bluuebunny/crossref_metadata_2025_split huggingface dataset:
Intratumoral Resolution of Driver Gene Mutation Heterogeneity in Renal Cancer Using Deep Learning
Authors: Acosta Paul H. , Panwar Vandana , Jarmale Vipul , Christie Alana , Jasti Jay , Margulis Vitaly , Rakheja Dinesh , Cheville John , Leibovich Bradley C. , Parker Alexander , Brugarolas James , Kapur Payal , Rajaram Satwik 
Published: August 2022

Abstract

Intratumoral heterogeneity arising from tumor evolution poses significant challenges biologically and clinically. Dissecting this complexity may benefit from deep learning (DL) algorithms, which can infer molecular features from ubiquitous hematoxylin and eosin (H&E)–stained tissue sections. Although DL algorithms have been developed to predict some driver mutations from H&E images, the ability of these DL algorithms to resolve intratumoral mutation heterogeneity at subclonal spatial resolution is unexplored. Here, we apply DL to a paradigm of intratumoral heterogeneity, clear cell renal cell carcinoma (ccRCC), the most common type of kidney cancer. Matched IHC and H&E images were leveraged to develop DL models for predicting intratumoral genetic heterogeneity of the three most frequently mutated ccRCC genes, BAP1, PBRM1, and SETD2. DL models were generated on a large cohort (N = 1,282) and tested on several independent cohorts, including a TCGA cohort (N = 363 patients) and two tissue microarray (TMA) cohorts (N = 118 and 365 patients). These models were also expanded to a patient-derived xenograft (PDX) TMA, affording analysis of homotopic and heterotopic interactions of tumor and stroma. The status of all three genes could be inferred by DL, with BAP1 showing the highest sensitivity and performance within and across tissue samples (AUC = 0.87–0.89 on holdout). BAP1 results were validated on independent human (AUC = 0.77–0.84) and PDX (AUC = 0.80) cohorts. Finally, BAP1 predictions correlated with clinical outputs such as disease-specific survival. Overall, these data show that DL models can resolve intratumoral heterogeneity in cancer with potential diagnostic, prognostic, and biological implications.

Significance:
This work demonstrates the potential for deep learning analysis of histopathologic images to serve as a fast, low-cost method to assess genetic intratumoral heterogeneity.
See related commentary by Song et al., p. 2672
Orthovoltage X-Rays Exhibit Increased Efficacy Compared with γ-Rays in Preclinical Irradiation
Authors: Bell Brett I. , Vercellino Justin , Brodin N. Patrik , Velten Christian , Nanduri Lalitha S.Y. , Nagesh Prashanth K.B. , Tanaka Kathryn E. , Fang Yanan , Wang Yanhua , Macedo Rodney , English Jeb , Schumacher Michelle M. , Duddempudi Phaneendra K. , Asp Patrik , Koba Wade , Shajahan Shahin , Liu Laibin , Tomé Wolfgang A. , Yang Weng-Lang , Kolesnick Richard , Guha Chandan 
Published: August 2022

Abstract

Radionuclide irradiators (137Cs and 60Co) are commonly used in preclinical studies ranging from cancer therapy to stem cell biology. Amidst concerns of radiological terrorism, there are institutional initiatives to replace radionuclide sources with lower energy X-ray sources. As researchers transition, questions remain regarding whether the biological effects of γ-rays may be recapitulated with orthovoltage X-rays because different energies may induce divergent biological effects. We therefore sought to compare the effects of orthovoltage X-rays with 1-mm Cu or Thoraeus filtration and 137Cs γ-rays using mouse models of acute radiation syndrome. Following whole-body irradiation, 30-day overall survival was assessed, and the lethal dose to provoke 50% mortality within 30-days (LD50) was calculated by logistic regression. LD50 doses were 6.7 Gy, 7.4 Gy, and 8.1 Gy with 1-mm Cu-filtered X-rays, Thoraeus-filtered X-rays, and 137Cs γ-rays, respectively. Comparison of bone marrow, spleen, and intestinal tissue from mice irradiated with equivalent doses indicated that injury was most severe with 1-mm Cu-filtered X-rays, which resulted in the greatest reduction in bone marrow cellularity, hematopoietic stem and progenitor populations, intestinal crypts, and OLFM4+ intestinal stem cells. Thoraeus-filtered X-rays provoked an intermediate phenotype, with 137Cs showing the least damage. This study reveals a dichotomy between physical dose and biological effect as researchers transition to orthovoltage X-rays. With decreasing energy, there is increasing hematopoietic and intestinal injury, necessitating dose reduction to achieve comparable biological effects.

Significance:
Understanding the significance of physical dose delivered using energetically different methods of radiation treatment will aid the transition from radionuclide γ-irradiators to orthovoltage X-irradiators.
Identification of a Molecularly-Defined Subset of Breast and Ovarian Cancer Models that Respond to WEE1 or ATR Inhibition, Overcoming PARP Inhibitor Resistance
Authors: Serra Violeta , Wang Anderson T. , Castroviejo-Bermejo Marta , Polanska Urszula M. , Palafox Marta , Herencia-Ropero Andrea , Jones Gemma N. , Lai Zhongwu , Armenia Joshua , Michopoulos Filippos , Llop-Guevara Alba , Brough Rachel , Gulati Aditi , Pettitt Stephen J. , Bulusu Krishna C. , Nikkilä Jenni , Wilson Zena , Hughes Adina , Wijnhoven Paul W.G. , Ahmed Ambar , Bruna Alejandra , Gris-Oliver Albert , Guzman Marta , Rodríguez Olga , Grueso Judit , Arribas Joaquin , Cortés Javier , Saura Cristina , Lau Alan , Critchlow Susan , Dougherty Brian , Caldas Carlos , Mills Gordon B. , Barrett J. Carl , Forment Josep V. , Cadogan Elaine , Lord Christopher J. , Cruz Cristina , Balmaña Judith , O'Connor Mark J. 
Published: August 2022

Abstract

Purpose:
PARP inhibitors (PARPi) induce synthetic lethality in homologous recombination repair (HRR)-deficient tumors and are used to treat breast, ovarian, pancreatic, and prostate cancers. Multiple PARPi resistance mechanisms exist, most resulting in restoration of HRR and protection of stalled replication forks. ATR inhibition was highlighted as a unique approach to reverse both aspects of resistance. Recently, however, a PARPi/WEE1 inhibitor (WEE1i) combination demonstrated enhanced antitumor activity associated with the induction of replication stress, suggesting another approach to tackling PARPi resistance.

Experimental Design:
We analyzed breast and ovarian patient-derived xenoimplant models resistant to PARPi to quantify WEE1i and ATR inhibitor (ATRi) responses as single agents and in combination with PARPi. Biomarker analysis was conducted at the genetic and protein level. Metabolite analysis by mass spectrometry and nucleoside rescue experiments ex vivo were also conducted in patient-derived models.

Results:
Although WEE1i response was linked to markers of replication stress, including STK11/RB1 and phospho-RPA, ATRi response associated with ATM mutation. When combined with olaparib, WEE1i could be differentiated from the ATRi/olaparib combination, providing distinct therapeutic strategies to overcome PARPi resistance by targeting the replication stress response. Mechanistically, WEE1i sensitivity was associated with shortage of the dNTP pool and a concomitant increase in replication stress.

Conclusions:
Targeting the replication stress response is a valid therapeutic option to overcome PARPi resistance including tumors without an underlying HRR deficiency. These preclinical insights are now being tested in several clinical trials where the PARPi is administered with either the WEE1i or the ATRi.
LncRNA A2M-AS1 Promotes Ferroptosis in Pancreatic Cancer via Interacting With PCBP3
Authors: Qiu Xin , Shi Qiuyue , Zhang Xianglian , Shi Xiaoyan , Jiang Haixing , Qin Shanyu 
Published: August 2022

Abstract

Ferroptosis is a newly-discovered cell death mechanism involved in the progression of various tumors, the role of noncoding RNAs (ncRNAs) in it was relatively less explored. This study identified the low levels of a recently studied long noncoding RNA (lncRNA), A2M-AS1, in pancreatic cancer and suggested its positive correlation with the overall survival time of patients with pancreatic cancer. A2M-AS1 was mainly localized in the cytoplasm, inhibiting the cellular proliferation, migration, and invasion as well as the tumor growth of the pancreatic cancer cells. Moreover, the Erastin-induced ferroptosis increased the expression levels of A2M-AS1. The overexpression of A2M-AS1 promoted ferroptosis in the pancreatic cancer, which was inhibited by the silencing of A2M-AS1. Mechanically, A2M-AS1 could directly interact with the poly (rC) binding protein 3 (PCBP3), which plays an important role in the process of iron metabolism, thereby promoting the ferroptosis in pancreatic cancer. In addition, the A2M-AS1/PCBP3 axis could facilitate the p38 activation and inhibit the phosphorylation of the AKT–mTOR signaling pathway; all these participate in regulating ferroptosis. In conclusion, the regulation of ferroptosis by targeting the A2M-AS1/PCBP3 axis might provide a novel target for the treatment of pancreatic cancer in the future.

Implications:
A2M-AS1 might be a potential novel therapeutic target for patients with pancreatic cancer in the future.
Modulating Lysine Crotonylation in Cardiomyocytes Improves Myocardial Outcomes
Authors: Cai Wenqian , Xu Dacai , Zeng Chui , Liao Fan , Li Ruiqi , Lin Yingjiong , Zhao Yue , Dong Wenyan , Wang Qingwen , Yang Haili , Wen Daqiang , Gu Jianbiao , Shentu Weihui , Yu Hongkui , Zhang Xiaochun , Wei Jianrui , Duan Jinzhu 
Published: August 2022

Background:
Ischemic heart disease is a major global public health challenge, and its functional outcomes remain poor. Lysine crotonylation (Kcr) was recently identified as a post-translational histone modification that robustly indicates active promoters. However, the role of Kcr in myocardial injury is unknown. In this study, we aimed to clarify the pathophysiological significance of Kcr in cardiac injury and explore the underlying mechanism.

Methods:
We investigated the dynamic change of both the Kcr sites and protein level in left ventricular tissues at 2 time points following sham or cardiac ischemia-reperfusion injury, followed by liquid chromatography-coupled tandem mass tag mass spectrometry. After validation of the enriched protein Kcr by immunoprecipitation and Western blot, the function and mechanism of specific Kcr sites were further investigated in vitro and in vivo by gain- or loss-of-function mutations targeting Kcr sites of selected proteins.

Results:
We found that cardiac ischemia-reperfusion injury triggers preferential Kcr of proteins required for cardiomyocyte contractility, including mitochondrial and cytoskeleton proteins, which occurs largely independently of protein-level changes in the same proteins. Those exhibiting Kcr changes were associated not only with disruption of cardiomyocyte mitochondrial, sarcomere architecture, and gap junction but also with cardiomyocyte autophagy and apoptosis. Modulating site-specific Kcr of selected mitochondrial protein IDH3a (isocitrate dehydrogenase 3 [NAD+] alpha) at K199 and cytoskeletal protein TPM1 (tropomyosin alpha-1 chain) at K28/29 or enhancing general Kcr via sodium crotonate provision not only protects cardiomyocyte from apoptosis by inhibiting BNIP3 (Bcl-2 adenovirus E18 19-kDa–interacting protein 3)-mediated mitophagy or cytoskeleton structure rearrangement but also preserves postinjury myocardial function by inhibiting fibrosis and apoptosis.

Conclusions:
Our results indicate that Kcr modulation is a key response of cardiomyocytes to ischemia-reperfusion injury and may represent a novel therapeutic target in the context of ischemic heart disease.
Towards the Perfect Jung
Authors: Karimi Zanjani Asl Mohammad , Durand-Guédy David 
Published: August 2022

Abstract
This article presents a set of four multitext manuscripts made in Tabriz during the reign of the Safavid Shāh Sulaymān (r. 1666–1694). The texts are organized around one core abstruse text (lughuz) penned by the patron of the work, the vizier of Azarbayjan and mustawfī al-mamālik, Ẓahīr al-Dīn Ibrāhīm (d. 1102/1690). Analysis of these manuscripts, copied successively over a period of 12 years by the same hand, reveals the endeavours of the patron and the copyist to produce an artefact that was increasingly refined in terms of layout. The Sackler manuscript is the most recent and also the most accomplished. The amount of time and money put into this project is unusual for a non-royal patron. This editorial project might be linked to Ẓahīr al-Dīn’s political ambitions to find a position or to restore his reputation at the royal court at Isfahan.
Językowo-kulturowy obraz przestrzeni miejskiej Moskwy na przełomie XIX i XX wieku (na bazie słownika W. Jelistratowa)
Authors: Juszczak Bartosz 
Published: August 2022

The Linguistic and Cultural Image of the Urban Space of Moscow in the Late Nineteenth and Early Twentieth Centuries (on the Basis of V. Elistratov’s Dictionary) The aim of this article is to reconstruct the linguistic and cultural image of Moscowat the turn of the twentieth century using the paradigm of cultural linguistics. This paradigm was selected as the theoretical framework of the study considering that it practically has not been applied in Russian linguistics. The article shows that the intricate image of the urban space is created by means of cultural elements (the coat of arms, the flag, the bugle call, architecture) and, most of all, linguistic elements whose major exponent is a given urban dialect. It is a wide-ranging construct whose lexis, apart from native elements, also includes a large number of foreign components and proprial (official and unofficial) vocabulary. The conglomerate of these elements can be regarded as a specific language of the urban space. Językowo-kulturowy obraz przestrzeni miejskiej Moskwy na przełomie XIX i XX wieku (na bazie słownika W. Jelistratowa) Artykuł podejmuje się rekonstrukcji językowo-kulturowych elementów przestrzeni miejskiej Moskwy w aspekcie diachronicznym (przełom XIX i XX wieku) przy użyciu metod lingwistyki kulturowej. Zasadność wyboru tego paradygmatu wynika z faktu, iż na gruncie językoznawstwa rosyjskiego nie jest on uprawiany. Artykuł pokazuje, że na skomplikowany obraz przestrzeni miejskiej składają się aspekty kulturowe (architektura, herb, hejnał, flaga), a przede wszystkim językowe (dialekt miejski, zapożyczenia obce, nieoficjalna urbanonimia). Wszystkie te elementy tworzą uniwersalny język przestrzeni, który może być zestawiany z innymi miastami Słowiańszczyzny.
Hurricane Ida (2021): Rapid Intensification Followed by Slow Inland Decay
Authors: Zhu Yi-Jie , Collins Jennifer M. , Klotzbach Philip J. , Schreck Carl J. 
Published: August 2022

Abstract
Hurricane Ida recently became one of the strongest hurricanes to hit Louisiana on record, with an estimated landfalling maximum sustained wind of 130 kt (1 kt ≈ 0.51 m s−1). Although Hurricane Ida made landfall at a similar time of year and landfall location as Hurricane Katrina (2005), Ida’s postlandfall decay rate was much weaker than Hurricane Katrina. This manuscript includes a comparative analysis of pre- and postlandfall synoptic conditions for Hurricane Ida and other historical major landfalling hurricanes (category 3+ on the Saffir–Simpson hurricane wind scale) along the Gulf Coast since 1983, with a particular focus on Hurricane Katrina. Abundant precipitation in southeastern Louisiana prior to Ida’s landfall increased soil moisture. This increased soil moisture along with extremely weak overland steering flow likely slowed the storm’s weakening rate postlandfall. Offshore environmental factors also played an important role, particularly anomalously high nearshore sea surface temperatures and weak vertical wind shear that fueled the rapid intensification of Ida just before landfall. Strong nearshore vertical wind shear weakened Hurricane Katrina before landfall, and moderate northward steering flow caused Katrina to move inland relatively quickly, aiding in its relatively fast weakening rate following landfall. The results of this study improve our understanding of critical factors influencing the evolution of the nearshore intensity of major landfalling hurricanes in the Gulf of Mexico. This study can help facilitate forecasting and preparation for inland hazards resulting from landfalling hurricanes with nearshore intensification and weak postlandfall decay.
Anatomical Study of Domain Rescue of Palatal Length in Patients With a Wide Cleft Palate: Buccal Flap Reconstruction in Primary Palatoplasty
Authors: Morrison Kerry A. , Park Jenn , Rochlin Danielle , Lico Margaret , Flores Roberto L. 
Published: August 2022

Background This study characterizes the potential loss of velar length in patients with a wide cleft and rescue of this loss of domain by local flap reconstruction, providing anatomic evidence in support of primary lengthening of the soft palate during palatoplasty. Methods A retrospective review was conducted of all patients with a cleft palate at least 10mm in width, who underwent primary palatoplasty with a buccal flap prior to 18 months of age over a 2-year period. All patients underwent primary palatoplasty with horizontal transection of the nasal mucosa, which was performed after nasal mucosa repair, but prior to muscular reconstruction. The resulting palatal lengthening was measured and the mucosal defect was reconstructed with a buccal flap. Results Of the 22 patients included, 3 (13.6%) had a history of Pierre Robin sequence, and 5 (22.7%) had an associated syndrome. No patients had a Veau I cleft, 7 (31.8%) had a Veau II, 12 (54.5%) had a Veau III, and 3 had (13.6%) a Veau IV cleft. All patients had a right buccal flap during primary palatoplasty. The mean cleft width at the posterior nasal spine was 10.6  ±  2.82mm, and mean lengthening of the velum after horizontal transection of the nasal mucosa closure was 10.5  ±  2.23mm. There were 2 (9.1%) fistulas, 1 (4.5%) wound dehiscence, 1 (4.5%) 30-day readmission, and no bleeding complications. Conclusions Patients with a wide cleft palate have a potential loss of 1cm velar length. The buccal flap can rescue the loss of domain in palatal length, and potentially improve palatal excursion.
Upadacitinib for the Treatment of Rheumatoid Arthritis: An Extensive Review
Authors: Boyce Eric G. , Rogan Edward L. , C. Lui May 
Published: August 2022

Objectives: To review the characteristics, efficacy, safety, pharmacoeconomics, and place in therapy of upadacitinib, a Janus kinase (JAK) inhibitor, in the treatment of rheumatoid arthritis (RA). Data Sources: PubMed (January 2003-May 2022) was searched using upadacitinib and ABT-494. Study Selection and Data Extraction: Human studies published in peer-reviewed publications in English were the primary sources for efficacy and safety data. Data Synthesis: In randomized, double-blind, controlled clinical studies, upadacitinib demonstrated statistically significant improvement in RA symptoms as monotherapy and in combination with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) when compared with csDMARD monotherapy or to adalimumab or abatacept in combination with csDMARD therapy in patients with RA. American College of Rheumatology 20% response rates were 68% to 79% for upadacitinib monotherapy and 64% to 84% for upadacitinib plus csDMARD therapy, compared with 28% to 59% for csDMARD-only therapy and 63% to 74% for biologic DMARD (bDMARD) plus csDMARD therapy. Long-term extension studies demonstrated similar findings. Upadacitinib had similar rates of serious infections, herpes zoster, major cardiovascular events, and venous thromboembolic events as other JAK inhibitors. Upadacitinib was similar in cost to tofacitinib and twice as high as baricitinib based on current estimated costs to patients, but actual costs may vary. Relevance to Patient Care and Clinical Practice: Upadacitinib is an alternative therapy to other JAK inhibitors and bDMARDs in patients with moderate to severe RA who have had an inadequate response to a tumor necrosis factor inhibitor alone or in combination with a csDMARD. Conclusions: Upadacitinib is an effective JAK inhibitor for use in RA.
Intravenous route for folate supplementation in a patient with celiac disease treated by pemetrexed-based chemotherapy for non-small-cell lung cancer
Authors: Beaurain Marie , Rioufol Catherine , Vantard Nicolas , Teixeira Alexandre , Baudouin Amandine , Herledan Chloe , Souquet Pierre-Jean , Couraud Sebastien , Ranchon Florence 
Published: August 2022

Introduction Oral folic acid supplementation is essential for patients treated with pemetrexed, to prevent the risk of severe hematologic toxicity. In case of intestinal absorption disorder, no recommendations exist for intravenous folic acid supplementation. Case report We describe a 74-year-old patient with multimetastatic non-small-cell lung adenocarcinoma, receiving first-line chemotherapy with carboplatin AUC5, pemetrexed 500 mg/m2 and pembrolizumab 200 mg intravenously every 3 weeks. The patient presented neglected celiac disease, resulting in malabsorption syndrome with iron and folic acid deficiency. The question was how to administer folic acid supplementation during the pemetrexed-based chemotherapy. Management and outcomes Intravenous injection of 200 mg levoleucovorin on day 1 of cycle 1 of pemetrexed-based chemotherapy was administered and well tolerated. During the second cycle, the levoleucovorin perfusion was not renewed by omission. The patient was hospitalized for 7 days because of febrile aplasia. Piperacillin–tazobactam was started, and then switched to amoxicillin–clavulanate plus ciprofloxacin. After this episode of post-chemotherapy febrile aplasia, it was decided to systematically supplement the patient with intravenous levoleucovorin, with blood folate concentration monitoring at each cycle. At 16 months after start of treatment, the patient was in complete remission, indicating that the immune-chemotherapy was effective, with no further febrile neutropenia. Discussion/conclusion This case report highlights intravenous levoleucovorin supplementation as an alternative to oral folic acid if needed during pemetrexed–antifolate-based chemotherapy.