bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clearing soluble MIC reverses the impaired function of natural killer cells from patients with multiple myeloma
Authors: Kim Sojeong , Chung Haerim , Kwak Jeong-Eun , Kim Yu Ri , Park Chung Hyun , Kim Yeonhee , Cheong June-Won , Wu Jennifer , Shin Eui-Cheol , Cho Hyunsoo , Kim Jin Seok 
Published: January 2024

BackgroundMajor histocompatibility complex (MHC) class I chain-related protein (MIC) is a stress-induced ligand released from multiple myeloma (MM) cells during progression, and soluble MIC impairs natural killer group 2D (NKG2D) activating receptor-mediated recognition and function of natural killer (NK) cells. However, whether clearing soluble MIC with a monoclonal antibody (mAb) can restore NK cell activity of MM patients remains undetermined.MethodsWe analyzed The Cancer Genome Atlas (TCGA) Multiple Myeloma Research Foundation (MMRF) CoMMpass data set to examine the prognostic significance ofMICexpression in MM. We examined the level of soluble MIC in paired peripheral blood (PB) and bone marrow (BM) plasma of patients with MM at diagnosis by ELISA. We evaluated the correlation between the level of soluble MIC and immunophenotype of NK cells from MM patients by multicolor flow cytometry. We also generated MIC-overexpressing MM cell line and characterized the cytotoxic function of patient NK cells in the presence of soluble MIC, and examined the impact of clearing soluble MIC with a humanized mAb (huB10G5).ResultsWe characterize the importance of MICA in MM by revealing the significantly better overall survival of patients with highMICAexpression from TCGA MMRF CoMMpass data set. The level of soluble MICA is more highly elevated in MM than in precursor stages, and the concentration of soluble MICA is higher in BM plasma than in PB. The concentration of soluble MICA in BM was correlated with myeloma burden, while it was negatively correlated with the frequency of NKG2D+NK cells in diagnostic BM aspirates of MM patients. Soluble MICA downregulated NKG2D expression and decreased cytotoxicity of MM patient NK cellsex vivo, which were reversed by a humanized soluble MIC-clearing mAb (huB10G5) with enhanced degranulation of NK cells.ConclusionsOur findings indicate targeting soluble MIC with huB10G5 might be a viable therapeutic approach to promote NKG2D-dependent cellular immunotherapy outcome in MM.
mRNA vaccines against SARS-CoV-2 induce divergent antigen-specific T-cell responses in patients with lung cancer
Authors: Song No-Joon , Chakravarthy Karthik B , Jeon Hyeongseon , Bolyard Chelsea , Reynolds Kelsi , Weller Kevin P , Reisinger Sarah , Wang Yi , Li Anqi , Jiang Sizun , Ma Qin , Barouch Dan H , Rubinstein Mark P , Shields Peter G , Oltz Eugene M , Chung Dongjun , Li Zihai 
Published: January 2024

BackgroundThe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant is highly transmissible and evades pre-established immunity. Messenger RNA (mRNA) vaccination against ancestral strain spike protein can induce intact T-cell immunity against the Omicron variant, but efficacy of booster vaccination in patients with late-stage lung cancer on immune-modulating agents including anti-programmed cell death protein 1(PD-1)/programmed death-ligand 1 (PD-L1) has not yet been elucidated.MethodsWe assessed T-cell responses using a modified activation-induced marker assay, coupled with high-dimension flow cytometry analyses. Peripheral blood mononuclear cells (PBMCs) were stimulated with various viral peptides and antigen-specific T-cell responses were evaluated using flow cytometry.ResultsBooster vaccines induced CD8+T-cell response against the ancestral SARS-CoV-2 strain and Omicron variant in both non-cancer subjects and patients with lung cancer, but only a marginal induction was detected for CD4+T cells. Importantly, antigen-specific T cells from patients with lung cancer showed distinct subpopulation dynamics with varying degrees of differentiation compared with non-cancer subjects, with evidence of dysfunction. Notably, female-biased T-cell responses were observed.ConclusionWe conclude that patients with lung cancer on immunotherapy show a substantial qualitative deviation from non-cancer subjects in their T-cell response to mRNA vaccines, highlighting the need for heightened protective measures for patients with cancer to minimize the risk of breakthrough infection with the Omicron and other future variants.
VB-111 (ofranergene obadenovec) in combination with nivolumab in patients with microsatellite stable colorectal liver metastases: a single center, single arm, phase II trial
Authors: Coffman-D'Annibale Kelley , Myojin Yuta , Monge Cecilia , Xie Changqing , Hrones Donna Mabry , Wood Bradford J , Levy Elliot B , Kleiner David , Figg William Douglas , Steinberg Seth M , Redd Bernadette , Greten Tim F 
Published: January 2024

BackgroundMicrosatellite stable colorectal liver metastases (MSS CLM) maintain an immunosuppressive tumor microenvironment (TME). Historically, immune-based approaches have been ineffective. VB-111 (ofranergene obadenovec) is a genetically-modified adenoviral vector targeting the TME; its unique dual mechanism induces an immune response and disrupts neovascularization. Checkpoint inhibition may synergize the immune response induced by viral-mediated anti-angiogenic gene therapy. We aimed to examine the safety and antitumor activity of VB-111 and nivolumab in patients with refractory MSS CLM and to characterize immunological treatment-response.MethodsThis was a phase II study of adult patients with histologically-confirmed MSS CLM who progressed on prior therapy. A priming dose of VB-111 1×1013viral particles was given intravenously 2 weeks prior to starting biweekly nivolumab 240 mg and continued every 6 weeks. The combination continued until disease progression or unacceptable toxicity. The primary objectives were overall response rate and safety/tolerability. Secondary objectives included median overall survival and progression-free survival. Correlative studies were performed on paired tumor biopsies and blood.ResultsBetween August 2020 and December 2021, 14 patients were enrolled with median age 50.5 years (40–75), and 14% were women. Median follow-up was 5.5 months. Of the 10 evaluable patients, the combination of VB-111 and nivolumab failed to demonstrate radiographic responses; at best, 2 patients had stable disease. Median overall survival was 5.5 months (95% CI: 2.3 to 10.8), and median progression-free survival was 1.8 months (95% CI: 1.4 to 1.9). The most common grade 3–4 treatment-related adverse events were fever/chills, influenza-like symptoms, and lymphopenia. No treatment-related deaths were reported. Qualitative analysis of immunohistochemical staining of paired tumor biopsies did not demonstrate significant immune infiltration after treatment, except for one patient who had exceptional survival (26.0 months). Immune analysis of peripheral blood mononuclear cells showed an increase of PD-1highKi67highCD8+T cells and HLA-DRhighT cells after VB-111 priming dose. Plasma cytokines interleukin-10 and tumor necrosis factor-α increased after treatment with both drugs.ConclusionIn patients with MSS CLM, VB-111 and nivolumab did not improve overall response rate or survival but were tolerated with minimal toxicities. While challenging to distinguish between antiviral or antitumor, correlative studies demonstrated an immune response with activation and proliferation of CD8+T cells systemically that was poorly sustained.Trial registration numberNCT04166383.
Clinically relevant orthotopic pancreatic cancer models for adoptive T cell transfer therapy
Authors: Horvat Natalie K. , Karpovsky Isaac , Phillips Maggie , Wyatt Megan M. , Hall Margaret A. , Herting Cameron J. , Hammons Jacklyn , Mahdi Zaid , Moffitt Richard A. , Paulos Chrystal M. , Lesinski Gregory B. 
Published: January 2024

BackgroundPancreatic ductal adenocarcinoma (PDAC) is an aggressive tumor. Prognosis is poor and survival is low in patients diagnosed with this disease, with a survival rate of ~12% at 5 years. Immunotherapy, including adoptive T cell transfer therapy, has not impacted the outcomes in patients with PDAC, due in part to the hostile tumor microenvironment (TME) which limits T cell trafficking and persistence. We posit that murine models serve as useful tools to study the fate of T cell therapy. Currently, genetically engineered mouse models (GEMMs) for PDAC are considered a “gold-standard” as they recapitulate many aspects of human disease. However, these models have limitations, including marked tumor variability across individual mice and the cost of colony maintenance.MethodsUsing flow cytometry and immunohistochemistry, we characterized the immunological features and trafficking patterns of adoptively transferred T cells in orthotopic PDAC (C57BL/6) models using two mouse cell lines, KPC-Luc and MT-5, isolated from C57BL/6 KPC-GEMM (KrasLSL-G12D/+p53−/−and KrasLSL-G12D/+p53LSL-R172H/+, respectively).ResultsThe MT-5 orthotopic model best recapitulates the cellular and stromal features of the TME in the PDAC GEMM. In contrast, far more host immune cells infiltrate the KPC-Luc tumors, which have less stroma, although CD4+and CD8+T cells were similarly detected in the MT-5 tumors compared with KPC-GEMM in mice. Interestingly, we found that chimeric antigen receptor (CAR) T cells redirected to recognize mesothelin on these tumors that signal via CD3ζ and 41BB (Meso-41BBζ-CAR T cells) infiltrated the tumors of mice bearing stroma-devoid KPC-Luc orthotopic tumors, but not MT-5 tumors.ConclusionsOur data establish for the first time a reproducible and realistic clinical system useful for modeling stroma-rich and stroma-devoid PDAC tumors. These models shall serve an indepth study of how to overcome barriers that limit antitumor activity of adoptively transferred T cells.
Short-course neoadjuvant radiotherapy combined with chemotherapy and toripalimab for locally advanced esophageal squamous cell carcinoma (SCALE-1): a single-arm phase Ib clinical trial
Authors: Jiang Ning , Zhang Jingyuan , Guo Zhen , Wu Yinan , Zhao Lijun , Kong Cheng , Song Xue , Gu Lingling , Zhao Yang , Li Si , He Xia , Ren Binhui , Zhu Xiangzhi , Jiang Ming 
Published: January 2024

BackgroundThe optimal dosages, timing, and treatment sequencing for standard-of-care neoadjuvant chemoradiotherapy necessitate re-evaluation when used in conjunction with immune checkpoint inhibitors for patients with resectable, locally advanced esophageal squamous cell carcinoma (RLaESCC). The SCALE-1 phase Ib study aimed to evaluate the safety and efficacy of short-course neoadjuvant radiotherapy combined with chemotherapy and toripalimab in this patient population.MethodsRLaESCC patients with clinical stages cT3-4aN0M0/cT1-4aN+M0 received neoadjuvant paclitaxel (135 mg/m2), carboplatin (area under the curve=5), and toripalimab (240 mg) every 3 weeks for two cycles. Short-course neoadjuvant radiotherapy (30 Gy in 12 fractions; 5 days per week) was administered between neoadjuvant immune-chemotherapy (nICT) doses. Esophagectomies were scheduled 4–6 weeks after completing neoadjuvant treatment. The primary endpoint was safety, with secondary endpoints including pathological complete response (pCR) rate, postoperative complications, progression-free survival (PFS), and overall survival (OS). Exploratory biomarker analysis used gene expression profiles via the nCounter platform.ResultsOf the 23 patients enrolled, all completed neoadjuvant radiotherapy, while 21 cases finished full nICT doses and cycles. Common grade 3/4 adverse events included neutropenia (57%), leukopenia (39%), and skin rash (30%). No grade 3 or higher esophagitis or pneumonitis occured. Twenty patients underwent surgery, and 11 achieved pCR (55%). Two patients (10%) experienced grade IIIb surgical complications. At the database lock, a 2-year PFS rate of 63.8% (95% CI 43.4% to 84.2%) and 2-year OS rate was 78% (95% CI 64.9% to 91.1%) were achieved. Tumor immune microenvironment analysis indicated that tumors with pCR exhibited significantly higher pretreatment T-cell-inflamed score and post-treatment reshaping of antitumor immunity.ConclusionsCombining short-course neoadjuvant radiotherapy with chemotherapy and toripalimab demonstrated favorable safety and promising efficacy in RLaESCC patients.Trial registration numberChiCTR2100045104.
Rates of cortical thinning in Alzheimer’s disease signature regions associate with vascular burden but not with β-amyloid status in cognitively normal adults at age 70
Authors: Keuss Sarah E , Coath William , Cash David M , Barnes Josephine , Nicholas Jennifer M , Lane Christopher A , Parker Thomas D , Keshavan Ashvini , Buchanan Sarah M , Wagen Aaron Z , Storey Mathew , Harris Matthew , Lu Kirsty , James Sarah-Naomi , Street Rebecca , Malone Ian B , Sudre Carole H , Thomas David L , Dickson John C , Barkhof Frederik , Murray-Smith Heidi , Wong Andrew , Richards Marcus , Fox Nick C , Schott Jonathan M 
Published: January 2024

BackgroundConsistent patterns of reduced cortical thickness have been identified in early Alzheimer’s disease (AD). However, the pathological factors that influence rates of cortical thinning within these AD signature regions remain unclear.MethodsParticipants were from the Insight 46 substudy of the MRC National Survey of Health and Development (NSHD; 1946 British birth cohort), a prospective longitudinal cohort study. Linear regression was used to examine associations of baseline cerebral β-amyloid (Aβ) deposition, measured using florbetapir positron emission tomography, and baseline white matter hyperintensity volume (WMHV) on MRI, a marker of cerebral small vessel disease, with subsequent longitudinal changes in AD signature cortical thickness quantified from baseline and repeat MRI (mean [SD] interval 2.4 [0.2] years).ResultsIn a population-based sample of 337 cognitively normal older white adults (mean [SD] age at baseline 70.5 [0.6] years; 48.1% female), higher global WMHV at baseline related to faster subsequent rates of cortical thinning in both AD signature regions (~0.15%/year faster per 10 mL additional WMHV), whereas baseline Aβ status did not. Among Aβ positive participants (n=56), there was some evidence that greater global Aβ standardised uptake value ratio at baseline related to faster cortical thinning in the AD signature Mayo region, but this did not reach statistical significance (p=0.08).ConclusionsCortical thinning within AD signature regions may develop via cerebrovascular pathways. Perhaps reflecting the age of the cohort and relatively low prevalence of Aβ-positivity, robust Aβ-related differences were not detected. Longitudinal follow-up incorporating additional biomarkers will allow assessment of how these relationships evolve closer to expected dementia onset.
Long-term disability progression in aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder: a retrospective analysis of 101 patients
Authors: Uzawa Akiyuki , Mori Masahiro , Masuda Hiroki , Uchida Tomohiko , Muto Mayumi , Ohtani Ryohei , Aoyama Shinji , Kuwabara Satoshi 
Published: January 2024

Background
Anti-aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder (AQP4Ab+NMOSD) is an inflammatory disorder of the central nervous system with relapse-dependent progression. Few studies have reported the effects of prednisolone and biologics on disability progression in AQP4Ab+NMOSD, although it is established that they prevent clinical relapses. This retrospective study investigated long-term disability progression and the effects of therapeutic interventions on disability progression in AQP4Ab+NMOSD.

Methods
This study included a total of 101 patients with AQP4Ab+NMOSD. Disease progression was investigated in the following two cohorts: (1) duration from disease onset to Expanded Disability Status Scale (EDSS) 3.0 in patients who did or did not receive oral prednisolone or biologics before reaching EDSS 3.0 and (2) duration from disease onset to EDSS 6.0 in patients who did or did not receive oral prednisolone or biologics before reaching EDSS 6.0.

Results
Approximately half of the untreated patients reached EDSS 3.0 and 6.0 at 10 and 46 months after disease onset, respectively. In addition, 88% and 71% of the untreated patients reached EDSS 3.0 and 6.0 within 10 years after disease onset, respectively. Disability progression, clinical relapses and attack severity were suppressed by prednisolone and biologics.

Conclusions
AQP4Ab+NMOSD is a severely disabling disease. Treatment interventions using prednisolone and biologics are useful in suppressing disability progression in AQP4Ab+NMOSD.
Inequitable barriers and opportunities for leadership and professional development, identified by early-career to mid-career allied health professionals
Authors: Mizzi Laura , Marshall Patrick 
Published: January 2024

IntroductionInterprofessional leadership is essential to sustain the National Health Service (NHS) in pressured times, which should include the NHS’s third largest clinical workforce in England: allied health professionals (AHPs) (AHPs as defined by NHS England: Art therapists; Dramatherapists; Music therapists; Dietitians; Occupational therapists; Operating department practitioners; Orthoptists; Osteopaths; Paramedics; Physiotherapists; Podiatrists, Prosthetists and Orthotists; Radiographers; Speech and language therapists). Therefore, a feasibility study was undertaken, to explore the views of AHPs working in early to mid-career positions, regarding the barriers and opportunities they encounter, in both leadership and career development.MethodsTwenty-seven participants, representing 8 of the 14 AHP professions across England, were interviewed across 10 focus groups.ResultsThematic analysis (TA) generated four themes, including the barriers and opportunities for AHP leadership development and career progression. Further TA identified three overarching themes: equitable and interprofessional leadership development; an equitable and structured AHP career pathway; and having AHP leaders at a strategical and/or very senior level. These overarching themes were subsumed under the umbrella category: equity of opportunity and voice. The AHPs, who were interviewed, reported inequitable access to both career and leadership development, compared with other professions, such as nurses, doctors and pharmacists.DiscussionFurther work is needed to ensure that interprofessional representation, within senior leadership levels, includes AHPs; which the data suggests would directly benefit all AHPs’ leadership and career development. Recommendations for organisations to facilitate leadership and career development were developed from the TA and at a system-wide level. Further research would be beneficial to gather the views of the six AHP professions not interviewed in this study and from other organisations, such as independent practice. However, this feasibility study does attempt to represent the voices of AHPs, which can be lacking in both organisations and research.
Introducing a framework to support the identification and tackling of health inequalities within specialised services
Authors: McGill Shaun , Davies Nathan , Addei Dianne , Bharkhada Dhiren , Elleray Rebecca , Wilson Robert , Day Matthew 
Published: January 2024

BackgroundThe potential for addressing healthcare inequalities in prescribed specialised services has historically been overlooked. There is evidence that prescribed specialised services can exacerbate inequalities even though they are often accessed at the end of complex pathways and by relatively small numbers of people. Leadership is required to facilitate a systematic approach to identifying and addressing inequalities in this area.MethodsA rapid literature review of articles from 2015 onwards and engagement with stakeholders was used to inform the development of a framework that both supports the identification of health inequalities within specialised services and provides recommendations for how to address them.ResultsThe framework aligns with existing national approaches in England to addressing health inequalities in other healthcare settings. It is prepopulated with features of services that may create inequalities and recommended ways of addressing them and can be readily adapted to suit population specific needs.ConclusionThe potential for addressing health inequalities should be considered at all points along a healthcare pathway. Local service leaders need to be empowered and encouraged to identify and deliver on opportunities for change to continually improve patient access, experience and outcomes.
Agricultural exposure and risk of ovarian cancer in the AGRIculture and CANcer (AGRICAN) cohort
Authors: Renier Marine , Hippert Juliette , Weiswald Louis-Bastien , Tual Séverine , Meryet-Figuiere Matthieu , Vigneron Nicolas , Marcotullio Elisabeth , Baldi Isabelle , Lebailly Pierre 
Published: January 2024

BackgroundOvarian cancer is rare with a poor prognosis and few established risk factors. Hormones and reproductive factors significantly impact its development, suggesting a potential link with endocrine disrupters.MethodsIn the AGRICAN cohort, 59 391 female farmers completed data on lifelong agricultural exposures and reproductive life. Cox models with attained age as timescale (HR and 95% CI) were used. The role of hormonal factors as potential confounders was considered along with specific time windows for exposure (childhood, puberty and menopause). Female farmers were the reference group (for the principal analyses).ResultsBetween enrolment (2005–2007) and the end of follow-up (31 December 2017), 262 incident ovarian cancers were identified. An increased risk was observed for females involved in pigs (HR=2.12 (95% CI 1.27 to 3.52)) including during puberty (HR=1.83 (95% CI 1.13 to 2.94)), fruit-growing (HR=2.17 (95% CI 1.09 to 4.30)) and potato seed treatment (HR=2.81 (95% CI 1.29 to 6.09)). Conversely, females born on farms growing grain cereals (HR=0.64 (95% CI 0.46 to 0.90)) or pig-breeding (HR=0.78 (95% CI 0.55 to 1.12)) presented a reduced risk of ovarian cancer. Triazine herbicide exposure was not associated with ovarian cancer. The effect of agricultural exposures remained unchanged in multivariate models considering contraception, parity, puberty age, menopause age and body mass index.ConclusionThis study is the first to assess the association between specific agricultural exposures and ovarian cancer comprehensively. Some of the positive associations observed suggest that some pesticide exposure (especially during puberty) could play a role in the development of ovarian cancer. On the other hand, agricultural exposure during early life could have a protective effect, as observed for lung cancer among farmers. Finally, we did not confirm the previous putative effect of exposure to triazine herbicides.