Cancer Res 2017;23(9):2159–68.Diab A, et al. Bempegaldesleukin (NKTR-214) plus nivolumab in patients with advanced solid tumors: Phase I dose-escalation study of safety, efficacy, and immune activation (PIVOT-02). Cancer Discov 2020;10:1–16.Erbe AK, et al. Genotyping single nucleotide polymorphisms and copy number variability of the FCGRs expressed on NK cells. Methods Mol Biol 2016;1441:43–56.Ethics ApprovalThe study was conducted in accordance with Good Clinical Practice guidelines and the Declaration of Helsinki. The Protocol (online only) was approved by independent ethics committees and the relevant institutional review board at each site. All patients provided written informed consent.

Background: This study examines the generic structure of corporate social responsibility (CSR) reports, which are becoming standard practice for corporate communication of social and environmental performance beyond financial disclosure. Literature review: Genre theories provide a framework for exploring genres contextualized in different cultures. Based on the English for Specific Purposes approach of genre analysis, this study compares the move structure of CSR reports in Italian, Chinese, and English from a corpus-based perspective . Research questions: 1. What are the main moves used in CSR reports? 2. Are there any cross-cultural similarities or variations in terms of generic features? Methodology: Combining genre theories with concepts from Systemic Functional Linguistics, we designed an observational framework for move identification. Based on a 15-move scheme, we annotated 18 CSR reports for comparative analysis. Results and conclusions: The CSR report is characterized by rhetorical recursivity and hybridity of speech acts: beyond “reporting” and “presenting,” it is also “demonstrating,” “evaluating,” and “committing.” As a globally established genre, it presents noticeable generic similarity in different languages, suggesting that the communicative purposes of CSR reports are recognized by different cultures. The top six moves in the Performance-reporting section of the CSR reports present identical trends in terms of extensiveness ranking in all three languages. Cross-cultural variations mainly involve the use of optional moves, such as the dominant use of the move “Presenting individual cases” in the Chinese sample. The observational framework for move identification may also be transferable to other genres. The limitations of this study include the sample size and the absence of an author survey. Future research could investigate the CSR report from a diachronic perspective, to explore how its genre structure has developed over time.

Efficient bifunctional electrocatalysts for the hydrogen evolution reaction (HER) and oxygen evolution reaction (OER) must be developed to realize an inexpensive water-splitting system for large-scale applications. Herein, a novel PdNi carbon nanofiber (PdNi/CNF) catalyst was synthesized by facile electrospinning and carbonization processes. The size and homogeneity of the Pd−Ni alloy nanoparticles (NPs) could be effectively tuned by controlling the molar feed ratio of metal precursors .The morphology and structure of the PdNi/CNFs were characterized, and the working electrodes fabricated from the prepared catalyst mats were directly employed in the HER and OER. The PdNi/CNFs-1:2 catalyst exhibits high catalytic activity in the HER with a low overpotential of 55 mV at a current density of 10 mA cm −2 in an acidic solution. Moreover, under 1 M KOH electrolyte, an overpotential of 187 mV is required in the HER over the catalyst to arrive 10 mA cm −2 and an overpotential of 289 mV is achieved in the OER at the same current density. The superior HER and OER activities of the PdNi/CNFs are attributed to the synergistic effects of the PdNi alloy nanoparticles (NPs) assembled on the CNFs. This work provides a simple route for synthesizing highly efficient bifunctional electrocatalysts from 3d transition metals and a small amount of noble metals for hydrogen and oxygen evolution reactions.

The bimetallic Au–Cu alloy nanoparticles have been constructed in electrospun carbon nanofibers (Au–Cu/CNFs), employing as high efficient hydrogen evolution reaction (HER) electrode. The morphology, structure, and composition of bimetallic Au–Cu alloy can be controlled by adjusting the precursor nanofibers through a facile approach. With the increased Cu content, the Au–Cu alloy have a transition from the homogeneous AuCu3 alloy phase to the Au3Cu phase with Cu shell. The self-supported bimetallic Au–Cu/CNFs hybrid can be directly employed as electrode materials for water splitting, and it showed excellent electrochemical activity, including long-term stability, high exchange current density, and low overpotential. The outstanding HER performance could be mainly attributed to the synergistic interactions and interfacial effects of Au–Cu alloy with high densities of uncoordinated surface atoms. In addition, the fast charge transport and the fast kinetic for the desorption of the gas were originated from th...

The search for new ways to make inexpensive and efficient electrocatalysts to replace precious-metal platinum catalysts for oxygen reduction and water splitting is still a great challenge. Here, we report a facile and effective strategy for the rational design and construction of three-dimensional (3D) architectures for superior electrocatalysis through the integration of one-dimensional (1D) electrospun carbon nanofibers (CNFs), 1D carbon nanotubes (CNTs) and 0D oxygen-deficient Mn3Co7–Co2Mn3O8 nanoparticles (NPs). The rationale behind the marriage and integration of nanostructures with different dimensions presented in this work is that during heat treatment, the in situ-produced CoMnO NPs are partly reduced to Co2Mn3O8 by a carbon precursor with an amount of metallic Mn3Co7 formed at the interface between the Co2Mn3O8 NPs and carbon, which can act as the catalysts for the growth of 3D CNT forests. The 3D CoMnO@CNT/CNF architectures exhibit superior electrocatalytic activity and stability for the oxygen reduction, oxygen evolution and hydrogen evolution reactions. The remarkable electrochemical properties are mainly attributed to the synergistic effects from the engineering of oxygen-deficient binary CoMn oxide NPs with exposed active sites and 3D hierarchical porous structures consisting of branched CNTs and interconnected CNFs. The present work demonstrates the first example of integrating multiple active catalytic centers onto/into 3D architectures for developing highly efficient non-precious metal nanocatalysts for electrochemical energy devices.

Mutations in ERK signaling drive a significant percentage of malignancies. LY3009120, a pan-RAF and dimer inhibitor, has preclinical activity in RAS- and BRAF-mutated cell lines including BRAF-mutant melanoma resistant to BRAF inhibitors. This multicenter, open-label, phase I clinical trial (NCT02014116) consisted of part A (dose escalation) and part B (dose confirmation) in patients with advanced/metastatic cancer. In part A, oral LY3009120 was dose escalated from 50 to 700 mg twice a day on a 28-day cycle. In part B, 300 mg LY3009120 was given twice a day. The primary objective was to identify a recommended phase II dose (RP2D). Secondary objectives were to evaluate safety, pharmacokinetics, and preliminary efficacy. Identification of pharmacodynamic biomarkers was exploratory. In parts A and B, 35 and 16 patients were treated, respectively (N = 51). In part A, 6 patients experienced eight dose-limiting toxicities. The RP2D was 300 mg twice a day. Common (>10%) any-grade drug-related treatment-emergent adverse events were fatigue (n = 15), nausea (n = 12), dermatitis acneiform (n = 10), decreased appetite (n = 7), and maculopapular rash (n = 7). The median duration of treatment was 4 weeks; 84% of patients completed one or two cycles of treatment. Exposures observed at 300 mg twice a day were above the preclinical concentration associated with tumor regression. Eight patients had a best overall response of stable disease; there were no complete or partial clinical responses. Despite adequate plasma exposure levels, predicted pharmacodynamic effects were not observed.

This article investigates direct quotations in a corpus of corporate social responsibility (CSR) reports in Italian, Chinese, and English. The corpus is composed of 60 CSR reports published by Italian, Chinese, and American companies in the banking and energy sector. The study aims at exploring what types of textual voices are involved in the discourse of CSR reporting and how different sources of voices are represented, using the framework of social actor representation proposed by Van Leeuwen. The results show that the voices presented in direct quotations are often “orchestrated” by companies into “symphony” rather than “polyphony.” Most of the sources of direct quotations are represented as individuals with specified names. The comparative analysis shows that companies from different cultural backgrounds present different preferences in selecting and representing the various sources. The Italian and American CSR reports present more voices from managers, while the Chinese CSR reports show a clearer preference for voices from employees and clients.

Corporate social responsibility (CSR) reports are becoming a widespread corporate discourse practice and are often considered corporate image-building documents. The present study examines forward-...

We developed a facile method to synthesize porous and N-rich carbon materials derived from Bombyx mori silk cocoons with an activation and thermal carbonization process. The silk-derived nanosheets carbon fibers consist of a porous and multilayer structure, endowing the materials with high surface area of 349.3 m2 g−1 and much exposed active sites. The synthesized N-rich (4.7%) carbon materials are employed as electrocatalysts for hydrogen evolution reaction (HER) and exhibit incredible catalytic performance as well as promising electrochemical durability, which are mainly attributed to the large amount of exposed active sites, high graphitization degree and the rich nitrogen elements, especially pyridine-N and graphitic-N. Typically, the silk-derived nanosheets carbon fibers activated by KCI afford a low onset potential of −63 mV (vs. RHE), a low overpotential of 137 mV at 10 mA cm−2 and a Tafel slope of 132 mV dec−1. The results may offer a novel and promising method for the preparation of non-metal HER catalysts derived from abundant biomass.

A facile twice-hydrothermal method is developed for large-scale growth of NiCo 2 S 4 nanotube array on Ni foam with robust adhesion. As-prepared materials are characterized by SEM, XRD and EDS. It can be observed that NiCo 2 S 4 nanotubes directly grow on Ni foam with an average inner-diameter of ∼ 55 nm, external-diameter of 100 nm, and length of ∼ 2 μm. When evaluated as a binder-free anode for LIBs, NiCo 2 S 4 nanotube array exhibits outstanding lithium-storage performance that includes high special capacity, excellent cyclic stability and desirable rate capability. At 0.2 C rate, NiCo 2 S 4 nanotube array delivers the average discharge capacity of 720 mAh g −1 during 50 cycles that slightly surpasses its theoretical capacity of 703 mAh g −1 . When the current comes back to 0.2 C after rate measurements, NiCo 2 S 4 nanotubes can still stably deliver the discharging capacity of 652 mAh g −1 , reaching 92.7% of that at the initial 0.2 C. Cyclic Voltammetry (CV) measurements reveal that NiCo 2 S 4 nanotube array contains two sets of electrochemical reaction behavior come from Ni and Co. The unique NiCo 2 S 4 nanotube array exhibits great potential as an anode material for high-performance Lithium-ion batteries.

Lithium ion batteries (LIBs) have achieved great success in powering portable electronic devices in our modern society, and are to find use in the electrification of transportation and the storage of wind or solar energy in smart grids in the near future. However, there is increasing concern on the safety issues of current LIBs based on organic liquid electrolytes, which are volatile and flammable. This leads to the exploration and development of solid electrolytes to improve the safety of next-generation high-energy LIBs. In this review, we describe two inorganic–organic hybrid solid electrolyte systems for LIBs. Firstly, we present polymer electrolytes with different types of inorganic fillers, discussing how the fillers affect the electrochemical and physical properties of the electrolyte. Secondly, we introduce recent progress in MOF-based solid electrolytes and show how MOFs can contribute to such an inorganic–organic hybrid system. Finally, outlook and future directions for safe and high performance inorganic–organic hybrid solid electrolytes are proposed.