bluuebunny/crossref_metadata_2025_split huggingface dataset:
PD-L1/TLR7 dual-targeting nanobody-drug conjugate mediates potent tumor regression via elevating tumor immunogenicity in a host-expressed PD-L1 bias-dependent way
Authors: Yu Xiaolu , Long Yiru , Chen Binfan , Tong Yongliang , Shan Mengwen , Jia Xiaomin , Hu Chao , Liu Meng , Zhou Ji , Tang Feng , Lu Henglei , Chen Runqiu , Xu Pan , Huang Wei , Ren Jin , Wan Yakun , Sun Jianhua , Li Jia , Jin Guangyi , Gong Likun 
Published: October 2022

BackgroundVarious tumors are insensitive to immune checkpoint blockade (ICB) therapy. Toll-like receptors (TLRs) establish the link between innate and adaptive immunity, which can assist T-cell activation and serve as promising targets for combination to enhance ICB therapy. Here, we aimed to improve efficacy for anti-programmed death ligand 1 (PD-L1) therapy by developing a PD-L1/TLR7 dual-targeting nanobody-drug conjugate (NDC), based on the PD-L1 nanobodies and TLR7 agonist we developed.MethodsPD-L1 nanobodies were obtained by phage display screening and identified through T-cell activation bioassay, in vivo imaging and quantitative biodistribution study. Immune activation and PD-L1-inducing of TLR7 agonists were evaluated in diverse innate cell models. We constructed PD-L1/TLR7 dual-targeting NDCs by chemically coupling PD-L1 nanobodies and TLR7 agonists. The antitumor effect was evaluated via several murine or humanized solid tumor models. Immunophenotyping, immune cell depletion, tumor rechallenge, RNA sequencing and PD-L1-deficient models were combined to determine the mechanism for NDCs function. The dynamics of the in vivo behaviors of NDCs were assessed based on multiorgan changes in PD-L1 levels.ResultsThe screened PD-L1 nanobodies were characterized as tumor-targeting and alleviated T-cell immunosuppression. The TLR7 agonists induced broad innate immune responses and intratumoral PD-L1 expression on antigen-presenting cells (APCs), and its antitumor effect was dependent on intratumoral delivery. The combination of TLR7 agonists and PD-L1 nanobodies activated both innate and adaptive immunity and upregulated PD-L1-related signaling pathways. After coupling to form dual-targeting NDCs, TLR7 agonists and PD-L1 nanobodies exerted synergistic antitumor effects and safety in either ‘hot’ or ‘cold’ tumor and early or advanced tumor models, reshaped the tumor immune microenvironment and induced antitumor immune memory. CD8+T cells and natural killer cells were the main effector cells for NDCs to function. NDCs can promote PD-L1 expression on intratumoral APCs and tumor cells, and subsequently achieve targeted enrichment in tumors. Moreover, the efficacy of NDCs is biased toward dependence on host expression of PD-L1.ConclusionsThe novel PD-L1/TLR7 dual-targeting NDC exhibited potent efficacy against heterogeneous tumors through orchestrating innate and adaptive immunity, which could act as a promising strategy to improve ICB therapy and shows prospects for clinical development.
Localized ablative immunotherapy drives de novo CD8+T-cell responses to poorly immunogenic tumors
Authors: Hoover Ashley R , Kaabinejadian Saghar , Krawic Jason R , Sun Xiao-Hong , Naqash Abdul Rafeh , Yin Qian , Yang Xinbo , Christopher Garcia K , Davis Mark M , Hildebrand William H , Chen Wei R 
Published: October 2022

BackgroundLocalized ablative immunotherapies hold great promise in stimulating antitumor immunity to treat metastatic and poorly immunogenic tumors. Tumor ablation is well known to release tumor antigens and danger-associated molecular patterns to stimulate T-cell immunity, but its immune stimulating effect is limited, particularly against metastatic tumors.MethodsIn this study, we combined photothermal therapy with a potent immune stimulant, N-dihydrogalactochitosan, to create a local ablative immunotherapy which we refer to as laser immunotherapy (LIT). Mice bearing B16-F10 tumors were treated with LIT when the tumors reached 0.5 cm3and were monitored for survival, T-cell activation, and the ability to resist tumor rechallenge.ResultsWe found that LIT stimulated a stronger and more consistent antitumor T-cell response to the immunologically ‘cold’ B16-F10 melanoma tumors and conferred a long-term antitumor memory on tumor rechallenge. Furthermore, we discovered that LIT generated de novo CD8+T-cell responses that strongly correlated with animal survival and tumor rejection.ConclusionIn summary, our findings demonstrate that LIT enhances the activation of T cells and drives de novo antitumor T-cell responses. The data presented herein suggests that localized ablative immunotherapies have great potential to synergize with immune checkpoint therapies to enhance its efficacy, resulting in improved antitumor immunity.
Phase Ib study of pembrolizumab in combination with trastuzumab emtansine for metastatic HER2-positive breast cancer
Authors: Waks Adrienne G , Keenan Tanya E , Li Tianyu , Tayob Nabihah , Wulf Gerburg M , Richardson Edward T , Attaya Victoria , Anderson Leilani , Mittendorf Elizabeth A , Overmoyer Beth , Winer Eric P , Krop Ian E , Agudo Judith , Van Allen Eliezer M , Tolaney Sara M 
Published: October 2022

BackgroundPreclinical and clinical data support potential synergy between anti-HER2 therapy plus immune checkpoint blockade. The safety and tolerability of trastuzumab emtansine (T-DM1) combined with pembrolizumab is unknown.MethodsThis was a single-arm phase Ib trial (registration date January 26, 2017) of T-DM1 plus pembrolizumab in metastatic, human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Eligible patients had HER2-positive, metastatic breast cancer previously treated with taxane, trastuzumab, and pertuzumab, and were T-DM1-naïve. A dose de-escalation design was used, with a dose-finding cohort followed by an expansion cohort at the recommended phase 2 dose (RP2D), with mandatory baseline biopsies. The primary endpoint was safety and tolerability. Secondary endpoints included objective response rate (ORR) and progression-free survival (PFS). Immune biomarkers were assessed using histology, protein/RNA expression, and whole exome sequencing. Associations between immune biomarkers and treatment response, and biomarker changes before and during treatment, were explored.Results20 patients received protocol therapy. There were no dose-limiting toxicities. The RP2D was 3.6 mg/kg T-DM1 every 21 days plus 200 mg pembrolizumab every 21 days. 85% of patients experienced treatment-related adverse events (AEs) ≥grade 2, 20% of patients experienced grade 3 AEs, and no patients experienced grade >4 AEs. Four patients (20%) experienced pneumonitis (three grade 2 events; one grade 3 event). ORR was 20% (95% CI 5.7% to 43.7%), and median PFS was 9.6 months (95% CI 2.8 to 16.0 months). Programmed cell death ligand-1 and tumor infiltrating lymphocytes did not correlate with response in this small cohort.ConclusionsT-DM1 plus pembrolizumab was a safe and tolerable regimen. Ongoing trials will define if there is a role for checkpoint inhibition in the management of HER2-positive metastatic breast cancer.Trial registration numberNCT03032107.
Tumor microenvironment shows an immunological abscopal effect in patients with NSCLC treated with pembrolizumab-radiotherapy combination
Authors: van der Woude Lieke L , Gorris Mark A J , Wortel Inge M N , Creemers Jeroen H A , Verrijp Kiek , Monkhorst Kim , Grünberg Katrien , van den Heuvel Michel M , Textor Johannes , Figdor Carl G , Piet Berber , Theelen Willemijn S M E , de Vries I Jolanda M 
Published: October 2022

BackgroundImmunotherapy is currently part of the standard of care for patients with advanced-stage non-small cell lung cancer (NSCLC). However, many patients do not respond to this treatment, therefore combination strategies are being explored to increase clinical benefit. The PEMBRO-RT trial combined the therapeutic programmed cell death 1 (PD-1) antibody pembrolizumab with stereotactic body radiation therapy (SBRT) to increase the overall response rate and study the effects on the tumor microenvironment (TME).MethodsHere, immune infiltrates in the TME of patients included in the PEMBRO-RT trial were investigated. Tumor biopsies of patients treated with pembrolizumab alone or combined with SBRT (a biopsy of the non-irradiated site) at baseline and during treatment were stained with multiplex immunofluorescence for CD3, CD8, CD20, CD103 and FoxP3 for lymphocytes, pan-cytokeratin for tumors, and HLA-ABC expression was determined.ResultsThe total number of lymphocytes increased significantly after 6 weeks of treatment in the anti-PD-1 group (fold change: 1.87, 95% CI: 1.06 to 3.29) and the anti-PD-1+SBRT group (fold change: 2.29, 95% CI: 1.46 to 3.60). The combination of SBRT and anti-PD-1 induced a 4.87-fold increase (95% CI: 2.45 to 9.68) in CD103+cytotoxic T-cells 6 weeks on treatment and a 2.56-fold increase (95% CI: 1.03 to 6.36) after anti-PD-1 therapy alone. Responders had a significantly higher number of lymphocytes at baseline than non-responders (fold difference 1.85, 95% CI: 1.04 to 3.29 for anti-PD-1 and fold change 1.93, 95% CI: 1.08 to 3.44 for anti-PD-1+SBRT).ConclusionThis explorative study shows that that lymphocyte infiltration in general, instead of the infiltration of a specific lymphocyte subset, is associated with response to therapy in patients with NSCLC.Furthermore, anti-PD-1+SBRT combination therapy induces an immunological abscopal effect in the TME represented by a superior infiltration of cytotoxic T cells as compared with anti-PD-1 monotherapy.
Cardiac care of children with dystrophinopathy and females carrying DMD-gene variations
Authors: Bourke John , Turner Cathy , Bradlow William , Chikermane Ashish , Coats Caroline , Fenton Matthew , Ilina Maria , Johnson Alexandra , Kapetanakis Stam , Kuhwald Lisa , Morley-Davies Adrian , Quinlivan Ros , Savvatis Konstantinos , Schiava Marianela , Yousef Zaheer , Guglieri Michela 
Published: October 2022

ObjectiveWe provide succinct, evidence-based and/or consensus-based best practice guidance for the cardiac care of children living with Duchenne muscular dystrophy (DMD) as well as recommendations for screening and management of female carriers of mutations in theDMD-gene.MethodsInitiated by an expert working group of UK-based cardiologists, neuromuscular clinicians and DMD-patient representatives, draft guidelines were created based on published evidence, current practice and expert opinion. After wider consultation with UK-cardiologists, consensus was reached on these best-practice recommendations for cardiac care in DMD.ResultsThe resulting recommendations are presented in the form of a succinct care pathway flow chart with brief justification. The guidance signposts evidence on which they are based and acknowledges where there have been differences in opinion. Guidelines for cardiac care of patients with more advanced cardiac dystrophinopathy at any age have also been considered, based on the previous published work of Quinlivanet aland are presented here in a similar format. The recommendations have been endorsed by the British Cardiovascular Society.ConclusionThese guidelines provide succinct, reasoned recommendations for all those managing paediatric patients with early or advanced stages of cardiomyopathy as well as females with cardiac dystrophinopathy. The hope is that this will result in more uniform delivery of high standards of care for children with cardiac dystrophinopathy, so improving heart health into adulthood through timely earlier interventions across the UK.
Creating MHC-Restricted Neoantigens with Covalent Inhibitors That Can Be Targeted by Immune Therapy
Authors: Hattori Takamitsu , Maso Lorenzo , Araki Kiyomi Y. , Koide Akiko , Hayman James , Akkapeddi Padma , Bang Injin , Neel Benjamin G. , Koide Shohei 
Published: October 2022

AbstractIntracellular oncoproteins can be inhibited with targeted therapy, but responses are not durable. Immune therapies can be curative, but most oncogene-driven tumors are unresponsive to these agents. Fragments of intracellular oncoproteins can act as neoantigens presented by the major histocompatibility complex (MHC), but recognizing minimal differences between oncoproteins and their normal counterparts is challenging. We have established a platform technology that exploits hapten–peptide conjugates generated by covalent inhibitors to create distinct neoantigens that selectively mark cancer cells. Using the FDA-approved covalent inhibitors sotorasib and osimertinib, we developed “HapImmune” antibodies that bind to drug–peptide conjugate/MHC complexes but not to the free drugs. A HapImmune-based bispecific T-cell engager selectively and potently kills sotorasib-resistant lung cancer cells upon sotorasib treatment. Notably, it is effective against KRASG12C-mutant cells with different HLA supertypes, HLA-A*02 and A*03/11, suggesting loosening of MHC restriction. Our strategy creates targetable neoantigens by design, unifying targeted and immune therapies.Significance:Targeted therapies against oncoproteins often have dramatic initial efficacy but lack durability. Immunotherapies can be curative, yet most tumors fail to respond. We developed a generalizable technology platform that exploits hapten–peptides generated by covalent inhibitors as neoantigens presented on MHC to enable engineered antibodies to selectively kill drug-resistant cancer cells.See related commentary by Cox et al., p. 19.This article is highlighted in the In This Issue feature, p. 1
Menstrual hygiene among early adolescent girls and its’ related factors
Authors: Ritanti Ritanti , Wahyuni Tri 
Published: October 2022

<p>This study aimed to determine the prevalence of menstrual hygiene and the association between mother’s role function and menstrual hygiene among early adolescent girls. This cross-sectional study used a simple random sampling technique. The target population including early adolescent girls aged 12-15 years old, had menarche. Hence, 367 respondents in this study passed the analysis's inclusion criteria. Multivariable logistic regression was used to determine the association. There were 46.32 % of respondents noticed the prevalence of good menstrual hygiene. There were 170 out of 367 respondents who reported the presence of good menstrual hygiene. The ultimate model of a multiple logistic regression designated that mother and information exposure support (adj. OR=6.89, 95% CI: 3.84–12.38, p&lt;0.001; adj. OR=2.17, 95% CI: 1.36–3.45, p=0.001) were meaningfully linked by the bad menstrual hygiene. Other significant covariate factors were organization (adj. OR=1.79, 95% CI: 1.10–2.91, p=0.018). The study found a high prevalence of good menstrual hygiene. Mother support, information exposure, and organization were linked with menstrual hygiene among early adolescent girls. </p>
Care and protection for healthcare workers during a COVID-19: a descriptive qualitative study in Indonesia
Authors: Helmi Mochamat , Sari Djayanti , Meliala Andreasta , Trisnantoro Laksono 
Published: October 2022

<p>This study aimed to explore the perspectives of care and protection of healthcare workers during the pandemic COVID-19 using a descriptive qualitative study in Indonesia. This study used a qualitative descriptive approach in COVID-19 National Referral Hospitals. Purposive sampling was used to collect the sample. There were 45 respondents, with 22 men and 23 women taking part in this study. The qualitative data were analyzed using the content analysis. Three themes that emerge from the data analysis: health protection, legal protection, and incentive schemes. Health protection including calculation of the medical team's workload and lack of a systematic procedure for medical team quarantine. There was a lack of legal basis for medical practice in long-term disaster services. Dimension of incentive scheme, including incentives shift from rewards to demands, changes in incentive regulations, and discrepancy in incentive calculation. By stressing protection and rewards for each level of the medical profession, it is hoped to boost motivation in actively participating and supporting the service of COVID-19 patients in critical conditions across Indonesia.</p>
HNRNPA2B1: RNA-Binding Protein That Orchestrates Smooth Muscle Cell Phenotype in Pulmonary Arterial Hypertension
Authors: Ruffenach Grégoire , Medzikovic Lejla , Aryan Laila , Li Min , Eghbali Mansoureh 
Published: October 2022

Background:
RNA-binding proteins are master orchestrators of gene expression regulation. They regulate hundreds of transcripts at once by recognizing specific motifs. Thus, characterizing RNA-binding proteins targets is critical to harvest their full therapeutic potential. However, such investigation has often been restricted to a few RNA-binding protein targets, limiting our understanding of their function. In cancer, the RNA-binding protein HNRNPA2B1 (heterogeneous nuclear ribonucleoprotein A2B1; A2B1) promotes the pro-proliferative/anti-apoptotic phenotype. The same phenotype in pulmonary arterial smooth muscle cells (PASMCs) is responsible for the development of pulmonary arterial hypertension (PAH). However, A2B1 function has never been investigated in PAH.

Method:
Through the integration of computational and experimental biology, the authors investigated the role of A2B1 in human PAH-PASMC. Bioinformatics and RNA sequencing allowed them to investigate the transcriptome-wide function of A2B1, and RNA immunoprecipitation and A2B1 silencing experiments allowed them to decipher the intricate molecular mechanism at play. In addition, they performed a preclinical trial in the monocrotaline-induced pulmonary hypertension rat model to investigate the relevance of A2B1 inhibition in mitigating pulmonary hypertension severity.

Results:
They found that A2B1 expression and its nuclear localization are increased in human PAH-PASMC. Using bioinformatics, they identified 3 known motifs of A2B1 and all mRNAs carrying them. In PAH-PASMC, they demonstrated the complementary nonredundant function of A2B1 motifs because all motifs are implicated in different aspects of the cell cycle. In addition, they showed that in PAH-PASMC, A2B1 promotes the expression of its targets. A2B1 silencing in PAH-PASMC led to a decrease of all tested mRNAs carrying an A2B1 motif and a concomitant decrease in proliferation and resistance to apoptosis. Last, in vivo A2B1 inhibition in the lungs rescued pulmonary hypertension in rats.

Conclusions:
Through the integration of computational and experimental biology, the study revealed the role of A2B1 as a master orchestrator of the PAH-PASMC phenotype and its relevance as a therapeutic target in PAH.
Prior SARS‐CoV‐2 Infection Is Associated With Coronary Vasomotor Dysfunction as Assessed by Coronary Flow Reserve From Cardiac Positron Emission Tomography
Authors: Weber Brittany , Parks Sean , Huck Daniel M. , Kim Andy , Bay Camden , Brown Jenifer M. , Divakaran Sanjay , Hainer Jon , Bibbo Courtney , Taqueti Viviany , Dorbala Sharmila , Blankstein Ron , Woolley Ann E. , Di Carli Marcelo F. 
Published: October 2022

Background
Cardiovascular complications from COVID‐19 contribute to its high morbidity and mortality. The effect of COVID‐19 infection on the coronary vasculature is not known. The objective of this study was to investigate the prevalence of coronary vasomotor dysfunction identified by coronary flow reserve from cardiac positron emission tomography in patients with previous COVID‐19 infection.

Methods and Results

All patients who had polymerase chain reaction–confirmed SARS‐CoV‐2 infection referred for myocardial stress perfusion positron emission tomography imaging at Brigham and Women's Hospital from April 2020 to July 2021 were compared with a matched control group without prior SARS‐CoV‐2 infection imaged in the same period. The main outcome was the prevalence of coronary vasomotor dysfunction. Myocardial perfusion and myocardial blood flow reserve were quantified using N13‐ammonia positron emission tomography imaging. Thirty‐four patients with prior COVID‐19 were identified and compared with 103 matched controls. The median time from polymerase chain reaction–confirmed SARS‐CoV‐2 to cardiac positron emission tomography was 4.6 months (interquartile range,1.2–5.6 months). There were 16 out of 34 (47%) patients previously hospitalized for COVID‐19 infection. Baseline cardiac risk factors were common, and 18 (53%) patients in the COVID‐19 group had abnormal myocardial perfusion. Myocardial blood flow reserve was abnormal (<2) in 44.0% of the patients with COVID‐19 compared with 11.7% of matched controls (
P
<0.001). The mean myocardial blood flow reserve was 19.4% lower in patients with COVID‐19 compared with control patients (2.00±0.45 versus 2.48±0.47,
P
<0.001).

Conclusions
Myocardial blood flow reserve was impaired in patients with prior COVID‐19 infection compared with cardiovascular risk factor–matched controls, suggesting a relationship between SARS‐CoV‐2 infection and coronary vascular health. These data highlight the need to assess long‐term consequences of COVID‐19 on vascular health in future prospective studies.
Findings of a Novel Barbershop‐Based Peripheral Artery Disease Screening Program for Black Men
Authors: White Solaru Khendi T. , Coy Tyler , DeLozier Sarah , Brinza Ellen , Ravenell Joseph , Longenecker Christopher T. , Wright Jackson T. , Gornik Heather L. 
Published: October 2022

Background
Peripheral artery disease (PAD) increases the risk of cardiovascular events and limb events including amputations. PAD is twice as prevalent in Black compared with non‐Hispanic White individuals, especially among men. Screening for PAD using the ankle–brachial index in community settings, such as the barbershop, could lead to earlier diagnosis and treatment.

Methods and Results

A pilot study was conducted at 2 barbershops in Cleveland, OH from June to December 2020 to assess the feasibility of screening for PAD in the barbershop setting and the effect of an educational intervention on PAD awareness. After screening with both automated and Doppler ankle–brachial index, PAD was identified in 5/31 (16.1%) of participants. Baseline systolic blood pressure, low‐density lipoprotein cholesterol, and random blood glucose were higher in participants who screened positive for PAD (
P
<0.001). PAD awareness was low overall. There was a significant improvement in PAD awareness assessment scores obtained at the initial and exit visits (9.93±4.23 to 12.50±4.41,
P
=0.004). An association was found between PAD awareness at baseline and highest education level achieved: compared with those with some college/associate's degree or higher, non–high school graduates scored lower on PAD awareness (
P
=0.022), as did those who only had a high school diploma or tests of General Educational Development (
P
=0.049).

Conclusions
In a pilot study, barbershop‐based screening for PAD among Black men revealed a higher than expected PAD prevalence and low PAD awareness. An educational video was effective at increasing PAD awareness. Ankle–brachial index screening and educational outreach in the barbershop may be a feasible and effective tool to diagnose PAD and reduce PAD disparities among Black men at highest risk.