bluuebunny/crossref_metadata_2025_split huggingface dataset:
Experimental Investigation of a Butylcyclohexane / Propylcyclohexane Based Naphthenic Bio-Blendstock Surrogate Fuel for Use in a Compression Ignition Engine
Authors: Ristow Hadlich Rodrigo , Ran Zhongnan , Yang Ruinan , Mante Ofei , Dayton David , Assanis Dimitris 
Published: January 2024

Abstract
Finding fuels derived from renewable sources that can displace fossil fuels is crucial to fight climate change as drop-in replacement fuels can immediately leverage ubiquitous, existing energy conversion hardware such as the reciprocating-piston internal combustion engine. However, any replacement fuel must necessarily maintain or ideally exceed the performance of fossil fuels. There are many possible pathways to obtain renewable fuels from biomass, but one pathway that has demonstrated the potential to meet the necessary thermophysical and performance requirements is the Catalytic Fast Pyrolysis pathway followed by hydrotreating to produce a bio-blendstock oil-rich in naphthenes. Due to the variability of bio-blendstock oil composition and variations in process parameters at such a production facility, developing a representative surrogate fuel is necessary for use in understanding compositional desirability and comparative experimental investigations are required to determine performance and emissions characteristics. This work builds upon past surrogate fuel formulation efforts to represent the naphthenic-rich bio-blendstock oils produced from a one ton per day (1TPD) catalytic biomass pyrolisis facility. Specifically, in this work a new formulation of surrogate fuel (SF), SF1.12, containing butylcyclohexane and propylcyclohexane, to represent the naphthenic hydrocarbon content, was created and produced and further blended (up to 30% by vol.) with research-grade No.2 diesel (DF2). These blends were then tested in a single-cylinder Ricardo Hydra compression ignition research engine. A range of conditions were evaluated by first holding the start of injection constant and varying the injection duration from max load (knock limit) to 40% of the max load value. In addition, experiments were performed by holding the fuel-air equivalence ratio constant while sweeping start of fuel injection, and the results were compared to previous generations of SF. It was demonstrated that increasing the proposed SF concentration in DF2 lead to an increase in load output, as well as to a decrease in sooting propensity without impacting NOx formation. It was also shown that this formulation of SF performs best in increasing load and reducing emissions compared to previously reported generations. This SF formulation in the concentrations evaluated (up to 30% by vol.) was shown to be a feasible candidate for displacing heavy distillate fossil fuels in engines.
Sub-inhibitory antibiotic treatment selects for enhanced metabolic efficiency
Authors: Aduru Sai Varun , Szenkiel Karolina , Rahman Anika , Ahmad Mehrose , Fabozzi Maya , Smith Robert P. , Lopatkin Allison J. 
Published: January 2024

ABSTRACT

Bacterial growth and metabolic rates are often closely related. However, under antibiotic selection, a paradox in this relationship arises: antibiotic efficacy decreases when bacteria are metabolically dormant, yet antibiotics select for resistant cells that grow fastest during treatment. That is, antibiotic selection counterintuitively favors bacteria with fast growth but slow metabolism. Despite this apparent contradiction, antibiotic resistant cells have historically been characterized primarily in the context of growth, whereas the extent of analogous changes in metabolism is comparatively unknown. Here, we observed that previously evolved antibiotic-resistant strains exhibited a unique relationship between growth and metabolism whereby nutrient utilization became more efficient, regardless of the growth rate. To better understand this unexpected phenomenon, we used a simplified model to simulate bacterial populations adapting to sub-inhibitory antibiotic selection through successive bottlenecking events. Simulations predicted that sub-inhibitory bactericidal antibiotic concentrations could select for enhanced metabolic efficiency, defined based on nutrient utilization: drug-adapted cells are able to achieve the same biomass while utilizing less substrate, even in the absence of treatment. Moreover, simulations predicted that restoring metabolic efficiency would re-sensitize resistant bacteria exhibiting metabolic-dependent resistance; we confirmed this result using adaptive laboratory evolutions of
Escherichia coli
under carbenicillin treatment. Overall, these results indicate that metabolic efficiency is under direct selective pressure during antibiotic treatment and that differences in evolutionary context may determine both the efficacy of different antibiotics and corresponding re-sensitization approaches.

IMPORTANCE
The sustained emergence of antibiotic-resistant pathogens combined with the stalled drug discovery pipelines highlights the critical need to better understand the underlying evolution mechanisms of antibiotic resistance. To this end, bacterial growth and metabolic rates are often closely related, and resistant cells have historically been characterized exclusively in the context of growth. However, under antibiotic selection, antibiotics counterintuitively favor cells with fast growth, and slow metabolism. Through an integrated approach of mathematical modeling and experiments, this study thereby addresses the significant knowledge gap of whether antibiotic selection drives changes in metabolism that complement, and/or act independently, of antibiotic resistance phenotypes.
Integration of Pan-Cancer Single-Cell and Spatial Transcriptomics Reveals Stromal Cell Features and Therapeutic Targets in Tumor Microenvironment
Authors: Du Yanhua , Shi Jintong , Wang Jiaxin , Xun Zhenzhen , Yu Zhuo , Sun Hongxiang , Bao Rujuan , Zheng Junke , Li Zhigang , Ye Youqiong 
Published: January 2024

Abstract

Stromal cells are physiologically essential components of the tumor microenvironment (TME) that mediates tumor development and therapeutic resistance. Development of a logical and unified system for stromal cell type identification and characterization of corresponding functional properties could help design antitumor strategies that target stromal cells. Here, we performed a pan-cancer analysis of 214,972 nonimmune stromal cells using single-cell RNA sequencing from 258 patients across 16 cancer types and analyzed spatial transcriptomics from 16 patients across seven cancer types, including six patients receiving anti–PD-1 treatment. This analysis uncovered distinct features of 39 stromal subsets across cancer types, including various functional modules, spatial locations, and clinical and therapeutic relevance. Tumor-associated PGF+ endothelial tip cells with elevated epithelial–mesenchymal transition features were enriched in immune-depleted TME and associated with poor prognosis. Fibrogenic and vascular pericytes (PC) derived from FABP4+ progenitors were two distinct tumor-associated PC subpopulations that strongly interacted with PGF+ tips, resulting in excess extracellular matrix (ECM) abundance and dysfunctional vasculature. Importantly, ECM-related cancer-associated fibroblasts enriched at the tumor boundary acted as a barrier to exclude immune cells, interacted with malignant cells to promote tumor progression, and regulated exhausted CD8+ T cells via immune checkpoint ligand–receptors (e.g., LGALS9/TIM-3) to promote immune escape. In addition, an interactive web-based tool (http://www.scpanstroma.yelab.site/) was developed for accessing, visualizing, and analyzing stromal data. Taken together, this study provides a systematic view of the highly heterogeneous stromal populations across cancer types and suggests future avenues for designing therapies to overcome the tumor-promoting functions of stromal cells.

Significance:
Comprehensive characterization of tumor-associated nonimmune stromal cells provides a robust resource for dissecting tumor microenvironment complexity and guiding stroma-targeted therapy development across multiple human cancer types.
Phase I Study of ORIC-101, a Glucocorticoid Receptor Antagonist, in Combination with Enzalutamide in Patients with Metastatic Castration-resistant Prostate Cancer Progressing on Enzalutamide
Authors: Abida Wassim , Hahn Andrew W. , Shore Neal , Agarwal Neeraj , Sieber Paul , Smith Matthew R. , Dorff Tanya , Monk Paul , Rettig Matthew , Patel Rupal , Page Anne , Duff Maureen , Xu Rongda , Wang Jian , Barkund Shravani , Pankov Aleksandr , Wang Amber , Junttila Melissa R. , Multani Pratik S. , Daemen Anneleen , Chow Maneval Edna , Logothetis Christopher J. , Morris Michael J. 
Published: January 2024

Abstract

Purpose:
Increased glucocorticoid receptor (GR) signaling is a proposed compensatory mechanism of resistance to androgen receptor (AR) inhibition in metastatic castration-resistant prostate cancer (mCRPC). ORIC-101 is a potent and selective orally-bioavailable GR antagonist.

Patients and Methods:
Safety, pharmacokinetic/pharmacodynamic, and antitumor activity of ORIC-101 in combination with enzalutamide were studied in patients with mCRPC progressing on enzalutamide. ORIC-101 doses ranging from 80 to 240 mg once daily were tested in combination with enzalutamide 160 mg once daily. Pharmacokinetics/pharmacodynamics was assessed after a single dose and at steady state. Disease control rate (DCR) at 12 weeks was evaluated at the recommended phase 2 dose (RP2D).

Results:
A total of 41 patients were enrolled. There were no dose-limiting toxicities and the RP2D was selected as 240 mg of ORIC-101 and 160 mg of enzalutamide daily. At the RP2D, the most common treatment-related adverse events were fatigue (38.7%), nausea (29.0%), decreased appetite (19.4%), and constipation (12.9%). Pharmacokinetic/pharmacodynamic data confirmed ORIC-101 achieved exposures necessary for GR target engagement. Overall, for 31 patients treated at the RP2D, there was insufficient clinical benefit based on DCR (25.8%; 80% confidence interval: 15.65–38.52) which did not meet the prespecified target rate, leading to termination of the study. Exploratory subgroup analyses based on baseline GR expression, presence of AR resistance variants, and molecular features of aggressive variant prostate cancer suggested possible benefit in patients with high GR expression and no other resistance markers, although this would require confirmation.

Conclusions:
Although the combination of ORIC-101 and enzalutamide demonstrated an acceptable tolerability profile, GR target inhibition with ORIC-101 did not produce clinical benefit in men with metastatic prostate cancer resistant to enzalutamide.
Abstract A007: Expression and activity of Rac, Cdc42, and their downstream effector PAK in Puerto Rican pancreatic cancer patients
Authors: Torres-Sanchez Anamaris , Berrios-Rodriguez Jahdiel , Cruz-Rodriguez Jerry , Contreras-Santini Jasmin , Carlo Victor , Dharmawardhane Suranganie 
Published: January 2024

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is often diagnosed after the localized tumor has metastasized, which decreases its survival rate to a grim 3%. Mortality from PDAC is also increasing in Puerto Rico with lower survival rates than in the US. Therefore, it is pivotal to identify viable targets for the late stages of PDAC. The small GTPase Ras is the most mutated oncogene in PDAC. Oncogenic Ras, as well as multiple oncogenic cell surface receptors, activate the related GTPases Rac and Cdc42, which in turn activate p21-activated kinase (PAK) by autophosphorylation (p-PAK), to drive cancer cell invasion, and thus metastasis. Rac and Cdc42 are overexpressed in 21% of PDAC patients and contribute to poor prognosis. To determine the feasibility of treating PDAC with Rac/Cdc42 inhibitors that we are developing, this study aims to identify the p-PAK levels and Rac/Cdc42 expression in PDAC tissue from Puerto Rican patients. The hypothesis is that p-PAK levels, as well as Rac/Cdc42 expression, are selectively elevated in high-grade invasive PDAC. Immunohistochemistry for p-PAK and immunofluorescence for Rac/Cdc42 were conducted in fixed, paraffin-embedded PDAC biopsy samples of Puerto Rican patients. Preliminary results demonstrate that higher p-PAK levels are correlated with stage 3 and stage 4 tissue, and Rac and Cdc42 are expressed in ductal regions of PDAC tissue. Taken together, p-PAK has potential as a diagnostic biomarker for high-grade PDAC and will aid patient stratification in the planned clinical trials for our lead Rac/Cdc42 inhibitor, MBQ-167.
Citation Format: Anamaris Torres-Sanchez, Jahdiel Berrios-Rodriguez, Jerry Cruz-Rodriguez, Jasmin Contreras-Santini, Victor Carlo, Suranganie Dharmawardhane. Expression and activity of Rac, Cdc42, and their downstream effector PAK in Puerto Rican pancreatic cancer patients [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A007.
Abstract A023: Cytokine loss leads to decreased tumor differentiation and a more aggressive phenotype
Authors: Bell Whitney J. , Kren Nancy , Wang Yan , Modliszewski Jennifer , Xu Yi , Guan Meijiang , DelGiorno Kathleen , Yeh Jen Jen , Pylayeva-Gupta Yuliya 
Published: January 2024

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers with a 5-year survival rate of only 11% and approximately half the patients present with distant metastasis at the time of diagnosis. PDAC is accompanied by pronounced alterations in stromal responses and immune surveillance programs, which are now recognized as some of the major drivers in PDAC tumor evolution. The role of immune modulators in driving aggressiveness of PDAC is poorly understood. We investigate how the loss of host-derived IL-12 and IL-23 in murine models of pancreatic cancer can lead to changes in changes in tumor morphology, cellular differentiation, and tumor immune microenvironment. In orthotopic tumors isolated from IL-12 and IL-23 knockout mice tumor morphology is altered and appears to be less differentiated. Noticeably, ductal area decreases in tumors from IL-23 and IL-12 knockout mice. Single cell RNA sequencing of tumors isolated from IL-12 and IL-23 knockout mice reveals a cluster of tumor cells with decreased gastric gene expression. Gastric genes such as TFF1, TFF2, MUC5AC, GKN1, and GKN2 have been implicated in pancreatic cancer development, progression, and tumor subtype. The classical pancreatic tumor subtype designation correlates with better differentiated pancreatic tumors as opposed to the more poorly differentiated tumors in the basal subtype. The classical expression signature is characterized by the expression of GATA6 and other epithelial cell terminal differentiation genes and includes several of these gastric genes. We hypothesize that loss of IL-12 and IL-23 leads to loss of tumor differentiation and to a more aggressive phenotype.
Citation Format: Whitney J. Bell, Nancy Kren, Yan Wang, Jennifer Modliszewski, Yi Xu, Meijiang Guan, Kathleen DelGiorno, Jen Jen Yeh, Yuliya Pylayeva-Gupta. Cytokine loss leads to decreased tumor differentiation and a more aggressive phenotype [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A023.
Abstract A026: Senescence driven by pharmacological RAS inhibition potentiates anti-tumor activity of combination therapies in pancreatic cancer
Authors: Broderick Caroline , Mezzadra Riccardo , Jiminez-Sanchez Alejando , Chaves-Perez Almudena , Simon Janelle , Ho Yu-Jui , Sisso Exequiel , Tian Sha , Kulick Amanda , DeStanchina Elisa , Lowe Scott W. 
Published: January 2024

Abstract
Senescence is a form of stable proliferative arrest that occurs in response to various forms of cellular stress. In established cancer, these include unresolved DNA damage triggered by chemotherapeutic agents or irradiation, re-establishment of tumor suppressive programs, and by drugs that target cell cycle progression. Senescent cells take on a “Senescence Associated Secretory Phenotype” or SASP, characterized by increased expression of proinflammatory cytokines and other factors that modulate the tissue environment. The SASP triggers immune cell infiltration and, in the context of cancer, potent antitumor immunity. This implicates the use of senescence-inducing agents clinically and suggests that senescence biology may be harnessed to increase the fraction of patients that respond to immunotherapy. RAS is mutated in over 90% of pancreatic cancers, but until recently, has been considered to be “undruggable” due to its small size and lack of drug binding pockets. Recent advances in chemical biology have led to the development of several mutant isoform-specific and broad-spectrum RAS-GTP inhibitors, which hold great clinical promise. We have found that, in mouse models of pancreatic cancer, the non-covalent broad-spectrum inhibitor RM-042 and the covalent KRASG12D specific inhibitor RM-044 trigger a senescence-like phenotype characterized by cell cycle arrest and increased SASP expression. RAS inhibitor-mediated senescence enhances the immune surveillance of tumor cells, and this effect is potentiated by certain combination agents. Our results suggest that senescence contributes to RAS inhibitor efficacy in PDAC and reveal strategies to harness the immune system to improve therapy outcomes and circumvent resistance.
Citation Format: Caroline Broderick, Riccardo Mezzadra, Alejando Jiminez-Sanchez, Almudena Chaves-Perez, Janelle Simon, Yu-Jui Ho, Exequiel Sisso, Sha Tian, Amanda Kulick, Elisa DeStanchina, Scott W. Lowe. Senescence driven by pharmacological RAS inhibition potentiates anti-tumor activity of combination therapies in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A026.
Abstract A047: ARID1A mutations drive metastasis of pancreatic neuroendocrine tumors and pancreatic adenocarcinomas by activation of NTN1/UNC5B signaling
Authors: Harris Chris , Nezhad Muhammad Sadeqi , Asad Asra , Narrow Wade , Prela Orjola , Carpizo Darren 
Published: January 2024

Abstract
ARID1A, a component of the SWI/SNF DNA chromatin remodeling complex, is recurrently mutated in many types of cancer. In pancreatic ductal adenocarcinomas (PDACs), mutations in ARID1A are found in 6-15% of cases, and ARID1A expression has previously been shown to associate with poor patient outcome. But the effect of ARID1A mutations on pancreatic neuroendocrine tumors (PNETs) has not been previously studied, and we observed that ARID1A mutations were 15-fold more common in patients with metastatic PNETs than in patients with localized disease, indicating the importance of ARID1A mutations in driving the progression of what is normally an indolent disease. We have studied ARID1A mutations in models of both PDACs and PNETs and observe that in both diseases ARID1A mutations associated with several properties common to metastatic cells including epithelial-mesenchymal transition, in vitro invasiveness, and insensitivity to anoikis. Mutation of ARID1A activated expression of the axonal guidance protein NTN1 in both PDACs and PNETs, and interaction between the NTN1 ligand and its dependence receptor UNC5b were required for the metastatic properties of ARID1A mutant cells. Treatment with a NTN1 inhibitor, NP137, overcame insensitivity to anoikis, while deletion or knockdown of UNC5b caused ARID1A mutant cells to undergo a mesenchymal-epithelial transition. In vivo, metastasis of PDACs was blocked by NP137 treatment, or by deletion of UNC5b. NP137 is currently in clinical trials for many tumor types including PDACs, and our data strongly indicate that NP137 should also be tested in patients with metastatic PNETs.
Citation Format: Chris Harris, Muhammad Sadeqi Nezhad, Asra Asad, Wade Narrow, Orjola Prela, Darren Carpizo. ARID1A mutations drive metastasis of pancreatic neuroendocrine tumors and pancreatic adenocarcinomas by activation of NTN1/UNC5B signaling [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A047.
Abstract A053: The effects of chemotherapy on B cells and T cells in blood and tumor tissue in patients with pancreatic cancer – from diagnosis to terminal disease
Authors: Jacobsen Hedda 
Published: January 2024

Abstract
Pancreatic cancer (PC) is a devastating disease and is almost always synonymous with a poor outcome. Chemotherapy is the standard treatment and is administered in either an adjuvant or palliative setting. However, nearly all patients, regardless of treatment intent, eventually develop chemoresistance. Little is known about the events causing chemoresistance, but increased knowledge is essential for improving patient outcomes. The aim of this study was to increase the knowledge of how the immune system, locally and systemically, is affected by chemotherapy and how this influences patient outcomes. Hence, immunohistochemical analysis of T and B cell prevalence in post-mortem tumor tissue was performed and combined with flow cytometric analysis of the dynamics of circulating T and B cell subsets during chemotherapy in nine PC patients enrolled in a clinical study. Despite the small number of patients included in this study, some interesting results were found. A high number of tertiary lymphoid-like structures (TLLSs) in the primary tumor was associated with shorter survival, which is contradictory to previous findings and possibly indicates a negative effect of chemotherapy on TLLSs. Certain subpopulations of T and B cells exhibited variations during treatment, possibly in response to chemotherapy. The frequency of T cells in blood also tended to correlate inversely with the frequency in primary tumor and liver metastases. Overall, this exploratory study provides insights into how the immune system in PC is affected by chemotherapy. Further study is warranted to shed more light on the intrinsic chemoresistance of PC and to identify new therapeutic strategies.
Citation Format: Hedda Jacobsen. The effects of chemotherapy on B cells and T cells in blood and tumor tissue in patients with pancreatic cancer – from diagnosis to terminal disease [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A053.