bluuebunny/crossref_metadata_2025 huggingface dataset:
Spatiotemporally controlled drug delivery via photothermally driven conformational change of self-integrated plasmonic hybrid nanogels
Authors: Lee Seungki , Kim Subeen , Kim Doyun , You Jieun , Kim Ji Soo , Kim Hakchun , Park Jungwon , Song Jihwan , Choi Inhee
Published: June 2023

Background

Spatiotemporal regulation is one of the major considerations for developing a controlled and targeted drug delivery system to treat diseases efficiently. Light-responsive plasmonic nanostructures take advantage due to their tunable optical and photothermal properties by changing size, shape, and spatial arrangement.

Results

In this study, self-integrated plasmonic hybrid nanogels (PHNs) are developed for spatiotemporally controllable drug delivery through light-driven conformational change and photothermally-boosted endosomal escape. PHNs are easily synthesized through the simultaneous integration of gold nanoparticles (GNPs), thermo-responsive poly (N-isopropyl acrylamide), and linker molecules during polymerization. Wave-optic simulations reveal that the size of the PHNs and the density of the integrated GNPs are crucial factors in modulating photothermal conversion. Several linkers with varying molecular weights are inserted for the optimal PHNs, and the alginate-linked PHN (A-PHN) achieves more than twofold enhanced heat conversion compared with others. Since light-mediated conformational changes occur transiently, drug delivery is achieved in a spatiotemporally controlled manner. Furthermore, light-induced heat generation from cellular internalized A-PHNs enables pinpoint cytosolic delivery through the endosomal rupture. Finally, the deeper penetration for the enhanced delivery efficiency by A-PHNs is validated using multicellular spheroid.

Conclusion

This study offers a strategy for synthesizing light-responsive nanocarriers and an in-depth understanding of light-modulated site-specific drug delivery.

Graphical Abstract
Community outbreak of COVID-19 among people who use drugs attending a harm reduction centre in Barcelona, Spain
Authors: Sánchez-Valdivia Nacho , Barbaglia Maria Gabriela , Olivella-Cirici Marc , Girona Marcos Noelia , Gotsens Mercè , Garrido Albaina Amaia , Rius Cristina , Bartroli Montse , Pérez Gloria
Published: June 2023

Background

The COVID-19 pandemic particularly affected the health of vulnerable population, such as people who use drugs. Due to compromised baseline health status, certain drug uses and settings and socioeconomic deprivation related to poverty and homelessness, drug users faced higher risk of COVID-19 infection. They had difficulty in adhering to the public health measures (i.e. physical distancing, hand hygiene and mask use). Also, the struggle to implement non-pharmaceutical actions (i.e. test–trace–isolate–quarantine strategy) among SARS-COV-2-infected drug users and their close contacts challenged the public health response. Therefore, this study aimed to describe a community COVID-19 outbreak and its approach among drug users of a harm reduction programme in an outpatient drug treatment centre in Barcelona, Spain.

Methods

We conducted an observational descriptive study of an outbreak of COVID-19 among people who use drugs attending the harm reduction programme of an outpatient drug treatment centre in the city of Barcelona, between July and October 2021 (n = 440). A passive search for cases was carried out with rapid antigens tests targeting symptomatic users who attended the facilities.

Results

Nineteen positive COVID-19 cases were identified among symptomatic drug users, between July and October 2021, with an attack rate of 4.3%. Specific measures were taken to control the outbreak, such as offering accommodation to self-isolate in a low-threshold residential resource to homeless drug users who tested positive and intensifying the vaccination strategy. The management of the outbreak was carried out in close collaboration between the outpatient centre and the main public health stakeholders in the city of Barcelona.

Conclusions

This study shows the complexity of managing and investigating COVID-19 outbreaks in vulnerable population groups. Epidemiological control measures, such as the test–trace–isolate–quarantine strategy, were challenging to implement due to technology-related barriers and socioeconomic vulnerabilities, especially homelessness. Community-based interventions, cooperation among stakeholders and housing-related policies were helpful in tackling outbreaks among people who use drugs. When addressing vulnerable and hidden populations, the perspective of inequalities should be included in epidemiological surveillance and outbreak control strategies.
The complexities of integrating evidence-based preventative health into England’s NHS: lessons learnt from the case of PrEP
Authors: Khan Tehseen , Coultas Clare , Kieslich Katharina , Littlejohns Peter
Published: June 2023

Background

The integration of preventative health services into England’s National Health Service is one of the cornerstones of current health policy. This integration is primarily envisaged through the removal of legislation that blocks collaborations between NHS organisations, local government, and community groups.

Aims and objectives

This paper aims to illustrate why these actions are insufficient through the case study of the PrEP judicial review.

Methods

Through an interview study with 15 HIV experts (commissioners, activists, clinicians, and national health body representatives), we explore the means by which the HIV prevention agenda was actively blocked, when NHS England denied responsibility for funding the clinically effective HIV pre-exposure prophylaxis (PrEP) drug in 2016, a case that led to judicial review. We draw on Wu et al.’s (Policy Soc 34:165–171, 2016) conceptual framing of ‘policy capacity’ in undertaking this analysis.

Results

The analyses highlight three main barriers to collaborating around evidence-based preventative health which indicate three main competence/capability issues in regard to policy capacity: latent stigma of ‘lifestyle conditions’ (individual-analytical capacity); the invisibility of prevention in the fragmented health and social care landscape related to issues of evidence generation and sharing, and public mobilisation (organizational-operational capacity); and institutional politics and distrust (systemic-political capacity).

Discussion and conclusion

We suggest that the findings hold implications for other ‘lifestyle’ conditions that are tackled through interventions funded by multiple healthcare bodies. We extend the discussion beyond the ‘policy capacity and capabilities’ approach to connect with a wider range of insights from the policy sciences, aimed at considering the range of actions needed for limiting the potential of commissioners to ‘pass the buck’ in regard to evidence-based preventative health.
Analysis of RAS and drug induced homo- and heterodimerization of RAF and KSR1 proteins in living cells using split Nanoluc luciferase
Authors: Rohrer Lino , Spohr Corinna , Beha Carina , Griffin Ricarda , Braun Sandra , Halbach Sebastian , Brummer Tilman
Published: June 2023

The dimerization of RAF kinases represents a key event in their activation cycle and in RAS/ERK pathway activation. Genetic, biochemical and structural approaches provided key insights into this process defining RAF signaling output and the clinical efficacy of RAF inhibitors (RAFi). However, methods reporting the dynamics of RAF dimerization in living cells and in real time are still in their infancy. Recently, split luciferase systems have been developed for the detection of protein–protein-interactions (PPIs), incl. proof-of-concept studies demonstrating the heterodimerization of the BRAF and RAF1 isoforms. Due to their small size, the Nanoluc luciferase moieties LgBiT and SmBiT, which reconstitute a light emitting holoenzyme upon fusion partner promoted interaction, appear as well-suited to study RAF dimerization. Here, we provide an extensive analysis of the suitability of the Nanoluc system to study the homo- and heterodimerization of BRAF, RAF1 and the related KSR1 pseudokinase. We show that KRASG12V promotes the homo- and heterodimerization of BRAF, while considerable KSR1 homo- and KSR1/BRAF heterodimerization already occurs in the absence of this active GTPase and requires a salt bridge between the CC-SAM domain of KSR1 and the BRAF-specific region. We demonstrate that loss-of-function mutations impairing key steps of the RAF activation cycle can be used as calibrators to gauge the dynamics of heterodimerization. This approach identified the RAS-binding domains and the C-terminal 14–3-3 binding motifs as particularly critical for the reconstitution of RAF mediated LgBiT/SmBiT reconstitution, while the dimer interface was less important for dimerization but essential for downstream signaling. We show for the first time that BRAFV600E, the most common BRAF oncoprotein whose dimerization status is controversially portrayed in the literature, forms homodimers in living cells more efficiently than its wildtype counterpart. Of note, Nanoluc activity reconstituted by BRAFV600E homodimers is highly sensitive to the paradox-breaking RAFi PLX8394, indicating a dynamic and specific PPI. We report the effects of eleven ERK pathway inhibitors on RAF dimerization, incl. third-generation compounds that are less-defined in terms of their dimer promoting abilities. We identify Naporafenib as a potent and long-lasting dimerizer and show that the split Nanoluc approach discriminates between type I, I1/2 and II RAFi.
Elraglusib (formerly 9-ING-41) possesses potent anti-lymphoma properties which cannot be attributed to GSK3 inhibition
Authors: Coats Josh T. , Tauro Sudhir , Sutherland Calum
Published: June 2023

Elraglusib (formerly 9-ING-41) is an ATP-competitive inhibitor of glycogen synthase kinase-3β (GSK3β) undergoing clinical trials for the treatment of various cancers including non-Hodgkin lymphoma (NHL). The drug reduces proliferation of several NHL cell lines and has efficacy in xenograft models of the disease. To confirm the importance of its action on GSK3β, we treated 3 lymphoma cell lines with selective, structurally distinct GSK3 inhibitors: CT99021, SB216763, LY2090314, tideglusib, and elraglusib. Stabilization of β-catenin and reduced phosphorylation of CRMP2, two validated targets of GSK3, were used as functional read-outs for GSK3 inhibition. CT99021, SB216763, and LY2090314 failed to reduce proliferation or viability in any cell line at concentrations that stabilized β-catenin and reduced CRMP2 phosphorylation. There was partial reduction of CRMP2 phosphorylation but no significant effect on β-catenin at cytotoxic doses of elraglusib. There was no indication of GSK3 inhibition at doses of tideglusib that affected cell viability and apoptosis. Cell-free kinase screening confirmed several other targets of elraglusib, distinct from the GSK3 inhibitors with no anti-lymphoma actions, including PIM kinases and MST2. These data question GSK3 as the target of elraglusib in lymphoma, and hence the utility of GSK3 expression as a ‘stand-alone’, therapeutic biomarker in NHL.
Cerebral Semaphorin3D is a novel risk factor for age-associated cognitive impairment
Authors: Chen Chien-Yuan , Chao Yung-Mei , Cho Ching-Chang , Chen Cheng-Sheng , Lin Wei-Yong , Chen Yi-Hung , Cassar Marlène , Lu Cecilia S. , Yang Jenq-Lin , Chan Julie Y. H. , Juo Suh-Hang H.
Published: June 2023

Background

We previously reported that miR-195 exerts neuroprotection by inhibiting Sema3A and cerebral miR-195 levels decreased with age, both of which urged us to explore the role of miR-195 and miR-195-regulated Sema3 family members in age-associated dementia.

Methods

miR-195a KO mice were used to assess the effect of miR-195 on aging and cognitive functions. Sema3D was predicted as a miR-195 target by TargetScan and then verified by luciferase reporter assay, while effects of Sema3D and miR-195 on neural senescence were assessed by beta-galactosidase and dendritic spine density. Cerebral Sema3D was over-expressed by lentivirus and suppressed by si-RNA, and effects of over-expression of Sema3D and knockdown of miR-195 on cognitive functions were assessed by Morris Water Maze, Y-maze, and open field test. The effect of Sema3D on lifespan was assessed in Drosophila. Sema3D inhibitor was developed using homology modeling and virtual screening. One-way and two-way repeated measures ANOVA were applied to assess longitudinal data on mouse cognitive tests.

Results

Cognitive impairment and reduced density of dendritic spine were observed in miR-195a knockout mice. Sema3D was identified to be a direct target of miR-195 and a possible contributor to age-associated neurodegeneration as Sema3D levels showed age-dependent increase in rodent brains. Injection of Sema3D-expressing lentivirus caused significant memory deficits while silencing hippocampal Sema3D improved cognition. Repeated injections of Sema3D-expressing lentivirus to elevate cerebral Sema3D for 10 weeks revealed a time-dependent decline of working memory. More importantly, analysis of the data on the Gene Expression Omnibus database showed that Sema3D levels were significantly higher in dementia patients than normal controls (p < 0.001). Over-expression of homolog Sema3D gene in the nervous system of Drosophila reduced locomotor activity and lifespan by 25%. Mechanistically, Sema3D might reduce stemness and number of neural stem cells and potentially disrupt neuronal autophagy. Rapamycin restored density of dendritic spines in the hippocampus from mice injected with Sema3D lentivirus. Our novel small molecule increased viability of Sema3D-treated neurons and might improve autophagy efficiency, which suggested Sema3D could be a potential drug target.

Conclusion

Our results highlight the importance of Sema3D in age-associated dementia. Sema3D could be a novel drug target for dementia treatment.
Simultaneous induction of vasculature and neuronal network formation on a chip reveals a dynamic interrelationship between cell types
Authors: Isosaari Lotta , Vuorenpää Hanna , Yrjänäinen Alma , Kapucu Fikret Emre , Kelloniemi Minna , Pakarinen Toni-Karri , Miettinen Susanna , Narkilahti Susanna
Published: June 2023

Background

Neuronal networks receive and deliver information to regulate bodily functions while the vascular network provides oxygen, nutrients, and signaling molecules to tissues. Neurovascular interactions are vital for both tissue development and maintaining homeostasis in adulthood; these two network systems align and reciprocally communicate with one another. Although communication between network systems has been acknowledged, the lack of relevant in vitro models has hindered research at the mechanistic level. For example, the current used in vitro neurovascular models are typically established to be short-term (≤ 7 days) culture models, and they miss the supporting vascular mural cells.

Methods

In this study, we utilized human induced pluripotent stem cell (hiPSC) -derived neurons, fluorescence tagged human umbilical vein endothelial cells (HUVECs), and either human bone marrow or adipose stem/stromal cells (BMSCs or ASCs) as the mural cell types to create a novel 3D neurovascular network-on-a-chip model. Collagen 1–fibrin matrix was used to establish long-term (≥ 14 days) 3D cell culture in a perfusable microphysiological environment.

Results

Aprotinin-supplemented endothelial cell growth medium-2 (EGM-2) supported the simultaneous formation of neuronal networks, vascular structures, mural cell differentiation, and the stability of the 3D matrix. The formed neuronal and vascular networks were morphologically and functionally characterized. Neuronal networks supported vasculature formation based on direct cell contacts and by dramatically increasing the secretion of angiogenesis-related factors in multicultures in contrast to cocultures without neurons. Both utilized mural cell types supported the formation of neurovascular networks; however, the BMSCs seemed to boost neurovascular networks to greater extent.

Conclusions

Overall, our study provides a novel human neurovascular network model that is applicable for creating in vivo-like tissue models with intrinsic neurovascular interactions. The 3D neurovascular network model on chip forms an initial platform for the development of vascularized and innervated organ-on-chip and further body-on-chip concepts and offers the possibility for mechanistic studies on neurovascular communication both under healthy and in disease conditions.
Disentangling the impact of cerebrospinal fluid formation and neuronal activity on solute clearance from the brain
Authors: Segeroth Martin , Wachsmuth Lydia , Gagel Mathias , Albers Franziska , Hess Andreas , Faber Cornelius
Published: June 2023

Background

Despite recent attention, pathways and mechanisms of fluid transposition in the brain are still a matter of intense discussion and driving forces underlying waste clearance in the brain remain elusive. Consensus exists that net solute transport is a prerequisite for efficient clearance. The individual impact of neuronal activity and cerebrospinal fluid (CSF) formation, which both vary with brain state and anesthesia, remain unclear.

Methods

To separate conditions with high and low neuronal activity and high and low CSF formation, different anesthetic regimens in naive rat were established, using Isoflurane (ISO), Medetomidine (MED), acetazolamide or combinations thereof. With dynamic contrast-enhanced MRI, after application of low molecular weight contrast agent (CA) Gadobutrol to cisterna magna, tracer distribution was monitored as surrogate for solute clearance. Simultaneous fiber-based Ca2+-recordings informed about the state of neuronal activity under different anesthetic regimen. T2-weighted MRI and diffusion-weighted MRI (DWI) provided size of subarachnoidal space and aqueductal flow as surrogates for CSF formation. Finally, a pathway and mechanism-independent two-compartment model was introduced to provide a measure of efficiency for solute clearance from the brain.

Results

Anatomical imaging, DWI and Ca2+-recordings confirmed that conditions with distinct levels of neuronal activity and CSF formation were achieved. A sleep-resembling condition, with reduced neuronal activity and enhanced CSF formation was achieved using ISO+MED and an awake-like condition with high neuronal activity using MED alone. CA distribution in the brain correlated with the rate of CSF formation. The cortical brain state had major influence on tracer diffusion. Under conditions with low neuronal activity, higher diffusivity suggested enlargement of extracellular space, facilitating a deeper permeation of solutes into brain parenchyma. Under conditions with high neuronal activity, diffusion of solutes into parenchyma was hindered and clearance along paravascular pathways facilitated. Exclusively based on the measured time signal curves, the two-compartment model provided net exchange ratios, which were significantly larger for the sleep-resembling condition than for the awake-like condition.

Conclusions

Efficiency of solute clearance in brain changes with alterations in both state of neuronal activity and CSF formation. Our clearance pathway and mechanism agnostic kinetic model informs about net solute transport, solely based on the measured time signal curves. This rather simplifying approach largely accords with preclinical and clinical findings.
Participant retention in paediatric randomised controlled trials published in six major journals 2015–2019: systematic review and meta-analysis
Authors: Gaunt Daisy M. , Papastavrou Brooks Cat , Pedder Hugo , Crawley Esther , Horwood Jeremy , Metcalfe Chris
Published: June 2023

Background

The factors which influence participant retention in paediatric randomised controlled trials are under-researched. Retention may be more challenging due to child developmental stages, involving additional participants, and proxy-reporting of outcomes. This systematic review and meta-analysis explores the factors which may influence retention in paediatric trials.

Methods

Using the MEDLINE database, paediatric randomised controlled trials published between 2015 and 2019 were identified from six general and specialist high-impact factor medical journals. The review outcome was participant retention for each reviewed trial’s primary outcome. Context (e.g. population, disease) and design (e.g. length of trial) factors were extracted. Retention was examined for each context and design factor in turn, with evidence for an association being determined by a univariate random-effects meta-regression analysis.

Results

Ninety-four trials were included, and the median total retention was 0.92 (inter-quartile range 0.83 to 0.98). Higher estimates of retention were seen for trials with five or more follow-up assessments before the primary outcome, those less than 6 months between randomisation and primary outcome, and those that used an inactive data collection method. Trials involving children aged 11 and over had the higher estimated retention compared with those involving younger children. Those trials which did not involve other participants also had higher retention, than those where they were involved. There was also evidence that a trial which used an active or placebo control treatment had higher estimated retention, than treatment-as-usual. Retention increased if at least one engagement method was used. Unlike reviews of trials including all ages of participants, we did not find any association between retention and the number of treatment groups, size of trial, or type of treatment.

Conclusions

Published paediatric RCTs rarely report the use of specific modifiable factors that improve retention. Including multiple, regular follow-ups with participants before the primary outcome may reduce attrition. Retention may be highest when the primary outcome is collected up to 6 months after a participant is recruited. Our findings suggest that qualitative research into improving retention when trials involve multiple participants such as young people, and their caregivers or teachers would be worthwhile. Those designing paediatric trials also need to consider the use of appropriate engagement methods.

Research on Research (RoR) registry

https://ror-hub.org/study/2561
Systemic lupus erythematosus presenting as lupus erythematosus tumidus and lupus nephritis: a case report
Authors: Hajji Meriam , Gorsane Imen , Badrouchi Samaraa , Litaiem Noureddine , Rammeh Soumaya , Ben Hamida Fethi , Abderrahim Ezzeddine
Published: June 2023

Background

Lupus nephritis and lupus erythematosus tumidus (LET) are uncommon manifestations of systemic lupus erythematosus (SLE), and their coexistence as the initial presentation of SLE is exceedingly rare. Here, we report such a case, emphasizing the diagnostic challenges and therapeutic implications of this unusual association.

Case report

A 38-year-old North African woman presented in Nephrology department with a history of lower extremity edema, fatigue, and weight loss of 3 kg in 4 weeks. Physical examination revealed LET lesions on the chest and the Neck. Laboratory investigations showed lymphopenia, low C3 and C4 complement levels, positive antinuclear antibodies, anti-dsDNA antibodies, and anti-SSA/Ro antibodies. Renal function tests showed normal serum creatinine and nephrotic proteinuria. Renal biopsy revealed Class V lupus nephritis. Skin biopsy confirmed the diagnosis of LET, with the presence of lymphohistiocytic infiltrates and dermal mucin. The patient was diagnosed with SLE based on the 2019 EULAR/ACR criteria and treated with prednisone (1 mg/kg/day) and hydroxychloroquine. She showed significant improvement in her cutaneous and renal symptoms at 6 and 12 months follow-up.

Conclusion

The rarity of the coexistence of LET and lupus nephritis as the initial manifestation of SLE, especially in the North African population, underscores the need for further research to elucidate the immunopathogenic mechanisms and prognostic factors associated with this association.
On Orlicz sequence algebras
Authors: Foralewski Paweł , Piszczek Krzysztof
Published: June 2023

We study Orlicz sequence algebras and their properties. In particular, we fully characterize biflat and biprojective Orlicz sequence algebras as well as weakly amenable and approximately (semi-)amenable Orlicz sequence algebras. As a consequence, we show the existence of a wide class of sequence algebras that behave differently—in terms of the amenability properties—from any of the algebras$\ell _{p}, 1\leqslant p\leqslant \infty $ℓp,1⩽p⩽∞.
Non-rigorous versus rigorous home confinement differently impacts mental health, quality of life and behaviors. Which one was better? A cross-sectional study with older Brazilian adults during covid-19 first wave
Authors: Bohn Lucimere , Abdalla Pedro Pugliesi , Gomide Euripedes Barsanulfo Gonçalves , da Silva Leonardo Santos Lopes , dos Santos André Pereira
Published: June 2023

Background

The implementation of social distancing measures during covid-19 influenced health outcomes and population´s behaviors, and its rigidity was very different across countries. We aimed to verify the association between the rigidity of social distancing measures of covid-19 first wave with depression symptoms, quality of life and sleep quality in older adults.

Methods

This is a cross-sectional study including 1023 older adults (90% women; 67.68 ± 5.92 years old) of a community-based program in Fortaleza (Brazil). Dependent variables (depression symptoms, sleep quality, and quality of life) were measured through phone calls along June 2020, during the first covid-19 wave. Confinement rigidity (non-rigorous and rigorous) was considered as independent variable. Sociodemographic characteristics (sex, marital status, scholarity, and ethnicity), number of health conditions, nutritional status, movement behavior (physical activity and sitting time), technological skills, and pet ownership were considered as confounding variables. A binomial logistic regression (odds ratio [OR]) was performed to verify the association of confinement rigidity and depression symptoms, sleep quality, and quality of life, adjusted by confounding variables.

Results

Older adults who adopted a less rigid lockdown had a higher frequency of depression symptoms, worse perception of quality of life, and bad sleep quality (p < 0.001). Confinement rigidity was able to explain the probability of depression symptoms occurrence (OR: 2.067 [95% CI: 1.531–2.791]; p < 0.001), worse quality of life (OR: 1.488 [95% CI: 1.139–1.944]; p < 0.05), and bad sleep quality (OR: 1.839 [95% CI: 1.412–2.395]; p < 0.001). Even adjusted by confounding variables, confinement rigidity was able to explain the poor outcomes analyzed in older adults.

Conclusion

Our findings showed that less rigid lockdown was associated with a superior frequency of depression symptoms, worse sleep quality, and lower perception of quality of life in older adults. Therefore, our study could improve comprehension regarding the impact of social distancing measures rigidity in health-related conditions and in the context of covid-19 and other similar pandemic situations.
Reuse of shipping materials in the intravitreal bevacizumab supply chain: feasibility, cost, and environmental impact
Authors: Vo Loi V. , Mastrorilli Vanessa , Muto Alfonse J. , Emerson Geoffrey G.
Published: June 2023

Background

Intravitreal injections are the most common ophthalmic procedure worldwide and are also a prime opportunity for waste reduction. This study analyzes the feasibility, environmental impact, and cost of reusing shipping materials for intravitreal injection medications, as compared to wasting coolers and cold packs after single-use.

Methods

In this prospective pilot study, shipping materials (cardboard boxes, polystyrene foam coolers, and cold packs) from repackaged bevacizumab delivered to our clinic (500 doses per week) were saved and reused over a 10-week study period. The shipping supplies were photographed and inspected for defects at point of care (Twin Cities, MN), and returned via standard ground shipping to the outsourcing facility (Tonawanda, NY).

Results

Polystyrene foam coolers (n = 3) survived 10 roundtrips between the outsourcing facility and retina clinic (600 mi each way), although wear-and-tear was visible in the form of marks and dents. Cold packs (n = 35) were less durable, lasting 3.1 ± 2.0 roundtrips. Total carbon dioxide equivalent (CO2e) emissions were reduced 43%, by reusing shipping materials (12.88 kgCO2e per 1000 bevacizumab doses), as compared to the standard practice of disposing containers after single-use (22.70 kgCO2e per 1000 bevacizumab doses), and landfill volume was reduced by 89%. Cost savings from reusing containers offset expenses incurred with return shipping and extra handling in the reuse cohort (net savings: $0.52 per 1000 bevacizumab doses).

Conclusions

Reusing shipping supplies can be cost neutral, with less CO2e emissions and reduced landfill. Robust environmental benefit is possible if retina clinics partner with manufacturers to reuse shipping containers.
Updated efficacy and safety of entrectinib in patients (pts) with locally advanced/metastatic NTRK fusion-positive (fp) non-small cell lung cancer (NSCLC).
Authors: Cho Byoung Chul , Chiu Chao-Hua , Massarelli Erminia , Buchschacher Gary L , Goto Koichi , Overbeck Tobias R. , Loong Herbert H. F. , Chee Cheng E. , Garrido Pilar , Heinzmann Sebastian , Bordogna Walter , Zeuner Harald , Osborne Stuart , John Tom
Published: June 2023

9047

Background: NTRK fusions, encoding for constitutively active oncogenic tropomyosin receptor kinase proteins, are present in many solid tumors, including NSCLC. As central nervous system (CNS) metastases are common in pts with advanced NSCLC, treatments with intracranial efficacy are needed. Entrectinib, a potent CNS-active tyrosine kinase inhibitor, has previously demonstrated efficacy in pts with NTRK-fp NSCLC in an integrated analysis of three phase I/II trials (ALKA-372-001 [EudraCT, 2012-000148–88], STARTRK-1 [NCT02097810], STARTRK-2 [NCT02568267]); objective response rate (ORR) was 63.6% (14/22; data cutoff: August 31 2020). We present updated data for this cohort. Methods: Pts ≥18 years old with locally advanced/metastatic NTRK-fp tumors were enrolled and received 600 mg oral entrectinib until disease progression, toxicity, or death. At Week 4 and then every 8 weeks, tumour response was assessed by blinded independent central review (BICR) per RECIST v1.1. Co-primary endpoints were ORR and duration of response (DoR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), intracranial efficacy, and safety. Enrolment cutoff: July 2 2020; data cutoff: August 2 2021. Results: The efficacy-evaluable population included 31 pts with NTRK-fp NSCLC. Median age was 60.0 years (range 22–88); 26 pts (83.9%) had adenocarcinoma; 11 pts (35.5%) had ≥2 prior lines of systemic therapy; 18 pts (58.1%) were current or former smokers; 15 pts (48.4%) had investigator-assessed baseline CNS metastases. Median survival follow up was 21.8 months (95% CI 19.5–30.2). Entrectinib treatment showed efficacy in pts with NTRK-fp NSCLC, including those with baseline CNS metastases by investigator (Table). In pts with BICR-assessed CNS metastases, intracranial ORR was 60.0% (6/10; 95% CI 26.2–87.8), median intracranial DoR was not estimable (NE), and median intracranial PFS was 8.9 months (95% CI 5.6–NE). In the safety-evaluable population (N=35), most treatment-related adverse events (TRAEs) were Grade 1–2 and non-serious. TRAEs led to dose reduction, interruption and discontinuation in 31.4%, 28.6%, and 5.7% of pts, respectively, and no treatment-related deaths occurred. Conclusions: In line with previously reported data, treatment with entrectinib was associated with deep and durable systemic and intracranial responses in pts with advanced NTRK-fp NSCLC. Clinical trial information: EUCTR 2012-000148-88 , NCT02097810 , NCT02568267 . [Table: see text]
Daratumumab, Cyclophosphamide, Bortezomib, Lenalidomide, and Dexamethasone as Induction and Extended Consolidation Improves Outcome in Ultra-High-Risk Multiple Myeloma
Authors: Kaiser Martin F. , Hall Andrew , Walker Katrina , Sherborne Amy , De Tute Ruth M. , Newnham Nicola , Roberts Sadie , Ingleson Emma , Bowles Kristian , Garg Mamta , Lokare Anand , Messiou Christina , Houlston Richard S. , Jackson Graham , Cook Gordon , Pratt Guy , Owen Roger G. , Drayson Mark T. , Brown Sarah R. , Jenner Matthew W.
Published: June 2023

PURPOSE

The multicenter OPTIMUM (MUKnine) phase II trial investigated daratumumab, low-dose cyclophosphamide, lenalidomide, bortezomib, and dexamethasone (Dara-CVRd) before and after autologous stem-cell transplant (ASCT) in newly diagnosed patients with molecularly defined ultra–high-risk (UHiR) multiple myeloma (NDMM) or plasma cell leukemia (PCL). To provide clinical context, progression-free survival (PFS) and overall survival (OS) were referenced to contemporaneous outcomes seen in patients with UHiR NDMM treated in the recent Myeloma XI (MyeXI) trial.

METHODS

Transplant-eligible all-comers NDMM patients were profiled for UHiR disease, defined by presence of ≥2 genetic risk markers t(4;14)/t(14;16)/t(14;20), del(1p), gain(1q), and del(17p), and/or SKY92 gene expression risk signature. Patients with UHiR MM/PCL were offered treatment with Dara-CVRd induction, V-augmented ASCT, extended Dara-VR(d) consolidation, and Dara-R maintenance. UHiR patients treated in MyeXI with carfilzomib, lenalidomide, dexamethasone, and cyclophosphamide, or lenalidomide, dexamethasone, and cyclophosphamide, ASCT, and R maintenance or observation were identified by mirrored molecular screening. OPTIMUM PFS at 18 months (PFS18m) was compared against MyeXI using a Bayesian framework, and patients were followed up to the end of consolidation for PFS and OS.

RESULTS

Of 412 screened NDMM OPTIMUM patients, 103 were identified as UHiR or PCL and subsequently treated on trial with Dara-CVRd; 117 MyeXI patients identified as UHiR formed the external comparator arm, with comparable clinical and molecular characteristics to OPTIMUM. Comparison of PFS18m per Bayesian framework resulted in a 99.5% chance of OPTIMUM being superior to MyeXI. At 30 months' follow-up, PFS was 77% for OPTIMUM versus 39.8% for MyeXI, and OS 83.5% versus 73.5%, respectively. Extended post-ASCT Dara-VRd consolidation therapy was highly deliverable, with limited toxicity.

CONCLUSION

Our results suggest that Dara-CVRd induction and extended post-ASCT Dara-VRd consolidation markedly improve PFS for UHiR NDMM patients over conventional management, supporting further evaluation of this strategy.
Wild-Type KRAS Is Required for Panitumumab Efficacy in Patients With Metastatic Colorectal Cancer
Authors: Amado Rafael G. , Wolf Michael , Peeters Marc , Van Cutsem Eric , Siena Salvatore , Freeman Daniel J. , Juan Todd , Sikorski Robert , Suggs Sid , Radinsky Robert , Patterson Scott D. , Chang David D.
Published: June 2023

PURPOSE

Panitumumab, a fully human antibody against the epidermal growth factor receptor (EGFR), has activity in a subset of patients with metastatic colorectal cancer (mCRC). Although activating mutations in KRAS, a small G-protein downstream of EGFR, correlate with poor response to anti-EGFR antibodies in mCRC, their role as a selection marker has not been established in randomized trials.

PATIENTS AND METHODS

KRAS mutations were detected using polymerase chain reaction on DNA from tumor sections collected in a phase III mCRC trial comparing panitumumab monotherapy to best supportive care (BSC). We tested whether the effect of panitumumab on progression-free survival (PFS) differed by KRAS status.

RESULTS

KRAS status was ascertained in 427 (92%) of 463 patients (208 panitumumab, 219 BSC). KRAS mutations were found in 43% of patients. The treatment effect on PFS in the wild-type (WT) KRAS group (hazard ratio [HR], 0.45; 95% CI: 0.34 to 0.59) was significantly greater ( P < .0001) than in the mutant group (HR, 0.99; 95% CI, 0.73 to 1.36). Median PFS in the WT KRAS group was 12.3 weeks for panitumumab and 7.3 weeks for BSC. Response rates to panitumumab were 17% and 0%, for the WT and mutant groups, respectively. WT KRAS patients had longer overall survival (HR, 0.67; 95% CI, 0.55 to 0.82; treatment arms combined). Consistent with longer exposure, more grade III treatment-related toxicities occurred in the WT KRAS group. No significant differences in toxicity were observed between the WT KRAS group and the overall population.

CONCLUSION

Panitumumab monotherapy efficacy in mCRC is confined to patients with WT KRAS tumors. KRAS status should be considered in selecting patients with mCRC as candidates for panitumumab monotherapy.
Current Status of Human Papillomavirus–Targeted Therapies Development in Head and Neck Cancer
Authors: Park Jong Chul , Bertaux Brittany , Park Junseok , Park Seongwoo
Published: June 2023

PURPOSE

While the incidence of smoking-related head and neck squamous cell carcinoma (HNSCC) has been declining, that of human papillomavirus (HPV)–mediated HNSCC has rapidly increased in the past decades worldwide. Despite rapid advances in therapeutics for solid tumors with novel immunotherapy and targeted therapeutic agents, no breakthroughs have yet been made in the treatment of advanced HPV+ HNSCCs. This review aims to summarize the concepts and designs, early trial results, and future directions of various HPV-targeted experimental therapeutics for HPV+ HNSCC.

MATERIALS AND METHODS

Guided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement, a systemic literature search of PubMed was conducted for HPV-targeted therapeutics using the following search terms: HPV, head and neck squamous cell carcinoma, and therapy. For clinical trial data, publications, major oncology conference abstracts, and the National Institutes of Health Clinical Trials Registry (ClinicalTrials.gov) information were reviewed. This review focused on the ones that are in the clinical stage and currently in active ongoing evaluation. The therapeutics not actively evaluated in HNSCC, in the preclinical stage, or terminated for further development were excluded.

RESULTS

Diverse approaches are being actively explored to target HPV+ HNSCC, including therapeutic vaccines of various modalities, HPV-specific immune cell–activating agents, and adaptive cellular therapeutics. All these novel agents use immune-based mechanisms and target constitutively expressed oncogenic HPV E6 and/or E7 viral proteins. Most therapeutics demonstrated excellent safety but single-agent activities are only modest. Many are being tested in combination with immune checkpoint inhibitors.

CONCLUSION

Our review summarized various novel HPV-targeted therapeutics that are in the clinical phase for HPV+ HNSCC. Early-phase trial data suggest the feasibility and promising efficacy. Further strategies, including selecting the optimal combination and understanding and overcoming resistant mechanisms, are warranted for successful development.
Protective Effects of Imeglimin and Metformin Combination Therapy on β-Cells in db/db Male Mice
Authors: Nishiyama Kuniyuki , Ono Masato , Tsuno Takahiro , Inoue Ryota , Fukunaka Ayako , Okuyama Tomoko , Kyohara Mayu , Togashi Yu , Fukushima Setsuko , Atsumi Takuto , Sato Aoi , Tsurumoto Asuka , Sakai Chisato , Fujitani Yoshio , Terauchi Yasuo , Ito Shuichi , Shirakawa Jun
Published: June 2023

Imeglimin and metformin act in metabolic organs, including β-cells, via different mechanisms. In the present study, we investigated the impacts of imeglimin, metformin, or their combination (Imeg + Met) on β-cells, the liver, and adipose tissues in db/db mice. Imeglimin, metformin, or Imeg + Met treatment had no significant effects on glucose tolerance, insulin sensitivity, respiratory exchange ratio, or locomotor activity in db/db mice. The responsiveness of insulin secretion to glucose was recovered by Imeg + Met treatment. Furthermore, Imeg + Met treatment increased β-cell mass by enhancing β-cell proliferation and ameliorating β-cell apoptosis in db/db mice. Hepatic steatosis, the morphology of adipocytes, adiposity assessed by computed tomography, and the expression of genes related to glucose or lipid metabolism and inflammation in the liver and fat tissues showed no notable differences in db/db mice. Global gene expression analysis of isolated islets indicated that the genes related to regulation of cell population proliferation and negative regulation of cell death were enriched by Imeg + Met treatment in db/db islets. In vitro culture experiments confirmed the protective effects of Imeg + Met against β-cell apoptosis. The expression of Snai1, Tnfrsf18, Pdcd1, Mmp9, Ccr7, Egr3, and Cxcl12, some of which have been linked to apoptosis, in db/db islets was attenuated by Imeg + Met. Treatment of a β-cell line with Imeg + Met prevented apoptosis induced by hydrogen peroxide or palmitate. Thus, the combination of imeglimin and metformin is beneficial for the maintenance of β-cell mass in db/db mice, probably through direct action on β-cells, suggesting a potential strategy for protecting β-cells in the treatment of type 2 diabetes.
Parallels between oncogene-driven cardiac hyperplasia and heart regeneration in zebrafish
Authors: Pfefferli Catherine , Bonvin Marylène , Grepper Dogan , Robatel Steve , König Désirée , Lischer Heidi E. L. , Bruggmann Rémy , Jaźwińska Anna
Published: June 2023

The human heart is poorly regenerative and cardiac tumors are extremely rare. Whether the adult zebrafish myocardium is responsive to oncogene overexpression and how this condition affects its intrinsic regenerative capacity remains unknown. Here, we have established a strategy of inducible and reversible expression of HRASG12V in zebrafish cardiomyocytes. This approach stimulated a hyperplastic cardiac enlargement within 16 days. The phenotype was suppressed by rapamycin-mediated inhibition of TOR signaling. As TOR signaling is also required for heart restoration after cryoinjury, we compared transcriptomes of hyperplastic and regenerating ventricles. Both conditions were associated with upregulation of cardiomyocyte dedifferentiation and proliferation factors, as well as with similar microenvironmental responses, such as deposition of nonfibrillar Collagen XII and recruitment of immune cells. Among the differentially expressed genes, many proteasome and cell-cycle regulators were upregulated only in oncogene-expressing hearts. Preconditioning of the heart with short-term oncogene expression accelerated cardiac regeneration after cryoinjury, revealing a beneficial synergism between both programs. Identification of the molecular bases underlying the interplay between detrimental hyperplasia and advantageous regeneration provides new insights into cardiac plasticity in adult zebrafish.
Ultra-Low Dose of Superparamagnetic Iron Oxide Nanoparticles for Sentinel Lymph Node Detection in Patients with Breast Cancer
Authors: Mirzaei Nushin , Wärnberg Fredrik , Zaar Pontus , Leonhardt Henrik , Olofsson Bagge Roger
Published: June 2023

Background

Sentinel lymph node (SLN) status is pivotal for treatment decision-making in patients with breast cancer. Superparamagnetic iron oxide nanoparticles (SPIO) have been shown to be equivalent to the dual technique with technetium99m (Tc99) and blue dye (BD) for SLN detection. The aim of this study was to determine the feasibility of detecting SLNs using an ultra-low dose of SPIO.

Method

Patients planned for breast conserving surgery and SLN biopsy were included. An intradermal injection of 0.1 mL SPIO was administered at the areolar border up to 7 days before surgery. Tc99/BD was administered according to clinical routine. SLNs were detected during surgery using a handheld magnetometer. All nodes with a magnetic and/or radioactive signal, as well as blue or clinically suspicious nodes, were harvested and analyzed.

Results

In 50 patients, SPIO was injected a median of 4 days before surgery. At least one SLN was found in all patients with both methods. A total of 98 SLNs were removed; 90 were detected using SPIO and 88 using Tc99/BD. Of the 90 SLNs detected by SPIO, 80 were Tc99/BD positive (concordance 89%). Histopathological analysis classified 16 patients with tumor cells deposit and 9 with macro-metastasis > 2mm, where one SLN was identified only by the radioactive technique and one only by the magnetic technique.

Discussion

SLN detection using 0.1 mL ultra-low dose SPIO injected intradermally was successful in all patients. A future analysis will determine whether the approach using an ultra-low dose of SPIO injected intradermally will minimize skin staining and MRI artefacts.
Real-time optical network in avionics applications
Authors: Solov'ev Andrey , Sel'vesyuk Nikolay , Zybin Evgeniy , Novikov Valeriy , Pikalov Aleksandr , Tolkachev Akim
Published: June 2023

This study analyzes existing approaches to building fault-tolerant onboard systems at the hardware and software levels. The main advantages of constructing an Avionics Integrated Vehicle System (AIVS) based on fiber optic components are considered, particularly for deploying a Unified Intelligent System (UIS) that provides intelligent decision-making in case of abnormal situations. Scenarios for countering various abnormal situations at different levels of aircraft equipment complex (AEC) operation are developed, aiming to enhance the fault tolerance of its systems and, consequently, flight safety as a whole. Algorithms for reconfiguring the AIVS in case of abnormal situations, both during flight and on the ground, are devised. Principles for creating a specialized knowledge base for information support (KBIS) based on operational documentation are proposed. Logical programming methods are employed to simplify the formalization of knowledge stored in the KBIS and to facilitate modification and supplementation of the KBIS with new data. Calculation methodologies for AIVS configuration characteristics based on the KBIS are developed. Dynamic synthesis methods for generating new AIVS configurations are designed to address abnormal situations arising during aircraft operation. State space information formalized using logical programming methods is used to solve the synthesis problem. A complete system graph is constructed considering its redundancy, and a search-synthesis for the most suitable AIVS architecture capable of countering failures is performed.
Customers as Friendly Shareholders: Uncovering the Complex Mutual Fund-Broker Relationship
Authors: Kumar Nitish , Tang Yuehua , Wei Kelsey D.
Published: June 2023

This paper examines mutual funds’ dual role as both clients and shareholders of broker banks. Mutual funds are more likely to hold and significantly overweight stocks of their broker banks. In line with the portfolio decisions, fund voting is biased toward broker management in contentious proposals. Such voting bias is inconsistent with maximizing broker banks’ shareholder value yet significantly affects voting outcomes and the presence of contentious proposals at the banks’ shareholder meetings. Furthermore, we show that although client funds are rewarded with preferential initial public offering allocations from connected brokers for their voting support, fund managers’ engagement in reciprocal practices is ultimately determined by the economic tradeoffs they face. Our study not only uncovers a new mechanism—being brokers’ friendly shareholders—through which the two parties maintain their quid pro quo relationships but also raises a broader concern about governance of important financial institutions.

This paper was accepted by Victoria Ivashina, finance.

Supplemental Material: The data files and online appendix are available at https://doi.org/10.1287/mnsc.2023.4820 .