bluuebunny/crossref_metadata_2025_split huggingface dataset:
Single Cell Analyses Reveal a Non-Canonical EZH2 Activity As a Main Driver of Retinoic Acid Resistance in PLZF/Rara Leukemia
Authors: Poplineau Mathilde , Platet Nadine , Mazuel Adrien , Hérault Léonard , Koide Shuhei , Kuribayashi Wakako , Carbuccia Nadine , N'Guyen Lia , Vernerey Julien , Oshima Motohiko , Birnbaum Daniel , Lachaud Christophe , Iwama Atsushi , Duprez Estelle 
Published: November 2021

Abstract
Resistance to treatment is due to the heterogeneity of the tumor which contains a subset of cancer cells that escape treatment and are responsible for the relapse. Acute Promyelocytic Leukemia (APL), the M3 subtype of AML, is a good model to illustrate these problematics. Indeed, APL driven by oncogenic fusion proteins such PML/RARA t(15;17) or PLZF/RARA t(11;17) behave differently to differentiation therapeutics. Both APLs differentiate in vivo upon Retinoic Acid (RA) treatment; however, while PML/RARA APL patients exhibit partial or complete remission, PLZF/RARA APL patients remain clinically resistant. In the present study we aim to decipher the transcriptional and epigenetic networks that is linked to t(11;17) APL resistance towards RA.
We took advantage of the PLZF/RARA RA resistant murine APL model to catch relapse-initiating cell features and their vulnerabilities. By developing an integrative single-cell multi-omics analysis (scRNA-seq and scATAC-seq), we uncovered transcriptional and chromatin heterogeneity of the PLZF/RARA APL blasts. We highlighted a subset of cells insensitive to RA-induced differentiation with a strong DNA repair signature ("Rep" cluster) and exhibiting a fine tuned transcriptional network targeting the histone methyltransferase Ezh2. To validate the function of Ezh2 in APL physiology, we combined epigenomic studies with RA-treated and non-RA-treated bone marrow transplantation experiments. We revealed high Ezh2 activity that marks the relapse of RA-treated APL. However, targeting Ezh2 methyltransferase activity was not sufficient to achieve disease cure and, suggests an independent methyltransferase Ezh2 activity linked to RA resistance.
These findings demonstrate the power of single-cell multi-omics integration to highlight path to sensitize therapy-resistant leukemia cells. In addition, our study uncovers a dual role of Ezh2 in APL and suggests that targeting non-canonical Ezh2 activity could be a new promising therapeutic approach for RA resistant APL.

Disclosures
Iwama: Nissan Chemical Corporation: Research Funding.
Serological Response to BNT162b2 Anti-Sars-Cov-2 mRNA Vaccine in Patients with Transfusion Dependent Thalassemia
Authors: Zucano Stefania , Tarantini Francesco , Vitucci Angelantonio , Palma Antonio , Campanale Daniela , Vimercati Luigi , Larocca Angela Maria Vittoria , Visceglie Domenico , Acquafredda Amalia , Tafuri Silvio , Musto Pellegrino 
Published: November 2021

Abstract
Thalassemia is an inherited blood disorder characterized by defective hemoglobin production, ineffective erythropoiesis and chronic hemolytic anemia. Patients with both transfusion-dependent thalassemia (TDT) and non-transfusion dependent thalassemia (NTDT) have risk factors associated with severe SARS-CoV-2 infection including iron overload, endocrinopathies, massive splenomegaly or previous splenectomy and coagulopathy (Motta et al, Am J Hematol, 95: E198-E199., 2020). Although vaccination is encouraged for these patients, data on the efficacy and safety of anti Sars-CoV-2 vaccines are limited (Karimi, M, et al, Br J Haematol, 190: e137-e140, 2020; Mandana Zafari, et al, Hemoglobin, 45:1, 1-4, 2021) due to exclusion of these patients from clinical trials. In a single center, prospective, cohort study we compared 67 patients affected by TDT to 61 healthy controls (HC), matched for age and sex. Study population and HC received two doses of BNT162b2 anti-SARS-Cov-2 mRNA vaccine on days 1 and 21, between April 1st and May 15 th, 2021. Serological tests were performed by a commercially available immunoassay for the quantitative determination of anti-spike IgG antibodies to SARS-CoV-2. The results were reported as Arbitrary Units (AU)/mL, with a cut-off for defining response as 50 or greater AU/ml. Patients and HC samples were collected four weeks after the second dose of vaccine. Median age of patients was 43 years (range 19-77), 39% of them were male and 61% were female. Median age of HC was 39 years (range 19-86), 43% of them were male and 57% were female. All controls achieved a response (50 or greater AU/mL) to vaccination, whereas 66/67 (98,5%) patients responded. Antibody titers were significantly higher (p=0.0005) in the HC group (mean 9863 ± 7784; median 7712, range 1206-51664) compared to patients (mean 7945 ± 12326; median 4025, range 19-89202) (Figure 1). When analyzing the patients' factors, age, sex, transfusion interval, serum ferritin level, and spleen size did not impact on the response to vaccination. With a median follow-up of 12 weeks, no relevant side effects were recorded after vaccination and no case of COVID19 occurred among vaccinated TDT patients. In conclusion, BNT162b2 anti-SARS-Cov-2 mRNA vaccine demonstrated efficacy and safety in our cohort of TDT patients. Response rate was similar to that of HC. Nevertheless, antibody titers in TDT patients were significantly lower than in HC. Further observations are ongoing to assess duration of response, efficacy and possible factors influencing this finding.
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.
Genome-wide CRISPR screen identifies CDK6 as a therapeutic target in adult T-cell leukemia/lymphoma
Authors: Ishio Takashi , Kumar Sarvesh , Shimono Joji , Daenthanasanmak Anusara , Dubois Sigrid , Lin Yuquan , Bryant Bonita , Petrus Michael N. , Bachy Emmanuel , Huang Da Wei , Yang Yandan , Green Patrick L. , Hasegawa Hiroo , Maeda Michiyuki , Goto Hideki , Endo Tomoyuki , Yokota Takashi , Hatanaka Kanako C. , Hatanaka Yutaka , Tanaka Shinya , Matsuno Yoshihiro , Yang Yibin , Hashino Satoshi , Teshima Takanori , Waldmann Thomas A. , Staudt Louis M. , Nakagawa Masao 
Published: November 2021

Abstract
Adult T-cell leukemia/lymphoma (ATLL) is an aggressive T-cell malignancy with a poor prognosis with current therapy. Here we report genome-wide CRISPR-Cas9 screening of ATLL models, which identified CDK6, CCND2, BATF3, JUNB, STAT3, and IL10RB as genes that are essential for the proliferation and/or survival of ATLL cells. As a single agent, the CDK6 inhibitor palbociclib induced cell cycle arrest and apoptosis in ATLL models with wild-type TP53. ATLL models that had inactivated TP53 genetically were relatively resistant to palbociclib owing to compensatory CDK2 activity, and this resistance could be reversed by APR-246, a small molecule activator of mutant TP53. The CRISPR-Cas9 screen further highlighted the dependence of ATLL cells on mTORC1 signaling. Treatment of ATLL cells with palbociclib in combination with mTORC1 inhibitors was synergistically toxic irrespective of the TP53 status. This work defines CDK6 as a novel therapeutic target for ATLL and supports the clinical evaluation of palbociclib in combination with mTORC1 inhibitors in this recalcitrant malignancy.
Opportunities and Challenges: Classification of Skin Disease Based on Deep Learning
Authors: Zhang Bin , Zhou Xue , Luo Yichen , Zhang Hao , Yang Huayong , Ma Jien , Ma Liang 
Published: November 2021

AbstractDeep learning has become an extremely popular method in recent years, and can be a powerful tool in complex, prior-knowledge-required areas, especially in the field of biomedicine, which is now facing the problem of inadequate medical resources. The application of deep learning in disease diagnosis has become a new research topic in dermatology. This paper aims to provide a quick review of the classification of skin disease using deep learning to summarize the characteristics of skin lesions and the status of image technology. We study the characteristics of skin disease and review the research on skin disease classification using deep learning. We analyze these studies using datasets, data processing, classification models, and evaluation criteria. We summarize the development of this field, illustrate the key steps and influencing factors of dermatological diagnosis, and identify the challenges and opportunities at this stage. Our research confirms that a skin disease recognition method based on deep learning can be superior to professional dermatologists in specific scenarios and has broad research prospects.
Diurnal variations in muscle and liver glycogen differ depending on the timing of exercise
Authors: Iwayama Kaito , Tanabe Yoko , Tanji Fumiya , Ohnishi Takahiro , Takahashi Hideyuki 
Published: November 2021

AbstractIt has been suggested that glycogen functions not only in carbohydrate energy storage, but also as molecular sensors capable of activating lipolysis. This study aimed to compare the variation in liver and muscle glycogen during the day due to different timing of exercise. Nine healthy young men participated in two trials in which they performed a single bout of exercise at 70% of their individual maximal oxygen uptake for 60 min in the post-absorptive (morning) or post-prandial (afternoon) state. Liver and muscles glycogen levels were measured using carbon magnetic resonance spectroscopy (13C MRS). Diurnal variations in liver and muscle glycogen compared to baseline levels were significantly different depending on the timing of exercise. The effect of the timing of exercise on glycogen fluctuation is known to be related to a variety of metabolic signals, and the results of this study will be useful for future research on energy metabolism.
Universal probe-based intermediate primer-triggered qPCR (UPIP-qPCR) for SNP genotyping
Authors: Li Baowei , Liu Yanran , Hao Xiaodan , Dong Jinhua , Chen Limei , Li Haimei , Wu Wei , Liu Ying , Wang Jianxun , Wang Yin , Li Peifeng 
Published: November 2021

AbstractBackgroundThe detection and identification of single nucleotide polymorphism (SNP) is essential for determining patient disease susceptibility and the delivery of medicines targeted to the individual. At present, SNP genotyping technology includes Sanger sequencing, TaqMan-probe quantitative polymerase chain reaction (qPCR), amplification-refractory mutation system (ARMS)-PCR, and Kompetitive Allele-Specific PCR (KASP). However, these technologies have some disadvantages: the high cost of development and detection, long and time consuming protocols, and high false positive rates. Focusing on these limitations, we proposed a new SNP detection method named universal probe-based intermediate primer-triggered qPCR (UPIP-qPCR). In this method, only two types of fluorescence-labeled probes were used for SNP genotyping, thus greatly reducing the cost of development and detection for SNP genotyping.ResultsIn the amplification process of UPIP-qPCR, unlabeled intermediate primers with template-specific recognition functions could trigger probe hydrolysis and specific signal release. UPIP-qPCR can be used successfully and widely for SNP genotyping. The sensitivity of UPIP-qPCR in SNP genotyping was 0.01 ng, the call rate was more than 99.1%, and the accuracy was more than 99.9%. High-throughput DNA microarrays based on intermediate primers can be used for SNP genotyping.ConclusionThis novel approach is both cost effective and highly accurate; it is a reliable SNP genotyping method that would serve the needs of the clinician in the provision of targeted medicine.
Endoscopic negative pressure therapy as stand-alone treatment for perforated duodenal diverticulum: presentation of two cases
Authors: Wichmann Dörte , Jansen Kai Tobias , Onken Flurina , Stüker Dietmar , Zerabruck Emanuel , Werner Christoph R. , Yurttas Can , Thiel Karolin , Königsrainer Alfred , Quante Markus 
Published: November 2021

Abstract
Background
Endoscopic negative pressure therapy is a novel and successful treatment method for a variety of gastrointestinal leaks. This therapy mode has been frequently described for rectal and esophageal leakages. Duodenal diverticular perforations are rare but life-threatening events. The early diagnosis of duodenal diverticular perforation is often complicated by inconclusive symptoms. This is the first report about endoscopic negative pressure therapy in patients with perforated duodenal diverticula.

Case presentation
We present two cases of duodenal diverticula perforations treated with endoscopic negative pressure therapy as stand-alone treatment. Start of symptoms varied from one to three days before hospital admission. Early sectional imaging led to the diagnosis of duodenal diverticular perforation. Both patients were treated with endoluminal endoscopic negative pressure therapy with simultaneous feeding option. Three respective changes of the suction device were performed. Both patients were treated with antibiotics and antimycotics during their hospital stay and be discharged from hospital after 20 days.

Conclusions
This is the first description of successful stand-alone treatment by endoscopic negative pressure therapy in two patients with perforated duodenal diverticulum. We thus strongly recommend to attempt interventional therapy with endoluminal endoscopic negative pressure therapy in patients with duodenal diverticular perforations upfront to surgery.
Investigation of the impact of SARS-CoV infection on the immunologic status and lung function after 15 years
Authors: Li Jia , Zheng Yali , Zhao Lili , Yue Zhihong , Pan Feng , Chen Yuehong , Yu Bing , Chen Yanwen , Zhao Guangyu , Zhou Yusen , Gao Zhancheng 
Published: November 2021

Abstract
Background
We investigate the long-term effects of SARS-CoV on patients’ lung and immune systems 15 years post-infection. SARS-CoV-2 pandemic is ongoing however, another genetically related beta-coronavirus SARS-CoV caused an epidemic in 2003–2004.

Methods
We enrolled 58 healthcare workers from Peking University People’s Hospital who were infected with SARS-CoV in 2003. We evaluated lung damage by mMRC score, pulmonary function tests, and chest CT. Immune function was assessed by their serum levels of globin, complete components, and peripheral T cell subsets. ELISA was used to detect SARS-CoV-specific IgG antibodies in sera.

Results
After 15 years of disease onset, 19 (36.5%), 8 (34.6%), and 19 (36.5%) subjects had impaired DL (CO), RV, and FEF25–75, respectively. 17 (30.4%) subjects had an mMRC score ≥ 2. Fourteen (25.5%) cases had residual CT abnormalities. T regulatory cells were a bit higher in the SARS survivors. IgG antibodies against SARS S-RBD protein and N protein were detected in 11 (18.97%) and 12 (20.69%) subjects, respectively. Subgroup analysis revealed that small airway dysfunction and CT abnormalities were more common in the severe group than in the non-severe group (57.1% vs 22.6%, 54.5% vs 6.1%, respectively, p < 0.05).

Conclusions
SARS-CoV could cause permanent damage to the lung, which requires early pulmonary rehabilitation. The long-lived immune memory response against coronavirus requires further studies to assess the potential benefit.
Trial registration ClinicalTrials.gov, NCT03443102. Registered prospectively on 25 January 2018
The CKD bowel health study: understanding the bowel health and gastrointestinal symptom management in patients with chronic kidney disease: a mixed-methods observational longitudinal study (protocol)
Authors: Cooper Tess E. , Dalton Amy , Kieu Anh , Howell Martin , Jayanti Sumedh , Khalid Rabia , Lim Wai H. , Scholes-Robertson Nicole , Craig Jonathan C. , Teixeira-Pinto Armando , Bourke Michael J. , Tong Allison , Wong Germaine 
Published: November 2021

Abstract
Background
Gastro-intestinal (GI) intolerance is a frequently reported outcome in patients with kidney failure receiving maintenance dialysis and those who have received kidney transplants. Symptoms of GI intolerance (diarrhoea, constipation, bloating, abdominal pain, heart burn, and reflux) are associated with significant reduction in quality of life, morbidity, and increased used of healthcare resources. Having chronic kidney disease (CKD), together with related changes in diet and medication, may alter the gut microbiota and the microbial-derived uraemic metabolites that accumulate in kidney failure, and contribute to various complications including chronic diarrhoea, opportunistic infections, and drug-related colitis. Despite the high disease burden among patients with kidney replacement therapies, GI symptoms are often under-recognised and, consequently limited resources and strategies are devoted to the management of gastrointestinal complications in patients with CKD.

Methods
The CKD Bowel Health Study is a multi-centre mixed-methods observational longitudinal study to better understand the bowel health and GI symptom management in patients with CKD. The program comprises of a longitudinal study that will assess the burden and risk factors of GI intolerance in patients treated with maintenance dialysis; a semi-structured interview study that will describe experiences of GI intolerance (including symptoms, treatment, self-management) in transplant candidates and recipients; and a discrete choice experience to elicit patient preferences regarding their experiences and perspectives of various intervention strategies for the management of GI symptoms after kidney transplantation.

Discussion
This proposed program of work aims to define the burden the GI intolerance in patients with kidney failure and generate evidence on the patients’ experiences of GI intolerance and their perspectives on their clinical and own management strategies of these symptoms, ensuring a patient-centred approach to guide clinical decision making and to inform the best study design for intervention trials.

Trial registration
This study is registered on the Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12621000548831. This study has been approved by the Western Sydney Local Health District Human Research Ethics Committee of New South Wales Health (HREC ETH03007). This study is supported by a National Health and Medical Research Council (NHMRC) Australia Investigator Grant (APP1195414), and an NHMRC Australia Postgraduate Scholarship (APP2005244).
Phase 1 trial of entinostat as monotherapy and combined with exemestane in Japanese patients with hormone receptor-positive advanced breast cancer
Authors: Masuda Norikazu , Tamura Kenji , Yasojima Hiroyuki , Shimomura Akihiko , Sawaki Masataka , Lee Min-Jung , Yuno Akira , Trepel Jane , Kimura Ryoko , Nishimura Yozo , Saji Shigehira , Iwata Hiroji 
Published: November 2021

Abstract
Background
Entinostat is an oral inhibitor of class I histone deacetylases intended for endocrine therapy-resistant patients with hormone receptor-positive (HR+) advanced or metastatic breast cancer (BC). We examined the safety, efficacy, and pharmacokinetics of entinostat monotherapy and combined entinostat/exemestane in Japanese patients.

Methods
This phase 1 study (3 + 3 dose-escalation design) enrolled postmenopausal women with advanced/metastatic HR+ BC previously treated with nonsteroidal aromatase inhibitors. Dose-limiting toxicities (DLTs) of entinostat monotherapy (3 mg/qw, 5 mg/qw, or 10 mg/q2w) and entinostat+exemestane (5 mg/qw + 25 mg/qd) were assessed. Pharmacokinetics, lysine acetylation (Ac-K), and T-cell activation markers were measured at multiple time points.

Results
Twelve patients were enrolled. No DLTs or grade 3–5 adverse events (AEs) occurred. Drug-related AEs (≥ 2 patients) during DLT observation were hypophosphatemia, nausea, and platelet count decreased. Six patients (50%) achieved stable disease (SD) for ≥ 6 months, including one treated for > 19 months. Median progression-free survival was 13.9 months (95% CI 1.9–not calculable); median overall survival was not reached. Area under the plasma concentration-time curve and Ac-K in peripheral blood CD19+ B cells increased dose-proportionally. The changing patterns of entinostat concentrations and Ac-K levels were well correlated. T-cell activation markers increased over time; CD69 increased more in patients with SD ≥ 6 months vs. SD < 6 months.

Conclusions
Entinostat monotherapy and combined entinostat/exemestane were well tolerated in Japanese patients, with no additional safety concerns compared with previous reports. The correlation between pharmacokinetics and Ac-K in peripheral blood CD19+ B cells, and also T-cell activation markers, merits further investigation.

Trial registration
JAPIC Clinical Trial Information, JapicCTI-153066. Registered 12 November 2015. ClinicalTrials.gov, NCT02623751. Registered 8 December 2015.
Spatial determinants of excess all-cause mortality during the first wave of the COVID-19 epidemic in France
Authors: Pilkington Hugo , Feuillet Thierry , Rican Stéphane , Goupil de Bouillé Jeanne , Bouchaud Olivier , Cailhol Johann , Bihan Hélène , Lombrail Pierre , Julia Chantal 
Published: November 2021

AbstractBackgroundThe first wave of the COVID-19 pandemic in France was associated with high excess mortality, and anecdotal evidence pointed to differing excess mortality patterns depending on social and environmental determinants. In this study we aimed to investigate the spatial distribution of excess mortality during the first wave of the COVID-19 pandemic in France and relate it at the subnational level to contextual determinants from various dimensions (socioeconomic, population density, overall health status, healthcare access etc.). We also explored whether the determinants identified at the national level varied depending on geographical location.MethodsWe used available national data on deaths in France to calculate excess mortality by department for three age groups: 0–49, 50–74 and > 74 yrs. between March 1st and April 27th, 2020. We selected 15 variables at the department level that represent four dimensions that may be related to overall mortality at the ecological level, two representing population-level vulnerabilities (morbidity, social deprivation) and two representing environmental-level vulnerabilities (primary healthcare supply, urbanization). We modelled excess mortality by age group for our contextual variables at the department level. We conducted both a global (i.e., country-wide) analysis and a multiscale geographically weighted regression (MGWR) model to account for the spatial variations in excess mortality.ResultsIn both age groups, excess all-cause mortality was significantly higher in departments where urbanization was higher (50–74 yrs.: β = 15.33,p < 0.001; > 74 yrs.: β = 18.24,p < 0.001) and the supply of primary healthcare providers lower (50–74 yrs.: β = − 8.10,p < 0.001; > 74 yrs.: β = − 8.27,p < 0.001). In the 50–74 yrs. age group, excess mortality was negatively associated with the supply of pharmacists (β = − 3.70,p < 0.02) and positively associated with work-related mobility (β = 4.62,p < 0.003); in the > 74 yrs. age group our measures of deprivation (β = 15.46,p < 0.05) and morbidity (β = 0.79,p < 0.008) were associated with excess mortality. Associations between excess mortality and contextual variables varied significantly across departments for both age groups.ConclusionsPublic health strategies aiming at mitigating the effects of future epidemics should consider all dimensions involved to develop efficient and locally tailored policies within the context of an evolving, socially and spatially complex situation.