bluuebunny/crossref_metadata_2025 huggingface dataset:
Dose-response effects of selective serotonin reuptake inhibitor monotherapy for the treatment of depression: systematic review of reviews and meta-narrative synthesis
Authors: Johnson Chris F , Maxwell Margaret , Williams Brian , Dougall Nadine , MacGillivray Stephen
Published: December 2022

Objective

To assess and clarify the relations between selective serotonin reuptake inhibitor (SSRI) dose efficacy, acceptability (early treatment discontinuation (dropouts)), and tolerability (reported adverse drug effects), and critically evaluate methods previously used to examine SSRI dose-response effects for the treatment of depression in adults.

Design

Systematic review of reviews and meta-narrative synthesis.

Data sources

Embase, Medline, PsycINFO, Scopus, and the Cochrane Collaboration library, from 1975 to December 2021. Reference lists of national depression treatment guidelines were systemically searched by hand.

Eligibility criteria for selecting studies

Reviews assessing SSRI monotherapy dose-response effects for the treatment of depression in adults (age ≥18 years) reporting efficacy, acceptability, or tolerability. Reviews meeting inclusion criteria had a high degree of heterogeneity, due to methodological diversity; therefore, a meta-narrative synthesis approach was applied. Standard daily doses were defined as 20 mg citalopram, fluoxetine, paroxetine; 50 mg sertraline; and 10 mg escitalopram. Risk of bias was assessed using the Risk of Bias in Systematic Reviews tool, in line with Cochrane recommendations.

Results

The search identified 9138 records; 387 full text reports were assessed for eligibility, 42 of which matched the inclusion criteria. The majority, 83% (n=35), of reviews included data for studies with a duration of ≤12 weeks (ie, the acute phase of depression treatment). Of 39 reviews assessing efficacy, the majority (n=26) indicated that individual SSRIs and SSRI class demonstrated flat dose-response effects; standard doses were optimal for efficacy. Acceptability or tolerability were assessed in 28 reviews. Higher than standard daily doses were associated with higher dropout rates and a greater incidence of adverse drug effects (eg, nausea, sexual dysfunction, fatigue, anxiety). Despite a range of methods being reported, there was an overall consensus regarding SSRI dose related efficacy, dropouts, and adverse drug effects.

Conclusion

Standard daily doses of SSRIs for the treatment of depression in adults provide a favourable balance between efficacy, acceptability, and tolerability. Patients are encouraged to talk to their prescriber or community pharmacist if they experience adverse effects or have any concerns about their drug treatments.
Long-term evaluation parameters in GNE myopathy: a 5-year observational follow-up natural history study
Authors: Mori-Yoshimura Madoka , Yajima Hiroyuki , Oya Yasushi , Mizuno Katsuhiro , Noguchi Satoru , Nishino Ichizo , Takahashi Yuji
Published: December 2022

Background

A number of clinical trials targeting GNE myopathy patients have been conducted. However, useful clinical parameters for postmarketing surveillance and long-term clinical observation have not yet been established.

Objective

We conducted a 5-year observational follow-up natural history study to identify evaluation parameters, which may be useful for the long-term observation of GNE myopathy patients.

Methods

Thirty-three genetically confirmed GNE myopathy patients were recruited and evaluated at study entry (baseline) and yearly in a 5-year follow-up. Hand-held dynamometer measurements of knee extension strength, grip power and pinch power, summed Manual Muscle Testing (MMT) score of 17 muscles, Gross Motor Function Measure (GMFM), 6 min walk test, percent vital capacity and percent forced vital capacity (%FVC), lean body mass (whole body, arms and legs), creatine kinase, Barthel Index, modified Rankin Scale and 36-item Short Form Survey national standard scores were examined.

Results

Of the 33 patients, 22 (66%) completed evaluations for the entire 5-year follow-up period. These patients had a significant reduction in summed MMT score (p=0.005), GMFM (p=0.005), pinch power (p<0.001) and %FVC (p<0.001) at the fifth year evaluation relative to baseline. Among these parameters, summed MMT score, GMFM, pinch power and %FVC showed significant changes even in non-ambulant patients.

Conclusions

MMT, GMFM, pinch power and %FVC are useful parameters for the long-term evaluation of GNE myopathy patients.
Influence of prior intravenous thrombolysis in patients treated with mechanical thrombectomy for M2 occlusions: insight from the Endovascular Treatment in Ischemic Stroke (ETIS) registry
Authors: Le Floch Agathe , Clarençon Frédéric , Rouchaud Aymeric , Kyheng Maeva , Labreuche Julien , Sibon Igor , Boulouis Gregoire , Gory Benjamin , Richard Sébastien , Caroff Jildaz , Blanc Raphaël , Seners Pierre , Eker Omer F , Cho Tae-Hee , Consoli Arturo , Bourcier Romain , guillon benoit , Dargazanli Cyril , Arquizan Caroline , Denier Christian , Eugene Francois , Vannier Stephane , Gentric Jean-Christophe , Gauberti Maxime , Naggara Olivier , Rosso Charlotte , Turc Guillaume , Ozkul-Wermester Ozlem , Cognard Christophe , Albucher Jean François , Timsit Serge , Bourdain Frederic , Le Bras Anthony , Richter Sebastian , Moulin Solène , Pop Raoul , Heck Olivier , Moreno Ricardo , L'Allinec Vincent , Lapergue Bertrand , Marnat Gaultier
Published: December 2022

Background

Intravenous thrombolysis (IVT) for patients treated with mechanical thrombectomy (MT) for proximal occlusions has recently been questioned through randomized trials. However, few patients with M2 occlusions were included. We investigated the influence of prior IVT for patients presenting M2 occlusions treated with MT in comparison with MT alone.

Methods

We conducted a retrospective analysis of the Endovascular Treatment in Ischemic Stroke (ETIS) registry, a multicenter observational study. Data from consecutive patients treated with MT for M2 occlusions between January 2015 and January 2022 at 26 comprehensive stroke centers were analyzed. The primary endpoint was 90-day modified Rankin Scale score of 0–2. Outcomes were compared using propensity score approaches. We also performed sensitivity analysis in relevant subgroups of patients.

Results

Among 1132 patients with M2 occlusions treated with MT, 570 received prior IVT. The two groups were comparable after propensity analysis. The rate of favorable functional outcome was significantly higher in the IVT+MT group compared with the MT alone group (59.8% vs 44.7%; adjusted OR 1.38, 95% CI 1.10 to 1.75, P=0.008). Hemorrhagic and procedural complications were similar in both groups. In sensitivity analysis excluding patients with anticoagulation treatment, favorable recanalization was more frequent in the IVT+MT group (OR 1.37, 95% CI 1.11 to 1.70, P=0.004).

Conclusions

In cases of M2 occlusions, prior IVT combined with MT resulted in better functional outcome than MT alone, without increasing the rate of hemorrhagic or procedural complications. These results suggest the benefit of IVT in patients undergoing MT for M2 occlusions.
Review of recent developments of the functional renormalization group for systems out of equilibrium
Authors: Camacho G. , Klöckner C. , Kennes D. M. , Karrasch C.
Published: December 2022

We recapitulate recent developments of the functional renormalization group (FRG) approach to the steady state of systems out of thermal equilibrium. In particular, we discuss second-order truncation schemes which account for the frequency-dependence of the two particle vertex and which incorporate inelastic processes. Our focus is on two different types of one-dimensional fermion chains: (i) infinite, open systems which feature a translation symmetry, and (ii) finite systems coupled to left and right reservoirs. In addition to giving a detailed and unified review of the technical derivation of the FRG schemes, we briefly summarize some of the key physical results. In particular, we compute the non-equilibrium phase diagram and analyze the fate of the Berezinskii–Kosterlitz–Thouless transition in the infinite, open system.

Graphic abstract
Global Dynamic Analysis of a Discontinuous Infectious Disease System with Two Thresholds
Authors: Wang Dongshu , Luo Shifan , Li Wenxiu
Published: December 2022

In this article, we consider a SIV infectious disease control system with two-threshold guidance, in which infection rate and vaccination rate are represented by a piecewise threshold function. We analyze the global dynamics of the discontinuous system using the theory of differential equations with discontinuous right-hand sides. We find some dynamical behaviors, including the disease-free equilibrium and endemic equilibria of three subsystems, a globally asymptotically stable pseudo-equilibrium and two endemic equilibria bistable, one of the two pseudo-equilibria or pseudo-attractor is stable. Conclusions can be used to guide the selection of the most appropriate threshold and parameters to achieve the best control effect under different conditions. We hope to minimize the scale of the infection so that the system can eventually stabilize at the disease-free equilibrium, pseudo-equilibrium or pseudo-attractor, corresponding to the disease disappearing or becoming endemic to a minimum extent, respectively.
A Multi-View Learning Approach for Detecting Personality Disorders Among Arab Social Media Users
Authors: Duwairi Rehab , Halloush Zain
Published: December 2022

Multi-view fusion approaches have gained increasing interest in the past few years by researchers. This interest comes due to the many perspectives that datasets can be looked at and evaluated. One of the most urging areas that require constant leveraging with latest technologies and multi-perspective judgments is the area of psychology. In this article, a novel multi-view fusion model using deep learning algorithms is presented to detect popular types of personality disorders among Arab users of the Twitter platform in an expert-driven fashion, based on the descriptions of the
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition.
To the best of our knowledge, the work presented is the first of its kind with no publicly available datasets that report statements around personality disorders in the Arabic language, and thus we created AraPerson, a dataset that consists of 8,000 textual tweets coupled with 8,000 images that prescribe mental statuses for a total of 150 users collected with regular expressions generated under the supervision of domain experts. The dataset was fed into a baseline multi-view model by combining a CNN model with a Bi-LSTM model to detect two types of popular personality disorders by analyzing textual and visual posts on 150 user profiles. The experiments were followed with fusing the DenseNet model with the Bi-LSTM model, experimenting with the effect of using concatenation, addition, and multiplication methods for vectors’ combination. The work presented in this article is unprecedented, specifically in a controversial area such as personality disorders detection among Arab communities. The best reported accuracy is 87%, which is quite promising, as the two types of personality disorders investigated are highly overlapping.
Efficacy of Nonpreserved Sodium Hyaluronate Artificial Tears in Dry Eye Disease Patients Treated with Prostaglandin Analogs for Primary Open-Angle Glaucoma: A Prospective, Nonrandomized, Open-Label Pilot Study
Authors: Coco Giulia , Iannetta Danilo , Febbraro Igino , Elmo Ester , Manni Gianluca
Published: December 2022

Purpose. Dry eye disease (DED) can be triggered using preserved ophthalmic formulations or prostaglandin analogs. In this prospective, nonrandomized, open-label pilot study, we evaluated the efficacy of a 0.15% hyaluronic acid (HA) nonpreserved ophthalmic formulation in decreasing DED symptoms in patients with open-angle glaucoma treated with prostaglandin analogs. Methods. 30 patients with DED receiving chronic treatment with prostaglandin analogs for primary open-angle glaucoma or ocular hypertension were administered ophthalmic formulations 3 times daily for 12 weeks. Foreign body sensation, burning, stinging, dryness, pain, frequency of symptoms, Ocular Surface Disease Index (OSDI), conjunctival hyperaemia, corneal fluorescein staining (CFS), tear film break-up time (TBUT), best-corrected visual acuity, Schirmer test results, and 25-item National Eye Institute Visual Function Questionnaire score between the baseline and 4 and 12 weeks were evaluated. Results. The analysis shows that all primary endpoints improved; in particular, burning sensation and the frequency of symptoms after 4 and 12 weeks of treatment (

p
<
0.001

) and dryness and pain after 12 weeks of treatment (

p
<
0.001

and

p
=
0.03

, respectively) were reduced significantly. Secondary outcomes confirmed the positive results, with a statistically significant change in the OSDI score and CFS between the baseline and 4 (

p
=
0.02

and

p
<
0.001

, respectively) or 12 weeks (both

p
<
0.001

) and TBUT after 4 weeks (

p
=
0.01

). Conjunctival hyperaemia improved in both eyes in >90% of cases at 12 weeks of treatment. Conclusion. The present study shows that the ophthalmic formulation containing 0.15% HA has a promising beneficial effect on reducing the signs and symptoms of DED in patients treated with prostaglandin analogs.
Probiotic-Based Optimization of Pistachio Paste Production and Detoxification of Aflatoxin B1 Using Bifidobacterium lactis
Authors: Pakizeh Mehdi , Nouri Leila , Azizi Mohammad Hossein
Published: December 2022

Pistachio paste is very popular for breakfast or supper thanks to its desirable taste, flavor, and texture. One of the hazards that are directly related to agricultural practices, processing, storage, and transportation of pistachios and the byproducts is aflatoxin, which can cause irreversible effects on the consumer. Probiotics are one of the most effective and safe methods to reduce aflatoxins. The variables under study were temperature and time, aflatoxin concentration, and probiotic content. In total, 30 treatments were determined through the rotatable central composite design. This is the first and most comprehensive study to optimize the production of probiotic pistachio paste and investigate the detoxification effects of aflatoxin B1 using Bifidobacterium lactis with six treatments and three replications in the pistachio paste matrix. In simple terms, it is possible to remove a higher percentage of toxins by increasing the number of microorganisms and decreasing the toxin level. The highest aflatoxin B1 reduction was observed in pistachio paste with aflatoxin B1 contamination of (19.7039 ng/g), which was spiked with Bifidobacterium lactis (109 CFU/g) and then stored at 25°C for 26.1853 days (aflatoxin B1: 8.00007 ng/g = 59.4% reduction), which is consistent with the permissible limits of the Iran National Standards Organization and the European Commission Regulation. The results showed a significant reduction in the aflatoxin B1 level in pistachio paste. The probiotics reduced aflatoxin B1 contamination to a permissible level. This is an important, safe, and effective solution, and unlike other methods, it increases the nutritional value of the product.
Pharmacological Activity of Quercetin: An Updated Review
Authors: Wang Guanzhen , Wang Yuanhui , Yao Liangliang , Gu Wei , Zhao Shengchao , Shen Ziyi , Lin Zihan , Liu Wei , Yan Tingdong
Published: December 2022

Quercetin, a natural flavonoid compound with a widespread occurrence throughout the plant kingdom, exhibits a variety of pharmacological activities. Because of the wide spectrum of health-promoting effects, quercetin has attracted much attention of dietitians and medicinal chemists. An updated review of the literature on quercetin was performed using PubMed, Embase, and Science Direct databases. This article presents an overview of recent developments in pharmacological activities of quercetin including anti-SARS-CoV-2, antioxidant, anticancer, antiaging, antiviral, and anti-inflammatory activities as well as the mechanism of actions involved. The biological activities of quercetin were evaluated both in vitro and in vivo, involving a number of cell lines and animal models, but metabolic mechanisms of quercetin in the human body are not clear. Therefore, further large sample clinical studies are needed to determine the appropriate dosage and form of quercetin for the treatment of the disease.
Mixed Intervillositis in SARS-CoV-2 Infection Associated with Fetal Death: A Case Report
Authors: Gjakov Boban , Kopač Darja , Vukmanič Pohar Mateja , Lučovnik Miha
Published: December 2022

Maternal severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been shown in epidemiological studies to be associated with an increased risk of stillbirth. Several histopathologic features of placental SARS-CoV-2 infection have been proposed as potential causes of fetal death. We present a case of an otherwise healthy G3P1 women with mild symptoms of SARS-CoV-2 infection at 23 6/7 weeks of gestation. At 25 2/7 weeks, she presented with signs and symptoms of preterm labor and decreased fetal movements. Fetal death was diagnosed at admission. Placental pathology showed pronounced placental mixed intervillositis. Inflammatory infiltrate caused extreme narrowing of intervillous space leading to placental malfunction and fetal death. Placental tissue SARS-CoV-2 infection was confirmed by positive immunohistochemistry staining of syncytiotrophoblasts with spike protein antibody. The case presented suggests that SARS-CoV-2 associated inflammatory placental changes pose an elevated risk for the fetus.
Elevated Serum Levels of CCL23 Are Associated with Poor Outcome after Resection of Biliary Tract Cancer
Authors: Roderburg Christoph , Labuhn Simon , Bednarsch Jan , Lang Sven A. , Schneider Anne T. , Hammerich Linda , Vucur Mihael , Ulmer Tom F. , Neumann Ulf P. , Luedde Tom , Loosen Sven H.
Published: December 2022

Background. Surgical tumor resection is the only potentially curative treatment option for patients with biliary tract cancer (BTC). However, 5-year survival rates are still below 50% mainly due to tumor recurrence. The preoperative identification of ideal surgical candidates has remained a major challenge and easily accessible algorithms including parameters of the individual tumor biology are missing. Chemokine (C-C motif) ligand 23 (CCl23) has been associated with tumor progression in hepatocellular carcinoma (HCC), but its role in the context of BTC is largely unknown. Here, we evaluated circulating levels of CCL23 as potential diagnostic and prognostic biomarker in patients with resectable BTC. Methods. CCl23 serum levels were analyzed by multiplex immunoassay in a cohort of 119 BTC patients receiving surgical tumor resection as well as 50 healthy control samples and 11 patients with primary sclerosing cholangitis (PSC). Results. Baseline serum CCL23 levels were significantly elevated in BTC patients compared to PSC patients as well as healthy controls. CCL23 increased the diagnostic sensitivity and specificity of established tumor markers including CA19-9 and correlated with patients’ age and makers of systemic inflammation. Elevated preoperative CCL23 levels were associated with a significantly impaired postoperative outcome. BTC patients with a preoperative CCL23 level above the optimal prognostic cut-off value of 702.4 pg/ml showed a median OS of only 110 days compared to 501 days for patients with low initial CCL23 levels. The prognostic value of circulating CCL23 was confirmed in Cox-regression analysis. Conclusion. Serum levels of CCL23 are elevated in patients with BTC, and high preoperative CCL23 levels were associated with an impaired postoperative survival. CCL23 serum levels could help to identify the ideal surgical candidates for BTC resection in the future.
Formononetin Inhibits Hepatic I/R-Induced Injury through Regulating PHB2/PINK1/Parkin Pathway
Authors: Ma Zhongying , Zhang Di , Sun Jin , Zhang Qi , Qiao Yi , Zhu Yixin , Niu Jing , Ren Qian , Zhou Lun , Wen Aidong , Wang Jingwen
Published: December 2022

Formononetin (FN), an isoflavone compound mainly isolated from soy and red clover, had showed its anti-inflammation, antioxidative effects in some degenerative diseases and cholestasis. However, the role of FN in protecting ischemia/reperfusion- (I/R-) induced liver injury and the possible mechanism were unclear. In this study, effects of FN on liver injury were investigated in a rat hepatic I/R model; further, mitophagy-related proteins were measured by immunoblotting or immunofluorescence. The possible roles of PHB2 and PINK1 in regulating mitophagy by FN were verified using adeno-associated virus knockdown. The results showed that FN had protective effects against hepatic I/R injury through regulating PINK1/Parkin-regulated mitophagy. Further, we found that FN inhibited PARL expression and prevented PGAM5 cropped by increasing the expression of PHB2. The knockdown of PINK1 or PHB2 both abolished the protective effects of FN. Taken together, our findings indicated that the isoflavone compound FN promoted PHB2/PINK1/Parkin-mediated mitophagy pathway to protect liver from I/R-induced injury. These results provided novel insights into the potential prevention strategies of FN and its underlying mechanisms.
Medical Image Compression Based on Variational Autoencoder
Authors: Liu Xuan , Zhang Lu , Guo Zihao , Han Tailin , Ju Mingchi , Xu Bo , Liu Hong
Published: December 2022

With the rapid growth of medical image data, it has become a current research hotspot that how to realize the large amounts of the real-time upload and storage of medical images with limited network bandwidth and storage space. However, currently, medical image compression technology cannot perform joint optimization of rate (the degree of compression) and distortion (reconstruction effect). Therefore, this study proposed a medical image compression algorithm based on a variational autoencoder. This algorithm takes rate and distortion as the common optimization goal and uses the residual network module to directly transmit information, which alleviates the contradiction between improving the degree of compression and optimizing the reconstruction effect. At the same time, the algorithm also reduces image loss in the medical image compression process by adding the residual network. The experimental results show that, compared with the traditional medical image compression algorithm and the deep learning compression algorithm, the algorithm in this study has smaller distortion, better reconstruction effect, and can obtain higher quality medical images at the same compression rate.
Abstract B006: PBRM1-deficient PBAF complexes target de novo genomic loci to activate NF-κB pathway in kidney cancer
Authors: Yao Xiaosai , Hong Jing Han , Nargund Amrita , Teh Bin Tean
Published: December 2022

Polybromo-1 (PBRM1) is the second most commonly mutated gene in kidney cancer after VHL, occurring at a frequency of 30-40%. PBRM1 loss represents a tumor-initiating event and the combined loss of VHL and PBRM1 is necessary and sufficient for renal malignancy. Functionally, PBRM1 is the defining subunit of the polybromo BRG1-associated factor (PBAF) subclass of SWItch/Sucrose Non-Fermentable (SWI/SNF) remodeling complex which regulates chromatin accessibility by sliding, depositing or evicting nucleosomes. Determining context-specific chromatin remodeling by PBRM1 is paramount to understanding how PBRM1 deficiency drives kidney tumorigenesis. We compared the association of SWI/SNF subunits in the presence or absence of PBRM1 and found that PBRM1 loss resulted in a PBAF complex that has undergone alterations in its configuration and targeting specificity: First, the histone binding lobe disengages from the central ATPase subunit. Second, the PBRM1-deficient complexes, despite retaining the DNA binding lobe, occupy aberrant sites, redistributing from promoter proxy regions to distal enhancer regions. The aberrant sites mapped to regions enriched for NF-κB motifs. Indeed, PBRM1-deficient tumors show enhanced NF-κB activity across isogenic tumor models, genetically modified mouse models and clinical samples. We believe that the PBRM1-deficient PBAF complexes enhance the recruitment of nuclear factor RELA, a subunit of the NF-κB complex - this recruitment requires the ATPase function of the SWI/SNF complexes since BRG1/BRM ATPase inhibitor dampens the expression of NF-κB target genes and RELA chromatin occupancy. Proteasome inhibitor bortezomib reverses NF-κB activity by reducing RELA binding at regions bound by PBRM1-deficient PBAF and delays PBRM1-deficient tumor growth. In conclusion, the PBRM1 tumor suppressor safeguards the chromatin by repressing aberrant liberation of pro-tumorigenic NF-κB target genes by residual PBRM1-deficient PBAF complexes. Inhibition of NF-κB activity by bortezomib could be a therapeutic strategy for PBRM1-deficient kidney cancer.

Citation Format: Xiaosai Yao, Jing Han Hong, Amrita Nargund, Bin Tean Teh. PBRM1-deficient PBAF complexes target de novo genomic loci to activate NF-κB pathway in kidney cancer. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr B006.
Abstract IA008: Chromatin regulation by reversible chromatin-associated RNA methylation
Authors: He Chuan
Published: December 2022

Over 150 types of post-transcriptional RNA modifications have been identified in all kingdoms of life. We have previously discovered two RNA demethylases, FTO and ALKBH5, which catalyze oxidative demethylation of the most prevalent modifications of mammalian messenger RNA (mRNA) and other nuclear RNA, N6-methyladenosine (m6A). We have also characterized reader proteins that preferentially recognize methylated transcripts to facilitate either decay or translation of these target RNAs. Most recently we have discovered m6A methylation of chromatin-associated regulatory RNAs (carRNAs), which modulates chromatin state and transcription in mouse embryonic stem cells (mESCs). These findings suggest that reversible RNA modification could impact chromatin regulation analogous to the reversible DNA and histone chemical modifications. I will present recent mechanistic investigation of chromatin and transcription regulation through m6A methylation and demethylation, and impacts on mammalian development and cancer progression.

Citation Format: Chuan He. Chromatin regulation by reversible chromatin-associated RNA methylation. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr IA008.
Abstract IA019: Ectopic levels of low-complexity domain interactions repress endogenous oncogenic transcription
Authors: Chong Shasha
Published: December 2022

Mammalian transcription factors (TFs) ubiquitously contain intrinsically disordered low-complexity domains (LCDs) that perform transactivation functions. Recent studies have shown that dynamic, multivalent, and selective interactions between TF LCDs play an essential role in transactivation, but how such interactions mediate gene transcription remains unclear. It has been proposed that liquid-liquid phase separation (LLPS) of TFs driven by extensive LCD-LCD interactions is the mechanism underlying transactivation. Here, we investigate how tuning the level and localization of LCD-LCD interactions in vivo affects transcription of endogenous human genes. By quantitative single-cell imaging, we reveal that efficient gene activation by the oncogenic TF EWS/FLI1 requires narrow optimum of LCD-LCD interactions at its target genes associated with GGAA microsatellites. Increasing LCD-LCD interactions toward putative LLPS represses transcription of these genes in Ewing sarcoma cells. Likewise, ectopically creating LCD-LCD interactions to sequester EWS/FLI1 into a well-documented LLPS compartment, the nucleolus, represses EWS/FLI1 -driven transcription and inhibits malignant transformation of Ewing sarcoma. In addition, using live-cell single-molecule imaging, we show that a TF diffuses significantly more slowly in the nucleolus than in the nucleoplasm, demonstrating an important impact of LLPS on TF dynamic behaviors and single-molecule diffusion measurement as an effective approach to diagnose LLPS in vivo. Our findings show how altering the balance of LCD-LCD interactions can influence transcriptional regulation and suggest a potential therapeutic strategy for targeting disease-causing TFs.

Citation Format: Shasha Chong. Ectopic levels of low-complexity domain interactions repress endogenous oncogenic transcription. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr IA019.
Abstract A004: Molecular adenoma features to predict metachronous colorectal cancer risk: A nested-case control study
Authors: Jodal Henriette C. , Akwiwu Eddymurphy U. , Leon Leticia G. , Lemmens Margriet , Delis-van Diemen Pien , Klotz Dagmar , de Wit Meike , Fijneman Remond , van Leerdam Monique , Dekker Evelien , Spaander Manon C. W. , Meijer Gerrit A. , Bretthauer Michael , Løberg Magnus , Coupé Veerle M. H. , Kalager Mette , Carvalho Beatriz
Published: December 2022

Introduction: In colorectal cancer (CRC) surveillance, adenoma characteristics such as size, number of adenomas, dysplasia, and villous components, are used as indicators for risk of developing metachronous cancer and guide the surveillance interval. The current risk groups (e.g., advanced adenomas) cannot optimally distinguish high risk from low risk, which may result in suboptimal surveillance strategies. Specific DNA copy number aberrations are associated with risk of colorectal adenoma-to-carcinoma progression, but these aberrations are present in only a subset of advanced adenomas. Therefore, we hypothesize that specific DNA copy number aberrations may better predict the risk of CRC than advanced adenoma. Aim: To evaluate whether a molecularly-defined high-risk adenoma is a better risk factor for CRC than the presently used advanced adenoma. Materials and methods: DNA copy number profiles were determined, by means of low-coverage whole genome sequencing, on a series of 529 adenomas, selected from a Norwegian adenoma cohort. We retrieved detailed information on adenoma characteristics and whether adenoma patients were subsequently diagnosed with CRC or not. By univariate and multivariate regression analysis we estimated the odds ratio for association between the development of CRC and baseline presence of advanced adenoma versus presence of a molecularly-defined high-risk adenoma, respectively. Results: Molecular high-risk features were observed in 85/267 (32%) of advanced adenomas and in 27/262 (10%) of non-advanced adenomas. The odds ratio for developing metachronous CRC was 3.58 (p=2.84E-8) and 1.90 (p=0.012), when an advanced adenoma or molecular high-risk adenoma was detected at the baseline colonoscopy, respectively. In the multivariate regression analysis only advanced adenoma was as a significant risk factor for CRC. Conclusion: Molecularly-defined high-risk adenomas are associated with an increased risk of CRC. However, the advanced adenoma is a stronger predictor for risk of CRC.

Citation Format: Henriette C. Jodal, Eddymurphy U. Akwiwu, Leticia G. Leon, Margriet Lemmens, Pien Delis-van Diemen, Dagmar Klotz, Meike de Wit, Remond Fijneman, Monique van Leerdam, Evelien Dekker, Manon C. W. Spaander, Gerrit A. Meijer, Michael Bretthauer, Magnus Løberg, Veerle M. H. Coupé, Mette Kalager, Beatriz Carvalho. Molecular adenoma features to predict metachronous colorectal cancer risk: A nested-case control study [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr A004.
Abstract PR007: Intestinal intraepithelial T cells limit colorectal cancer progression
Authors: Ghilas Sonia , Raghu Dinesh , Tran Kelly , Liao Yang , Pal Bhupinder , Sterle Shoukat , Dijkstra Christine , Yakou Marina , Parathan Pavitha , Mariadason John , Ernst Matthias , Behren Andreas , Drummond Grant , Shi Wei , Mielke Lisa A.
Published: December 2022

Homeostasis in the gut is achieved by impeccable functioning of tissue resident immune cells that reside and closely interact with the epithelium. The tissue resident immune cells of the intestinal epithelium are predominantly lymphocytes, known as intraepithelial lymphocytes (IELs) and mainly consist of TCRαβ T cells and TCRgd T cells. These IELs are well known to sense microbes, nutrients, and cellular stress but their role in intestinal cancer progression has been controversial. On one hand, gd Τ cells are the primary source of IL-17, an important proinflammatory cytokine that aid in colorectal cancer (CRC) progression. On the other hand, mice lacking gd Τ cells have been showed to have an increased risk of developing carcinogen-induced CRC. Here we used two different mouse model of colon cancer to investigate the role of gd T IELs in colon tumor growth. We showed that in both orthotopic implantation of cancer cells in the colon, and inflammation-driven colon cancer models, gd T cells are essentials to limit tumor growth. Indeed, mice lacking gd T cells had increased tumor incidence with high-grade adenomas compared to control mice. We also performed gene expression analysis of the adenomas in control mice and in mice lacking gd T cells. They revealed distinct transcription profiles with CRC-associated gene expression profile, including inflammatory genes and epithelial to mesenchymal transition genes, particularly enriched in adenomas from gd T cell deficient mice. Moreover, using human tissue microarrays, we investigated whether the presence of gd T cells in tumors of patients with advanced CRC could be used to predict disease outcomes. We revealed that patient disease-free survival was improved if gd T cells could be detected within tumors. Therefore, we showed that gd T cells are primordial in limiting colorectal cancer progression in both mice and humans.

Citation Format: Sonia Ghilas, Dinesh Raghu, Kelly Tran, Yang Liao, Bhupinder Pal, Shoukat Sterle, Christine Dijkstra, Marina Yakou, Pavitha Parathan, John Mariadason, Matthias Ernst, Andreas Behren, Grant Drummond, Wei Shi, Lisa A. Mielke. Intestinal intraepithelial T cells limit colorectal cancer progression [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr PR007.
Abstract A05: ARF6 inhibition enhances T cell-mediated cytotoxicity in triple negative breast cancer
Authors: Moulana Ishara , Lu Xiongbin
Published: December 2022

Triple negative breast cancer (TNBC) has the poorest clinical outcome owing to the lack of effective treatments out of all the breast cancer subtypes. Immune checkpoint blockade (ICB) therapies have shown promise in these patients but only a small proportion of patients respond to ICB therapy partly due to immune evasion. A primary mechanism by which tumor cells evade immune surveillance is downregulation of antigen presentation by decreasing the levels of antigen-MHC-I (major histocompatibility complex-I) complexes on the cancer cell surface. However, there are no known targets that would boost antigen presentation in the tumor cells and increase T cell functionality simultaneously to increase the efficacy of ICB therapy. The small GTPase ARF6 has been implicated in the internalization of MHC-I molecules into the cell. Additionally, ARF6 also plays a role in CD8+ T cell activation by reorganization of the actin cytoskeleton and inhibits the formation of the immunological sypnase. We hypothesize that by inhibiting ARF6 in both tumor cells and CD8+ T cells, T cell-mediated cytotoxicity would be increased. In cancer cells, ARF6 inhibition will inhibit endocytosis of MHC-I complexes and enhance antigen presentation, while in CD8+ T cells, Arf6 inhibition will promote the formation of the immunological synapse. We tested the dose-dependent effect of an ARF6 inhibitor NAV-2729 on the GTPase activity of ARF6 in tumor cells as it specifically inhibits ARF6 by blocking its GTP-binding domain. We observed a dose-dependent decrease in ARF6-GTP levels with NAV-2729 treatment. To this end, we inhibited ARF6 via the small molecule inhibitor NAV-2729 or knockdown by shRNA in murine and human TNBC cells and found that antigen presentation is enhanced when MHC-I mean fluorescence intensity (MFI) was measured by flow cytometry. We also inhibited ARF6 in CD8+ T cells by NAV-2729 pretreatment, activated them in vitro and measured their functionality by flow cytometry. Interestingly, inhibitor treatment led to higher IFNg, TNFa and IL2 production. In a T cell cytotoxicity assay, we observed increased T cell cytotoxicity in the coculture of T cells and tumor cells when either the tumor cells or CD8+ T cells were treated with inhibitor. Collectively, we show here that ARF6 inhibition in tumor cells and CD8+ T cells will enhance tumor cell killing due to enhanced antigen presentation and T cell functionality respectively. These results give us more insight into the use of Arf6 inhibitors in combination with ICB therapy, thus enhancing treatment efficacy.

Citation Format: Ishara Moulana, Xiongbin Lu. ARF6 inhibition enhances T cell-mediated cytotoxicity in triple negative breast cancer [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr A05.
Abstract A19: The joint effect of HLA class I and II alleles shapes antitumor immunity in melanoma patients
Authors: Papp Benjamin Tamás , Fülöp Anna Tácia , Koncz Balázs , Balogh Gergő Mihály , Spekhardt Dóra , Manczinger Máté
Published: December 2022

Neopeptide presentation to T cells by both HLA class I and II molecules is necessary for antitumor immune response. Both classes are extremely diverse and different variants have distinct peptide-binding specificities. HLA diversity and certain HLA variants have been suggested to influence antitumor immunity, however, the findings are controversial. As both HLA class I and II molecules have an essential role in the recognition of tumor cells, we examined their joint effect in melanoma patients. We found numerous HLA class I and II allele combinations associated with better or worse survival in metastatic melanoma patients receiving immune checkpoint blockade (ICB) immunotherapy. Moreover, these combinations predicted the survival of ICB-naive patients, too. Importantly, allele combinations had a much stronger and more robust effect than any HLA class I or II variants alone. In the case of beneficial combinations, both HLA class I and II alleles were likely to bind melanoma-associated mutations. Paradoxically, they bound these mutations even stronger in detrimental combinations. Beneficial and detrimental combinations had a diametrical effect on antitumor immune response in primary and metastatic samples. The former was associated with dendritic cell infiltrate in the microenvironment of primary tumors and an active cytotoxic immune response in metastatic samples. On the contrary, detrimental combinations were associated with cytotoxic immune response in primary tumors, while metastases showed signs of immune evasion and ineffective antitumor immunity. Our results provide evidence of the joint effect of HLA class I and II variants on antitumor immunity. The findings also highlight the importance of the timing of immune response during tumor evolution. While beneficial combinations resulted in an effective immune response in metastases only, detrimental ones caused excessive inflammation already in primary tumors leading to immune evasion in metastatic samples.

Citation Format: Benjamin Tamás Papp, Anna Tácia Fülöp, Balázs Koncz, Gergő Mihály Balogh, Dóra Spekhardt, Máté Manczinger. The joint effect of HLA class I and II alleles shapes antitumor immunity in melanoma patients [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr A19.
Abstract A24: Cancer cells reduce macrophage CXCR3/CXCL10 axis expression through canonical NF-κB signaling
Authors: Korkaya Ahmet K , Bradford Jennifer W
Published: December 2022

Tumor-associated macrophage (TAM) infiltration of tumors via chemokine axis are linked with tumor progression and metastasis. There are forty-seven known chemokines and nineteen known chemokine receptors in humans. Many of these chemokines have a dual functionality in cell survival and growth. Notably, CXCL10 and its receptor CXCR3 are associated with both angiogenesis and angiostasis, among other functions, both pro and anti-tumor. This duality is coupled with the uncertainty of which signaling pathways are responsible for CXCL10 expression and supression during tumor progression. Recent literature states that nuclear factor-kappaB (NF-κB) signaling is required for driving the expression of CXCL10 during traditional macrophage activation; however, little is known about the chemokine’s suppression. To determine the role of NF-κB on CXCR3/CXCL10 modulation in macrophages within the context of cancer, we performed three co-culture experiments to examine the gene expression level changes within bone marrow-derived macrophages (BMDMs) from an NF-κB (p65) deficient mouse model (p65fl/fl/LysMCre) and compared them to control BMDMs (LysMCre). The first co-culture included a murine glioblastoma multiforme (GBM) cell line (GL261), while the other two included different murine triple-negative breast cancer (TNBC) cell lines (AT-3, 4T1). BMDMs, from either LysMCre or p65fl/fl/LysMCre mice, were seeded into 6-well plates, let rest for 24 hours, and then cancer cells were seeded onto the transwell insert. Cells shared the growth medium for 24 hours before collection and subsequent RNA isolation, cDNA synthesis, and qPCR analysis. Here, we identified that BMDM CXCL10 gene expression is drastically reduced when co-cultured with the three different cancer cell lines. Furthermore, we found that conditional deletion of canonical NF-κB signaling (p65) in BMDMs significantly recovered their CXCL10 expression when co-cultured with GL261 glioma cells and AT-3 breast cancer cells. Co-culture with 4T1 breast cancer cells also showed a recovering CXCL10 gene expression in the NF-κB (p65) deficient BMDMs. Additionally, the chemokine’s receptor, CXCR3, gene expression was signficantly reduced in all three co-culture conditions. However, in comparison, there was no significant difference in CXCR3 gene expression in the NF-κB (p65) deficient BMDMs in the same co-cultures. Thus, canonical NF-κB signaling is implicated in maintenance of CXCL10 expression in BMDMs, but not obviously involved in the alteration of their CXCR3 expression.

Citation Format: Ahmet K Korkaya, Jennifer W Bradford. Cancer cells reduce macrophage CXCR3/CXCL10 axis expression through canonical NF-κB signaling [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr A24.
Abstract A31: CDK4/6 inhibition plus radiotherapy enhances anti-tumor immune responses in non-small cell lung cancer
Authors: Huang Zhengrong , Xie Hongxin , Wang Mengqin , Xie Conghua , Gong Yan
Published: December 2022

Background: Lung cancer is the main cause of cancer-related mortality, of which non-small cell lung cancer (NSCLC) accounts for 85%. Abemaciclib, a selective CDK4/6 inhibitor, enhanced the radiosensitivity of NSCLC in vivo and in vitro and improved the prognosis of advanced NSCLC patients according to a Phase Ⅰ clinical trial. This study aimed to explore the impact of CDK4/6 inhibition combined with irradiation and immunotherapy on NSCLC.Methods: The in vivo xenograft tumor mouse model was used to investigate the synergistic effects of CDK4/6 inhibitor abemaciclib and irradiation together with anti-PD-1 antibodies. The tumor infiltrating lymphocytes (TILs) in tumor microenvironment (TME) were analyzed by flow cytometry. The complete blood count and serum tests were used to determine the safety of this combination therapy. The human phospho-kinase array and dual-luciferase report assay were used to study the regulatory mechanisms of abemaciclib and irradiation combination on PD-L1 transcription in NSCLC cells in vitro.Results: Our results indicated the significantly synergistic effects of abemaciclib, irradiation and anti-PD-1 antibodies on NSCLC growth in vivo, accompanied by increased CD8+ T cell infiltration and decreased regulatory T cells and myeloid-derived suppressor cells (MDSCs), suggesting a strong anti-tumor combination of CDK4/6 inhibition, radiotherapy and immunotherapy. This synergistic effect could be partially impaired by CD8 depletion, and alleviated the anemia and inflammation caused by tumor burden without hepatorenal toxicity. Abemaciclib induced PD-L1 transcription through JNK/c-Jun pathway in vitro, which might elevate PD-L1 expression synergistically with irradiation through TBK1/IRF3 pathway.Conclusions: Our studies suggested that CDK4/6 inhibition plus irradiation enhanced anti-tumor immune responses in NSCLC. Together with immunotherapy, the combination of CDK4/6 inhibitors and radiotherapy could lower the doses of individual treatment, thus alleviating the potential toxicity and side effects of CDK4/6 inhibition and irradiation on normal cells.

Citation Format: Zhengrong Huang, Hongxin Xie, Mengqin Wang, Conghua Xie, Yan Gong. CDK4/6 inhibition plus radiotherapy enhances anti-tumor immune responses in non-small cell lung cancer [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr A31.