bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract LB290: Intracranial, intratumoral drug-releasing microdevices in patients with high grade gliomas may identify biomarkers of drug activity and predict tumor response to systemic chemotherapy
Authors: Jonas Oliver , Peruzzi Pier Paolo
Published: April 2023

The lack of reliable predictive biomarkers to guide effective therapy is a major obstacle for the advancement of therapy for high grade gliomas (HGG), and particularly glioblastoma (GBM), one of the few cancers whose prognosis has not improved over the past several decades. With this pilot clinical trial we provide first in human evidence that drug-releasing intratumoral microdevices (IMD) can be safely and effectively used to obtain patient-specific, high throughput molecular and histopathological data to inform selection of drugs based on their observed antitumor effect in situ. The use of IMD is seamlessly integrated in standard surgical practice during tumor resection. None of the six enrolled patients experienced adverse events related to the IMD, and the retrieved tissue was usable for downstream analysis for 11 out of 12 retrieved specimens. Molecular analysis of the specimens provided, for the first time in humans, preliminary evidence of the robustness of the readout, with strong correlation between IMD analysis and clinic-radiological responses to temozolomide. We also identified novel transcriptomic and metabolomic biomarkers of response and resistance to a range of targeted and cytotoxic agents used on the IMD. From an investigational aspect, the amount of information obtained with IMD allows unprecedented characterization of tissue effects of any drugs of interest, within the physiological context of the intact tumor.

Citation Format: Oliver Jonas, Pier Paolo Peruzzi. Intracranial, intratumoral drug-releasing microdevices in patients with high grade gliomas may identify biomarkers of drug activity and predict tumor response to systemic chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB290.
Abstract LB314: Epigenetic regulator Menin-MLL1 maintains cancer stem cells and promotes neuroblastoma growth
Authors: Chilamakuri Rameswari , Agarwal Saurabh
Published: April 2023

Epigenetic regulators MLL1 and Menin plays important role in cancer progression, metastasis, and relapse. Apart from the oncogenic translocations in leukemias, MLL1 forms a COMPASS complex with Menin and other binding partners to act as an H3K4 methyltransferase. Inhibition of COMPASS complex by blocking the Menin-MLL1 interaction is reported to be effective in different cancers. In this study, we found that a specific Menin-MLL1 inhibitor, MI-503 inhibits neuroblastoma cancer stem cells (NB CSCs; CD114+ cells) to inhibit overall neuroblastoma (NB) growth in both in vitro and in vivo NB tumor models. NB is an extracranial solid pediatric cancer that accounts for about 15% of all pediatric cancer-related deaths, with the long-term survival of relapsed NB patients being less than 10%. We found that MI-503 significantly and in a dose-dependent manner inhibits cell proliferation in nine NB cell lines tested including MYCN amplified (NGP, LAN-5, IMR-32), MYCN non-amplified (SH-SY5Y, SK-N-AS, CHLA-255), and primary patient-derived NB cell lines (COG-N-415, COG-N-269, COG-N-357), in contrast to control fibroblasts. Additionally, MI-503 significantly inhibits NB 3D spheroidal tumor growth and live cell counts compared to control treatments. Further, flow cytometry analysis revealed that MI-503 specifically induces apoptosis and blocks cell cycle progression at the S phase in the NB CSCs (CD114+ cells) in comparison to non-CSCs (CD114- cells) that leads to significant inhibition of overall NB CSC levels in different NB cell lines. By inhibiting the COMPASS complex, MI-503 significantly inhibits H3K4me3 levels as determined by the histone immunoblot assays. This leads to the inhibition of multiple cancer stemness-related genes expression such as OCT4, Nanog, HOXA, AF9, and MEIS1. Further, we determined the efficacy of MI-503 in NB xenograft mouse models and found that MI-503 significantly inhibits overall NB tumor growth (12.3 fold; p<0.001) and tumor burden (10.2 fold; p<0.01) by directly inhibiting tumor NB CSCs (p<0.01). We have not observed any drug-treatment-related toxicities or gender bias. Overall, our study highlights a novel epigenetic-based therapeutic approach for high-risk NB and underlines the role of epigenetic regulators in maintaining the NB CSCs and NB growth. In our future efforts, we will develop concomitant therapeutic approaches by combining MI-503 with current chemotherapies to target both NB CSCs and bulk tumor cells. This will lead to the development of effective, targeted, and clinically tractable therapies for NB patients.

Citation Format: Rameswari Chilamakuri, Saurabh Agarwal. Epigenetic regulator Menin-MLL1 maintains cancer stem cells and promotes neuroblastoma growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB314.
Abstract LB334: Assessment of the potential of graphene oxide as an antigen delivery platform for cancer immunotherapy
Authors: Chattrakarn Sorayut , Mallett Grace , Parker Helen , Lozano Neus , Kostarelos Kostas , MacDonald Andrew S.
Published: April 2023

Introduction: Novel cancer immunotherapies are urgently needed due to a lack of definitive treatments, as well as toxicity and cost of current therapies. 2-dimensional carbon graphene oxide (GO) nanomaterials provide a large surface area, high protein loading efficiency and good biocompatibility, as well as being inexpensive. Given these properties, we investigated whether and how GO could be an effective antigen delivery system for targeted cancer immunotherapies.

Methods: GO was non-covalently complexed with the model antigen ovalbumin peptide (OVA257-264) and the immunostimulant and toll-like receptor 3 agonist polyinosinic:polycytidylic acid (Poly (I:C)). We examined innate and adaptive immune responses after subcutaneous injection of GO complexes by histology and flow cytometry.

Results: We found that GO without Poly (I:C) had a very limited immunogenic potential. In contrast, GO complexed with Poly (I:C) significantly increased immune cell recruitment to the injection site, and enhanced activation and migration of dendritic cell subsets (cDC1s and cDC2s) in skin-draining lymph nodes 24 hours after injection. Additionally, we found that GO complexed with Poly (I:C) dramatically enhanced OVA-specific CD8+ T cell expansion and cytotoxic potential in both spleen and skin-draining lymph nodes 7 days after subcutaneous complex administration to mice which had previously been injected intravenously with traceable, OVA-specific (OT-I) CD8+ T cells.

Conclusion: Our results have revealed the immunomodulatory potential of GO when complexed with Poly (I:C) by attracting immune cells to the injection site and augmenting antigen-specific cytotoxic responses both locally and systemically. Ongoing work is determining the anti-tumor potential of this approach, and potential mechanisms by which GO complexes might limit tumor progression.

Citation Format: Sorayut Chattrakarn, Grace Mallett, Helen Parker, Neus Lozano, Kostas Kostarelos, Andrew S. MacDonald. Assessment of the potential of graphene oxide as an antigen delivery platform for cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB334.
Abstract LB337: Inhibition of the E3 ligase CBL-B enhances the effector function and proliferation of natural killer cells
Authors: Qi Yilin , Kuai Jun , Bi Yingzhi , Greco David , Jaeger Samira , Carson Ken , Danaee Hadi , Reilly Timothy , Harriman Geraldine , Wang Fang
Published: April 2023

The E3 ubiquitin ligase CBL-B is a master regulator of effector T cells through its downstream regulation of T-cell receptor and co-stimulatory stimulation, but it has also been shown to play a negative feedback role in NK cells. CBL-B depletion enhances the production of IFNγ and the cytotoxicity of activated NK cells. Similar to the effect of depleting CD8 T cells in mice, depletion of NK cells abolishes the tumor growth delay observed in Cbl-b-/- mice. With emerging data supporting the potential role of exogenous NK cells in anti-tumor immunity, inhibition of CBL-B represents a promising approach to enhance both adaptive and innate immunity for cancer immunotherapy. Using one of our small molecules, allosteric CBL-B inhibitors, HOT-A, we demonstrated that CBL-B inhibition enhanced NK activation, IFNγ production and granzyme B secretion in response to the various stimulation conditions, including cytokines (such as IL-15 and IL12 + IL-18) and stimulatory receptors (such as NKp30 and NKG2D + CD244). NK cell proliferation was also enhanced in the presence of HOT-A. Single cell analysis further suggested that HOT-A increased NK polyfunctional cytokine expression during IL-12 + IL-18 activation. In a coculture system of NK cells and K562 target cells, HOT-A dose-dependently promoted primary human NK cell activation, cytokine production and cytotoxicity in the K562 cells. In the in vivo CT-26 tumor model, granzyme B+ NK cells in the TIL were significantly increased in the HOT-A treated tumor bearing mice and NK function gene signature was also increased by Nanostring analysis, suggesting an enhanced NK function in the tumor microenvironment. Taken together, the pre-clinical data presented here demonstrate that our CBL-B inhibitor enhances NK cell function in vitro and in vivo, suggesting that its enhancement of anti-tumor immunity may be driven through both effector T cell and NK cell-driven biology.

Citation Format: Yilin Qi, Jun Kuai, Yingzhi Bi, David Greco, Samira Jaeger, Ken Carson, Hadi Danaee, Timothy Reilly, Geraldine Harriman, Fang Wang. Inhibition of the E3 ligase CBL-B enhances the effector function and proliferation of natural killer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB337.
Abstract LB339: PARP inhibition reprograms CD8 T cells, enhancing their function and generation of prolonged memory, leading to greater anti-tumor immune response
Authors: Traboulsi Wael , Kundu Subhadip , Gaur Pankaj , Ramlaoui Zainab , Sarhan Dareen , Shobaki Nour , Lee Jacob , Jafarzadeh Nazli , Barry Simon T. , Valge-Archer Viia E. , Verma Vivek , Gupta Seema , Khleif Samir N.
Published: April 2023

Olaparib is the most widely studied third-generation PARP inhibitor (PARPi) in clinical practice with a significant clinical outcome in BRCA deficient tumors such as breast and ovarian cancers. However, innate and adaptive resistance in patients with DNA damage repair (DDR) gene mutations were reported after treatment with PARPi, highlighting the potential implication of other compartments such as the role of immune cells in the mechanism of resistance. Importantly, PARPi is shown to have an immune-modulatory capacity within the tumor microenvironment (TME) by activating the STING pathway and increasing interferon gamma (INF-gamma) and chemokine secretion and hence increasing the recruitment and function of CD8 T cells. In addition, PARPi is shown to affect other cells within the TME such as, macrophages, myeloid-derived suppressor cells (MDSCs) and cancer associated fibroblasts (CAFs), promoting either an immune enhancement or immune suppressor milieu that could indirectly affect CD8 T cell function. However, little is known about the direct effect of PARPi on CD8 T cells. In this study using two cold tumor models, we show that PARPi controls the tumor growth and increases survival in tumor-bearing mice. This effect is due to the enhancement of number and cytotoxicity of antigen-specific CD8 T cells and the maintenance of memory population within the TME. In vitro study shows that PARPi activates the SIRT-1/FOXO1 pathway, leading to the modification of gene expression related to memory and fatty acid oxidation (FAO) metabolism in CD8 T cells. As a result, a unique subpopulation of superior central memory cells with high recall responses and anti-tumor effects are generated after PARPi treatment. Interestingly this unique subpopulation was also generated after PARPi in human cells. Together, our findings highlight the direct effect of PARP inhibition on CD8 T cells and its ability to modulate and reprogram CD8 T cells within the TME, leading to a greater anti-tumor immune response.

Citation Format: Wael Traboulsi, Subhadip Kundu, Pankaj Gaur, Zainab Ramlaoui, Dareen Sarhan, Nour Shobaki, Jacob Lee, Nazli Jafarzadeh, Simon T. Barry, Viia E. Valge-Archer, Vivek Verma, Seema Gupta, Samir N. Khleif. PARP inhibition reprograms CD8 T cells, enhancing their function and generation of prolonged memory, leading to greater anti-tumor immune response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB339.
Abstract LB346: Mapping of shared tumor antigen reactivity with nanoparticle encapsulated mRNA in prostate cancer patients
Authors: Montauti Elena , Haabeth Ole , Rae Chris , Deutsch Samuel , Fong Lawrence , Oh David
Published: April 2023

Background: Prostate cancer (PC) remains refractory immune checkpoint therapies (CPT) despite having an FDA-approved cancer vaccine. PC is known to have a low mutation burden resulting in low level of neoantigens, so shared tumor associated antigens (TAAs) and translocations presumably represent a dominant source of antigens in this disease. While PC is thought to be a poorly immunogenic tumor, the frequency and breadth of tumor antigen reactivity in PC patients is unclear.

Methods: We utilized novel programmable immunogenic mRNA nanoparticle platform and created formulations encoding a range of full-length prostate TAAs (TAAmRNA) to systemically study T cell immune responses to across a range of TAAs in PC patients. We administered 8 PC TAAmRNAs (NY-ESO-1, HK2, STEAP1, TMPRSS2-ERG, PAP, PSA, PSCA and PSMA) to in-vitro cultured peripheral blood mononuclear cells (PBMC) from 43 treatment-naïve localized PC patients compared to 17 age-matched non-cancer control patients. We assessed upregulation of early T cell activation markers and interferon-gamma (INFg) cytokine production through flow cytometry and ELISPOT, respectively.

Results: 20% of PC patients possessed TAA-specific CD8+ T cell responses to at least one antigen. NY-ESO-1, HK2 and TMPRSS2-ERG had the highest T cell recall responses at an average of 35%, with NY-ESO-1 demonstrating the strongest responses per patient. Of the patients that respond to any given TAA, 47% of patients responded to three or more antigens, with 11% of PC patients responding to all TAAs. PC patients also showed heightened production of IFNg, with 35% of patients showing pan-responsiveness to three or more antigens. Particularly, HK2 stimulated the highest levels of INFg production. These levels of responsiveness are not seen in the control cohort.

Conclusions: Encapsulated mRNA nanoparticles can be used to systematically map antigen reactivity across a cohort of cancer patients and reveal frequent pan-responsiveness to multiple TAAs in what has considered to be an immunologically cold cancer These results also reveal a hierarchy in immunogenicity of candidates that can enable future vaccine development. Continual efforts to assess the immunogenicity of shared PC TAAs in more advanced disease, and how patient responses to TAAs are modulated by immunotherapies, can aid in refining combinatorial therapies for PC.

Citation Format: Elena Montauti, Ole Haabeth, Chris Rae, Samuel Deutsch, Lawrence Fong, David Oh. Mapping of shared tumor antigen reactivity with nanoparticle encapsulated mRNA in prostate cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB346.
Abstract LB353: The switch from cap-dependent to cap-independent translation reshapes the immunopeptidome of lung cancer
Authors: Ali Anika N. , Weeden Andrew D. , Jaeger Alex M.
Published: April 2023

Cancer immunosurveillance relies on the presentation of peptide antigens on human leuckocyte antigen class I (HLA-I). HLA-I molecules present a diverse array of antigens, known as the “immunopeptidome”, which are recognized by cytotoxic CD8+ T cells. Recent evidence suggests that cryptic peptide antigens derived from non-canonical open reading frames (nuORFs) contribute to the immunopeptidome and drive CD8+ T cell responses. Integrating ribosome profiling (Ribo-seq) with mass spectrometry (MS) analyses has enabled the identification of several cryptic peptides derived from nuORFs including from putative non-coding regions including the 5’UTR, 3’UTR, long non coding RNAs (lncRNAs) and retained introns. Notably, many nuORFs undergo cap-independent translation. Various physiological and pharmacological stressors arrest canonical cap-dependent translation initiation and induce cap-independent translation. However, how this shift in translational dynamics influences the immunopeptidome is unknown. Using lung cancer cell lines, we show that the eIF4A inhibitor silvestrol induces cap-independent translation and reshapes the landscape of nuORF-derived peptide antigens. Silvestrol induced changes in the immunopeptidome strongly contrast with the global translation inhibitor homoharringtonine, which dampens antigen presentation. These observations suggest that the presentation of nuORF antigens in lung cancer is dynamic and tightly controlled by translational dynamics. More broadly, our study provokes reconsideration of translation inhibitors as immunomodulatory drugs that can change the HLA-I antigen repertoire and generate peptides that can act as new targets for cancer immunotherapy.

Citation Format: Anika N. Ali, Andrew D. Weeden, Alex M. Jaeger. The switch from cap-dependent to cap-independent translation reshapes the immunopeptidome of lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB353.
Single-Session Fractional CO2 Laser following Urea Occlusion in Management of Onychomycosis: A Pilot Study
Authors: Ranjan Eeshaan , Arora Sandeep , Sharma Ajay Shanker , Sharma Neha , Dabas Rajeshwari
Published: April 2023

Introduction: Onychomycosis is a common nail disorders. Antifungal resistance, interactions, and side effects limit treatment options. Fractional CO2 (FCO2) laser along with topical antifungal is effective in multiple monthly sessions. A modification reducing repeated visits and hence better compliance is preferable. Single-session FCO2 laser following urea occlusion is reported to be effective. Thus, we conducted a study to determine the efficacy of single-session FCO2 laser with 1% terbinafine cream with and without “urea cream occlusion” in managing onychomycosis. Methods: A prospective, randomized, parallel-group study was conducted at a tertiary centre. Onychomycosis was confirmed by positive fungal mount and culture. Patients were randomized into 2 groups and administered single-session FCO2 laser. Group A was treated after overnight urea cream occlusion and group B without occlusion. Both groups applied 1% terbinafine cream twice daily for 3 months. Response was assessed by improvement in Onychomycosis Severity Index (OSI) at 6 months. Results: Group A had 10 patients, 14 nails. Clinical improvement was seen in 12/14 (85.7%) nails. Average reduction in OSI was 10.78. Group B had 10 patients, 11 nails. Clinical improvement was seen in 5/11 (45.5%) nails. Average reduction in OSI was 1.73. “Reduction in OSI” was statistically significant (p < 0.05) only in group A. Conclusion: Single-session FCO2 laser following overnight urea cream occlusion, followed by 1% terbinafine cream, is effective for management of onychomycosis.
Durable Response to Pazopanib in a Patient with Fumarate Hydratase-Mutant Tubulocystic Renal Cell Carcinoma
Authors: Othman Anjum , Kumar Shiyam , Qureshi Asim , Jawa Zabah M. , Burney Ikram A.
Published: April 2023

Tubulocystic carcinoma of the kidney (TC-RCC) is a rare renal tumor and has been recently included as a distinct entity in WHO classification of renal neoplasms. We report the case of a patient with metastatic tubulocystic RCC whose disease progressed through standard of care treatment for nonclear RCC. However, genetic analysis revealed a germline pathogenic variant of fumarate hydratase (FH) gene, and the patient had a sustained and durable response to pazopanib.
Zanubrutinib in the Maintenance Treatment of Elderly People with Primary Central Nervous System Lymphoma: A Report of 2 Cases
Authors: Liu Ying , Sun Jie , Tuo Kangxin
Published: April 2023

Primary central nervous system lymphoma (PCNSL) is a rare and aggressive extranodal non-Hodgkin lymphoma. The predominant subtype is diffuse large B-cell lymphoma (DLBCL), and no systematic lesion is identified at diagnosis. BTKi (Bruton’s tyrosine kinase inhibitor) has demonstrated significant clinical activity in DLBCL. We retrospectively reported on 2 patients who began with memory deterioration or right limb movement disabilities. A cranial magnetic resonance imaging (MRI) scan and a brain biopsy were used to diagnose PCNSLs. Middle-dose methotrexate (MD-MTX) regimens were initiated for induction treatment. Zanubrutinib was chosen as the maintenance regimen due to the patients' inability to tolerate continuous MTX regimens. For 1 patient, he achieved sustained complete remission (CR) demonstrated by MRI. Another patient achieved partial remission (PR). The two patients are both alive until now. We successfully extended the PFS and OS in elderly PCNSL patients treated with zanubrutinib.
Better Anti-Spike IgG Antibody Response to SARS-CoV-2 Vaccine in Patients on Haemodiafiltration than on Haemodialysis
Authors: Carrera Fernando , Jacobson Stefan H , Costa Joana , Marques Marco , Ferrer Francisco
Published: April 2023

Introduction: The antibody response to SARS-CoV-2 vaccine in haemodialysis (HD) patients is diminished compared to healthy subjects. The aim of this study was to compare the presence of reactive SARS-CoV-2 antibodies in patients with high-flux HD and on-line haemodiafiltration (HDF) three and 6 months after the second dose of SARS-CoV-2 vaccine since previous studies indicate that a sustained antibody response correlates with protection from disease. Methods: We included 216 HD patients of which 157 had on-line HDF and 59 high-flux HD and 46 health care workers as controls and studied the presence of reactive anti-spike IgG antibodies three and 6 months after the second dose of SARS-CoV-2 vaccine. Clinical features between the patient groups were similar, but patients with on-line HDF had significantly higher Kt/V. Results: The percentage of participants with reactive antibodies was significantly lower in patients compared to controls, both three and 6 months after the second dose of vaccine. Furthermore, the proportion of patients with reactive anti-spike IgG ≥1.0 6 months after the second dose of vaccine was significantly higher in patients with on-line HDF compared to in patients with high-flux HD. In logistic regression analyses adjusted for several clinical features, the variables associated with presence of reactive anti-spike IgG at 3 months after the second dose of vaccine were lower age, HDF treatment, not being obese and not having a previous solid organ transplant. The two variables with the strongest influence on the presence of reactive anti-spike IgG levels 6 months after the second dose of vaccine were treatment with on-line HDF and not having immunosuppressive therapy. Conclusion: This is the first study to show that on-line HDF preserves the antibody response better than high-flux HD after vaccination with SARS-CoV-2 vaccine. Treatment strategies that sustain the vaccine response are essential to apply in this vulnerable group of patients.
Clinicopathological Characteristics and Outcomes of Immunoglobulin A Nephropathy with Different Types of Dyslipidemia: A Retrospective Single-Center Study
Authors: Liu Sidi , Lu Zhenzhen , Fu Zhike , Li Huijie , Gui Chuying , Deng Yueyi
Published: April 2023

Introduction: Immunoglobulin A nephropathy (IgAN) is one of the most common glomerulonephritic diseases in the world. Several lines of evidence have suggested that dyslipidemia is related to the disease progression and prognosis of IgAN. However, the study is scarce on the clinicopathological characteristics and outcomes of IgAN with dyslipidemia. Methods: This study retrospectively analyzed 234 patients with biopsy-proven idiopathic IgAN at the Department of Nephrology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, between January 2015 and June 2021. The participants were divided into dyslipidemia (n = 119) and non-dyslipidemia (n = 115), and the dyslipidemia group was also divided into the following 4 groups: hypertriglyceridemia group, hypercholesterolemia group, mixed hyperlipidemia group, and low high-density lipoprotein cholesterol group. The estimated glomerular filtration rate (eGFR) was estimated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. Results: The prevalence of dyslipidemia in IgAN patients in our center was 50.9% (119/234). The patients with dyslipidemia presented with higher systolic blood pressure (BP), diastolic BP, serum creatinine, uric acid, hemoglobin, proteinuria, and eGFR (p < 0.05). Proportions of males, hypertension, and chronic kidney disease stage 2∼5 were also higher in the dyslipidemia group (p < 0.05). Similarly, the pathological characteristics performed were worse in the dyslipidemia group. Most dyslipidemia patients had a higher percentage of mesangial hypercellularity (M1) and tubular atrophy/interstitial fibrosis (T1∼2) in the Oxford Classification’s scoring system (p < 0.05). Multivariate logistic regression analysis revealed that male gender (odds ratio [OR] = 2.397, 95% confidence interval [CI]: 1.051–5.469, p = 0.038) and proteinuria (OR = 1.000, 95% CI: 1.000–1.001, p = 0.035) were possible risk factors for dyslipidemia. A total of 13 patients (13.8%) in the dyslipidemia group had an endpoint event, of which 6 patients (6.4%) had a ≥50% decrease in eGFR from baseline and 7 patients (7.4%) reached the end-stage renal disease stage. Kaplan-Meier survival curve analysis showed that patients in the dyslipidemia group had a worse outcome than those in the non-dyslipidemia group (log-rank test, p = 0.048). Conclusions: IgAN patients with dyslipidemia presented more severe clinicopathological characteristics. Male gender and proteinuria are significantly associated with the occurrence of dyslipidemia in IgAN patients. Patients in the dyslipidemia group had a worse prognosis than those in the non-dyslipidemia group, which may be essential for the disease management of IgAN and help identify the high-risk patients.
Comparison of Social-Evaluative Anxiety and Theory of Mind Functions in Social Anxiety Disorder, Schizophrenia, and Healthy Controls
Authors: Yilmaz Gorkem , Yildirim Ejder Akgun , Tabakcı Abdulkadir Sencer
Published: April 2023

Introduction: Despite the similarities in poor social competence and clinical manifestations of poor social behavior, no study has compared the theory of mind performance between social anxiety disorder (SAD) and schizophrenia, considering the effect of social-evaluative anxiety and neurocognitive functions. In our study, we aimed to compare the theory of mind functions and social-evaluative anxiety between patients with SAD and schizophrenia and healthy controls and to examine the relationship between the theory of mind, neurocognitive skills, and social-evaluative anxiety. Methods: Thirty-four consecutive patients with schizophrenia, 29 patients with SAD, and 30 controls matched by age, education level, and sex were enrolled in the study. Structured Clinical Interview for DSM, Beck Depression Inventory, Liebowitz Social Anxiety Scale, Theory of Mind measures (Reading the Mind in the Eyes Test, Hinting Task, Faux Pas Test), Social Appearance Anxiety Scale, Fear of Positive Evaluation Scale, Fear of Negative Evaluation Scale-Short Form, and neuropsychological tests were administered to all participants. Results: A greater significant deterioration in theory of mind and neurocognitive functions was found in patients with schizophrenia compared to those with SAD and healthy controls. Social evaluation anxiety was highest in patients with SAD. Although social-evaluative anxiety was associated with the theory of mind function in schizophrenia, only fear of positive evaluation was associated with SAD. In all groups, neither theory of mind nor neurocognitive ability measures were correlated with social anxiety levels and related symptoms. Conclusions: The impaired theory of mind functioning detected in our study is more prominent in the schizophrenia group and largely independent of anxiety in schizophrenia and SAD. Although social evaluation anxiety, as a transdiagnostic concept, seems to be independent of theory of mind function in general, fear of positive evaluation seems to be associated with hinting in both disorders.
Asbest und andere gefährliche faserige Mineralien: Potenzielle Expositionswege und damit verbundene Gesundheitsrisiken
Authors: Berry Terri-Ann , Belluso Elena , Vigliaturo Ruggero , Gieré Reto , Emmett Edward A. , Testa Joseph R. , Steinhorn Gregor , Wallis Shannon L.
Published: April 2023

Es gibt 6 Arten länglicher Mineralpartikel (EMP), die bestimmten dimensionalen und morphologischen Kriterien entsprechen und als Asbest bekannt sind. Da Asbest für Gesundheitsprobleme wie die Asbestose und das maligne Mesotheliom verantwortlich ist, wurde er gut erforscht. Trotzdem kommt es weltweit weiterhin zu einer erheblichen Exposition, die möglicherweise 125 Millionen Menschen am Arbeitsplatz betrifft und jährlich Tausende von Todesfällen durch Exposition in Haushalten verursacht. Es gibt jedoch andere EMP, wie z.B. faserigen/asbestiformen Erionit, die als Karzinogene eingestuft sind und in Gebieten, in denen sie in lokale Baumaterialien eingebaut oder durch Erdbewegungen in die Umwelt freigesetzt wurden, mit Krebs in Verbindung gebracht wurden. Erionit ist ein stärkeres Karzinogen als Asbest, da es aber selten für kommerzielle Zwecke verwendet wird, wurden die Expositionswege weniger gut untersucht. Trotz der offensichtlichen Ähnlichkeiten zwischen Asbest und faserigem Erionit unterscheiden sich ihre Gesundheitsrisiken und Expositionspfade erheblich. Dieser Artikel untersucht die Gefahren, die von EMP ausgehen, mit besonderem Schwerpunkt auf Erionitfasern. Er umfasst eine Diskussion der globalen Standorte von Erionit und ähnlichen gefährlichen Mineralien, einen Vergleich der vielfältigen Expositionspfade für Asbest und faserigen Erionit, eine kurze Diskussion der verwirrenden Nomenklatur im Zusammenhang mit EMP und Überlegungen zur Zunahme globaler Mesotheliomfälle.
The Patterns of Visual Field Defects in Primary Angle-Closure Glaucoma Compared to High-Tension Glaucoma and Normal-Tension Glaucoma
Authors: Jiang Junhong , Ye Cong , Zhang Cong , Lin Zhong , Tang Yihua , Ye Wenqing , Xu Xiang , Zhang Shaodan , Lu Fan , Liang Yuanbo
Published: April 2023

Introduction: The aim of this study was to compare the patterns of visual field (VF) defects in primary angle-closure glaucoma (PACG) to control groups of eyes with high-tension glaucoma (HTG) and normal-tension glaucoma (NTG). Methods: Forty-eight eyes with PACG were enrolled, and control eyes with HTG and NTG matched for age, sex, and mean deviation of VF defect were selected. VF tests were performed using the 24-2 program of the Humphrey field analyzer. VF defects were classified into six patterns with the Ocular Hypertension Treatment Study classification system and were categorized into three stages (early, moderate, and advanced). Each hemifield was divided into five regions according to the Glaucoma Hemifield Test (GHT). The mean total deviation (TD) of each GHT region was calculated. Results: Compared with HTG and NTG groups, the partial arcuate VF defects were more common in the PACG group. In the PACG group, the nasal GHT region in the inferior hemifield had the worst mean TD (−8.48 ± 8.62 dB), followed by the arcuate 1 (−7.81 ± 7.91 dB), arcuate 2 (−7.46 ± 7.43 dB), paracentral (−7.19 ± 7.98 dB), and central (−5.14 ± 6.24 dB) regions; the mean TD of the central region was significantly better than those for all other regions (all p < 0.05). A similar trend was observed in the superior hemifield in the PACG group but not the VF hemifields of the HTG and NTG groups. Conclusion: Patterns of VF defect in PACG patients differ from those with HTG and NTG. This discrepancy might be due to the differences in the pathogenic mechanisms of glaucomatous optic neuropathy.
Gesamtüberlebensvorteil durch Tebentafusp beim metastasierten uvealen Melanom
Authors: Seibel Ira
Published: April 2023

Background: Uveal melanoma is a disease that is distinct from cutaneous melanoma, with a low tumor mutational burden and a 1-year overall survival of approximately 50% in patients with metastatic uveal melanoma. Data showing a proven overall survival benefit with a systemic treatment are lacking. Tebentafusp is a bispecific protein consisting of an affinity-enhanced T-cell receptor fused to an anti-CD3 effector that can redirect T cells to target glycoprotein 100-positive cells. Methods: In this open-label, phase 3 trial, we randomly assigned previously untreated HLA-A*02:01-positive patients with metastatic uveal melanoma in a 2:1 ratio to receive tebentafusp (tebentafusp group) or the investigator’s choice of therapy with single-agent pembrolizumab, ipilimumab, or dacarbazine (control group), stratified according to the lactate dehydrogenase level. The primary end point was overall survival. Results: A total of 378 patients were randomly assigned to either the tebentafusp group (252 patients) or the control group (126 patients). Overall survival at 1 year was 73% in the tebentafusp group and 59% in the control group (hazard ratio for death, 0.51; 95% confidence interval [CI], 0.37 to 0.71; P<0.001) in the intention-to-treat population. Progression-free survival was also significantly higher in the tebentafusp group than in the control group (31% vs. 19% at 6 months; hazard ratio for disease progression or death, 0.73; 95% CI, 0.58 to 0.94; P = 0.01). The most common treatment-related adverse events in the tebentafusp group were cytokine-mediated events (due to T-cell activation) and skin-related events (due to glycoprotein 100-positive melanocytes), including rash (83%), pyrexia (76%), and pruritus (69%). These adverse events decreased in incidence and severity after the first three or four doses and infrequently led to discontinuation of the trial treatment (2%). No treatment-related deaths were reported. Conclusions: Treatment with tebentafusp resulted in longer overall survival than the control therapy among previously untreated patients with metastatic uveal melanoma. (Funded by Immunocore; ClinicalTrials.gov number, NCT03070392; EudraCT number, 2015-003153-18.).
Single-Cell Transcriptome Sequencing Reveals Molecular Mechanisms of Renal Injury in Essential Hypertension
Authors: Huyan Yige , Wang Chunyue , Kang Hongen , Chen Xiao , Chang Yuan , Liu Sheng , Song Jiangping
Published: April 2023

Introduction: Hypertensive nephropathy is characterized by glomerular and tubulointerstitial damage, but we know little about changes in cell-specific gene expression in the early stages of hypertensive kidney injury, which usually has no obvious pathological changes. Methods: We performed unbiased single-cell RNA sequencing of rat kidney samples from hypertensive kidney injury to generate 10,602 single-cell transcriptomes from 2 control and 2 early stage hypertensive kidney injury samples. Results: All major cell types of the kidney were represented in the final dataset. Side-by-side comparisons showed that cell type-specific changes in gene expression are critical for functional impairment of glomeruli and tubules and activation of immune cells. In particular, we found a significantly reduced gene expression profile of maintaining vascular integrity in glomerular cells of hypertensive kidney injury. Meanwhile, the expression of genes associated with oxidative stress injury and fibrosis in the renal tubules and collecting ducts was elevated, but the degree of tubular cells response to injury differed between parts. We also found a signature of immune cell infiltration in hypertensive kidney injury. Conclusion: Exploring the changes of gene expression in hypertension-injured kidneys may be helpful to identify the early biomarkers and signal pathways of this disease. Our data provide rich resources for understanding the pathogenesis of hypertensive renal injury and formulating effective treatment strategies.
Real-Time Fluorescence Imaging to Identify Cholangiocarcinoma in the Extrahepatic Biliary Tree Using an Enzyme-Activatable Probe
Authors: Takahashi Ryugen , Ishizawa Takeaki , Inagaki Yoshinori , Tanaka Mariko , Ogasawara Akira , Kuriki Yugo , Fujita Kyohhei , Kamiya Mako , Ushiku Tetsuo , Urano Yasuteru , Hasegawa Kiyoshi
Published: April 2023

Introduction: Complete resection is the only possible treatment for cholangiocarcinoma in the extrahepatic biliary tree (eCCA), although current imaging modalities are limited in their ability to accurately diagnose longitudinal spread. We aimed to develop fluorescence imaging techniques for real-time identification of eCCA using an enzyme-activatable probe, which emits fluorescence immediately after activation by a cancer-specific enzyme. Methods: Using lysates and small tissue fragments collected from surgically resected specimens, we selected the most specific probe for eCCA from among 800 enzyme-activatable probes. The selected probe was directly sprayed onto resected specimens and fluorescence images were acquired; these images were evaluated for diagnostic accuracy. We also comprehensively searched for enzymes that could activate the probe, then compared their expression levels in cancer and non-cancer tissues. Results: Analyses of 19 samples (four cancer lysates, seven non-cancer lysates, and eight bile samples) and 54 tissue fragments (13 cancer tissues and 41 non-cancer tissues) revealed that PM-2MeSiR was the most specific fluorophore for eCCA. Fluorescence images of 7 patients were obtained; these images enabled rapid identification of cancerous regions, which closely matched histopathology findings in 4 patients. Puromycin-sensitive aminopeptidase was identified as the enzyme that might activate the probe, and its expression was upregulated in eCCA. Conclusion: Fluorescence imaging with PM-2MeSiR, which may be activated by puromycin-sensitive aminopeptidase, yielded generally high accuracy. This technique may be useful for real-time identification of the spread of eCCA during surgery and endoscopic examinations.
Advancing Equitable Hearing Care: Innovations in Technology and Service Delivery
Authors: Swanepoel De Wet
Published: April 2023

Background: Hearing loss is a neglected global health priority affecting 1.5 billion persons. Global access to hearing care is severely limited with management options, like hearing aids, inaccessible to most. The cost and centralised nature of traditional service-delivery approaches in hearing care have undermined equitable access alongside poor awareness. Summary: Recent innovations in digital and mHealth hearing technologies used by health workers through task shifting are enabling novel community-based services across the continuum of care. This narrative review explores technology-enabled hearing care in communities. We provide examples focused on our work over the past decade to explore more equitable hearing care across primary, secondary, and tertiary levels of prevention. Key Messages: Hearing health innovations have the potential to increase access to care, improve the quality of life for those affected by hearing loss, and reduce global costs associated with untreated hearing loss. More equitable hearing care is a global health priority that requires scalable service-delivery models enabled by innovative technologies within communities and integrated into public health initiatives including hearing health promotion.
A morte de Quixote e o Teatro do Futuro: uma visão pedagógica da obra de Mikhail Tchekhov
Authors: Dias Natacha
Published: April 2023

O artigo toma como ponto de partida o relato autobiográfico de Mikhail Tchekhov (1891-1955) em que narra a morte simbólica de seu alter ego, Dom Quixote, em Paris, após o fracasso da montagem do espetáculo Le Château s’éveille em 1931. Tentativa frustrada de concretização cênica de seu “Teatro do Futuro”, o momento é analisado como marco de renovação do caráter pedagógico da obra tchekhoviana. Ao longo do texto, destaca-se a importância dada à imagem como fenômeno que articula elementos artísticos, orgânicos e inanimados na pedagogia de atuação tchekhoviana e que reflete a presença constante da problemática da morte na trajetória pessoal desse artista lendário. O texto referencia publicações em idiomas diversos e documentos originais reunidos no Dartington Trust and The Elmgrant Trust Archive (Devon, Inglaterra).
Sestrinska skrb u prevenciji poremećaja mentalnoga zdravlja u adolescenata
Authors: Grgić Ilijana
Published: April 2023

Adolescencija predstavlja prijelazno razdoblje između djetinjstva i odrasle dobi u kojoj se događaju razne emocionalne i kognitivne promjene praćene individualizacijom – razdobljem izgradnje vlastitog identiteta, vlastitih vrijednosti i stavova. Na globalnoj razini, procjenjuje se da 15 – 20 % adolescenata ima problem s poremećajima mentalnoga zdravlja među kojima su vodeći uzroci bolesti: poremećaji ponašanja, depresija i anksioznost. Kako bi se smanjio porast poremećaja mentalnoga zdravlja, Svjetska zdravstvena organizacija pokrenula je niz inicijativa s ciljem unaprjeđenja intervencija usmjerenih na razvoj skrbi adolescenata. Mentalni poremećaji treći su najčešći razlog posjete liječniku školske medicine u hrvatskim osnovnim i srednjim školama. U najčešće poremećaje mentalnoga zdravlja u adolescenata spadaju: afektivni i anksiozni poremećaji, psihotični poremećaji, poremećaji ponašanja, ovisnosti i poremećaji jedenja. Prioritetne i ključne strategije u očuvanju zdravlja čine programi prevencije mentalnih poremećaja usmjereni na osiguravanje psihosocijalne i individualne podrške. Jedna od najznačajnijih uloga medicinske sestre / medicinskog tehničara u prevenciji poremećaja mentalnoga zdravlja jest edukacija adolescenta, njegove obitelji i šire zajednice da bi se što bolje razumjeli adolescentovi osjećaji te na vrijeme uočile promjene u ponašanju koje bi mogle dovesti do razvoja poremećaja mentalnoga zdravlja. Procjena mentalnoga zdravlja adolescenta, holistički pristup, motivacijski i pozitivan odnos s adolescentom, aktivno slušanje, izgradnja terapijskog odnosa, razumijevanje i empatija te podrška predstavljaju sestrinsku skrb u prevenciji poremećaja mentalnoga zdravlja.
Degrowth, Air Travel, and Global Environmental Governance: Scaffolding a Multilateral Agreement for a Smaller and More Sustainable Aviation Sector
Authors: Katz-Rosene Ryan , Ambe-Uva Terhemba
Published: April 2023

In recent years, a growing body of literature on degrowth has compellingly identified limitations involved in decoupling economic growth from its environmental impacts. Despite this, the institutions governing the global environment continue to pursue “green growth” principles. In this article, we showcase how global environmental governance might differ if the degrowth critique were taken more seriously. We use the United Nations–based Carbon Offsetting and Reduction Scheme for International Aviation (CORSIA) to illustrate how a multilateral environmental agreement (MEA) might differ if its foundational premises were centered on degrowth as opposed to green growth. To do this, we develop a conceptual scaffold to support the construction of a degrowth-centered MEA on sustainable global aviation. While a degrowth alternative to CORSIA is admittedly unlikely given contemporary capitalist norms in global environmental governance, our proposed scaffold nevertheless adds to the growing body of work envisioning alternative scenarios for a just and sustainable postgrowth future.
AIBL-CIS de Ricci no. 2
Authors: Moore James D. , Gorea Maria
Published: April 2023

This article presents a previously unknown Jewish and Aramaic religious literary composition dating between the early second and early fourth centuries CE. The document focuses on a righteous man within the context of angels, demons, and spirits. The manuscript, which is housed in the Académie des Inscriptions et Belles-Lettres, Cabinet du Corpus Inscriptionum Semiticarum, has a clear acquisition history and comes from Egypt. The text is edited, translated, and provided with a philological commentary. Discussion of the text’s content is briefly brought into dialogue with the Dead Sea Scrolls and early Jewish texts.
The ‘Logics’ of Public Diplomacy: In Search of What Unites a Multidisciplinary Research Field
Authors: Pamment James , Fjällhed Alicia , Smedberg Martina
Published: April 2023

A decade ago, Matt Armstrong noted that the War on Terror set the scene for US public diplomacy (PD) to be heavily focused on security. Other countries have focused their PD on image promotion, relationship-building or cultural relations. As digital media practices have slowly been adopted by the majority of foreign ministries, the logics governing social and digital media have also been increasingly internalised into diplomatic practice. Lacking in current PD research is a theory of the ‘logics’ that drive and motivate public diplomacy. This article explores the application of ‘PD logics’ as a theoretical framework for interpreting the ways in which foreign policy priorities, such as securitisation, trade promotion and strategic partnerships, shape PD practices. With a particular focus on the most recent wave of social and digital media adoption practices, this article establishes a theory of ‘PD logics’ that could provide new avenues for developing theories of public diplomacy.
A Critical Reflection on Chinese Masculinity: Are Chinese Men in Modern Hong Kong and Taiwan the Same?
Authors: Yau Hoi Yan
Published: April 2023

This paper offers a critical review of the study of masculinity among overseas Chinese. Rather than turning to Confucianism which has been deployed as the “deep structure” for explaining Chinese masculinity, this paper argues that attention should be directed to the Chinese kinship ideology, which will prove to be a more helpful tool in conceptualizing Chinese masculinity. Through ethnographic cases in Taiwan and Hong Kong, I will show how Chinese masculinity has derived from the Chinese kinship system, on the one hand, and how men in Taiwan and Hong Kong ended up expressing Chinese masculinity differently because of the different geopolitics on the other. This paper concludes that the nature and character of Chinese masculinity overseas, after all, hinges upon another two contexts: geopolitics and its relationship with femininity. It follows that Chinese masculinity cannot be studied in isolation but must be considered in relation to contexts.