bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract SY05-02: Applications of base editor technology in small molecule: Target validation
Authors: Griffith Audrey , Sangree Annabel , Roy Priyanka , Hanna Ruth , Doench John 
Published: June 2022

Abstract
CRISPR screens that focus on the gene as the unit of information - whether using knockout, interference, or activation - have reinvigorated the field of functional genomics. The recent development of Base Editor technology allows nucleotide-level manipulation, enabling fine-scale investigation of endogenous loci. The low upfront costs of generating a pooled base editing library, coupled with the small scale and relative ease of executing such screens, makes the financial barrier to entry for such experiments low while also not requiring deep experience with screening.
One application of this technology is screens that aim to identify resistance mutations in putative targets of small molecules, which provides excellent evidence that the phenotype is caused by on-target activity of the small molecule. This has heretofore typically been an extraordinarily laborious and time-consuming experimental path, by either slowly cultivating spontaneous drug resistant mutants or by generating and screening large scale ORF-variant pools. Base editor screens are well-suited to vastly accelerate this process.
Using both A&gt;G and C&gt;T base editors, coupled with variants of the SpCas9 enzyme, we have conducted drug resistance screens with small molecules that target the anti-apoptotic proteins MCL1, BCL2L1, and BCL2, as well as the DNA repair regulator PARP1. These screens identified resistance residues that were also observed in clinical samples, illustrating the utility of this approach. Additionally, base editor screens are excellent tools for studying genetic variants, as we will demonstrate with screens identifying loss-of-function mutations in BRCA1, BRCA2, and TP53. We anticipate that the tools and methodologies described here will facilitate the investigation of impactful variants at a finer and deeper resolution for any locus of interest.
Citation Format: Audrey Griffith, Annabel Sangree, Priyanka Roy, Ruth Hanna, John Doench. Applications of base editor technology in small molecule: Target validation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr SY05-02.
Abstract SY18-02: Beyond tumor antigen immunogenicity: Determinants of protective immunity induced by therapeutic cancer vaccines
Authors: Delamarre Lelia 
Published: June 2022

Abstract
Cancer-specific mutations can generate neoantigens that are recognized as foreign by the immune system and elicit potent T cell responses against cancer. The identification of neoantigens as drivers of effective anti-tumor immunity has promoted the development of neoantigen-based therapeutic strategies, including vaccines and cell-based therapies. One challenge for these approaches is to accurately predict neoantigens. Most mutations are unique to each patient and only a fraction are immunogenic. The generation of large-scale mass spectrometry-based immunopeptidomics training data for the development of deep learning models has resulted in significantly improved computational methods for prediction of neoantigen presentation on HLA. In addition, on-going efforts to characterize antigen determinants involved in TCR recognition may also contribute to further improving immunogenicity prediction. However, induction of neoantigen-specific T cells may not be sufficient for efficacy. We used the MC38 cancer model to characterize the factors associated with effective neoantigen-specific T cell responses after vaccination. We designed two RNA-LPX vaccines (Deca-1 and Deca-2), each encoding 10 MC38 neoantigens. The two vaccines elicited T cell responses with comparable magnitude and functionality. Prophylactic vaccination with either vaccine prevented establishment of MC38 tumors, confirming that vaccine-induced T cells can recognize and kill tumor cells. Surprisingly, while vaccination with Deca-2 was protective in therapeutic settings, vaccination with Deca-1 was unable to reverse growth of established tumors. Neoantigen-specific CD8 T cell migration to the tumor was comparable between the two vaccines, but the phenotypes of the T cells were significantly different. Gene expression analysis revealed specific activation states of T cells that differed according to their antigenic specificity and clonal expansion, suggesting intrinsic differences across different T cell specificities. Remarkably, T cells elicited by Deca-1 exhibited a gene signature of reduced functionality at the tumor site and also in the spleen, the primary site of vaccine activity. Our study has important implications for the development of neoantigen therapies, as it suggests that the properties of the neoantigen/TCR pairs influence the phenotype of vaccine-induced T cells at the tumor site and therapeutic outcome. Furthermore, our results indicate that the tumor may influence the phenotype of vaccine-induced T cells outside the tumor microenvironment. Additional experiments are on-going to further define the exact nature of these determinants.
Citation Format: Lelia Delamarre. Beyond tumor antigen immunogenicity: Determinants of protective immunity induced by therapeutic cancer vaccines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr SY18-02.
Abstract SY19-01: Investigating cancer determinants of tumor immune composition
Authors: Brown Brian 
Published: June 2022

Abstract
The cellular composition, spatial architecture, and tissue localization of a tumor have a major impact on a cancer’s progression and response to therapy. These factors are particularly relevant to tumor immunity as immune cell composition and localization within the tumor microenvironment (TME) is one of the major determinants of response to immunotherapy and patient outcome. Spatially resolved single cell genome sequencing has revealed that many genetically distinct sub-clones exist in proximity in tumors and can have different TME compositions, but how specific genes influence the TME, or how neighboring clones influence one another is not well-defined. Indeed, while some genes involved in orchestrating the TME have been identified, the potential roles of many genes in influencing the architecture and immune composition of different tumors are not established. To enable scale up studies to identify determinants of TME biology and tumor immunity, we established a first-of-its-kind in vivo spatial functional genomics platform called Perturb-map. We applied Perturb-map to knockout (KO) dozens of genes in parallel in a mouse model of lung cancer and simultaneously assessed how each KO influenced tumor growth, histopathology, and immune composition. Additionally, we paired Perturb-map and spatial transcriptomics for unbiased analysis of CRISPR-edited tumors. In contrast to in vitro CRISPR screens, we found KO of positive regulators of IFNγ signaling led to a major reduction of tumor burden, with varying impact from different pathway components. KO of Socs1, a negative regulator of IFNγ signaling, provided a growth advantage though was accompanied by increased T cell infiltration and notably, Socs1 KO tumors were more responsive to PDL1 blockade. Perturb-map also found that KO of the TGFβ Receptor 2 (Tgfbr2) resulted in a growth advantage, but unlike Socs1 KO, T cells were excluded from the lesions and the TME converted to a fibro-mucinous state. Spatial transcriptomics revealed TGFβ signaling was upregulated in Tgfbr2 KO tumors. Further analysis indicated this signal was from TGFβ-mediated activation of fibroblasts in tumors where cancer cells lost Tgfbr2, suggesting the mechanism for TME remodeling and T cell exclusion in Tgfbr2 KO tumors. These studies establish Perturb-map for functional genomics within tissue at single cell-resolution with spatial architecture preserved and provide insight into how TGFβ responsiveness of cancer cells can affect the TME (Dhainaut, Rose et al. BioRxiv 2021, doi.org/10.1101/2021.07.13.451021).
Citation Format: Brian Brown. Investigating cancer determinants of tumor immune composition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr SY19-01.
Abstract SY41-02: Epigenetic influence of our (fatty) diet on metastatic-initiating cells: Role of intra-tumor Schwann cells
Authors: Aznar-Benitah Salvador 
Published: June 2022

Abstract
We have recently identified the cells uniquely responsible for the formation of metastasis in different types of human tumors. These cells have intriguing characteristics: i) they form primary lesions as efficiently as their tumor-initiating counterparts, but are exclusive in their ability to generate metastases; ii) they express the fatty acid translocase CD36, and are characterized by a unique lipid metabolic signature; iii) they are exquisitely sensitive to the levels of fat in circulation, and consequently, they relate the predisposition of metastasis directly to the content of dietary fat; iv) they are highly sensitive to CD36 inhibition, which almost completely abolishes their metastatic potential in preclinical models. In my talk, I will present our latest data on the molecular characterization of metastatic-initiating cells. I will place special emphasis showing how specific dietary lipids exert a striking long-term epigenetic effect over metastatic-initiating cells related to activation of intra-tumor Schwann cells, putting forward a novel concept of ¨metastatic epigenetic memory¨ elicited by our diet.
Citation Format: Salvador Aznar-Benitah. Epigenetic influence of our (fatty) diet on metastatic-initiating cells: Role of intra-tumor Schwann cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr SY41-02.
Rise of the Clones: Myelodysplastic Syndrome to Secondary Acute Myeloid Leukemia
Authors: Romine Kyle A. , van Galen Peter 
Published: June 2022

Summary:
Myelodysplastic syndrome (MDS) describes a family of blood disorders driven by the clonal expansion of mutated blood cells that can evolve into secondary acute myeloid leukemia (sAML). Two new studies use single-cell and deep sequencing to elucidate the progression of MDS to AML, revealing discrete clonal architectures and the driving role of signaling mutations.
See related article by Guess et al., p. 316 (8) .
See related article by Menssen et al., p. 330 (9) .
Dialéctica da periferia: formas de resistência na literatura-mundial
Authors: Medeiros Paulo de 
Published: June 2022

O presente ensaio tem como objetivo principal uma tentativa de reconceptualisar a noção de literatura-mundial, partindo da enunciação proposta pelo Warwick Research Collective em Desenvolvimento Combinado e Desigual (2015; 2020), num movimento duplo de concentração e expansão. Concentração devido a um foco específico na questão de resistência aos modelos neoliberais e neocoloniais de desumanização, expropriação e extinção. Expansão, na sugestão de se considerar o cinema-mundial enquanto texto como parte integrativa do conceito de literatura-mundial. A reflexão teórica assenta numa articulação entre as perspectivas críticas de Roberto Schwarz, Theodor Adorno, Fredric Jameson e do WReC. Os textos submetidos a análise incluem um romance de Clarice Lispector, A Hora da Estrela (1977), e um filme, Yvone Kane de Margarida Cardoso (2014).
Neutrophil gelatinase-associated lipocalin: a biochemical marker for acute kidney injury and long-term outcomes in patients presenting to the emergency department
Authors: Teo Kah Hui Brian , Lim Swee Han , Hao Ying , Lo Yin Keong Daryl , Lin Ziwei , Kaushik Manish , Tan Chieh Suai , Thajudeen Mohammed Zuhary , Wee Choon Peng Jeremy 
Published: June 2022

Introduction:
Creatinine has limitations in identifying and predicting acute kidney injury (AKI). Our study examined the utility of neutrophil gelatinase-associated lipocalin (NGAL) in predicting AKI in patients presenting to the emergency department (ED), and in predicting the need for renal replacement therapy (RRT), occurrence of major adverse cardiac events (MACE) and all-cause mortality at three months post visit.

Methods:
This is a single-centre prospective cohort study conducted at Singapore General Hospital (SGH). Patients presenting to SGH ED from July 2011 to August 2012 were recruited. They were aged ≥21 years, with an estimated glomerular filtration rate <60 mL/min/1.73 m2, and had congestive cardiac failure, systemic inflammatory response syndrome or required hospital admission. AKI was diagnosed by researchers blinded to experimental measurements. Serum NGAL was measured as a point-of-care test.

Results:
A total of 784 patients were enrolled, of whom 107 (13.6%) had AKI. Mean serum NGAL levels were raised (P < 0.001) in patients with AKI (670.0 ± 431.9 ng/dL) compared with patients without AKI (490.3 ± 391.6 ng/dL). The sensitivity and specificity of NGAL levels >490 ng/dL for AKI were 59% (95% confidence interval [CI] 49%–68%) and 65% (95% CI 61%–68%), respectively. Need for RRT increased 21% per 100 ng/dL increase in NGAL (P < 0.001), whereas odds of death in three months increased 10% per 100 ng/dL increase in NGAL (P = 0.028). No clear relationship was observed between NGAL levels and MACE.

Conclusion:
Serum NGAL identifies AKI and predicts three-month mortality.
Kenyan Muslims’ Minority Status: Theological Divisions, Ethno-Racial Competition and Ambiguous Relations with the State
Authors: Ndzovu Hassan Juma 
Published: June 2022

Abstract
On the surface, Islam in Kenya presents a continued competition between Sufi-oriented orders and the Salafi-minded Muslims. This article argues that the controversies between “traditional” and “modern” forms of Islam in the country is an indication of the plurality of ways in which Muslims, in a minority context, makes sense of their religious identities. Changing political circumstances in Kenya in the colonial and the post-colonial eras changed the conditions of Muslims in Kenya, thereby explaining their present attitude towards the state. Since the commencement of the war on terror in 2001, Kenyan Muslims have been confronted with rising radicalization amongst certain members of the community and increasing cases of kidnapping and extra judicial killing targeting members of the Muslim population. The result is a complex and problematic relationship with the state, characterised by Muslims’ continuous demands for justice and equal treatment as citizens by the state.
Ambiguous Positionings: The Politics and Experiences of Moral Learning at Gülen Movement Schools in Urban Tanzania
Authors: Mashimi Kristina 
Published: June 2022

Abstract
This article examines the ambiguous positionings of the Gülen Movement (gm) in the religiously mixed setting of urban Tanzania, particularly in education. It argues that the gm has capitalised on its identity as a not-explicitly-Muslim minority group within the privatised educational market in Tanzania, making its schools an option for Muslim and Christian families alike. Against the backdrop of Tanzania’s larger histories of religious inequalities and sentiments of injustice among the Muslim population, gm schools fill a significant gap through their elite orientation and inclination towards Islam. The article further argues that the moral education offered by gm schools binds them to the broader ideological mission of the movement. Foregrounding the experiences of female students, it shows that moral education at gm schools is a highly gendered and open-ended process that entails the embodiment of different and at times contradictory understandings of femininity, modesty, and shame.
Novel composite yarn with a wavy-network structure produced by various delivery speed ratios and untwisting factors
Authors: Duo Xu , Can Ge , Chong Gao , Yingcun Liu , Ziyi Su , Changjin Ke , Keshuai Liu , Jian Fang , Weilin Xu 
Published: June 2022

Yarn structure variation and property improvement have been widely investigated for applications in fancy fabric production. Thus, a novel composite yarn was fabricated by dynamically forcing strand migrations around filaments with varied tension control, regulating the geometric configuration between the filaments and staple fibers. The geometrical principle of wavy-network structure variations of novel composite yarns caused by tension interference and helical migrations between filaments and staple fibers was theoretically analyzed. Subsequently, the coordination of delivery speed ratios and untwisting factors was applied on a ring frame with a delivery roller to control the tensile difference and spiral trajectory, which oscillated the helical convergence between filaments and strands to conduct confirmatory tests. The online observations of the convergent formation in the spinning-triangle zone were technically applied to evaluate the dynamic helical migrations between strands and filaments, and the spiral structural variations of the yarn were caused by various tension difference interference and twist tracks. Experimental results revealed that the novel composite yarn had a network structure with wavy-dense wrapping, and the yarn hairiness, irregularity, tensile, and snarling properties were successively measured to compare the yarn property improvements with other composite yarns. Generally, the systematic tensile oscillation between strands and filaments in the yarn formation zone, which are produced by various delivery speed ratios and untwisting factors, are promising as a novel method for controlling the helical configurations and inter-stress between filaments and staple strands.
Vision impairment: To register or not to register? That is the question
Authors: Tooth Cirta , Cackett Peter 
Published: June 2022

For patients to enjoy the benefits of vision impairment registration, they need to be certified by an ophthalmologist. There have been concerns about barriers and a lack of awareness of benefits and certification criteria among ophthalmologists leading to under-registration. The purpose of this study was to gain insight into the certification process in terms of potential barriers, clinical decision-making, and understanding of current guidelines and registration benefits. Ophthalmologists completed a survey on understanding registration benefits and barriers for certification ( n = 22) and a survey on clinical decision-making in certification ( n = 21). Furthermore, visual function and registration data were collected at a hospital Low Vision Clinic in Edinburgh from all new referrals ( n = 89) over a 4-month period from August to November 2020. Our study showed that the main barriers for vision impairment certification were insufficient awareness of registration benefits, uncertainty of when to certify, and a lack of time in clinic. Ophthalmologists were more confident about certification of ocular versus neurological visual impairment. In terms of clinical decision-making, the ophthalmologists’ survey placed most importance on visual-field assessments, followed by visual acuity. Very little importance was placed on contrast sensitivity. Our findings suggest that ophthalmologists would benefit from more education into the benefits of registration and more guidance when registering patients with neurological conditions affecting functional vision in particular. It may be beneficial to highlight the role of contrast sensitivity during the certification process to ophthalmologists.
A homogeneous treatment for non-DIPG diffuse midline glioma
Authors: Schiavello Elisabetta , Biassoni Veronica , Gattuso Giovanna , Podda Marta , Chiaravalli Stefano , Barretta Francesco , Antonelli Manila , De Cecco Loris , Pecori Emilia , Gandola Lorenza , Massimino Maura 
Published: June 2022

Introduction: The H3K27M-mutant diffuse midline glioma (DMG) was first included in the World Health Organization (WHO) Classification of central nervous system (CNS) tumors in 2016, and confirmed in its fifth edition. The biological behavior and dismal prognosis of this tumor resemble diffuse intrinsic pontine gliomas (DIPG). Homogeneously-treated series are rarely reported. Methods: From 2016 onwards, we treated patients with DMG with radiotherapy and concomitant/adjuvant nimotuzumab/vinorelbine, plus re-irradiation at relapse, as already done for DIPG. Results: We treated nine patients, seven females, with a median age at diagnosis of 13 years. Tumor sites were: thalamic in five cases, pontocerebellar in two, pineal in one, and paratrigonal with nodular/leptomeningeal dissemination in one. Three patients were biopsied, and six had partial tumor resections. Central pathological review was always performed. The median time to local progression was 12.7 months, and the median overall survival was 17.8 months. Six patients died of tumor progression, one of cerebral bleeding at progression. Two were alive, one in continuous remission, the other after relapsing, at 38.6 and 46.3 months after diagnosis. Progression-free survival was 33.3% at one year. Overall survival was 88.9%, 33.3% and 22.2% at 1, 2 and 3 years, respectively. Conclusions: This is a small series of homogeneously-treated DMG patients. The results obtained are comparable with those of DIPG patients. Given the phenotypically- and molecularly-defined setting of DMG and severe outcome in this orphan population, they should be treated and included in registries and protocols of DIPG.
Photobiomodulation associated with lipid nanoparticles and hyaluronic acid accelerate the healing of excisional wounds
Authors: Zaccaron Rubya Pereira , Barbieri Rusilania Tozi , Mendes Carolini , Venturini Ligia Milanez , Alves Naiara , Mariano Samara de Souza , de Andrade Thiago Antônio Moraes , Hermes de Araújo Pedro Henrique , Feuser Paulo Emílio , Thirupathi Anand , Machado-de-Ávila Ricardo Andrez , Lock Silveira Paulo Cesar 
Published: June 2022

Objectives: This article aimed to investigate the effects of the association between photobiomodulation and hyaluronic acid incorporated in lipid nanoparticles in an epithelial lesion model in inflammatory parameters and oxidative stress. Methods: Eighty Wistar rats were randomly assigned to the following groups: epithelial lesion group (EL); EL+PBM; EL+HA; EL+SLNs; EL+SLNs-HA; EL+PBM+HA; EL+PBM+SLNs; EL+PBM+SLNs-HA. The animals were anesthetized with 4% isofluorane after shaving and induced to an epithelial lesion. Topical treatment with a gel containing HA (0.9%) and/or SLNs (10 mg/mL) and with laser irradiation occurred daily for 1 week. Results: The results showed an increase in wound contraction on the seventh day in the LE + LBM + AH-NPL group, a reduction in pro-inflammatory cytokines (IL-6, IL-1β, and TNF-α), an increase in anti-inflammatory cytokines (IL- 4 and IL-10) and TGF-β. The levels of pro-inflammatory cytokine IL-4 and TGF-β also showed an increase in the LE + NPL-AH, LE + FBM + AH, LE + FBM + NPL and LE + FBM + NPL-AH groups. Regarding oxidative stress parameters, the levels of DCF and nitrite decreased in the combined therapy group when compared to the control group, as well as oxidative damage (carbonyl and sulfhydryl). In the antioxidant defense, there was an increase in GSH and SOD in the combination therapy group. Histological analysis showed a reduction in inflammatory infiltrate in the combination therapy group. The number of fibroblasts and the compaction of collagen fibers did not obtain significant responses. Conclusions: Results analyzed together showed that the combined therapy favored the repair process, and that studies can be carried out to enhance the histological analysis therapy favored the tissue repair process and that studies can be carried out to enhance the histological analysis.