bluuebunny/crossref_metadata_2025_split huggingface dataset:
Refactoring in Computational Notebooks
Authors: Liu Eric S. , Lukes Dylan A. , Griswold William G. 
Published: December 2022

Due to the exploratory nature of computational notebook development, a notebook can be extensively evolved even though it is small, potentially incurring substantial technical debt. Indeed, in interview studies notebook authors have attested to performing ongoing tidying and big cleanups. However, many notebook authors are not trained as software developers, and environments like JupyterLab possess few features to aid notebook maintenance.
As software refactoring is traditionally a critical tool for reducing technical debt, we sought to better understand the unique and growing ecology of computational notebooks by investigating the refactoring of public Jupyter notebooks. We randomly selected 15,000 Jupyter notebooks hosted on GitHub and studied 200 with meaningful commit histories. We found that notebook authors do refactor, favoring a few basic classic refactorings as well as those involving the notebook cell construct. Those with a computing background refactored differently than others, but not more so. Exploration-focused notebooks had a unique refactoring profile compared to more exposition-focused notebooks. Authors more often refactored their code as they went along, rather than deferring maintenance to big cleanups. These findings point to refactoring being intrinsic to notebook development.
PARP Inhibition Induces Synthetic Lethality and Adaptive Immunity in LKB1-Mutant Lung Cancer
Authors: Long Li-Li , Ma Si-Cong , Guo Ze-Qin , Zhang Yan-Pei , Fan Zhenzhen , Liu Li-Juan , Liu Li , Han Duan-Duan , Leng Meng-Xin , Wang Jian , Guo Xue-Jun , Tan Jia-Le , Cai Xiao-Ting , Lin Yan , Pan Xinghua , Wu De-Hua , Bai Xue , Dong Zhong-Yi 
Published: December 2022

AbstractContradictory characteristics of elevated mutational burden and a “cold” tumor microenvironment (TME) coexist in liver kinase B1 (LKB1)–mutant non–small cell lung cancers (NSCLC). The molecular basis underlying this paradox and strategies tailored to these historically difficult to treat cancers are lacking. Here, by mapping the single-cell transcriptomic landscape of genetically engineered mouse models with Kras versus Kras/Lkb1-driven lung tumors, we detected impaired tumor-intrinsic IFNγ signaling in Kras/Lkb1-driven tumors that explains the inert immune context. Mechanistic analysis showed that mutant LKB1 led to deficiency in the DNA damage repair process and abnormally activated PARP1. Hyperactivated PARP1 attenuated the IFNγ pathway by physically interacting with and enhancing the poly(ADP-ribosyl)ation of STAT1, compromising its phosphorylation and activation. Abrogation of the PARP1-driven program triggered synthetic lethality in NSCLC on the basis of the LKB1 mutation–mediated DNA repair defect, while also restoring phosphorylated STAT1 to favor an immunologically “hot” TME. Accordingly, PARP1 inhibition restored the disrupted IFNγ signaling and thus mounted an adaptive immune response to synergize with PD-1 blockade in multiple LKB1-deficient murine tumor models. Overall, this study reveals an unexplored interplay between the DNA repair process and adaptive immune response, providing a molecular basis for dual PARP1 and PD-1 inhibition in treating LKB1-mutant NSCLC.Significance:Targeting PARP exerts dual effects to overcome LKB1 loss–driven immunotherapy resistance through triggering DNA damage and adaptive immunity, providing a rationale for dual PARP and PD-1 inhibition in treating LKB1-mutant lung cancers.
Long-Chain Acylcarnitines Induce Senescence of Invariant Natural Killer T Cells in Hepatocellular Carcinoma
Authors: Cheng Xue , Tan Xiaosheng , Wang Wei , Zhang Ziyao , Zhu Rongfei , Wu Mi , Li Mingyu , Chen Yiqing , Liang Zhihui , Zhu Peng , Wu Xiongwen , Weng Xiufang 
Published: December 2022

AbstractCD1d-restricted invariant natural killer T (iNKT) cells actively patrol the liver and possess valuable antitumor potential. However, clinical trials evaluating administration of iNKT cell–specific agonist α-galactosylceramide (α-GalCer) have failed to achieve obvious tumor regression. Improving the efficacy of iNKT cell–based immunotherapy requires a better understanding of the factors restraining the clinical benefits. In the context of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), we found circulating and hepatic iNKT cells were hyperactivated but demonstrated imbalances in ratio and defective α-GalCer responsiveness. Exogenous IL2 helped to expand residual α-GalCer–responsive clones with reduced T-cell receptor diversity. However, transcriptome-wide analysis revealed activation of the senescence-associated secretory phenotype and dampened cytotoxicity in iNKT cells, weakening their immune surveillance capacity. The senescent status of iNKT cells from the patients was further illustrated by cell-cycle arrest, impaired telomere maintenance, perturbed calcium transport-related biological processes, and altered metabolism. Lipidomic profiling revealed the accumulation of long-chain acylcarnitines (LCAC) and aberrant lipid metabolism in HCC tissue. Exogenous LCACs, especially palmitoyl-carnitine and stearoyl-carnitine, inhibited iNKT cell expansion and promoted senescence. Collectively, our results provide deeper insights into iNKT cell dysregulation and identify a cell senescence–associated challenge for iNKT cell–based immunotherapy in HBV-related HCC. The mechanistic links between iNKT cell senescence and accumulated LCACs suggest new targets for anti-HCC immunotherapies.Significance:Patients with HBV-related HCC exhibit a cell senescence–associated dysregulation of invariant natural killer cells that is related to altered lipid metabolism and accumulated LCACs in tumor tissue.
Deregulation of SPOP in Cancer
Authors: Zhang Hui , Jin Xiaofeng , Huang Haojie 
Published: December 2022

AbstractSpeckle-type POZ protein (SPOP) is a substrate-binding adaptor of the CULLIN3/RING-box1 E3 ubiquitin ligase complex. SPOP is frequently mutated in prostate and endometrial cancers, whereas it is overexpressed in renal cell carcinoma (RCC). SPOP can mediate both degradable and nondegradable polyubiquitination of a number of substrates with diverse biological functions such as androgen receptor (AR), SRC-3, TRIM24, BRD4, PD-L1, 53BP1, GLP/G9a, c-Myc, SENP7, among others. Cancer-associated SPOP mutants often impair SPOP binding and polyubiquitination of its substrates to influence various cancer-relevant pathways, which include androgen/AR signaling, DNA repair and methylation, cellular stress surveillance, cancer metabolism, and immunity. Although SPOP is recognized as a tumor suppressor in prostate and endometrial cancers, it acts like an oncoprotein in RCC. This review provides an overview of the recent progress in understanding of the upstream regulators of SPOP and its downstream targets, highlights the significant impact of SPOP mutations and overexpression on cancer pathogenesis, and discusses the potential of targeting SPOP for cancer treatment.
Association of Lp(a) (Lipoprotein[a]) and Hypertension in Primary Prevention of Cardiovascular Disease: The MESA
Authors: Rikhi Rishi , Bhatia Harpreet S. , Schaich Christopher L. , Ashburn Nicklaus , Tsai Michael Y. , Michos Erin D. , Chevli Parag A. , Herrington David M. , Tsimikas Sotirios , Shapiro Michael D. 
Published: December 2022

Background:
This study explored the longitudinal relationship of Lp(a) (lipoprotein[a]) and hypertension to cardiovascular outcomes in a large multiethnic cohort free of baseline cardiovascular disease.

Methods:
Individuals from the MESA (Multi-Ethnic Study of Atherosclerosis; N=6674) were grouped as follows: group 1: Lp(a) <50 mg/dL and no hypertension; group 2: Lp(a) ≥50 mg/dL and no hypertension; group 3: Lp(a) <50 mg/dL and hypertension; and group 4: Lp(a) ≥50 mg/dL and hypertension. Kaplan-Meier curves and multivariable Cox proportional hazard models were used to assess the relationship of Lp(a) and hypertension with time to cardiovascular disease events.

Results:

Mean follow-up time was 13.9 (5.0) years and 809 participants experienced a cardiovascular disease event. A statistically significant interaction was found between Log[Lp(a)] and hypertension status (
P
=0.091). Compared with the reference group (Lp[a] <50 mg/dL and no hypertension), those with Lp[a] ≥50 mg/dL and no hypertension had no increased risk for cardiovascular disease events (hazard ratio, 1.09 [95% CI, 0.79–1.50]). However, those with Lp(a) <50 mg/dL and hypertension or Lp(a) ≥50 mg/dL and hypertension demonstrated a statistically significant increase in risk compared to the reference group (hazard ratio, 1.66 [95% CI, 1.39–1.98]) and (hazard ratio, 2.07 [95% CI, 1.63–2.62]), respectively. Among those with hypertension, Lp(a) was associated with a significant increase in cardiovascular disease risk (hazard ratio, 1.24 [95% CI, 1.01–1.53]).

Conclusions:
Although the major contribution to cardiovascular risk was hypertension, elevated Lp(a) significantly modified the association of hypertension with cardiovascular disease. More research is needed to understand mechanistic links among Lp(a), hypertension, and cardiovascular disease.
The impact of regional heterogeneity in whole-brain dynamics in the presence of oscillations
Authors: Perl Yonatan Sanz , Zamora-Lopez Gorka , Montbrió Ernest , Monge-Asensio Martí , Vohryzek Jakub , Fittipaldi Sol , Campo Cecilia González , Moguilner Sebastián , Ibañez Agustín , Tagliazucchi Enzo , Yeo B. T. Thomas , Kringelbach Morten L. , Deco Gustavo 
Published: December 2022

Abstract
Large variability exists across brain regions in health and disease, considering their cellular and molecular composition, connectivity, and function. Large-scale whole-brain models comprising coupled brain regions provide insights into the underlying dynamics that shape complex patterns of spontaneous brain activity. In particular, biophysically grounded mean-field whole-brain models in the asynchronous regime were used to demonstrate the dynamical consequences of including regional variability. Nevertheless, the role of heterogeneities when brain dynamics are supported by synchronous oscillating state, which is a ubiquitous phenomenon in brain, remains poorly understood. Here, we implemented two models capable of presenting oscillatory behavior with different levels of abstraction: a phenomenological Stuart–Landau model and an exact mean-field model. The fit of these models informed by structural- to functional-weighted MRI signal (T1w/T2w) allowed us to explore the implication of the inclusion of heterogeneities for modeling resting-state fMRI recordings from healthy participants. We found that disease-specific regional functional heterogeneity imposed dynamical consequences within the oscillatory regime in fMRI recordings from neurodegeneration with specific impacts on brain atrophy/structure (Alzheimer’s patients). Overall, we found that models with oscillations perform better when structural and functional regional heterogeneities are considered, showing that phenomenological and biophysical models behave similarly at the brink of the Hopf bifurcation.
Miconia amplipedunculata (Melastomataceae: Miconieae), a new species from the Caribbean lowlands of Panama
Authors: ALMEDA FRANK , ORTÍZ ORLANDO O. 
Published: December 2022

Miconia amplipedunculata is described as a new species that is known from a limited area in the Caribbean lowland rainforests of Panama. Line drawings, field photographs, a distribution map, and a comparative discussion of morphologically similar species are provided. This species is readily distinguished by its short-petiolate alternately 3-plinerved leaf blades, brown amorphous stellulate-lepidote indumentum on the primary and secondary veins of abaxial foliar surfaces and inflorescence, long-pedunculate (up to 12.5 cm) inflorescence, persistent bracts and bracteoles, unlobed truncate calyx, prominent subulate calyx teeth that exceed the calyx, 5-merous flowers, distally constricted anther filaments, and isometric and isomorphic stamens that lack appendages. The new species is compared with M. iteophylla, M. jefensis, M. ligulata, and M. peltata. All of these species, except M. ligulata, are also endemic to Panama.
An epithelial–mesenchymal transition-related prognostic model for colorectal cancer based on weighted gene co-expression network analysis
Authors: Zhang Lina , Qian Yucheng 
Published: December 2022

Objective To identify susceptibility modules and genes for colorectal cancer (CRC) using weighted gene co-expression network analysis (WGCNA). Methods Four microarray datasets were downloaded from the Gene Expression Omnibus database. We divided the tumor samples into three subgroups based on consensus clustering of gene expression, and analyzed the correlations between the subgroups and clinical features. The genetic features of the subgroups were investigated by gene set enrichment analysis (GSEA). A gene expression network was constructed using WGCNA, and a protein–protein interaction (PPI) network was used to identify the key genes. Gene modules were annotated by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses. Results We divided the cancer cases into three subgroups based on consensus clustering (subgroups I, II, III). The green module identified by WGCNA was correlated with clinical characteristics. Ten key genes were identified according to their degree of connectivity in the protein–protein interaction network: FYN, SEMA3A, AP2M1, L1CAM, NRP1, TLN1, VWF, ITGB3, ILK, and ACTN1. Conclusion We identified 10 hub genes as candidate biomarkers for CRC. These key genes may provide a theoretical basis for targeted therapy against CRC.
Gaps in Evidence-based Treatment of Concurrent Attention Deficit Hyperactivity Disorder and Opioid Use Disorder: A Scoping Review
Authors: Ramey Olivia L. , Bonny Andrea E. , Silva Almodóvar Armando , Nahata Milap C. 
Published: December 2022

Objectives: To describe the effectiveness of medications for the treatment of opioid use disorder (OUD) and attention deficit/hyperactivity disorder (ADHD). Data Sources: Literature search of PubMed, Embase, Web of Science, CINAHL, Medline, PsycINFO, and Google Scholar was performed for studies published from inception to October 25, 2022. Study Selection and Data Extraction: Studies were included if patients were diagnosed with OUD and ADHD and had pharmacotherapy for either condition. Abstracts, commentaries, reviews, case reports, case series, non-English articles, and animal studies were omitted. Data Synthesis: This review found 18 studies. Treatment of ADHD was evaluated for impact on ADHD and OUD outcomes, while treatment of OUD was evaluated for OUD-related outcomes. Outcomes assessed included markers for symptom intensity, adherence, and treatment failure. While results were mixed, treatment of ADHD was largely associated with improvements in ADHD severity and retention in OUD treatment programs. ADHD severity was associated with higher rates of illicit substance abuse and worse OUD-related outcomes. It could not be determined which medications for treatment of OUD should be prioritized. Relevance to Patient Care and Clinical Practice: This review summarized key findings from studies that treated ADHD or OUD among dually diagnosed patients and highlighted methodological considerations for future research. Conclusions: Treatment of ADHD is warranted among patients with OUD and ADHD to improve retention in OUD treatment programs and reduce illicit substance abuse. Pharmacotherapy for the treatment of ADHD or OUD should continue to be determined based on patients' characteristics and the capabilities of the treatment program.
Implementation of pharmaceutical care service to elderly cancer patients in a tertiary care hospital in South India
Authors: Fariya Shaik , Mary Martin Daniel Priya Jovita , Raj John Stephen , Sureshkumar Kaoshik , Suthakar Monisha , Muhasaparur Ganesan Rajanandh 
Published: December 2022

Purpose The goal of this study is to identify drug-related problems (DRPs) for elderly cancer patients receiving chemotherapy by implementing pharmaceutical care services. Methods In this interventional study, patients were followed after each cycle till 12 weeks. The MOATT-MASCC teaching tool was used to educate patients about their therapy. The outcome measures included the occurrences of any DRPs such as inappropriate medication dose, dosage form, route of administration, therapeutic duplication, failure of the patient to adhere to the medication regimen, adverse drug reactions (ADRs), and drug–drug interactions (DDIs) and to resolve it. Results On 186 patients, there were 38% ADRs, 16% DDIs, 6% non-adherence to therapy, 4% medical conditions for which no medication was prescribed, and 1% therapeutic duplication and transcribing error was identified. A total of 226 ADRs were documented. Nausea and vomiting were the most frequently occurring ADRs (24%) and platinum compounds caused the highest number of ADRs. Assessments of causality showed that the majority of cases are ‘probable’ (50%). In evaluating the severity of ADRs, 53% of ADRs were ‘moderate’ and 51% of ADRs were ‘probably’ preventable. Upon assessing the DDIs, 35% of the prescriptions had ‘monitor therapy’. All of the DRPs, that were identified were notified to the treating oncologists and resolved without any disagreement. Conclusions Pharmaceutical care is essential for elderly cancer patients. Oncologists and pharmacists should work together to identify and manage DRPs as well as educate patients about their disease. This will help in improved patient care and a better therapeutic outcome.
Fat tissue is a poor predictor of 1 year outcomes after total knee arthroplasty: A secondary analysis of a randomized clinical trial
Authors: Palanne Riku , Rantasalo Mikko , Vakkuri Anne , Olkkola Klaus T. , Vahlberg Tero , Skants Noora 
Published: December 2022

Background and objective: Obesity may increase the risk of adverse events after total knee arthroplasty (TKA). Although body mass index (BMI) is commonly used in categorizing obesity, its accuracy is limited. Body fat percentage (BFP) might indicate adiposity status and predict arthroplasty-related outcomes better than BMI. We investigated whether BFP is predictive of TKA-related outcomes. Methods: In this secondary analysis, BFP was measured preoperatively from 294 participants of a randomized trial that investigated the effects of tourniquet and anesthesia methods on TKA. Data concerning in-hospital assessments and events were collected. Knee range of motion (ROM) was measured, the Brief Pain Inventory–short form and Oxford Knee Score questionnaires were used to collect data on patient-reported pain and function, and the 15-dimensional health-related questionnaire was used to assess quality of life preoperatively and 3 and 12 months postoperatively. The patients reported satisfaction to TKA 3 and 12 months postoperatively. Data concerning infectious and thromboembolic events within 90 postoperative days and revision surgery, manipulation under anesthesia, and mortality within 1 year were collected. A separate post hoc analysis was performed for 399 participants to assess the effects of BMI on the respective outcomes. Results: A 1-unit increase in BFP affected the ROM by −0.37° (95% confidence interval (CI) = −0.60 to −0.13) 12 months after surgery. BFP was not significantly associated with the operation time or adverse events. However, the number of most adverse events remained too low for adjusted analysis. A 1-unit increase in BMI increased the operation time by 0.57 min (95% CI = 0.10 to 1.04) and affected the ROM by −0.47° (95% CI = −0.74 to −0.20) 12 months postoperatively. Neither BFP nor BMI was significantly associated with acute pain, pain management, length of stay, or with pain, function, quality of life, or satisfaction to TKA at 12 months after surgery. Conclusions: BFP seems to be a poor predictor of in-hospital results and of patient-reported outcomes 1 year after TKA. Twitter handle In this secondary analysis of a randomized trial, body fat percentage was poorly predictive of clinical outcomes during hospital stay and of patient-reported outcomes 1 year after TKA.
Monocyte or white blood cell counts and β2 microglobulin predict the durable efficacy of daratumumab with lenalidomide
Authors: Shimazu Yutaka , Kanda Junya , Kaneko Hitomi , Imada Kazunori , Yamamura Ryosuke , Kosugi Satoru , Shimura Yuji , Ito Tomoki , Fuchida Shin-ichi , Uchiyama Hitoji , Fukushima Kentaro , Yoshihara Satoshi , Hanamoto Hitoshi , Tanaka Hirokazu , Uoshima Nobuhiko , Ohta Kensuke , Yagi Hideo , Shibayama Hirohiko , Onda Yoshiyuki , Tanaka Yasuhiro , Adachi Yoko , Matsuda Mitsuhiro , Iida Masato , Miyoshi Takashi , Matsui Toshimitsu , Takahashi Ryoichi , Takakuwa Teruhito , Hino Masayuki , Hosen Naoki , Nomura Shosaku , Shimazaki Chihiro , Matsumura Itaru , Takaori-Kondo Akifumi , Kuroda Junya ,   The Kansai Myeloma Forum
Published: December 2022

Background: Daratumumab is one of the most widely used treatments for relapsed/refractory multiple myeloma (MM) patients. However, not all patients achieve a lasting therapeutic response with daratumumab. Objectives: We hypothesized that a durable response to daratumumab could be predicted by the balance between the MM tumor burden and host immune status. Design: We conducted a retrospective study using the real-world data in the Kansai Myeloma Forum (KMF) database. Methods: We retrospectively analyzed 324 relapsed/refractory MM patients who were treated with daratumumab in the KMF database. Results: In this study, 196 patients were treated with daratumumab, lenalidomide, and dexamethasone (DLd) regimen and 128 patients were treated with daratumumab, bortezomib, and dexamethasone (DBd) regimen. The median age at treatment, number of prior treatment regimens and time-to-next-treatment (TTNT) were 68, 4 and 8.02 months, respectively. A multivariate analysis showed that the TTNT under the DLd regimen was longer with either higher monocyte counts (analysis 1), higher white blood cell (WBC) counts (analysis 2), lower β2 microglobulin (B2MG < 5.5 mg/L) or fewer prior regimens (<4). No parameters were correlated with TTNT under the DBd regimen. Conclusion: We propose a simple scoring model to predict a durable effect of the DLd regimen by classifying patients into three categories based on either monocyte counts (0 points for ⩾200/μl; 1 point for <200/μl) or WBC counts (0 points for ⩾3500/μl; 1 point for <3500/μl) plus B2MG (0 points for <5.5 mg/L; 1 point for ⩾5.5 mg/L). Patients with a score of 0 showed significantly longer TTNT and significantly better survival compared to those with a score of 1 or 2 (both p < 0.001). To confirm this concept, our results will need to be validated in other cohorts.