bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract A083: Low dose abiraterone in prostate cancer - Safety, efficacy and pharmacoeconomic implications
Authors: Acharya Suryakanta
Published: June 2023

Background and aim: Survival has improved in metastatic castration-resistant prostate cancer (mCRPC) because of the development of effective drugs such as abiraterone acetate, but universal accessibility to treatment is not always possible because of cost constraints in lower- and middle-income countries. Abiraterone in fasting state is the standard of care in mCRPC. Despite a large food effect, it was administered under fasting conditions in its pivotal trials. Recently, the National Comprehensive Cancer Network (NCCN) has included low-dose abiraterone (250 mg/day) with food as an alternative treatment option to full-dose abiraterone (1,000 mg/day) fasting. This translates to 75% cost reduction. This study aims to find safety, efficacy and pharmacoeconomic implications of low dose abiraterone in mCRPC. Materials and Methods: In this cohort study mCRPC Patients with progression were offered low dose abiraterone with low fat meal along with prednisone 5 mg twice daily. Prostate-specific antigen (PSA) was assessed monthly and toxicity assessment was made every week. Final PSA response (≥ 50% reduction) and toxicity assessment were done at 12 weeks. In case of grade IV toxicity (Anemia, Hypertension, Hypokalemia, Hypocalcemia – CTC AE V5.0) because of higher drug bioavailability, patient would be offered full dose abiraterone. 10 patients were offered low dose abiraterone in 2022. Results: 6 out of 10 patients achieved desired PSA response at 12 weeks which is a bit on higher side compared to standard dose abiraterone (recent literature). Fortunately, none of the patient developed grade IV toxicity. This finding was assuring, and no patient shifted to standard dosing. Conclusions: Low dose abiraterone (with low-fat breakfast) is noninferior to full dose abiraterone with respect to PSA metrics. Toxicity is the major thing to look at and given the pharmacoeconomic implications it’s imperative to adopt this strategy in places where affordability is the issue. Let the patients have something rather than nothing!

Citation Format: Suryakanta Acharya. Low dose abiraterone in prostate cancer - Safety, efficacy and pharmacoeconomic implications [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr A083.
Abstract B003: EVI1 oncogenic role in non-canonical AR driven lethal prostate cancer
Authors: Gulla Surendra , Bard Jonathan E. , VanderWeele David J. , Kelly Kathleen , Adelaiye-Ogala Remi
Published: June 2023

Androgen receptor (AR) remains active in castration-resistant prostate cancer (CRPC), and AR cistrome can become extensively reprogrammed with disease progression. Recent findings from our group and others have shown an association with non-canonical AR signature with resistance to enzalutamide. However, the complete mechanism is not fully revealed. EVI1 belongs to the zinc-finger transcription factor family, and overexpression of EVI1 is associated with poor patient outcomes. However, its role in the context of resistance to AR-targeted therapy remains unclear. Our preliminary data from ChIP-seq and GSEA analysis shows a significant enrichment of EVI1 target gene-set captured from annotated enzalutamide-resistant AR binding sites. Hypothesis: EVI1 cooperates in regulating the non-canonical AR activity associated with resistance to AR targeted therapy and blocking EVI1 may overcome resistance to target therapy. Methods : Using a PDX model of advanced enzalutamide-resistant CRPC, we performed single-cell ATAC-seq + gene expression multi-omic assay. Next, we determined the enrichment of canonical vs. non-canonical AR signatures across cell populations. Using motif analysis and transcription factor foot printing, we determine EVI1 (MECOM) motif z score and enrichment. Results: Our findings demonstrate enrichment of non-canonical AR signatures in distinct population of cells following exposure to enzalutamide. In addition, the subpopulation of cells enriched for non-canonical AR cistrome also exhibited high EVI1 (MECOM) motif z-scores. Conclusion : Our data suggests a potential link between EVI1 and non-canonical AR signaling. Ongoing mechanistic studies will provide insight mechanism by which EVI1 controls non canonical AR activity and its vulnerabilities.

Citation Format: Surendra Gulla, Jonathan E. Bard, David J. VanderWeele, Kathleen Kelly, Remi Adelaiye-Ogala. EVI1 oncogenic role in non-canonical AR driven lethal prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B003.
Abstract B005: The oncogenic transcription factor ERG has distinct roles and signaling regulation in different prostate cancer cell types
Authors: Hollenhorst Peter C. , Rajendran Saranya , Jerde Travis J.
Published: June 2023

Background: ERG is the most common oncogene in prostate cancer, as it is aberrantly expressed in about 50% of cases due to the TMPRSS2/ERG gene rearrangement. ERG is not normally expressed in the adult prostate. The normal function of ERG is confined to hematopoietic stem cells and blood vessels. Aberrant expression of ERG in prostate epithelial cells is oncogenic when combined with mutations that activate the PI3K/AKT signaling pathway. The RAS/MAPK pathway can also regulate ERG function through direct phosphorylation of ERG by ERK. The function of these regulatory events and how they can be exploited to develop therapy for ERG-positive prostate cancer remains unclear. Results: ERG expression in prostate basal epithelial cells drives epithelial to mesenchymal transition and stemness properties. This function requires ERG phosphorylation via a positive feedback loop with the TLR4 signaling pathway, and can be repressed by a TLR4 inhibitor. Activation of the PI3K/AKT pathway rearranges the ERG cistrome and alters ERG function, where ERG now promotes luminal epithelial differentiation. In the presence of activated AKT, new ERG targets include genes involved in vascular development and ERG phosphorylation is regulated through a positive feedback loop with the VEGF signaling pathway. Conclusions: ERG function in basal and luminal prostate epithelial cells appear to mirror ERG functions in hematopoietic stem cells and blood vessels, respectively. These findings suggest strategies of combinatorial inhibition of ERG function in both cell types.

Citation Format: Peter C. Hollenhorst, Saranya Rajendran, Travis J. Jerde. The oncogenic transcription factor ERG has distinct roles and signaling regulation in different prostate cancer cell types [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B005.
Abstract B024: Nuclear size and nuclear shape instability in prostate cancer epithelial cells during metastatic progression
Authors: Cavassani Karen , Posadas Edwin , Teng Pai-Chi , Pustchi Sadaf Pustchi , Kim Minhyung , Bhowmick Neil , You Sungyong , Freeman Michael , Ellis Leigh , Vizio Dolores Di , Tseng Hsian-Rong , Chung Leland W. , Yao Susan , Grasso Catherine
Published: June 2023

Very small nuclear (vsn) circulating tumor cells (CTCs) are detected in a subgroup of metastatic, castration resistant prostate cancer (mCRPC) patients who develop visceral metastasis following intensive androgen receptor suppression. In addition, we have previously observed that nuclear shape instability (characterized by the loss and/or mis-localization of the nuclear envelop protein emerin) is present in human prostate cancer tissues, and in CTCs from patients with metastatic disease. Herein, we investigated the biological and clinical implications of the vsn phenotype in prostate CTCs. Patients with vsnCTCs had poor overall survival and low PSA response to androgen receptor suppression compared with non-vsnCTC patients. The vsnCTCs exhibited a loss/downregulation of emerin (EMD) and we found a direct correlation between emerin loss and nuclear size reduction in CTC from mCRPC patients. Further, in vitro studies revealed that the vsn phenotype was characterized by high invasive capacity, enhanced cellular plasticity, and resistance to AR target therapy. Finally, depletion of EMD in prostate tumor cells resulted in the vsn phenotype. Together, these findings demonstrate that the vsnCTC phenotype is characterized by deregulation of EMD expression, and the presence of these cells result in poor clinical outcomes in prostate cancer.

Citation Format: Karen Cavassani, Edwin Posadas, Pai-Chi Teng, Sadaf Pustchi Pustchi, Minhyung Kim, Neil Bhowmick, Sungyong You, Michael Freeman, Leigh Ellis, Dolores Di Vizio, Hsian-Rong Tseng, Leland W. Chung, Susan Yao, Catherine Grasso. Nuclear size and nuclear shape instability in prostate cancer epithelial cells during metastatic progression [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B024.
Abstract B052: Prostate cancer prevention is possible thanks to the evaluation of the primary exons of the BRCA1 biomarker in men
Authors: Moussa Haboubacar Elhadji Yaou , Chichi Callinis Capo
Published: June 2023

Prostate cancer is a public health concern among 50 year old the men worldwide and its incidence keep rising. It is triggered by genome instability or epigenetic modifications impacting DNA repair and tumor suppression genes and proteins. In African countries, little data is available on prostate cancer and the loss of BRCA1 exons responsible for tumor suppression. It is in this context that we undertook this study, the general objective of which is to assess the association between BRCA1 instability in patients with prostate cancer, These men with prostate cancer usually present with symptoms like nocturia and poor urinary flow, erectile dysfunction and visible hematuria.

Citation Format: Haboubacar Elhadji Yaou Moussa, Callinis Capo Chichi. Prostate cancer prevention is possible thanks to the evaluation of the primary exons of the BRCA1 biomarker in men [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B052.
Abstract B057: ZBTB7A as a novel vulnerability in neuroendocrine prostate cancer
Authors: Bae Song Yi , Bergom Hannah E. , Day Abderrahman , Greene Joseph T. , Freedman Tanya S. , Hwang Justin H. , Drake Justin M.
Published: June 2023

Neuroendocrine prostate cancer (NEPC) is a lethal variant of aggressive prostate cancer. Hallmarks of NEPC include the loss of androgen receptor (AR) signaling and transdifferentiation toward small-cell neuroendocrine (SCN) phenotypes, which result in resistance to AR-targeted therapy. NEPC resembles other SCN carcinomas clinically, histologically and genomically. Here, we leveraged SCN phenotype scores of various cancer cell lines and gene depletion screens from the Cancer Dependency Map (DepMap) to identify vulnerabilities in NEPC. We discovered ZBTB7A, a transcription factor, as a candidate promoting the progression of NEPC. Cancer cells with high SCN phenotype scores showed a strong dependency with RET kinase, an emerging therapeutic target of NEPC, suggesting the NEPC-like phenotype of the cells. Then, we observed a strong correlation between dependencies of RET and ZBTB7A in these cells. Utilizing informatic modeling of whole transcriptome sequencing data from patient samples, we revealed distinct gene networking patterns of ZBTB7A in NEPC versus prostate adenocarcinoma. Specifically, we observed a robust association of ZBTB7A with genes promoting cell cycle progression in NEPC, and this result was confirmed through Gene Set Enrichment Analysis. Furthermore, we showed a potential interaction of ZBTB7A with apoptosis regulating genes. Silencing ZBTB7A in a NEPC cell line confirmed the dependency of cells on ZBTB7A for cell growth, and the role of ZBTB7A in regulating G1/S transition in cell cycle and inducing apoptosis. Collectively, our results highlight the oncogenic function of ZBTB7A in NEPC, and emphasize the value of ZBTB7A as a promising therapeutic strategy for targeting NEPC tumors.

Citation Format: Song Yi Bae, Hannah E. Bergom, Abderrahman Day, Joseph T. Greene, Tanya S. Freedman, Justin H. Hwang, Justin M. Drake. ZBTB7A as a novel vulnerability in neuroendocrine prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B057.
Abstract B069: SPOP loss places the prostate luminal epithelial cells at a selective disadvantage
Authors: Rizwan Kinza , Skapura Darlene , Mason Cammy , Coarfa Cristian , Mitsiades Nicholas , Young Damian , Kaochar Salma
Published: June 2023

Background: Prostate cancer (PC) is the single most common and second-most lethal cancer in men, with over 268,000 estimated cases and over 34,500 estimated deaths in the US in 2022. The Speckle-Type POZ protein (SPOP) mutant subclass of PC accounts for 10% to 15% of all primary PC cases. SPOP is an adaptor for Cullin3/Ring (CUL3-RING)-type E3 ubiquitin ligase complexes and provides substrate specificity. The Cancer Genome Atlas (TCGA) studies show that SPOP is the most frequently mutated gene in primary prostate cancer (PC). Interestingly, PC-associated SPOP mutations are always missense and occur in a heterozygous fashion. The current gap in knowledge is the lack of understanding of the role of wildtype SPOP in PC. Methods: By utilizing prostate specific SPOP knockout (KO) mice, we recently reported increased levels of AR and MYC protein and increased cellular turnover (both proliferation and apoptosis) in the prostate luminal epithelium compared to wildtype prostates. We now characterized these mice for the expression of Cre protein and SPOP mRNA at different age using immunohistochemistry and RNA in situ hybridization. Furthermore, we performed RNA-sequencing analysis in the SPOP knockout mice and matched control littermates. Moreover, we performed RNA-seq in LNCaP, LNCaP-Abl, and RWPE1 cells following SPOP inhibition via siRNA targeting SPOP. Finally, we compared our SPOP inhibition signature from in vitro cell lines and prostate specific SPOP knockout murine model to gain insights about the role of wildtype SPOP protein in the prostate epithelium. Result: Using our Spopfl/fl;PBCre+ model, we observed SPOP floxed cells are rapidly lost and the murine prostate epithelium was repopulated with SPOP wildtype carrying cells. Similarly, knockdown (KD) of SPOP through siRNA treatment in a panel of PC cell lines resulted in a significant reduction in cell viability. These observations suggest that SPOP is important for the normal prostate cell viability. Further transcriptomic profiling of SPOP KO (from transgenic murine model) as well as siSPOP treated in vitro prostate cell lines revealed a significant reduction in the transcriptional activity of the AR. Conclusion: Our data illustrate for the first time a critical role for SPOP in the growth and survival of the prostate epithelium and prostate cancer cell. Our findings further validates SPOP as a important therapeutic target for the treatment of prostate cancer.

Citation Format: Kinza Rizwan, Darlene Skapura, Cammy Mason, Cristian Coarfa, Nicholas Mitsiades, Damian Young, Salma Kaochar. SPOP loss places the prostate luminal epithelial cells at a selective disadvantage [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B069.
Abstract IA014: Drug sensitivity of multifocal primary prostate cancer
Authors: Kruithof-de Julio Marianna , Kang Juening , Karkampouna Sofia , Ovchinnikova Katja , Chouvardas Panagiotis , Thalmann George N
Published: June 2023

Prostate cancer (PCa) is a highly heterogeneous disease with multiple and distinct cancer foci within the same prostate gland. We hypothesize that heterogeneous lesions, in terms of genomic aberrations and tumour staging, may be linked to different functional properties e.g. differential drug response sensitivity. We investigate which histopathological and molecular properties are associated with ability to maintain PCa cells as ex vivo organoid cultures and possibly specific drug responses. Interestingly, the majority of primary PCa cases showed genetic and histopathological multifocality, representing a highly heterogeneous cohort. PDOs recapitulated the genetic signature of the parental tissues. Drug responses of PDOs did not follow patient-specific patterns but rather revealed high inter- and intra-patient heterogeneity. Therapy response could be predicted based on transcriptomic profile for personalized treatment decision. The transcriptomic profile of each case was overall preserved among different cores. Drug responses in PDOs revealed not only inter- but also intra-patient heterogeneity with only 2 patient cases having positive correlation within the different cores of the same case. Statistically significant correlations were found among 8 genomic mutations and sensitivity to 5 drug compounds. Different features were tested for ML model, with RNA-seq outperforming the rest features; on average 260-1800 genes per drugs were selected for the drug prediction. ML linear regression models showed high Pearson’s correlation between predicted and observed drug response values.

Citation Format: Marianna Kruithof-de Julio, Juening Kang, Sofia Karkampouna, Katja Ovchinnikova, Panagiotis Chouvardas, George N Thalmann. Drug sensitivity of multifocal primary prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr IA014.
Abstract PR009: Basal cell lineage plasticity in prostate homeostasis, repair and tumor initiation
Authors: Gao Dong
Published: June 2023

Androgen deprivation is the paradigm of prostate cancer treatment. It is often linked to the loss of luminal cells, but the basal cell fates under androgen deprivation, prostatitis and cancer initiation remain unclear. Using a genetic proliferation tracer (ProTracer) system, we found that adult prostate basal cells also had extensive cell loss and proliferation during androgen-mediated prostate regression and regeneration. A rare basal population that expresses luminal cell genes (termed Basal-B) and a large basal population (termed Basal-A) were identified in the mouse prostate by single-cell RNA sequencing. Basal-B cells exhibited greater capacity for organoid formation and luminal cell differentiation in vitro. Basal-A and Basal-B cells were specifically tracked at the same time in vivo using a genetic lineage-tracing system that uses dual recombinases (Cre and Dre). Fate-mapping showed that prostate basal regeneration is not driven by rare Basal-B cells. Clonal analysis showed that Basal-B cells had the better tendency to generate luminal cells under bacteria-induced prostatitis. Moreover, oncogenic transformation of basal cells promoted the Basal-B cell marker gene expression in vivo. This study provides genetic evidence of a bona fide of basal cell lineage plasticity under androgen deprivation, prostatitis and oncogenic transformation contexts.

Citation Format: Dong Gao. Basal cell lineage plasticity in prostate homeostasis, repair and tumor initiation [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr PR009.
Abstract PR010: First-in-class TRPV6 inhibitors for the treatment of prostate cancer
Authors: Beaumont Kimberley , Pouwer Rebecca , Rahmani Raphael , McLachlan Matthew , Levrier Claire , Farrow Rebecca , Yeh Mei , Johnson Therese , Kumarasiri Malika , Wijesekera Hasanthi , Stuchbury Grant , Cock Terrie-Anne , Harvey Andrew , Monteith Gregory , Dymock Brian
Published: June 2023

TRPV6, a calcium channel, is an oncochannel that is overexpressed in epithelial cancers including prostate cancer. We have developed a novel series of first-in-class small molecule TRPV6 inhibitors for the treatment of advanced prostate cancer. Our preclinical candidate QED-203 has been shown to inhibit calcium influx at low nM potency in TRPV6 cellular assays (FLIPR, electrophysiology), and has low nM potency in a TRPV6-driven NFAT assay (NFAT luciferase reporter). Inhibition of TRPV6 with our TRPV6 inhibitors or by siRNA knockdown causes changes in genes related to NFAT and WNT signalling, ER stress and the cell cycle (RNAseq and qPCR analysis), and causes cell cycle arrest, decreased proliferation and apoptosis in prostate cancer cells (demonstrated via imaging and FACS analysis). Importantly, QED-203 demonstrates potency in enzalutamide resistant cell lines (in vitro proliferation inhibition) and has superior potency over enzalutamide and darolutamide [androgen receptor targeting agents (ARTA)] in prostate cancer cell lines with clinically relevant AR mutations or the ARV7 splice variant. The ARV7 variant in particular is represented in a significant portion of patients no longer responding to ARTA SoC interventions. QED-203 has high bioavailability with a pharmacokinetic profile amenable to once-a-day oral dosing. QED-203 is well tolerated in rodents and has similar in vivo efficacy (tumour growth and PSA inhibition) to enzalutamide in a castrated LNCaP mouse model of prostate cancer. We have also shown QED-203 target engagement in rodents by demonstrating a change in calcium levels in the urine, and have observed changes in genes consistent with a TRPV6-specific mode of action in xenograft tumours (demonstrated via qPCR). QED-203 targets a novel, non-hormonal mechanism in prostate cancer, and could be used to treat prostate cancer patients who have developed resistance to AR therapies, where there is a large unmet need.

Citation Format: Kimberley Beaumont, Rebecca Pouwer, Raphael Rahmani, Matthew McLachlan, Claire Levrier, Rebecca Farrow, Mei Yeh, Therese Johnson, Malika Kumarasiri, Hasanthi Wijesekera, Grant Stuchbury, Terrie-Anne Cock, Andrew Harvey, Gregory Monteith, Brian Dymock. First-in-class TRPV6 inhibitors for the treatment of prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr PR010.
Pancreatic Neoplasms Are Frighteningly Common: A Role for Immune Surveillance?
Authors: Hoffman Megan T. , Dougan Stephanie K.
Published: June 2023

Carpenter and colleagues analyze organ donors to find that pancreatic intraepithelial neoplasia (PanIN), the precursor lesions of pancreatic ductal adenocarcinoma, are highly prevalent in the average healthy adult starting from a young age. Why these precursor lesions do not progress to cancer in most people is a mystery.

See related article by Carpenter et al., p. 1324 (1).
Melanoma Genomics: Shifting Focus from Inter- to Intrapatient Variation
Authors: Shain A. Hunter
Published: June 2023

Traditionally, omic studies have prioritized the number of patients over the number of tumors per patient, but in a reversal of this study design, Spain and colleagues performed the largest intrapatient analysis of melanoma to date. Their work reveals mechanisms of treatment resistance, patterns of metastatic dissemination, and new insights into the evolutionary trajectories of melanoma.

See related article by Spain et al., p. 1364 (1).
Data from EBV-Upregulated B7-H3 Inhibits NK cell–Mediated Antitumor Function and Contributes to Nasopharyngeal Carcinoma Progression
Authors: Chen Haiwen , Duan Xiaobing , Deng Xiaohong , Huang Yingping , Zhou Xiang , Zhang Shanshan , Zhang Xiao , Liu Pingjuan , Yang Chaopin , Liu Guojun , Ren Qinqin , Xiong Yan , Zhu Bo , Zhang Jiexia , Xiang Tong
Published: June 2023

Abstract
Nasopharyngeal carcinoma (NPC) is an Epstein–Barr virus (EBV)–associated epithelial malignancy characterized by the presence of prominent infiltration of lymphocytes, including natural killer (NK) cells. Although NK cells can directly target EBV-infected tumor cells without restriction by the MHC, EBV-positive (EBV+) NPC cells often develop resistance mechanisms that allow them to evade immune surveillance by NK cells. Elucidating the mechanisms involved in EBV-induced NK-cell dysfunction will contribute to the design of novel NK cell–based immunotherapies to treat NPC. Herein, we confirmed that the cytotoxic function of NK cells was impaired in EBV+ NPC tissues and found that EBV infection–induced expression of B7-H3 in NPC negatively correlated with NK-cell function. The inhibitory effect of EBV+ tumor expression of B7-H3 on NK-cell function was clarified in vitro and in vivo. Mechanistically, activation of the PI3K/AKT/mTOR signaling pathway via EBV latent membrane protein 1 (LMP1) was responsible for EBV infection–induced upregulation of B7-H3 expression. In an NPC xenograft mouse model with adoptive transfer of primary NK cells, deletion of B7-H3 on tumor cells in combination with anti–PD-L1 treatment restored NK cell–mediated antitumor activity and significantly improved the antitumor efficacy of NK cells. On the basis of our findings, we conclude that EBV infection can inhibit NK cell–mediated antitumor function by inducing upregulation of B7-H3 expression and provide a rationale for NK cell–based immunotherapies in combination of PD-L1 blockade and overcoming the immunosuppression of B7-H3 to treat EBV-associated NPC.
Data from iBRIDGE: A Data Integration Method to Identify Inflamed Tumors from Single-cell RNA-Seq Data and Differentiate Cell Type–Specific Markers of Immune-Cell Infiltration
Authors: Turan Tolga , Kongpachith Sarah , Halliwill Kyle , McLaughlin Robert T. , Binnewies Mikhail , Reddy Dhemath , Zhao Xi , Mathew Rebecca , Ye Shiming , Jacob Howard J. , Samayoa Josue
Published: June 2023

Abstract
The development of immune checkpoint–based immunotherapies has been a major advancement in the treatment of cancer, with a subset of patients exhibiting durable clinical responses. A predictive biomarker for immunotherapy response is the preexisting T-cell infiltration in the tumor immune microenvironment (TIME). Bulk transcriptomics–based approaches can quantify the degree of T-cell infiltration using deconvolution methods and identify additional markers of inflamed/cold cancers at the bulk level. However, bulk techniques are unable to identify biomarkers of individual cell types. Although single-cell RNA sequencing (scRNA-seq) assays are now being used to profile the TIME, to our knowledge there is no method of identifying patients with a T-cell inflamed TIME from scRNA-seq data. Here, we describe a method, iBRIDGE, which integrates reference bulk RNA-seq data with the malignant subset of scRNA-seq datasets to identify patients with a T-cell inflamed TIME. Using two datasets with matched bulk data, we show iBRIDGE results correlated highly with bulk assessments (0.85 and 0.9 correlation coefficients). Using iBRIDGE, we identified markers of inflamed phenotypes in malignant cells, myeloid cells, and fibroblasts, establishing type I and type II interferon pathways as dominant signals, especially in malignant and myeloid cells, and finding the TGFβ-driven mesenchymal phenotype not only in fibroblasts but also in malignant cells. Besides relative classification, per-patient average iBRIDGE scores and independent RNAScope quantifications were used for threshold-based absolute classification. Moreover, iBRIDGE can be applied to in vitro grown cancer cell lines and can identify the cell lines that are adapted from inflamed/cold patient tumors.
Data from Regional variation in the tumor microenvironment, immune escape and prognostic factors in breast cancer in sub-Saharan Africa
Authors: Bauer Marcus , Vetter Martina , Stückrath Kathrin , Yohannes Meron , Desalegn Zelalem , Yalew Tewodros , Bekuretsion Yonas , Kenea Tariku W. , Joffe Maureen , Van Den Berg Eunice J. , Nikulu Julien Ilunga. , Bakarou Kamaté , Manraj Shyam S. , Ogunbiyi Olufemi J. , Ekanem Ima-Obong , Igbinoba Festus , Diomande Mohenou , Adebamowo Clement , Dzamalala Charles P. , Anele Angelica A. , Zietsman Annelle , Galukande Moses , Foerster Milena , dos-Santos-Silva Isabel , Liu Biying , Santos Pablo , Jemal Ahmedin , Abebe Tamrat , Wickenhauser Claudia , Seliger Barbara , McCormack Valerie , Kantelhardt Eva J.
Published: June 2023

Abstract
The low overall survival rates of breast cancer (BC) patients in sub-Saharan Africa (SSA) are driven by regionally differing tumor biology, advanced tumor stages at diagnosis and limited access to therapy. However, it is not known whether regional differences in the composition of the tumor microenvironment (TME) exist and affect patients’ prognosis. In this international, multicentre cohort study, 1,237 formalin-fixed, paraffin-embedded BC samples, including samples of the ‘African Breast Cancer-Disparities in Outcomes (ABC-DO) Study’, were analyzed. The immune cell phenotypes, their spatial distribution in the TME and immune escape mechanisms of BC samples from SSA and Germany (n=117) were investigated using histomorphology, conventional and multiplex immunohistochemistry (IHC), and RNA expression analysis. The data revealed no regional differences in the number of tumor-infiltrating lymphocytes (TILs) in the 1,237 SSA BC samples, while the distribution of TILs in different BC IHC subtypes showed regional diversity, particularly when compared to German samples. Higher TIL densities were associated with better survival in the SSA cohort (n=400), but regional differences concerning the predictive value of TILs existed. High numbers of CD163+ macrophages and CD3+CD8+ T cells accompanied by reduced cytotoxicity, altered IL10 and IFNγ levels and downregulation of MHC class I components were predominantly detected in BC samples from Western SSA. Features of non-immunogenic BC phenotypes were associated with reduced patient survival (n=131). We therefore conclude that regional diversity in the distribution of BC subtypes, TME composition and immune escape mechanisms should be considered for therapy decisions in SSA and the design of personalized therapies.
Callicles as a Potential Tyrant in Plato's Gorgias
Authors: Lopes Daniel R. N.
Published: June 2023

This essay argues that Callicles is depicted by Plato in the Gorgias as a potential tyrant from a psychological standpoint. To this end I will contend that the Calliclean moral psychology sketched at 491e-492c points towards the analysis of the tyrannical individual pursued by Plato in books VIII and IX of the Republic based upon the tripartite theory of the soul. I will thereby attempt to show that (i) in the Gorgias, Callicles does not actually personify the ideal of the superior person advocated by himself insofar as he is still susceptible to shame, as evinced by Socrates' cross-examination (494c-495a); and that (ii) looking forward to the Republic, he can be understood for this same reason as being precisely on the threshold between the democratic and the tyrannical soul.
Temporal Truth and Bivalence: an Anachronistic Formal Approach to Aristotle’s De Interpretatione 9
Authors: Santos Luiz Henrique Lopes dos
Published: June 2023

Regarding the famous Sea Battle Argument, which Aristotle presents in De Interpretatione 9, there has never been a general agreement not only about its correctness but also, and mainly, about what the argument really is. According to the most natural reading of the chapter, the argument appeals to a temporal concept of truth and concludes that not every statement is always either true or false. However, many of Aristotle’s followers and commentators have not adopted this reading. I believe that it has faced so much resistance for reasons of hermeneutic charity: denying the law of universal bivalence seems to be overly disruptive to logical orthodoxy – the kind of logical orthodoxy represented by what we now call classical propositional logic, much of which Aristotle clearly supports in many texts. I intend to show that the logical-semantic theses that the traditional reading finds in De Interpretatione 9 are much more conservative than they may seem to be at first glance. First, I will show that they complement, and do not contradict in any way, the orthodox definitions of the concepts of truth and statement that Aristotle advances in other texts. Second, by resorting in an anachronistic vein to concepts and methods peculiar to contemporary logic, I will show that a trivalent modal semantics conforming to those theses can be built for a standard formal language of the classical propositional calculus. It is remarkable that reasonable concepts of logical truth and logical consequence that may be defined on the basis of this trivalent modal semantics are coextensive with their orthodox counterparts, the concepts of tautology and tautological consequence of classical bivalent and extensional semantics.
Niétotchka, de Dostoiévski, e Júlia, de Aline Bei: existências dolorosas e construções inacabadas à luz da psicanálise
Authors: Saves Fernando Guimarães
Published: June 2023

Dostoiévski, um dos maiores escritores russos, autor de obras como Os Irmãos Karamázov (1879), de acordo com Freud, foi “o mais grandioso romance já escrito”. Aline Bei, por sua vez, desponta no cenário da literatura a partir de seu primeiro romance, O Peso do Pássaro Morto (2017). A despeito da fama, do espaço geográfico, do contexto histórico e dos quase dois séculos que os separam, é possível estabelecer uma fronteira entre os dois autores? Pois é precisamente este o objetivo deste artigo, que procurou comparar as obras Niétotchka Niezvânova e Pequena Coreografia do Adeus, dos respectivos autores, a fim de demarcar um terreno onde as similaridades e as diferenças possam ser identificadas e alinhavadas à luz do conhecimento freudiano. Tomando-se as experiências singulares e as idiossincrasias das protagonistas Niétotchka e Júlia, este artigo buscou aprofundar algumas questões de especial interesse para os estudiosos da psique, demonstrando que, independentemente da época e do contexto histórico-cultural, alguns temas tocam os indivíduos de forma similar, aproximando-os na grande experiência da existência humana.
Penhascos e Abismos: a representação do mar em A Tempestade de Aleksandr Púchkin
Authors: Vilara Karina Vilela
Published: June 2023

O presente trabalho busca analisar o poema “A Tempestade” (1825), de Aleksandr Púchkin, já traduzido para o português por José Casado e Felipe Munhoz, a fim de lhe conferir certo espaço na recepção de sua obra no Brasil. Mostrar-se-á como uma produção poética, não obstante sua pequena extensão, doze versos, faz emergir importantes questões semânticas e estruturais da poética do autor. Por fim, será discutido como ele se insere no contexto de produção dos anos 1820 e quais repercussões tem a figura do mar na obra.
Água, cimento e brita: um Maiakóvski de concreto
Authors: Bonavina Rafael
Published: June 2023

A partir da discussão ampla das relações culturais entre Brasil e Rússia no século XX, o presente trabalho buscou levantar uma hipótese quanto à inserção tardia da obra de Vladimir Maiakóvski no cerne duro das teorizações do grupo Noigandres, em especial dos irmãos Campos. Para isso, mobilizamos documentos que colaboram com a tentativa de precisar historicamente esse contato e levantamos a hipótese de ele ter ocorrido entre 1958 e 1962, o que é corroborado pela fortuna crítica.
Power Analysis for Ordinal Analyses of the Modified Rankin Scale and an Online and Downloadable Tool for Practical Use
Authors: Johns Hannah , Campbell Bruce , Turc Guillaume , Churilov Leonid
Published: June 2023

BACKGROUND:

Several methods for conducting power analysis of studies with outcomes across the full ordinal modified Rankin Scale are proposed in the literature. No systematic comparison of accuracy, agreement, and sensitivity to small changes in hypothesized effect sizes for these methods is available. Our aim is to conduct such a systematic comparative analysis and to introduce a comprehensive freely available online tool to facilitate appropriate power analyses for ordinal outcomes.

METHODS:

We performed simulation studies utilizing the control arm modified Rankin Scale distributions from the AVERT (A Very Early Rehabilitation Trial), EXTEND (Extending the Time for Thrombolysis in Emergency Neurological Deficits), and HERMES (Highly Effective Reperfusion Evaluated in Multiple Endovascular Stroke Trials) studies, as well as a uniform distribution, in combination with hypothetical treatment effects. We systematically evaluated published power formulas for Ordinal Logistic Regression and Tournament Methods (generalized odds ratio; Win Probability; Win Ratio; and Wilcoxon-Mann-Whitney
U
test). We also developed an online and downloadable Shiny R app facilitating sample size calculation for, and ordinal analysis of, modified Rankin Scale data.

RESULTS:

Power formulas for Tournament Methods performed well, while the formula for ordinal logistic regression was inaccurate. Tang’s Wilcoxon-Mann-Whitney
U
test sample size formula exhibited the highest accuracy. All methods, including ordinal logistic regression, had almost identical empirical power for a given sample size. All power methods exhibited sensitivity to small changes in hypothesized effect size. The developed freely available online app supports analytical and visualization requirements for all investigated methods for power and statistical analyses of ordinal modified Rankin Scale outcomes.

CONCLUSIONS:

As Tournament Method sample size formulas are assumption-free and accurately calculate power, stroke researchers should use these methods when designing studies with outcomes measured on the full or partially collapsed modified Rankin Scale as well as other ordinal scales, even if they intend to use ordinal logistic regression for analysis. Conducting sensitivity analyses of the effect size assumptions are essential for appropriate sample size estimation. Our developed tool supports both of these recommendations (
https://www.thembc.com.au/tournamentmethods
).
Beyond Language Deficits: Working Alliance and Resources as Predictors of Recovery From Aphasia
Authors: Stahl Benjamin
Published: June 2023

Large-scale clinical trials and meta-analyses have determined neurobiological and linguistic predictors of recovery from aphasia, while more recent work is opening the field to factors of efficacy previously established in psychiatry—and little known in neurology. To map this evolving area of research, the present essay explores key factors of efficacy in psychotherapy as potential predictors of recovery from aphasia. In particular, the essay addresses (1) working alliance, including consensus between patient and therapist on treatment goals and tasks alongside interpersonal bonds, as well as (2) focus on resources rather than deficits in language performance. Finally, the essay outlines why research on impaired communication ability may help advance and complement existing methods in psychotherapy.
Voices of the Dying
Authors: Kucharski Janek
Published: June 2023

This paper discusses the convention of off-stage cries deployed in Greek tragedy and satyr play chiefly to represent violent events. Unlike other studies dedicated to this topic, it is primarily focused on the cries themselves and to a lesser extent on their context, both dramatic and theatrical. Using the familiar distinction between word and action, it begins with a simple question: how exactly does an off-stage cry represent a violent event taking place within? Examined first as textual phenomena the voices from within are found to acquire their meaning through the discourse of the characters, and not as cries per se. The performative approach, however, also brings their auditory dimension into perspective. Although the evidence is mostly circumstantial, its cumulative weight does suggest that the vocal qualities of the off-stage cries could endow them with meanings unaccounted for in the textual perspective.
Two new species of sedentary nematodes of the genus Meloidodera Chitwood, Hannon & Esser, 1956 (Tylenchida: Heteroderidae) from Mexico
Authors: Cid del Prado Vera Ignacio , Subbotin Sergei A.
Published: June 2023

Two new species of the genus Meloidodera collected in Mexico are described here: M. ferrisi sp. n. parasitising roots of an oak tree in the State of Mexico and M. tecoacensis sp. n. parasitising roots of buffalo bur nightshade in the Tlaxcala State. Meloidodera ferrisi sp. n. is characterised by a spherical female body covered completely by a dark thick cuticular layer, length/width of the female body = 0.8-1.6, stylet = 35-43 μm and second-stage juvenile with average body = 340 μm and average tail length = 35.6 μm. Meloidodera tecoacensis sp. n. is characterised by the female having a spherical body covered with a yellow transparent material, length/width of the female body = 1.1-2.8, stylet = 20-33 μm and second-stage juvenile with average body = 340 μm and average tail length = 29.8 μm. These two species were molecularly characterised using the D2-D3 expansion segments of 28S rRNA, ITS rRNA and COI gene sequences. Phylogenetic analysis revealed that the two new species represent a separate evolutionary lineage within the subfamily Meloidoderinae. An identification key for 12 Meloidodera species is provided.
Difference analysis of respiratory pore flora between dolphins in the wild and in captivity
Authors: Li Siyao , Liao Jianxun , Liu Xiaodan , Zhang Lihuan , Luo Zhanqing , Zhang Huixiang , Cao Xue
Published: June 2023

Dolphins are marine mammals with unique anatomical structures in their airways. These particular respiratory structures make dolphins very sensitive to microorganisms in the air, and the habitats of dolphins in captivity and in the wild are quite different. This causes captive dolphins to suffer from illnesses, especially respiratory diseases. Previous studies have shown that the respiratory flora plays an essential role in the health of humans and animals. Therefore, by comparative analysis of the respiratory flora of wild dolphins and dolphins in captivity, we want to find the flora related to dolphins’ respiratory diseases, and try to improve dolphin health through flora homeostasis. For this purpose, we performed 16S rRNA gene sequencing and analyses. We found that Proteobacteria, Firmicutes, Actinobacteria, Campilobacterota, Paracoccus, and other flora differed between wild and healthy and sub-healthy captive dolphins. Some of them are the dominant flora for promoting health, and the others may be essential pathogenic bacteria in the sub-healthy state of dolphins in captivity.
Through the Lens of Urdu
Authors: Mian Zain R.
Published: June 2023

This essay examines Adabī dunyā, or Literary World, to argue for a dialectical relationship between world literature and the Urdu magazine. Adabī dunyā carved a niche for itself in a competitive Indian magazine ecology by positioning itself as a worldly and world-class magazine in terms of its content and material form. How this publication circulated world literature was inspired by the educational impetus of the ‘ilmī o adabī magazine genre (roughly translatable as “educational and literary”). Adabī dunyā mediated readers’ appreciation of world authors by relying on a range of forms such as the survey essay, image, and original Urdu texts inspired by those authors. By focusing on its representation of Dante Alighieri, I show how the magazine sought to nurture a multidimensional relationship between Indian readers and foreign writers. In so doing, Adabī dunyā produced a local iteration of world literature centered on Urdu culture.
Luke 22:36 and Hsiao’s Libertarian ‘Theology’ of Gun Ownership
Authors: Barrigar Chris
Published: June 2023

Christian philosopher Timothy Hsiao has recently provided in this journal a defence of gun ownership and public gun carrying. I will respond with an argument against gun ownership for self-defence. In particular I will argue that Hsiao’s argument misuses Scripture, fails to employ a range of important theological categories, and leads to increased harms. I argue these failings occur because Hsiao’s fundamental objective is not to seek a Kingdom of God theology of guns but rather to defend a libertarian social vision. In effect, his thin theology is really a veneer for a libertarian defence of guns and gun culture, whereas I argue that a Kingdom of God theology seeks to provide a safer society and thus would move society away from gun culture.
Tailoring the Band Gap of Carbon Nanoparticles in Carbon Soot by Ball Milling
Authors: Das Sandip , Pramanik Subhamay , Mukherjee Sumit , Nath Rajib , Kuiri Probodh K.
Published: June 2023

Carbon nanoparticles (CNPs) in carbon soot have been ball milled in air for time durations of 1, 3, and 5 hours. A reduction of the average height of CNPs, measured using atomic force microscopy, with increase in ball milling time has been observed with values about 22.54 nm, 11.09
nm, 9.48 nm, and 7.25 nm for un-milled and ball milled samples for durations of 1, 3, and 5 hours, respectively. The optical band gaps of the CNPs have been estimated from the optical absorption data with values of about 5.06 eV, 3.77 eV, 2.08 eV, and 1.55 eV for the as-synthesized CNPs and
1, 3, and 5 hours of ball milled CNPs, respectively. Such observations of reduction of height and decrease in band gap of the CNPs are due to the mainly increase in in-plane graphitic ordering in the CNPs and simultaneous attachment of oxygen from the air ambient. The ball milling provided
the required energy to acquire the in-plane graphitic order in the CNPs reducing the disorders in it. Also changes in the functional groups (formation of carbon and oxygen bonds) in the surfaces of the in-plane graphite in the CNPs can lead to the formation of graphene oxide (GO) leading to
change in the surface states which can result in decrease in band gap of the CNPs. With increase in ball milling time, amount of GO has been increased resulted in further decrease in the band gap of the CNPs.
The Soil Moisture–Surface Flux Relationship as a Factor for Extreme Heat Predictability in Subseasonal to Seasonal Forecasts
Authors: Benson David O. , Dirmeyer Paul A.
Published: June 2023

Thresholds of soil moisture exist below which the atmosphere becomes hypersensitive to land surface drying, inducing thermal feedbacks that can exacerbate heatwaves. Realistic representation of threshold transitions in forecast models could improve extreme heat predictability and understanding of the role of land–atmosphere coupling. This study evaluates the performance of several forecast models from the Subseasonal Experiment (SubX) and several prototype versions of the Unified Forecast System (UFS) in their representation of threshold transitions by validation against reanalysis data. A metric of skill (true skill score) is applied to soil moisture breakpoint values, which mark the transition to heatwave hypersensitivity for drying soils. Forecast models have poor skill at being initialized on the correct side of the breakpoint, but show improvement when normalized to account for deficiencies in their soil moisture climatologies. Regionally, models performed best in the U.S. Northwest and worst in the Southwest. They effectively capture the tendency of western regions to spend more summer days in the hypersensitive regime than the eastern United States. Models represent well extreme heat as a consequence of atmospheric initial state for the first week of the forecast, but struggle to represent the soil moisture feedback regime. Forecast models generally perform better at extreme heat prediction when they are already dry and in the hypersensitive regime, even when erroneously so, implying that errors or biases exist in model parameterizations. Nevertheless, composite analysis shows encouraging model performance of the “hit” category, suggesting that an improvement in soil moisture initialization could further improve extreme heat forecast skill.