bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A014: Targeting TAK1 for intercepting PanIN progression to ductal adenocarcinoma in an inducible KC mouse model
Authors: Madka Venkateshwar , Pathuri Gopal , Kuma Gaurav , Singh Anil , Stratton Nicole , Houchen Courtney , Mohammed Altaf , Rao Chinthalapally V. 
Published: December 2022

Abstract
Despite advances in our knowledge of human pancreatic ductal adenocarcinoma (PDAC), targeted therapies have not yet significantly translated to an improved overall survival for patients. Pancreatic tumor microenvironment enriched by infiltrating immune cells and consisting of dense fibrotic stroma is characterized by desmoplasia, the major contributors of tumor-associated inflammation. Transforming growth factor-β (TGF-β)-activated kinase 1 (TAK1) is widely accepted as a key player in the TNF-α and TGF-β -induced signaling, and principal contributor of tumor fibrosis, inflammation and cell proliferation. Here, we show that pancreatic tumors over- express TAK1, and are associated with fibrotic-stroma and infiltrating immune cells. Also, p-TAK1(ser412) expression is correlated with progression of pancreatic intraepithelial neoplasia (PanIN) lesions to PDAC. Thus, we hypothesized TAK1 as an important target for inhibition of the tumor-associated fibrosis, inflammation and PanIN progression to PDAC.
To prove above hypothesis, we tested a selective TAK1 inhibitor, Takinib for its toxicity and efficacy against PanIN progression in the inducible Ptf1CreERT.LSL-KrasG12D (KC) mouse model. Takinib was synthesized and fed to wild type C57BL/6J mice (n=6) at 250 ppm and 500ppm in diet for 6 weeks to determine toxicity. Bodyweight gain, organ weights and serum enzyme analysis did not indicate any toxicity at the tested doses. For efficacy study, LSL-KrasG12D mice were bred with Ptf1-CreERTmice. Pups were genotyped and randomized to groups (n=12).
PanINs -PDAC was induced in the KC mice by tamoxifen (oral gavage) followed by 250ppm Takinib administration in diet for 20 weeks. After termination, pancreas tissue sections were evaluated for PanIN multiplicity and PDAC incidence/spread. Administration of Takinib led to significant reduction in PanIN 1 by 54% (p&lt;0.02), PanIN 2 by 77% (p&lt;0.001) and PanIN 3 by 80% (p&lt;0.02) in the KC mice compared to untreated mice. PDAC incidence was also reduced with an increase in normal pancreas in Takinib administered KC mice. Taken together our results suggest that TAK1 is a valuable target for PDAC, and Takinib possesses efficacy against the PanIN and PDAC progression in the KC mouse model warranting further studies. (Supported by PHF Team Science grant and Kerley-Cade Endowed Chair).
Citation Format: Venkateshwar Madka, Gopal Pathuri, Gaurav Kuma, Anil Singh, Nicole Stratton, Courtney Houchen, Altaf Mohammed, Chinthalapally V. Rao. Targeting TAK1 for intercepting PanIN progression to ductal adenocarcinoma in an inducible KC mouse model [abstract]. In: Proceedings of the Second Biennial NCI Meeting: Translational Advances in Cancer Prevention Agent Development (TACPAD); 2022 Sep 7-9. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_2): Abstract nr A014.
Abstract A022: Limonene as a vehicle in topical delivery of carvedilol for skin cancer chemoprevention
Authors: Wang Janell , Chao Lawrence , Yeung Steven , Huang Ying 
Published: December 2022

Abstract
Skin cancer is currently one of the most common cancers and is defined as an abnormal growth of the skin cells. The goal of this study is to develop a topical delivery system of carvedilol with limonene as the vehicle. Limonene is a major component found in the rinds of citrus fruits and other herbs. It is one of many natural compounds that have demonstrated inhibitory activity in different types of cancers such as breast, lung, and stomach cancer. Furthermore, limonene has shown to increase skin permeation of drugs including carvedilol. The soft agar colony formation assay was used to evaluate anchorage-independent growth of JB6 mouse epidermal cells.
This assay tested concentrations of carvedilol (0.1, 1.0 and 10 μM); limonene (1.0, 10, 100 and 1000 μM); and a combination of carvedilol (1.0 μM) and limonene (1.0, 10 or 100 μM). Results demonstrated that carvedilol and limonene as single treatment inhibited colony formation.
The combination of carvedilol and limonene showed higher colony inhibition than single treatment, although not statistically significant. Franz diffusion cell was used to test for permeation of the drug. The device has two chambers separated by a membrane, which in this case is rat skin. The drugs, in vehicles of 40% polyethylene glycol (PEG) 400 in PBS or 40% PEG400 in PBS plus 5% limonene were applied into the donor chamber while the samples are collected through the receptor chamber as the drug permeates through the skin. The samples were collected at 16 hours, 20 hours, and 24 hours. Results showed that limonene significantly increased permeation. Therefore, our data indicate that limonene was able to increase skin permeation and the chemopreventive activity of carvedilol. This new formulation will be further examined in animal models for its efficacy against UV-induced skin cancer.
Citation Format: Janell Wang, Lawrence Chao, Steven Yeung, Ying Huang. Limonene as a vehicle in topical delivery of carvedilol for skin cancer chemoprevention [abstract]. In: Proceedings of the Second Biennial NCI Meeting: Translational Advances in Cancer Prevention Agent Development (TACPAD); 2022 Sep 7-9. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_2): Abstract nr A022.
Abstract IA003: SC144 and the next generation IL6/GP130/STAT3 inhibitors for cancer prevention
Authors: Neamati Nouri 
Published: December 2022

Abstract
IL6/GP130/STAT3 signaling plays a crucial role in multiple diseases, and all components of this signaling cascade are directly or indirectly implicated in tumorigenesis. Therefore, blockade of this signaling axis is expected to provide novel therapeutic opportunities to treat various diseases including cancer. IL6 binds to IL6R and GP130 to activate downstream signaling pathways to promote proliferation, survival and metastasis of cancer cells, and to stimulate angiogenesis on endothelial cells. Although GP130 is positioned at the junction of this oncogenic signaling network and is essential for activation of the network, there are no small-molecule inhibitors of GP130 under clinical development. Previously, we identified SC144 as a first-in-class, efficacious, safe, and orally active inhibitor of GP130. SC144 selectively inhibits the activation of downstream signaling pathways induced by GP130 ligands (IL6, LIF), with no significant effects on the activation by non-GP130 ligands, such as IFN-γ, SDF-1α, and PDGF. SC144 exhibits cytotoxicity in a panel of platinum-sensitive and platinum-resistant cells, with no significant cytotoxicity to human normal epithelial cells. In mouse xenograft models, SC144 significantly inhibited tumor growth through GP130 inhibition and induction of necrosis in the tumor. No toxicity was evident in normal tissues. Furthermore, SC144 showed significant in vivo efficacy in immune competent syngeneic mouse models. Unfortunately, clinical development of SC144 was delayed due to its poor solubility and metabolic instability. During the past two years, we have identified metabolic liabilities of SC144 and have undertaken an extensive medicinal chemistry lead optimization campaign to produce analogs with increased solubility and metabolic stability. The new analogs show favorable properties in single- and repeat-dosing pharmacokinetic (PK) studies. As a result, we have in hand a series of 2nd-generation analogs that are orally active, water-soluble, and display desirable PK properties suitable for advanced preclinical studies to support IND filing.
Citation Format: Nouri Neamati. SC144 and the next generation IL6/GP130/STAT3 inhibitors for cancer prevention [abstract]. In: Proceedings of the Second Biennial NCI Meeting: Translational Advances in Cancer Prevention Agent Development (TACPAD); 2022 Sep 7-9. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_2): Abstract nr IA003.
Abstract IA016: Lessons learned from clinical trials of MUC1 peptide vaccines for cancer prevention
Authors: Schoen Robert E. 
Published: December 2022

Abstract
We report on three trials of a MUC1 peptide vaccine for cancer prevention. Two trials were pilot studies evaluating vaccine immunogenicity and safety. One was in subjects with advanced colon adenomas, and the other in smokers at risk for lung cancer. The third trial was a multi-center, randomized placebo-controlled trial in subjects with advanced adenoma that included an assessment of the clinical efficacy of the vaccine to prevent recurrent adenoma. All trials successfully recruited their full complement of participants and the vaccine was well tolerated with no safety concerns. The response rate in the colon adenoma trials was 43% in the pilot study and 25% in the placebo- controlled multicenter trial. Only 10% of smokers responded to the vaccine. Higher levels of circulating myeloid derived suppressor cells (MDSC) were consistently associated with the lack of an immune response. This suggests that even in pre-malignancy immunosuppressive tendencies can impair vaccine immunogenicity. Responders to the vaccine demonstrated immune memory at one year. In the multicenter adenoma trial that evaluated the efficacy of the vaccine on adenoma recurrence, immune responders demonstrated an association with a reduced rate of adenoma recurrence. In future studies, patient selection based on circulating MDSC levels, or concomitant use of agents to counter MDSC immunosuppressive function or otherwise improve T cell function, should be considered.
Citation Format: Robert E. Schoen. Lessons learned from clinical trials of MUC1 peptide vaccines for cancer prevention [abstract]. In: Proceedings of the Second Biennial NCI Meeting: Translational Advances in Cancer Prevention Agent Development (TACPAD); 2022 Sep 7-9. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_2): Abstract nr IA016.
Abstract IA018: Cancer immune-interception in Lynch Syndrome: Neoantigen-based vaccine development
Authors: Vilar-Sanchez Eduardo 
Published: December 2022

Abstract
Lynch Syndrome (LS) is the most common cause of hereditary colorectal cancer and also conveys significantly increased risks for several other malignancies, including endometrial, small bowel, gastric, ovarian, adrenocortical tumors, and others. LS results from a heterozygous germline mutation in one of four DNA mismatch repair (MMR) genes. The acquisition of a somatic “second hit” causes affected cells to lose the ability to repair DNA mismatch replication errors that frequently occur in microsatellite regions of the genome. Consequently, hundreds to thousands of small insertion/deletions (indels) accumulate in these regions, and when expressed, result in frameshift peptides that are recognized as neoantigens that are then presented on the cell surface via the major histocompatibility complexes (MHC-I/II) for immune cell recognition. Vaccine development efforts in this high-risk population have been challenged by the substantial inter-individual variability in both the set of expressed neoantigens and MHC I/II responses. Yet, recent advances in next-generation sequencing and associated bioinformatic approaches are now allowing for more accurate profiling of the most frequently recurring and shared mutated neoantigens in LS-associated tumors. This allows for identification of the most immunogenic neoantigens that can be incorporated into different vaccine platforms to test the development of a population-based vaccine. The Vilar Lab has collaborated with industry and academic partners such as Nouscom, s.r.l. and the National Cancer Institute to develop two different clinical trials to bring new vaccines to the LS population based on mutated neoantigens and tumor associated antigens. In this presentation, we will focus on mutated neoantigen-based strategies and present the Phase I clinical trial (NCT05078866) using a viral-based vaccine including 209 distinct neoantigens. The primary endpoint of this trial is safety and immunogenicity. A total of 45 participants will be enrolled to receive a prime and boost vaccination. Different secondary biomarkers will explore immunological aspects of this novel immune-interception strategy.
Citation Format: Eduardo Vilar-Sanchez. Cancer immune-interception in Lynch Syndrome: Neoantigen-based vaccine development [abstract]. In: Proceedings of the Second Biennial NCI Meeting: Translational Advances in Cancer Prevention Agent Development (TACPAD); 2022 Sep 7-9. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_2): Abstract nr IA018.
Abstract IA020: Targeting mTOR signaling in oral premalignant lesions: From bench to clinic and back
Authors: Gutkind J. Silvio 
Published: December 2022

Abstract
Despite encouraging recent results from novel treatment options, such as immunotherapy, for head and neck squamous cell carcinoma (HNSCC), limited progress has been made in improving outcomes for most patients. Prevention and early detection are key to improving the prognosis of HNSCC. Our team has focused on decoding the oncogenic signaling circuitries driving HNSCC initiation and progression, aimed at identifying novel druggable targets to treat and prevent this aggressive malignancy. These efforts led to the early discovery that persistent activation of PI3K/mTOR signaling circuitry is the most frequent dysregulated signaling mechanism in HNSCC, and that in turn, the overreliance on PI3K/mTOR for HNSCC initiation and progression can be exploited for therapeutic purposes. Evidence will presented that mTOR inhibition exerts a potent antitumor activity in HNSCC patients in a recently reported window of opportunity clinical trial (NCT01195922). Thus, mTOR inhibitors can be considered for the prevention of HNSCC development and for the treatment of existing HNSCC lesions. However, their safety profile and tolerability may hamper their potential long-term use for HNSCC prevention. In this regard, we have shown that the repurposed drug metformin, which is safely used by millions of type 2 diabetes patients, decreases mTOR signaling in HNSCC and displays potent chemopreventive activity in experimental oral premalignancy models. Based on these findings, we have conducted a Phase IIa Clinical Trial using metformin for HNSCC prevention (NCT02581137) in patients with oral premalignant lesions (OPL), which was recently completed. Metformin administration resulted in mTOR inhibition, and improvement in the histological severity of 60% of the OPLs, including a subset (17%) of patients that exhibited complete responses. Ongoing experimental and planned clinical studies will be presented, which may provide a mechanistic framework for the use of metformin as a precision preventive agent for HNSCC.
Citation Format: J. Silvio Gutkind. Targeting mTOR signaling in oral premalignant lesions: From bench to clinic and back [abstract]. In: Proceedings of the Second Biennial NCI Meeting: Translational Advances in Cancer Prevention Agent Development (TACPAD); 2022 Sep 7-9. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_2): Abstract nr IA020.
ReXistências musicais entre arte e política
Authors: Hikiji Rose Satiko Gitirana , Grunvald Vi , Guerra Paula 
Published: December 2022

O que têm em comum o musicar (Small, 1998) de Apeshit, o videoclipe do casal de artistas estadunidenses Beyoncé e Jay-Z, as performances musicais de João do Crato no interior do Ceará, um projeto entre uma cantora lírica, um musicólogo e um líder indígena na Colômbia, o álbum AmerElo do rapper paulistano Emicida, o artivismo musical de Linn da Quebrada e a música de imigrantes africanos em São Paulo? À primeira vista, nada. Mas neste Dossiê estes fazeres musicais servem todos ao mesmo intuito: são formas de reXistência.[1] A ligação entre música e política é vetusta e nem sempre perceptível. Do clamor patente, ao simples comentário, do motim pessoal ao social, a música tem atuado para agitar consciências e – menos frequentemente – sistemas, instituições e estruturas (Blacking, 1995). Schreiber (2019) considera que a música é plena energia para a ação. Uma expressão de poder, não apenas sônica ou emocional. A música, especialmente quando criada em resposta aos problemas sociais do mundo, torna-se uma força única (Guerra et al., 2019). E talvez desse poder criador e criativo é que venha a insistência de DeNora (2003) para considerarmos a música uma prática social de fato e de direito e não apenas um mero reflexo da estrutura social. Portanto, a música é uma parte da nossa vida social.

[1] Para a noção de reXistência com a qual trabalhamos, cf. Grunvald, neste dossiê.
Association Between Copayment Amount and Filling of Medications for Angiotensin Receptor Neprilysin Inhibitors in Patients With Heart Failure
Authors: Mukhopadhyay Amrita , Adhikari Samrachana , Li Xiyue , Dodson John A. , Kronish Ian M. , Shah Binita , Ramatowski Maggie , Chunara Rumi , Kozloff Sam , Blecker Saul 
Published: December 2022

Background
Angiotensin receptor neprilysin inhibitors (ARNI) reduce mortality and hospitalization for patients with heart failure. However, relatively high copayments for ARNI may contribute to suboptimal adherence, thus potentially limiting their benefits.

Methods and Results

We conducted a retrospective cohort study within a large, multi‐site health system. We included patients with: ARNI prescription between November 20, 2020 and June 30, 2021; diagnosis of heart failure or left ventricular ejection fraction ≤40%; and available pharmacy or pharmacy benefit manager copayment data. The primary exposure was copayment, categorized as $0, $0.01 to $10, $10.01 to $100, and >$100. The primary outcome was prescription fill nonadherence, defined as the proportion of days covered <80% over 6 months. We assessed the association between copayment and nonadherence using multivariable logistic regression, and nonbinarized proportion of days covered using multivariable Poisson regression, adjusting for demographic, clinical, and neighborhood‐level covariates. A total of 921 patients met inclusion criteria, with 192 (20.8%) having $0 copayment, 228 (24.8%) with $0.01 to $10 copayment, 206 (22.4%) with $10.01 to $100, and 295 (32.0%) with >$100. Patients with higher copayments had higher rates of nonadherence, ranging from 17.2% for $0 copayment to 34.2% for copayment >$100 (
P
<0.001). After multivariable adjustment, odds of nonadherence were significantly higher for copayment of $10.01 to $100 (odds ratio [OR], 1.93 [95% CI, 1.15–3.27],
P
=0.01) or >$100 (OR, 2.58 [95% CI, 1.63–4.18],
P
<0.001), as compared with $0 copayment. Similar associations were seen when assessing proportion of days covered as a proportion.

Conclusions
We found higher rates of not filling ARNI prescriptions among patients with higher copayments, which persisted after multivariable adjustment. Our findings support future studies to assess whether reducing copayments can increase adherence to ARNI and improve outcomes for heart failure.
The Rights of God's Stewards: Property, Conscience, and the Great Awakening in Canterbury, Connecticut
Authors: Nordbye Erik 
Published: December 2022

Abstract
The struggle for religious liberty in Canterbury, CT, was fought over property. When the Great Awakening divided church against town, evangelical “Separates” withdrew from the establishment and launched a campaign against ecclesiastical taxation, using concepts of conscience, stewardship, and property rights to defend estates and create a voluntary religious economy.
Beyond “Sectional Superiority”: Memorializing Black History in Northern New England
Authors: Raimon Eve Allegra 
Published: December 2022

Abstract
New England's lingering sense of itself as the locus of abolitionist virtue makes it imperative to interrogate this self-perception while examining the cultural import of contemporary African American memorials in the region. Twenty-first century commemorations in Northern New England are attempting to correct the visual and historical record of the suppression and expulsion of African Americans by erecting memorials that celebrate New England's Black history.
Selling Books in Eighteenth-Century Boston: The Daybook of Benjamin Guild
Authors: Orr Leah 
Published: December 2022

Abstract
Through an analysis of the daybook of late-eighteenth-century Boston bookseller Benjamin Guild, this essay presents a microhistory of retail bookselling in Boston just after the Revolutionary War. It argues that American customers mainly bought British books and that prices varied, with implications for book history, literature, and cultural studies.
Differentiated Rehabilitation and the Geographies of Unfreedom in Post-Colonial Bombay
Authors: Thatra Geeta 
Published: December 2022

Abstract
The “refugee crisis” after the 1947 Partition of British India generated new contestations over urban resources, especially for securing accommodation. It resulted in a proliferation of encampment laws and policies with outcomes at multiple levels: city, neighborhood, and community. This article traces the uneven geographies produced by Bombay’s encampment laws and the (spatial) politics of refugee rehabilitation. It focuses on the state’s use of “camps” to segregate impoverished refugees and consolidate the urban periphery. The article explores the interplay between law, space, and property to illustrate how refugee entitlements created and sustained various forms of power and precarity in the metropolis. Refugee camps provided “conditional access” to shelter for indigent Sindhi refugees and became markers of social identification. Middle-class Sindhi refugees, on the other hand, secured their place in the city by establishing cooperative housing societies. This article highlights how caste and regional distinctions in pre-Partition Sindh translated into class-based spatial divisions among the displaced Sindhis in post-colonial Bombay.
Retained functional normal and preleukemic HSCs at diagnosis are associated with good prognosis in DNMT3AmutNPM1mut AMLs
Authors: Donato Elisa , Correia Nadia , Andresen Carolin , Karpova Darja , Würth Roberto , Klein Corinna , Sohn Markus , Przybylla Adriana , Zeisberger Petra , Rothfelder Kathrin , Salih Helmut , Bonig Halvard , Stasik Sebastian , Röllig Christoph , Dolnik Anna , Bullinger Lars , Buchholz Frank , Thiede Christian , Hübschmann Daniel , Trumpp Andreas 
Published: December 2022

Abstract
Acute myeloid leukemia (AML) is a heterogeneous disease characterized by high rate of relapse and mortality. Current chemotherapies whilst successful in eradicating blasts, are less effective in eliminating relapse-causing leukemic stem cells (LSCs). Although LSCs are usually identified as CD34+CD38- cells, there is significant heterogeneity in surface marker expression, and CD34- LSCs exist particularly in NPM1mut AMLs. By analyzing diagnostic primary DNMT3AmutNPM1mut AML samples, we suggest a novel flow cytometry sorting strategy particularly useful for CD34neg AML subtypes. To enrich for LSCs independently of CD34 status, positive selection for GPR56 and negative selection for NKG2D ligands are used. We show that the functional reconstitution capacity of CD34- and CD34+ LSCs as well as their transcriptomes are very similar which support phenotypic plasticity. Furthermore, we show that although CD34+ subpopulations can contain next to LSCs also normal and/or preleukemic hematopoietic stem cells (HSCs), this is not the case in CD34-GPR56+NKG2DL- enriched LSCs which thus can be isolated with high purity. Finally, we show that patients with AML, who retain at the time of diagnosis a reserve of normal and/or preleukemic HSCs in their bone marrow able to reconstitute immunocompromised mice, have significantly longer relapse-free and overall survival than patients with AML in whom functional HSCs are no longer detectable.