bluuebunny/crossref_metadata_2025_split huggingface dataset:
The impact of financial incentives on HIV incidence among adolescent girls and young women in Eswatini: Sitakhela Likusasa, a cluster randomised trial
Authors: Gorgens Marelize , Ketende Sosthenes , Longosz Andrew F , Mabuza Mbuso , Nkambule Muziwethu , Dlamini Tengetile , Sikwibele Kelvin , Tsododo Vimbai , Chipepera Tendai , Ndikandika Mxolisi Leroy , Heard Wendy , Maphalala Gugu , Dlamini Lindiwe , Wilson David , de Walque Damien , Mabuza Khanya 
Published: September 2022

IntroductionIncentives conditional on school attendance or on remaining free of sexually transmitted infections have produced mixed results in reducing HIV incidence.MethodsHIV-negative adolescent girls and young women aged 15–22%–50% of whom were out of school—were recruited from 293 clusters in Eswatini from urban (30%) and rural areas (70%).Financial incentives conditional on education attendance were randomly allocated at the cluster level. All participants were further individually randomised into eligibility for a raffle incentive conditional on random selection into the raffle, on negative tests for syphilis andTrichomonas vaginalisand on being a raffle winner, creating four subarms in a 2×2 factorial design: no-intervention, raffle incentive, education incentive and raffle & education incentive. Randomisation was unblinded to participants.Logistic regressions were used in intention-to-treat analysis of HIV incidence over 3 years to estimate the impact of incentives conditional on school attendance and raffle incentives conditional on remaining sexually transmitted infection free.ResultsThe study recruited 4389 HIV-negative participants, who were distributed into four subarms: no intervention (n=1068), raffle incentive (n=1162), education incentive (n=1088) and raffle and education incentive (n=1071).At endline, 272 participants from 3772 for whom endline data were collected, tested positive for HIV. HIV incidence among participants in education treatment arm was significantly lower than in the education control arm, 6.34% (119/1878) versus 8.08% (153/1894) (p=0.041); OR: 0.766 (0.598 to 0.981); adjusted OR (aOR): 0.754 (0.585 to 0.972). Compared with the no intervention subarm, HIV incidence in the raffle and education incentive subarm was significantly lower, 5.79% (54/878) versus 8.84% (80/905); OR: 0.634 (0.443 to 0.907); aOR: 0.622 (0.433 to 0.893), while it was not significantly lower in the raffle incentive subarm.ConclusionFinancial incentives conditional on education participation significantly reduced HIV infection among adolescent girls and young women in Eswatini and appear to be a promising tool for prevention in high HIV prevalence settings.Trial registration numberWestern Institutional Review Board—protocol number 20 141 630.Eswatini National Health Research Review Board—FWA00026661.Pan African Clinical Trials Registry—PACTR201811609257043.
Impact of harm reduction care in HIV clinical settings on stigma and health outcomes for people with HIV who use drugs: study protocol for a mixed-methods, multisite, observational study
Authors: Kay Emma Sophia , Creasy Stephanie , Batey D Scott , Coulter Robert , Egan James E , Fisk Stuart , Friedman Mackey Reuel , Kinsky Suzanne , Krier Sarah , Noble Victor , Turan Bulent , Turan Janet M , Yu Lan , Hawk Mary 
Published: September 2022

IntroductionOur previous pilot work suggests relational harm reduction strengthens relationships between people with HIV (PWH) who use drugs and their healthcare providers and improves HIV health outcomes. However, there is limited research examining ways that structural (eg, strategies like syringe service programmes) and/or relational (patient-provider relationship) harm reduction approaches in HIV clinical settings can mitigate experiences of stigma, affect patient-provider relationships and improve outcomes for PWH who use drugs. Our mixed methods, multisite, observational study aims to fill this knowledge gap and develop an intervention to operationalise harm reduction care for PWH who use drugs in HIV clinical settings.Methods and analysisAim 1 will explore the relationship between healthcare providers’ stigmatising attitudes towards working with PWH who use drugs and providers’ acceptance and practice of structural and relational harm reduction through surveys (n=125) and interviews (n=20) with providers. Aim 2 will explore the interplay between patient-perceived harm reduction, intersectional stigma and clinical outcomes related to HIV, hepatitis C (if applicable) and substance use-related outcomes through surveys (n=500) and focus groups (k=6, total n=36) with PWH who use drugs. We will also psychometrically evaluate a 25-item scale we previously developed to assess relational harm reduction, the Patient Assessment of Provider Harm Reduction Scale. Aim 3 will use human-centred design approaches to develop and pretest an intervention to operationalise harm reduction care for PWH who use drugs in HIV clinical settings.Ethics and disseminationThis study was approved via expedited review by the University of Pittsburgh Institutional Review Board (STUDY21090002). Study findings will be presented in peer-reviewed journals and public health conferences as well as shared with patient participants, community advisory boards and harm reduction organisations.Trial registration numberNCT05404750.
IGHcytogenetic abnormalities can be detected in multiple myeloma by imaging flow cytometry
Authors: Hui Henry , Fuller Kathy A , Eresta Jaya Luna , Konishi Yusuke , Ng Teng Fong , Frodsham Richard , Speight Graham , Yamada Kazuhiro , Clarke Sarah E , Erber Wendy N 
Published: September 2022

AimsCytogenetic abnormalities involving theIGHgene are seen in up to 55% of patients with multiple myeloma. Current testing is performed manually by fluorescencein situhybridisation (FISH) on purified plasma cells. We aimed to assess whether an automated imaging flow cytometric method that uses immunophenotypic cell identification, and does not require cell isolation, can identifyIGHabnormalities.MethodsAspirated bone marrow from 10 patients with multiple myeloma were studied. Plasma cells were identified by CD38 and CD138 coexpression and assessed with FISH probes for numerical or structural abnormalities ofIGH. Thousands of cells were acquired on an imaging flow cytometer and numerical data and digital images were analysed.ResultsUp to 30 000 cells were acquired andIGHchromosomal abnormalities were detected in 5 of the 10 marrow samples. FISH signal patterns seen included fusedIGHsignals forIGH/FGFR3andIGH/MYEOV, indicating t(4;14) and t(11;14), respectively. In addition, threeIGHsignals were identified, indicating trisomy 14 or translocation with an alternate chromosome. The lowest limit of detection of anIGHabnormality was in 0.05% of all cells.ConclusionsThis automated high-throughput immuno-flowFISH method was able to identify translocations and trisomy involving theIGHgene in plasma cells in multiple myeloma. Thousands of cells were analysed and without prior cell isolation. The inclusion of positive plasma cell identification based on immunophenotype led to a lowest detection level of 0.05% marrow cells. This imaging flow cytometric FISH method offers the prospect of increased precision of detection of critical genetic lesions involvingIGHand other chromosomal defects in multiple myeloma.
Clinical diversity and molecular mechanism of VPS35L-associated Ritscher-Schinzel syndrome
Authors: Otsuji Shiomi , Nishio Yosuke , Tsujita Maki , Rio Marlene , Huber Céline , Antón-Plágaro Carlos , Mizuno Seiji , Kawano Yoshihiko , Miyatake Satoko , Simon Marleen , van Binsbergen Ellen , van Jaarsveld Richard H , Matsumoto Naomichi , Cormier-Daire Valerie , J.Cullen Peter , Saitoh Shinji , Kato Kohji 
Published: September 2022

PurposeThe Retriever subunitVPS35Lis the third responsible gene for Ritscher-Schinzel syndrome (RSS) afterWASHC5andCCDC22. To date, only one pair of siblings have been reported and their condition was significantly more severe than typical RSS. This study aimed to understand the clinical spectrum and underlying molecular mechanism in VPS35L-associated RSS.MethodsWe report three new patients with biallelicVPS35Lvariants. Biochemical and cellular analyses were performed to elucidate disease aetiology.Results.In addition to typical features of RSS, we confirmed hypercholesterolaemia, hypogammaglobulinaemia and intestinal lymphangiectasia as novel complications of VPS35L-associated RSS. The latter two complications as well as proteinuria have not been reported in patients withCCDC22andWASHC5variants. One patient showed a severe phenotype and the other two were milder. Cells established from patients with the milder phenotypes showed relatively higher VPS35L protein expression. Cellular analysis found VPS35L ablation decreased the cell surface level of lipoprotein receptor-related protein 1 and low-density lipoprotein receptor, resulting in reduced low-density lipoprotein cellular uptake.ConclusionVPS35L-associated RSS is a distinct clinical entity with diverse phenotype and severity, with a possible molecular mechanism of hypercholesterolaemia. These findings provide new insight into the essential and distinctive role of Retriever in human development.
Investigation of seepage near the interface between an embankment dam and a concrete structure: monitoring and modelling of seasonal temperature trends
Authors: Yun Tana , Butler Karl E. , MacQuarrie Kerry T.B. 
Published: September 2022

Seasonal subsurface temperature monitoring, which exploits the fact that increased seepage flow may locally alter the temperature distribution, is a useful approach for leakage monitoring and evaluation within embankment dams and their foundations. At the Mactaquac Generating Station, New Brunswick, Canada, spatial and temporal variations of temperature have been monitored and modelled at the steeply inclined interface between the compacted clay till core of the embankment dam and an abutting concrete diversion sluiceway. Over a 4-year period, two seasonally recurring anomalies at different depths were observed by fibre optic distributed temperature sensing in the concrete structure close to the interface. A 3D coupled flow and heat transport model was developed in FEFLOW to simulate temperature distribution within the dam resulting from seasonal variations in air and reservoir temperature. Leakage zones near the interface were simulated in the concrete and embankment. At a depth of 13 m below the crest, the significant lag time between temperature variations in the reservoir and dam core shows that the leakage responsible for an observed temperature anomaly must be limited to enhanced flow within the concrete. At much shallower depths, where seasonal reservoir and dam core temperatures fluctuate nearly in phase, seepage paths are more challenging to determine.
A Probody T Cell–Engaging Bispecific Antibody Targeting EGFR and CD3 Inhibits Colon Cancer Growth with Limited Toxicity
Authors: Boustany Leila M. , LaPorte Sherry L. , Wong Laurie , White Clayton , Vinod Veena , Shen Joel , Yu Wendy , Koditek David , Winter Michael B. , Moore Stephen J. , Mei Li , Diep Linnea , Huang Yuanhui , Liu Shouchun , Vasiljeva Olga , West Jim , Richardson Jennifer , Irving Bryan , Belvin Marcia , Kavanaugh W. Michael 
Published: September 2022

Abstract

T cell–engaging bispecific antibodies (TCB) are highly potent therapeutics that can recruit and activate cytotoxic T cells to stimulate an antitumor immune response. However, the development of TCBs against solid tumors has been limited by significant on-target toxicity to normal tissues. Probody therapeutics have been developed as a novel class of recombinant, protease-activated antibody prodrugs that are “masked” to reduce antigen binding in healthy tissues but can become conditionally unmasked by proteases that are preferentially active in the tumor microenvironment (TME). Here, we describe the preclinical efficacy and safety of CI107, a Probody TCB targeting EGFR and CD3. In vitro, the protease-activated, unmasked CI107 effectively bound EGFR and CD3 expressed on the surface of cells and induced T-cell activation, cytokine release, and cytotoxicity toward tumor cells. In contrast, dually masked CI107 displayed a &gt;500-fold reduction in antigen binding and &gt;15,000-fold reduction in cytotoxic activity. In vivo, CI107 potently induced dose-dependent tumor regression of established colon cancer xenografts in mice engrafted with human peripheral blood mononuclear cells. Furthermore, the MTD of CI107 in cynomolgus monkeys was more than 60-fold higher than that of the unmasked TCB, and much lower levels of toxicity were observed in animals receiving CI107. Therefore, by localizing activity to the TME and thus limiting toxicity to normal tissues, this Probody TCB demonstrates the potential to expand clinical opportunities for TCBs as effective anticancer therapies for solid tumor indications.

Significance:
A conditionally active EGFR-CD3 T cell–engaging Probody therapeutic expands the safety window of bispecific antibodies while maintaining efficacy in preclinical solid tumor settings.
Postoperative Plasmacytoid Dendritic Cells Secrete IFNα to Promote Recruitment of Myeloid-Derived Suppressor Cells and Drive Hepatocellular Carcinoma Recurrence
Authors: Pang Li , Yeung Oscar W.H. , Ng Kevin T.P. , Liu Hui , Zhu Jiye , Liu Jiang , Yang Xinxiang , Ding Tao , Qiu Wenqi , Wang Yuewen , Chiu T.L. Shirley , Chen Zhiwei , Lo Chung-Mau , Man Kwan 
Published: September 2022

Abstract

Patients with hepatocellular carcinoma (HCC) confront a high incidence of tumor recurrence after curative surgical resection. Hepatic ischemia-reperfusion injury (IRI) is the major consequence of surgical stress during hepatectomy. Although it has been suggested that hepatic IRI-induced immunosuppression could contribute to tumor relapse after surgery, the underlying mechanisms have not been fully defined. Here, using a multiplex cytokine array, we found that levels of postoperative IFNα serve as an independent risk factor for tumor recurrence in 100 patients with HCC with curative hepatectomy. Plasmacytoid dendritic cells (pDC), the major source of IFNα, were activated after surgery and correlated with poor disease-free survival. Functionally, IFNα was responsible for mobilization of myeloid-derived suppressor cells (MDSC) following hepatic IRI. Conditioned medium from IFNα-treated hepatocytes mediated the migration of MDSCs in vitro. Mechanistically, IFNα upregulated IRF1 to promote hepatocyte expression of CX3CL1, which subsequently recruited CX3CR1+ monocytic MDSCs. Knockdown of Irf1 or Cx3cl1 in hepatocytes significantly inhibited the accumulation of monocytic MDSCs in vivo. Therapeutically, elimination of pDCs, IFNα, or CX3CR1 could restore the tumor-killing activity of CD8+ T cells, hence limiting tumor growth and lung metastasis following hepatic IRI. Taken together, these data suggest that IFNα-producing pDCs drive CX3CR1+ MDSC recruitment via hepatocyte IRF1/CX3CL1 signaling and lead to tumor recurrence after hepatectomy in HCC. Targeting pDCs and the IFNα/CX3CL1/CX3CR1 axis could inhibit surgical stress–induced HCC recurrence by attenuating postoperative immunosuppression.

Significance:
IFNα secreted by plasmacytoid dendritic cells drives postoperative immunosuppression and early recurrence of hepatocellular carcinoma, providing new biomarkers and therapeutic targets to improve patient outcomes after surgical resection.
Multi-omic Characterization of Pancreatic Ductal Adenocarcinoma RelatesCXCR4mRNA Expression Levels to Potential Clinical Targets
Authors: Kocher Florian , Puccini Alberto , Untergasser Gerold , Martowicz Agnieszka , Zimmer Kai , Pircher Andreas , Baca Yasmine , Xiu Joanne , Haybaeck Johannes , Tymoszuk Piotr , Goldberg Richard M. , Petrillo Angelica , Shields Anthony F. , Salem Mohamed E. , Marshall John L. , Hall Michael , Korn W. Michael , Nabhan Chadi , Battaglin Francesca , Lenz Heinz-Josef , Lou Emil , Choo Su-Pin , Toh Chee-Keong , Gasteiger Silvia , Pichler Renate , Wolf Dominik , Seeber Andreas 
Published: September 2022

AbstractPurpose:Chemokines are essential for immune cell trafficking and are considered to have a major impact on the composition of the tumor microenvironment. CX-chemokine receptor 4 (CXCR4) is associated with poor differentiation, metastasis, and prognosis in pancreatic ductal adenocarcinoma (PDAC). This study provides a comprehensive molecular portrait of PDAC according to CXCR4 mRNA expression levels.Experimental Design:The Cancer Genome Atlas database was used to explore molecular and immunologic features associated with CXCR4 mRNA expression in PDAC. A large real-word dataset (n = 3,647) served for validation and further exploratory analyses. Single-cell RNA analyses on a publicly available dataset and in-house multiplex immunofluorescence (mIF) experiments were performed to elaborate cellular localization of CXCR4.Results:High CXCR4 mRNA expression (CXCR4high) was associated with increased infiltration of regulatory T cells, CD8+ T cells, and macrophages, and upregulation of several immune-related genes, including immune checkpoint transcripts (e.g., TIGIT, CD274, PDCD1). Analysis of the validation cohort confirmed the CXCR4-dependent immunologic TME composition in PDAC irrespective of microsatellite instability–high/mismatch repair–deficient or tumor mutational burden. Single-cell RNA analysis and mIF revealed that CXCR4 was mainly expressed by macrophages and T-cell subsets. Clinical relevance of our finding is supported by an improved survival of CXCR4high PDAC.Conclusions:High intratumoral CXCR4 mRNA expression is linked to a T cell– and macrophage-rich PDAC phenotype with high expression of inhibitory immune checkpoints. Thus, our findings might serve as a rationale to investigate CXCR4 as a predictive biomarker in patients with PDAC undergoing immune checkpoint inhibition.
Subtype and Site Specific–Induced Metabolic Vulnerabilities in Prostate Cancer
Authors: Mossa Federica , Robesti Daniele , Sumankalai Ramachandran , Corey Eva , Titus Mark , Kang Yuqi , Zhang Jianhua , Briganti Alberto , Montorsi Francesco , Vellano Christopher P. , Marszalek Joseph R. , Frigo Daniel E. , Logothetis Christopher J. , Gujral Taranjit S. , Dondossola Eleonora 
Published: September 2022

Abstract

Aberrant metabolic functions play a crucial role in prostate cancer progression and lethality. Currently, limited knowledge is available on subtype-specific metabolic features and their implications for treatment. We therefore investigated the metabolic determinants of the two major subtypes of castration-resistant prostate cancer [androgen receptor–expressing prostate cancer (ARPC) and aggressive variant prostate cancer (AVPC)]. Transcriptomic analyses revealed enrichment of gene sets involved in oxidative phosphorylation (OXPHOS) in ARPC tumor samples compared with AVPC. Unbiased screening of metabolic signaling pathways in patient-derived xenograft models by proteomic analyses further supported an enrichment of OXPHOS in ARPC compared with AVPC, and a skewing toward glycolysis by AVPC. In vitro, ARPC C4–2B cells depended on aerobic respiration, while AVPC PC3 cells relied more heavily on glycolysis, as further confirmed by pharmacologic interference using IACS-10759, a clinical-grade inhibitor of OXPHOS. In vivo studies confirmed IACS-10759′s inhibitory effects in subcutaneous and bone-localized C4–2B tumors, and no effect in subcutaneous PC3 tumors. Unexpectedly, IACS-10759 inhibited PC3 tumor growth in bone, indicating microenvironment-induced metabolic reprogramming. These results suggest that castration-resistant ARPC and AVPC exhibit different metabolic dependencies, which can further undergo metabolic reprogramming in bone.

Implications:
These vulnerabilities may be exploited with mechanistically novel treatments, such as those targeting OXPHOS alone or possibly in combination with existing therapies. In addition, our findings underscore the impact of the tumor microenvironment in reprogramming prostate cancer metabolism.
Astrocyte Progenitors Derived From Patients With Alzheimer Disease Do Not Impair Stroke Recovery in Mice
Authors: Välimäki Nelli-Noora , Bakreen Abdulhameed , Häkli Sara , Dhungana Hiramani , Keuters Meike H. , Dunlop Yannick , Koskuvi Marja , Keksa-Goldsteine Velta , Oksanen Minna , Jäntti Henna , Lehtonen Šárka , Malm Tarja , Koistinaho Jari , Jolkkonen Jukka 
Published: September 2022

Background:
Species-specific differences in astrocytes and their Alzheimer disease-associated pathology may influence cellular responses to other insults. Herein, human glial chimeric mice were generated to evaluate how Alzheimer disease predisposing genetic background in human astrocytes contributes to behavioral outcome and brain pathology after cortical photothrombotic ischemia.

Methods:

Neonatal (P0) immunodeficient mice of both sexes were transplanted with induced pluripotent stem cell–derived astrocyte progenitors from Alzheimer disease patients carrying
PSEN1
exon 9 deletion (PSEN1 ΔE9), with isogenic controls, with cells from a healthy donor, or with mouse astrocytes or vehicle. After 14 months, a photothrombotic lesion was produced with Rose Bengal in the motor cortex. Behavior was assessed before ischemia and 1 and 4 weeks after the induction of stroke, followed by tissue perfusion for histology.

Results:
Open field, cylinder, and grid-walking tests showed a persistent locomotor and sensorimotor impairment after ischemia and female mice had larger infarct sizes; yet, these were not affected by astrocytes with PSEN1 ΔE9 background. Staining for human nuclear antigen confirmed that human cells successfully engrafted throughout the mouse brain. However, only a small number of human cells were positive for astrocytic marker GFAP (glial fibrillary acidic protein), mostly located in the corpus callosum and retaining complex human-specific morphology with longer processes compared with host counterparts. While host astrocytes formed the glial scar, human astrocytes were scattered in small numbers close to the lesion boundary. Aβ (beta-amyloid) deposits were not present in PSEN1 ΔE9 astrocyte-transplanted mice.

Conclusions:
Transplanted human cells survived and distributed widely in the host brain but had no impact on severity of ischemic damage after cortical photothrombosis in chimeric mice. Only a small number of transplanted human astrocytes acquired GFAP-positive glial phenotype or migrated toward the ischemic lesion forming glial scar. PSEN1 ΔE9 astrocytes did not impair behavioral recovery after experimental stroke.