bluuebunny/crossref_metadata_2025_split huggingface dataset:
Anti-VEGF therapy selects for clones resistant to glucose starvation in ovarian cancer xenografts
Authors: Boso Daniele , Tognon Martina , Curtarello Matteo , Minuzzo Sonia , Piga Ilaria , Brillo Valentina , Lazzarini Elisabetta , Carlet Jessica , Marra Ludovica , Trento Chiara , Rasola Andrea , Masgras Ionica , Caporali Leonardo , Del Ben Fabio , Brisotto Giulia , Turetta Matteo , Pastorelli Roberta , Brunelli Laura , Navaglia Filippo , Esposito Giovanni , Grassi Angela , Indraccolo Stefano 
Published: August 2023

Abstract
Background
Genetic and metabolic heterogeneity are well-known features of cancer and tumors can be viewed as an evolving mix of subclonal populations, subjected to selection driven by microenvironmental pressures or drug treatment. In previous studies, anti-VEGF therapy was found to elicit rewiring of tumor metabolism, causing marked alterations in glucose, lactate ad ATP levels in tumors. The aim of this study was to evaluate whether differences in the sensitivity to glucose starvation existed at the clonal level in ovarian cancer cells and to investigate the effects induced by anti-VEGF therapy on this phenotype by multi-omics analysis.

Methods
Clonal populations, obtained from both ovarian cancer cell lines (IGROV-1 and SKOV3) and tumor xenografts upon glucose deprivation, were defined as glucose deprivation resistant (GDR) or glucose deprivation sensitive (GDS) clones based on their in vitro behaviour. GDR and GDS clones were characterized using a multi-omics approach, including genetic, transcriptomic and metabolic analysis, and tested for their tumorigenic potential and reaction to anti-angiogenic therapy.

Results
Two clonal populations, GDR and GDS, with strikingly different viability following in vitro glucose starvation, were identified in ovarian cancer cell lines. GDR clones survived and overcame glucose starvation-induced stress by enhancing mitochondrial oxidative phosphorylation (OXPHOS) and both pyruvate and lipids uptake, whereas GDS clones were less able to adapt and died. Treatment of ovarian cancer xenografts with the anti-VEGF drug bevacizumab positively selected for GDR clones that disclosed increased tumorigenic properties in NOD/SCID mice. Remarkably, GDR clones were more sensitive than GDS clones to the mitochondrial respiratory chain complex I inhibitor metformin, thus suggesting a potential therapeutic strategy to target the OXPHOS-metabolic dependency of this subpopulation.

Conclusion
A glucose-deprivation resistant population of ovarian cancer cells showing druggable OXPHOS-dependent metabolic traits is enriched in experimental tumors treated by anti-VEGF therapy.
Cross-protein transfer learning substantially improves disease variant prediction
Authors: Jagota Milind , Ye Chengzhong , Albors Carlos , Rastogi Ruchir , Koehl Antoine , Ioannidis Nilah , Song Yun S. 
Published: August 2023

Abstract
Background
Genetic variation in the human genome is a major determinant of individual disease risk, but the vast majority of missense variants have unknown etiological effects. Here, we present a robust learning framework for leveraging saturation mutagenesis experiments to construct accurate computational predictors of proteome-wide missense variant pathogenicity.

Results
We train cross-protein transfer (CPT) models using deep mutational scanning (DMS) data from only five proteins and achieve state-of-the-art performance on clinical variant interpretation for unseen proteins across the human proteome. We also improve predictive accuracy on DMS data from held-out proteins. High sensitivity is crucial for clinical applications and our model CPT-1 particularly excels in this regime. For instance, at 95% sensitivity of detecting human disease variants annotated in ClinVar, CPT-1 improves specificity to 68%, from 27% for ESM-1v and 55% for EVE. Furthermore, for genes not used to train REVEL, a supervised method widely used by clinicians, we show that CPT-1 compares favorably with REVEL. Our framework combines predictive features derived from general protein sequence models, vertebrate sequence alignments, and AlphaFold structures, and it is adaptable to the future inclusion of other sources of information. We find that vertebrate alignments, albeit rather shallow with only 100 genomes, provide a strong signal for variant pathogenicity prediction that is complementary to recent deep learning-based models trained on massive amounts of protein sequence data. We release predictions for all possible missense variants in 90% of human genes.

Conclusions
Our results demonstrate the utility of mutational scanning data for learning properties of variants that transfer to unseen proteins.
Duroplasty for injured cervical spinal cord with uncontrolled swelling: protocol of the DISCUS randomized controlled trial
Authors: Saadoun Samira , Grassner Lukas , Belci Maurizio , Cook Jonathan , Knight Ruth , Davies Lucy , Asif Hasan , Visagan Ravindran , Gallagher Mathew J. , Thomé Claudius , Hutchinson Peter J. , Zoumprouli Argyro , Wade Julia , Farrar Nicola , Papadopoulos Marios C. 
Published: August 2023

Abstract
Background
Cervical traumatic spinal cord injury is a devastating condition. Current management (bony decompression) may be inadequate as after acute severe TSCI, the swollen spinal cord may become compressed against the surrounding tough membrane, the dura. DISCUS will test the hypothesis that, after acute, severe traumatic cervical spinal cord injury, the addition of dural decompression to bony decompression improves muscle strength in the limbs at 6 months, compared with bony decompression alone.

Methods
This is a prospective, phase III, multicenter, randomized controlled superiority trial. We aim to recruit 222 adults with acute, severe, traumatic cervical spinal cord injury with an American Spinal Injury Association Impairment Scale grade A, B, or C who will be randomized 1:1 to undergo bony decompression alone or bony decompression with duroplasty. Patients and outcome assessors are blinded to study arm. The primary outcome is change in the motor score at 6 months vs. admission; secondary outcomes assess function (grasp, walking, urinary + anal sphincters), quality of life, complications, need for further surgery, and mortality, at 6 months and 12 months from randomization. A subgroup of at least 50 patients (25/arm) also has observational monitoring from the injury site using a pressure probe (intraspinal pressure, spinal cord perfusion pressure) and/or microdialysis catheter (cord metabolism: tissue glucose, lactate, pyruvate, lactate to pyruvate ratio, glutamate, glycerol; cord inflammation: tissue chemokines/cytokines). Patients are recruited from the UK and internationally, with UK recruitment supported by an integrated QuinteT recruitment intervention to optimize recruitment and informed consent processes. Estimated study duration is 72 months (6 months set-up, 48 months recruitment, 12 months to complete follow-up, 6 months data analysis and reporting results).

Discussion
We anticipate that the addition of duroplasty to standard of care will improve muscle strength; this has benefits for patients and carers, as well as substantial gains for health services and society including economic implications. If the addition of duroplasty to standard treatment is beneficial, it is anticipated that duroplasty will become standard of care.

Trial registration
IRAS: 292031 (England, Wales, Northern Ireland) - Registration date: 24 May 2021, 296518 (Scotland), ISRCTN: 25573423 (Registration date: 2 June 2021); ClinicalTrials.gov number : NCT04936620 (Registration date: 21 June 2021); NIHR CRN 48627 (Registration date: 24 May 2021).
Efficacy of five-step shoulder manipulation for rotator cuff-related shoulder pain: protocol for a multicenter randomized controlled trial
Authors: Liu Shuang , Liu Jin-Tao , Chen Lin , Fan Tian-You , Cui Xue-Jun , Cheng Shao-Dan , Chen Yan-Jiao , Shi Qi , Xue Chun-Chun , Li Xiao-Feng 
Published: August 2023

Abstract
Background
Rotator cuff-related shoulder pain (RCRSP) is the most common cause of shoulder disorders. In China, manipulation has been used extensively for the treatment of patients with RCRSP. However, high-quality clinical evidence to support the therapeutic effect of manipulation is still limited.

Methods
A multicenter, participant-, outcome assessor-, and data analyst-blinded, randomized, placebo-controlled trial will be conducted. A total of 280 participants with RCRSP will be recruited from three hospitals and randomly assigned to a five-step shoulder manipulation (FSM) group or a sham manipulation (SM) group. Each group will receive four weekly treatment sessions, with all participants performing exercises at home for 12 weeks. Assessments, namely the Constant–Murley score, visual analog scale, range of motion, and 36-Item Short Form Survey, will be made at baseline, 4, 12, 18, and 24 weeks. Adverse events during the study will also be recorded.

Discussion
This is a pragmatic clinical trial to evaluate the efficacy and safety of FSM in patients with RCRSP. The findings of this study will provide worthy clinical evidence for manual therapy for RCRSP.

Trial registration
China Registered Clinical Trial Registration Center ChiCTR2000037577. Registered on 29 August 2020.
Proximal ROw carpectOmy versus four-corner Fusion (PROOF-trial) for osteoarthritis of the wrist: study protocol for multi-institutional double-blinded randomized controlled trial
Authors: Alanen Mikko , Stjernberg-Salmela Susanna , Waris Eero , Karjalainen Teemu , Miettunen Jouko , Ryhänen Jorma , Aspinen Samuli 
Published: August 2023

Abstract
Background
Scapholunate advanced collapse (SLAC) and scaphoid non-union advanced collapse (SNAC) are common types of wrist osteoarthritis (OA). Non-operative treatment consists of pain medication, splinting, and avoiding activities that induce pain. However, in case a course of conservative treatment is unsuccessful, operative treatment is needed. The two most conventional operative approaches for SLAC/SNAC OA are four-corner arthrodesis (FCA) and proximal row carpectomy (PRC). Although FCA is the gold-standard operative technique and may lead to superior grip strength, the evident benefit of PRC is that it obviates any need for hardware removal and controlling for bony union. To date, no high-quality randomized controlled trial comparing FCA and PRC exists. As clinical outcomes seem comparable, a trial that assesses patient-reported outcomes, adverse events, and secondary operations may guide clinical decision making between these two procedures. Thus, the aim of this multi-institutional double-blind randomized controlled trial is to study whether PRC is non-inferior to FCA in treating SLAC/SNAC OA. We hypothesize that PRC is non-inferior to FCA with lower economic expanses.

Methods
The trial is designed as a randomized, controlled, patient- and outcome-assessor blinded multicenter, two-armed 1:1 non-inferiority trial. Patients with SLAC/SNAC-induced wrist pain meeting trial inclusion criteria will undergo wrist arthroscopy to further assess eligibility. Each patient eligible for the trial will be randomly assigned to undergo either FCA or PRC. The primary endpoint of this study is the Patient Rated Wrist Evaluation (PRWE) at 1-year after FCA versus PRC. Secondary outcomes include Quick-Disabilities of the Arm, Shoulder and Hand, EQ-5D-5L, pain, grip strength, wrist active range of motion, radiographic evaluation, and adverse events. Trial design, methods, and statistical analysis plan will be presented here.

Discussion
We present an RCT design comparing FCA vs PRC for SLAC/SNAC-induced OA. The results of this trial will assist in decision making when planning surgery for SLAC/SNAC.

Trial registration
ClinicalTrials.gov NCT04260165. Registered February 7, 2020.
Transcriptional variation in Babesia gibsoni (Wuhan isolate) between in vivo and in vitro cultures in blood stage
Authors: Han Zhen , Zheng Yaxin , Shi Yu , Chen Fangwei , Wu Chenglong , Wang Lingna , Lu Shiyu , Li Dongfang , Guan Xingai , He Lan , Zhao Junlong 
Published: August 2023

Abstract
Background
Babesia gibsoni, the causative agent of canine babesiosis, belongs to the phylum Apicomplexa. The development of in vitro culture technology has driven research progress in various kinds of omics studies, including transcriptomic analysis of Plasmodium spp. between in vitro and in vivo environments, which has prompted the observation of diagnostic antigens and vaccine development. Nevertheless, no information on Babesia spp. could be obtained in this respect, which greatly hinders the further understanding of parasite growth and development in the blood stage.

Methods
In this study, considerable changes in the morphology and infectivity of continuous in vitro cultured B. gibsoni (Wuhan isolate) were observed compared to in vivo parasites. Based on these changes, B. gibsoni (Wuhan isolate) was collected from both in vivo and in vitro cultures, followed by total RNA extraction and Illumina transcriptome sequencing. The acquired differentially expressed genes (DEGs) were validated using qRT-PCR, and then functionally annotated through several databases. The gene with the greatest upregulation after in vitro culture was cloned from the genome of B. gibsoni (Wuhan isolate) and characterized by western blotting and indirect immunofluorescence assay for detecting the native form and cellular localization.

Results
Through laboratory cultivation, multiple forms of parasites were observed, and the infectivity of in vitro cultured parasites in dogs was found to be lower. Based on these changes, Illumina transcriptome sequencing was conducted, showing that 377 unigenes were upregulated and 334 unigenes were downregulated. Notably, an AP2 transcription factor family, essential for all developmental stages of parasites, was screened, and the transcriptional changes in these family members were tested. Thus, the novel AP2 transcription factor gene (BgAP2-M) with the highest upregulated expression after in vitro adaptation was selected. This gene comprises an open reading frame (ORF) of 1989 base pairs encoding a full-length protein of 662 amino acids. BgAP2-M contains one AP2 domain and one ACDC conserved domain, which may be involved in the nuclear biology of parasites. The prepared polyclonal antibodies against the BgAP2-M peptides further detected a native size of ~ 73 kDa and were localized to the nuclei of B. gibsoni.

Conclusion
This study presents a thorough transcriptome analysis of B. gibsoni in vivo and in vitro for the first time, contributing to a detailed understanding of the effects of environmental changes on the growth and development of parasites in the blood stage. Moreover, it also provides a deeper investigation for the different members of the ApiAP2 transcription factor family as various life stage regulators in Babesia spp.

Graphical Abstract
The potential for zoonotic malaria transmission in five areas of Indonesia inhabited by non-human primates
Authors: Permana Dendi Hadi , Hasmiwati  , Suryandari Dwi Anita , Rozi Ismail Ekoprayitno , Syahrani Lepa , Setiadi Wuryantari , Irawati Nuzulia , Rizaldi  , Wangsamuda Suradi , Yusuf Yenni , Irdayanti  , Aswad Hijral , Asih Puji Budi Setia , Syafruddin Din 
Published: August 2023

Abstract
Background
Indonesia is home to many species of non-human primates (NHPs). Deforestation, which is still ongoing in Indonesia, has substantially reduced the habitat of NHPs in the republic. This has led to an intensification of interactions between NHPs and humans, which opens up the possibility of pathogen spillover. The aim of the present study was to determine the prevalence of malarial parasite infections in NHPs in five provinces of Indonesia in 2022. Species of the genus Anopheles that can potentially transmit malarial pathogens to humans were also investigated.

Methods
An epidemiological survey was conducted by capturing NHPs in traps installed in several localities in the five provinces, including in the surroundings of a wildlife sanctuary. Blood samples were drawn aseptically after the NHPs had been anesthetized; the animals were released after examination. Blood smears were prepared on glass slides, and dried blood spot tests on filter paper. Infections with Plasmodium spp. were determined morphologically from the blood smears, which were stained with Giemsa solution, and molecularly through polymerase chain reaction and DNA sequencing using rplU oligonucleotides. The NHPs were identified to species level by using the mitochondrial cytochrome c oxidase subunit I gene and the internal transcribed spacer 2 gene as barcoding DNA markers. Mosquito surveillance included the collection of larvae from breeding sites and that of adults through the human landing catch (HLC) method together with light traps.

Results
Analysis of the DNA extracted from the dried blood spot tests of the 110 captured NHPs revealed that 50% were positive for Plasmodium, namely Plasmodium cynomolgi, Plasmodium coatneyi, Plasmodium inui, Plasmodium knowlesi and Plasmodium sp. Prevalence determined by microscopic examination of the blood smears was 42%. Species of the primate genus Macaca and family Hylobatidae were identified by molecular analysis. The most common mosquito breeding sites were ditches, puddles and natural ponds. Some of the Anopheles letifer captured through HLC carried sporozoites of malaria parasites that can cause the disease in primates.

Conclusions
The prevalence of malaria in the NHPs was high. Anopheles letifer, a potential vector of zoonotic malaria, was identified following its collection in Central Kalimantan by the HLC method. In sum, the potential for the transmission of zoonotic malaria in several regions of Indonesia is immense.

Graphical Abstract
Effectiveness of home-based exercise in breast cancer survivors: a randomized clinical trial
Authors: Farajivafa Vahid , Khosravi Nasim , Rezaee Nilofar , Koosha Maryam , Haghighat Shahpar 
Published: August 2023

Abstract
Background
Breast cancer patients are recommended to engage in regular exercise. In developing countries, where there is a lack of facilities to offer specialized, supervised exercise for this population, regularly exercising might be a challenge. We aimed to evaluate the effectiveness of a home-based intervention in this population.

Methods
Breast cancer survivors were randomly assigned to either the home-based exercise program or the usual care group. Exercise intervention included walking, balance, and stretch exercises, along with weekly follow-up telephone calls. Quality of life (QOL) was evaluated using EORTC QLQ-C30 and EORTC QLQ-BR23 questionnaires and the predicted VO2 peak was measured using the Ebbeling submaximal treadmill test.

Results
Eighty-nine patients were enrolled in the study. Reported minutes of exercise gradually increased from 40.7 min per week in week 1 to 116.9 min per week in week 12. This intervention improved global QOL (P = 0.001), social functioning (P = 0.04), and the predicted VO2 peak (P = 0.01).

Conclusion
This home-based exercise regime effectively increased quality of life and physical activity levels.

Trial registry
Iranian Registry of Clinical Trials identifier: IRCT20140810018746N1, prospectively registered 08/01/2018, https://en.irct.ir/trial/27959.
NSP4 as adjuvant for immunogenicity and design of effective therapeutic HPV16 E6/E7/L1 DNA vaccine in tumor-bearing and healthy C57BL/6 mice
Authors: Sadr-Momtaz Sahar , Aftabi Maryam , Behboudi Emad , Naderi Malihe , Hashemzadeh-Omran Anahita , Moradi Abdolvahab 
Published: August 2023

Abstract
Introduction
In humans, approximately 5% of all cancers are attributable to HPV infection. Prophylactic vaccines can inhibit viral migration and persistence. However, further studies are still required to develop such treatments. To achieve this goal, we designed a therapeutic HPV DNA vaccine encoding a construct of E6/E7/L1 and used NSP4 antigen as an adjuvant to assess the efficiency of this construct in generating antigen-specific antitumor immune responses.

Materials and methods
Sixty female C57BL/6 mice (6–8 weeks old) were purchased from the Institute Pasteur of Iran. Through a subcutaneous (s.c) injection of a suspension of 100 µl PBS containing 106 TC-1 cells/mouse in the back side, 30 of them became cancerous, while 30 of them were healthy control mice. To amplify E6/E7/L1-pcDNA3 and NSP4-pcDNA3, the competent cells of DH5α and to generate a tumor, TC-1 cell line was used. Mice were then immunized with the HPV DNA vaccine. Cell proliferation was assessed by MTT assay. Finally, cytokine responses (IL-4, IL-12, IFN- γ) were measured in the supernatant of mice spleen cells.

Result
Mice receiving the NSP4/E6-E7-L1 vaccine had the highest stimulatory index compared to other groups, although it was not statistically significant. Interleukin 4/12 and IFN-γ production were significantly higher in E6-E7-L1 / NSP4 group and E6-E7-L1 group compared to other groups (P < 0.05). Among different groups, E6/E7/L1 + NSP4 group was able to slow down the tumor growth process, but it was not significant (p > 0.05). Among the aforementioned cytokines, IFN-γ and IL-12 are among the cytokines that stimulate the Th1 pathway and IL-4 cytokine stimulates the Th2 pathway and B lymphocytes.

Conclusion
Our data revealed that the present vaccine can reduce tumor size, and cytokine measurement showed that it stimulates innate and acquired immune responses, thus it can be a therapeutic vaccine in the tumor-bearing mice model.
Myelin oligodendrocyte glycoprotein antibody-associated disease as a novel presentation of central nervous system autoimmunity in a pediatric patient with Wiskott-Aldrich syndrome
Authors: Xie Vivien X. , File Wilson , Wiedl Christina , Ward Brant R. , Saldaña Blachy Dávila , Keller Michael D. , Kornbluh Alexandra B. 
Published: August 2023

Abstract
Background
Wiskott-Aldrich syndrome (WAS) is an X-linked primary immunodeficiency caused by mutations in the WAS gene that leads to increased susceptibility to infections, thrombocytopenia, eczema, malignancies, and autoimmunity. Central nervous system (CNS) autoimmune manifestations are uncommon.

Case Presentation
We describe the case of a five-year-old boy with refractory thrombocytopenia and iron deficiency anemia who developed relapsing bilateral optic neuritis. Myelin oligodendrocyte glycoprotein antibody (MOG-IgG) via serum fluorescence-activated cell sorting assay was positive (titer 1:100), confirming a diagnosis of myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). At age six, molecular panel testing for genes associated with primary immunodeficiency identified a missense WAS gene variant. He was subsequently found to have decreased WAS protein expression, consistent with a diagnosis of WAS.

Conclusions
This case expands the reported spectrum of CNS autoimmunity associated with WAS and may help to inform long-term therapeutic options.
Trivalvular nonbacterial thrombotic endocarditis in a patient with colon adenocarcinoma: a case report
Authors: Bagheri Abdolhamid , Khani Mohammad , Akbari Tooba , Ghadirzadeh Erfan , Charkazi Elham , Ghorbani Parastoo 
Published: August 2023

Abstract
Background
Nonbacterial thrombotic endocarditis is a rare complication of prothrombotic states such as neoplasms that can cause valvular dysfunction and life-threatening complications. Nonbacterial thrombotic endocarditis usually affects the left-sided valves; however, only a minority of cases involving the tricuspid valve have been reported in medical literature.

Case presentation
The current report describes trivalvular involvement by nonbacterial thrombotic endocarditis in a 54-year-old Azeri female patient with metastatic colorectal carcinoma. This case underlines the necessity of evaluating nonbacterial thrombotic endocarditis as a possible consequence in cancer patients. When thromboembolic events are found in the presence of a hypercoagulable state (such as malignancy) and no growth on blood cultures, nonbacterial thrombotic endocarditis could be suspected as the cause.

Conclusion
It is critical to achieve early diagnosis in such a setting to initiate treatment plans and prevent further complications rapidly.