bluuebunny/crossref_metadata_2025_split huggingface dataset:
Improving lung function in adolescents with CF by tracking annual rate of lung function decline
Authors: Schiff Sydney , Starks Miah , Linnemann Rachel W 
Published: August 2021

BackgroundFor patients with cystic fibrosis (CF), sustaining lung function through the adolescent years is crucial to slow the progressive decline that leads to significant morbidity and early mortality. This holds true for patients with high per cent predicted forced expiratory volume in 1 s (ppFEV1), as they may receive less vigilant monitoring and treatment. Early identification of lung function decline followed by aggressive treatment can lead to preservation of lung function.InterventionThe Emory+Children’s Pediatric Cystic Fibrosis Program implemented multiple quality improvement (QI) initiatives to identify and aggressively treat adolescent patients with a rapid decline in lung function. These initiatives included (1) lung zones to categorise and highlight lung function decline, (2) individual lung decline tables for quick reference, (3) a lung health algorithm to encourage uniformity, (4) a rapid decliner checklist to identify potential reasons for individual decline and (5) an automated individual patient-level data report and centre scorecard. We tested these interventions with plan–do–study–act cycles and refined as needed.ResultsImplementation of these QI initiatives resulted in overall improvement in lung function and slowing of lung function decline among adolescents with CF . This improvement could be attributed to the more standardised and proactive approach to decreases in lung function and the increased clinician attention to patients with rapid decline, especially for patients with high baseline ppFEV1.
Prevalence and significance of pulmonary disease on lung ultrasonography in outpatients with SARS-CoV-2 infection
Authors: Fairchild Robert M , Horomanski Audra , Mar Diane A , Triant Gabriela R , Lu Rong , Lu Di , Guo Haiwei Henry , Baker Matthew C 
Published: August 2021

BackgroundThe majority of patients with SARS-CoV-2 infection are diagnosed and managed as outpatients; however, little is known about the burden of pulmonary disease in this setting. Lung ultrasound (LUS) is a convenient tool for detection of COVID-19 pneumonia. Identifying SARS-CoV-2 infected outpatients with pulmonary disease may be important for early risk stratification.ObjectivesTo investigate the prevalence, natural history and clinical significance of pulmonary disease in outpatients with SARS-CoV-2.MethodsSARS-CoV-2 PCR positive outpatients (CV(+)) were assessed with LUS to identify the presence of interstitial pneumonia. Studies were considered positive based on the presence of B-lines, pleural irregularity and consolidations. A subset of patients underwent longitudinal examinations. Correlations between LUS findings and patient symptoms, demographics, comorbidities and clinical outcomes over 8 weeks were evaluated.Results102 CV(+) patients underwent LUS with 42 (41%) demonstrating pulmonary involvement. Baseline LUS severity scores correlated with shortness of breath on multivariate analysis. Of the CV(+) patients followed longitudinally, a majority showed improvement or resolution in LUS findings after 1–2 weeks. Only one patient in the CV(+) cohort was briefly hospitalised, and no patient died or required mechanical ventilation.ConclusionWe found a high prevalence of LUS findings in outpatients with SARS-CoV-2 infection. Given the pervasiveness of pulmonary disease across a broad spectrum of LUS severity scores and lack of adverse outcomes, our findings suggest that LUS may not be a useful as a risk stratification tool in SARS-CoV-2 in the general outpatient population.
Coil embolisation for massive haemoptysis in cystic fibrosis
Authors: Dohna Martha , Renz Diane Miriam , Stehling Florian , Dohna-Schwake Christian , Sutharsan Sivagurunathan , Neurohr Claus , Wirtz Hubert , Eickmeier Olaf , Grosse-Onnebrink Jörg , Sauerbrey Axel , Soditt Volker , Poplawska Krystyna , Wacker Frank , Montag Michael Johannes 
Published: August 2021

IntroductionMassive haemoptysis is a life-threatening event in advanced cystic fibrosis (CF) lung disease with bronchial artery embolisation (BAE) as standard of care treatment. The aim of our study was to scrutinise short-term and long-term outcomes of patients with CF and haemoptysis after BAE using coils.MethodsWe carried out a retrospective cohort study of 34 adult patients treated for massive haemoptysis with super selective bronchial artery coil embolisation (ssBACE) between January 2008 and February 2015. Embolisation protocol was restricted to the culprit vessel(s) and three lobes maximum. Demographic data, functional end-expiratory volume in 1 s in % predicted (FEV1% pred.) and body mass index before and after ssBACE, sputum colonisation, procedural data, time to transplant and time to death were documented.ResultsPatients treated with ssBACE showed significant improvement of FEV1% pred. after embolisation (p=0.004) with 72.8% alive 5 years post-ssBACE. Mean age of the patients was 29.9 years (±7.7). Mean FEV1% pred. was 45.7% (±20.1). Median survival to follow-up was 75 months (0–125). Severe complication rate was 0%, recanalisation rate 8.8% and 5-year-reintervention rate 58.8%. Chronic infection withPseudomonas aeruginosawas found in 79.4%,Staphylococcus areusin 50% andAspergillus fumigatusin 47.1%.DiscussionssBACE is a safe and effective treatment for massive haemoptysis in patients with CF with good results for controlling haemostasis and excellent short-term and long-term survival, especially in severely affected patients with FEV<40% pred. We think the data of our study support the use of coils and a protocol of careful and prudent embolisation.
Outpatient Neuromodulation May Avert the Need for Surgery in Patients with Painful Cutaneous Neuromas
Authors: Das Abhishek K. , Ng Chye Yew 
Published: August 2021

Background: Traumatic neuromas are a result of abnormal neural regeneration after nerve injury. Neuropathic pain arising from neuroma can be debilitating. Methods: This was a retrospective review of a consecutive series of patients who presented with a painful cutaneous neuroma secondary to direct trauma or surgery. The diagnosis was made by the presence of neuropathic symptoms in the dermatome of a cutaneous nerve and a positive Tinel sign. Local anaesthetic injection was performed for confirmation of diagnosis. Each patient was offered optimisation of medical therapy and physiotherapy for desensitisation. Outpatient neuromodulation was offered as an alternative to neuroma surgery. The primary aim of treatment was symptom reduction such that neuroma surgery was no longer required. Results: This study included 50 patients with painful cutaneous neuromas. Surgery was the commonest cause. The most frequently injured nerves were superficial radial nerve, digital nerve and dorsal ulnar cutaneous nerve, together comprising over 60% of cases. After receiving neuromodulation, 18 (36%) patients experienced sufficient symptom relief and did not wish to pursue neuroma surgery. Conclusions: Surgery is the commonest cause of a painful cutaneous neuroma. Following optimisation of pharmacotherapy and physiotherapy, neuromodulation may offer symptom relief such that neuroma surgery may be avoided in approximately one third of cases.
Radial Osteotomy for Kienböck Disease: Clinical and Radiological Comparison between Younger and Older Patients
Authors: Yamamoto Michiro , Tatebe Masahiro , Nakagawa Yasunobu , Kurimoto Shigeru , Iwatsuki Katsuyuki , Hirata Hitoshi 
Published: August 2021

Background: The usefulness of radial osteotomy for older patients remains unclear. The purpose of this study was to compare the clinical and radiological outcomes of radial osteotomy with volar locking plate between younger and older patients with Kienböck disease stages II to IIIB. Methods: This was a retrospective comparative study of 21 consecutive patients treated at our department. Lichtman’s classification was used for staging, and four patients had stage II, six patients had stage IIIA, and 11 patients had stage IIIB disease. We divided them into two groups to compare the radiological and clinical results between younger (younger than 40 years) and older patients. The mean follow-up periods in the younger and older groups were 4 and 3.6 years, respectively. For radiological assessment, we evaluated the carpal height ratio (CHR), Stahl index, and union of the fractured lunate. For clinical assessment, we examined the range of motion of the wrist, grip strength, numeric rating scale (NRS) for pain, and the patient-reported Hand20 score preoperatively and at the final follow-up. Results: There were 12 patients in the younger group with a mean age of 23 years (range, 12–37 years), and 9 in the older group with a mean age of 56 years (range, 40–74 years). There were no intra- and post-operative complications in either group. Radiological improvement, including CHR, Stahl index, and union of the fractured lunate, was more common in the younger group than in the older one, as was the case for clinical improvement. However, even in the older group, significant clinical improvement, including the range of motion of the wrist, NRS for pain, and the Hand20 score, was seen postoperatively. Conclusions: Radial osteotomy appears to be a safe and reliable option in older symptomatic patients with Kienböck disease stages II to IIIB.
MTAP Deficiency–Induced Metabolic Reprogramming Creates a Vulnerability to Cotargeting De Novo Purine Synthesis and Glycolysis in Pancreatic Cancer
Authors: Hu Qiangsheng , Qin Yi , Ji Shunrong , Shi Xiuhui , Dai Weixing , Fan Guixiong , Li Shuo , Xu Wenyan , Liu Wensheng , Liu Mengqi , Zhang Zheng , Ye Zeng , Zhou Zhijun , Yang Jingxuan , Zhuo Qifeng , Yu Xianjun , Li Min , Xu Xiaowu 
Published: August 2021

Abstract

Methylthioadenosine phosphorylase (MTAP) is a key enzyme associated with the salvage of methionine and adenine that is deficient in 20% to 30% of pancreatic cancer. Our previous study revealed that MTAP deficiency indicates a poor prognosis for patients with pancreatic ductal adenocarcinoma (PDAC). In this study, bioinformatics analysis of The Cancer Genome Atlas (TCGA) data indicated that PDACs with MTAP deficiency display a signature of elevated glycolysis. Metabolomics studies showed that that MTAP deletion–mediated metabolic reprogramming enhanced glycolysis and de novo purine synthesis in pancreatic cancer cells. Western blot analysis revealed that MTAP knockout stabilized hypoxia-inducible factor 1α (HIF1α) protein via posttranslational phosphorylation. RIO kinase 1 (RIOK1), a downstream kinase upregulated in MTAP-deficient cells, interacted with and phosphorylated HIF1α to regulate its stability. In vitro experiments demonstrated that the glycolysis inhibitor 2-deoxy-d-glucose (2-DG) and the de novo purine synthesis inhibitor l-alanosine synergized to kill MTAP-deficient pancreatic cancer cells. Collectively, these results reveal that MTAP deficiency drives pancreatic cancer progression by inducing metabolic reprogramming, providing a novel target and therapeutic strategy for treating MTAP-deficient disease.

Significance:
This study demonstrates that MTAP status impacts glucose and purine metabolism, thus identifying multiple novel treatment options against MTAP-deficient pancreatic cancer.
Radiation-Induced Phosphorylation of a Prion-Like Domain Regulates Transformation by FUS-CHOP
Authors: Chen Mark , Foster Joseph P. , Lock Ian C. , Leisenring Nathan H. , Daniel Andrea R. , Floyd Warren , Xu Eric , Davis Ian J. , Kirsch David G. 
Published: August 2021

Abstract

Chromosomal translocations generate oncogenic fusion proteins in approximately one-third of sarcomas, but how these proteins promote tumorigenesis is not well understood. Interestingly, some translocation-driven cancers exhibit dramatic clinical responses to therapy, such as radiotherapy, although the precise mechanism has not been elucidated. Here we reveal a molecular mechanism by which the fusion oncoprotein FUS-CHOP promotes tumor maintenance that also explains the remarkable sensitivity of myxoid liposarcomas to radiation therapy. FUS-CHOP interacted with chromatin remodeling complexes to regulate sarcoma cell proliferation. One of these chromatin remodelers, SNF2H, colocalized with FUS-CHOP genome-wide at active enhancers. Following ionizing radiation, DNA damage response kinases phosphorylated the prion-like domain of FUS-CHOP to impede these protein–protein interactions, which are required for transformation. Therefore, the DNA damage response after irradiation disrupted oncogenic targeting of chromatin remodelers required for FUS-CHOP–driven sarcomagenesis. This mechanism of disruption links phosphorylation of the prion-like domain of an oncogenic fusion protein to DNA damage after ionizing radiation and reveals that a dependence on oncogenic chromatin remodeling underlies sensitivity to radiation therapy in myxoid liposarcoma.

Significance:
Prion-like domains, which are frequently translocated in cancers as oncogenic fusion proteins that drive global epigenetic changes, confer sensitivity to radiation via disruption of oncogenic interactions.
Stem Cell Factor SOX2 Confers Ferroptosis Resistance in Lung Cancer via Upregulation of SLC7A11
Authors: Wang Xinbo , Chen Yueqing , Wang Xudong , Tian Hongling , Wang Yanjin , Jin Jiali , Shan Zezhi , Liu Yu'e , Cai Zhenyu , Tong Xinyuan , Luan Yi , Tan Xiao , Luan Bing , Ge Xin , Ji Hongbin , Jiang Xuejun , Wang Ping 
Published: August 2021

Abstract

Ferroptosis is a lipid peroxidation-dependent cell death caused by metabolic dysfunction. Ferroptosis-associated enzymes are promising therapeutic targets for cancer treatment. However, such therapeutic strategies show limited efficacy due to drug resistance and other largely unknown underlying mechanisms. Here we report that cystine transporter SLC7A11 is upregulated in lung cancer stem-like cells (CSLC) and can be activated by stem cell transcriptional factor SOX2. Mutation of SOX2 binding site in SLC7A11 promoter reduced SLC7A11 expression and increased sensitivity to ferroptosis in cancer cells. Oxidation at Cys265 of SOX2 inhibited its activity and decreased the self-renewal capacity of CSLCs. Moreover, tumors with high SOX2 expression were more resistant to ferroptosis, and SLC7A11 expression was positively correlated with SOX2 in both mouse and human lung cancer tissue. Together, our study provides a mechanism by which cancer cells evade ferroptosis and suggests that oxidation of SOX2 can be a potential therapeutic target for cancer treatment.

Significance:
This study uncovers a SOX2–SLC7A11 regulatory axis that confers resistance to ferroptosis in lung cancer stem-like cells.
Testicular Cancer: Biology to Bedside
Authors: King Jennifer , Adra Nabil , Einhorn Lawrence H. 
Published: August 2021

Abstract
Testicular cancer is the first solid tumor with a remarkably high cure rate. This success was only made possible through collaborative efforts of basic and clinical research. Most patients with distant metastases can be cured. However, the majority of these patients are diagnosed at a young age, leaving many decades for the development of treatment-related complications. This has magnified the importance of research into survivorship issues after exposure to platinum-based chemotherapy. This research, along with research into newer biomarkers that will aid in the diagnosis and surveillance of patients and survivors of testicular cancer, will continue to advance the field and provide new opportunities for these patients. There also remains the need for further therapeutic options for patients who unfortunately do not respond to standard treatment regimens and ultimately die from this disease, including a cohort of patients with late relapses and platinum-refractory disease. Here we discuss the advancements in management that led to a highly curable malignancy, while highlighting difficult situations still left to solve as well as emerging research into novel biomarkers.
TargetingHER2Exon 20 Insertion–Mutant Lung Adenocarcinoma with a Novel Tyrosine Kinase Inhibitor Mobocertinib
Authors: Han Han , Li Shuai , Chen Ting , Fitzgerald Michael , Liu Shengwu , Peng Chengwei , Tang Kwan Ho , Cao Shougen , Chouitar Johara , Wu Jiansheng , Peng David , Deng Jiehui , Gao Zhendong , Baker Theresa E. , Li Fei , Zhang Hua , Pan Yuanwang , Ding Hailin , Hu Hai , Pyon Val , Thakurdin Cassandra , Papadopoulos Eleni , Tang Sittinon , Gonzalvez Francois , Chen Haiquan , Rivera Victor M. , Brake Rachael , Vincent Sylvie , Wong Kwok-Kin 
Published: August 2021

AbstractNo targeted treatments are currently approved for HER2 exon 20 insertion–mutant lung adenocarcinoma patients. Mobocertinib (TAK-788) is a potent irreversible tyrosine kinase inhibitor (TKI) designed to target human epidermal growth factor receptor 2 (HER2/ERBB2) exon 20 insertion mutations. However, the function of mobocertinib on HER2 exon 20 insertion–mutant lung cancer is still unclear. Here we conducted systematic characterization of preclinical models to understand the activity profile of mobocertinib against HER2 exon 20 insertions. In HER2 exon 20 insertion–mutant cell lines, the IC50 of mobocertinib was higher than poziotinib and comparable with or slightly lower than afatinib, neratinib, and pyrotinib. Mobocertinib had the lowest HER2 exon 20 insertion IC50/wild-type (WT) EGFR IC50 ratio, indicating that mobocertinib displayed the best selectivity profile in these models. Also, mobocertinib showed strong inhibitory activity in HER2 exon 20YVMA allograft and patient-derived xenograft models. In genetically engineered mouse models, HER2 exon 20G776&gt;VC lung tumors exhibited a sustained complete response to mobocertinib, whereas HER2 exon 20YVMA tumors showed only partial and transient response. Combined treatment with a second antibody–drug conjugate (ADC) against HER2, ado-trastuzumab emtansine (T-DM1), synergized with mobocertinib in HER2 exon 20YVMA tumors. In addition to the tumor cell autonomous effect, sustained tumor growth control derived from M1 macrophage infiltration and CD4+ T-cell activation. These findings support the ongoing clinical development of mobocertinib (NCT02716116) and provide a rationale for future clinical evaluation of T-DM1 combinational therapy in HER2 exon 20YVMA insertion–mutant lung adenocarcinoma patients.Significance:This study elucidates the potent inhibitory activity of mobocertinib against HER2 exon 20 insertion–mutant lung cancer and the synergic effect of combined mobocertinib and T-DM1, providing a strong rationale for clinical investigation.
Preclinical and Clinical Characterization of Fibroblast-derived Neuregulin-1 on Trastuzumab and Pertuzumab Activity in HER2-positive Breast Cancer
Authors: Guardia Cristina , Bianchini Giampaolo , Arpí-LLucià Oriol , Menendez Silvia , Casadevall David , Galbardi Barbara , Dugo Matteo , Servitja Sonia , Montero Juan Carlos , Soria-Jiménez Luis , Sabbaghi MohammadA , Peña Raul , Madoz-Gúrpide Juan , Lloveras Belen , Lluch Ana , Eroles Pilar , Arribas Joaquin , Pandiella Atanasio , Gianni Luca , Rojo Federico , Rovira Ana , Albanell Joan 
Published: August 2021

Abstract

Purpose:
To characterize expression of neuregulin-1 (NRG1), an HER3 ligand, in HER2-positive breast cancer and its relation with the efficacy of trastuzumab with or without pertuzumab.

Experimental Design:
Characterization of NRG1 expression in tumor cell lines, in tumor specimens, and in cancer-associated fibroblasts (CAFs). Patient-derived CAFs were used to investigate NRG1 impact on the activity of trastuzumab with or without pertuzumab in HER2-positive breast cancer cells. The relationship between NRG1 expression and pathologic response to anti-HER2–based neoadjuvant therapy was assessed in a retrospective patient cohort and in the NeoSphere trial.

Results:
NRG1 was expressed in HER2-positive breast cancer–derived fibroblasts at significantly higher levels than in cancer cells. NRG1 and the conditioned media (CM) from CAFs phosphorylated HER3 and AKT in cancer cells and mediated trastuzumab resistance. Stable genetic depletion of NRG1 from CAFs overcame trastuzumab resistance. Pertuzumab effectively suppressed trastuzumab resistance mediated by either NRG1 or CAF's CM. NRG1 engaged an epithelial-to-mesenchymal transition that was prevented by trastuzumab and pertuzumab. In clinical samples, stromal and/or tumor cell expression of NRG1 determined by immunohistochemistry was uncommon (13.2%) yet significantly linked with residual disease following trastuzumab-based neoadjuvant therapy. In the NeoSphere trial, the magnitude of the difference of pathologic complete response rates favoring the pertuzumab arm was higher in the NRG1-high group.

Conclusions:
CAF-derived NRG1 mediates trastuzumab resistance through HER3/AKT, which might be reverted by pertuzumab. In patients with HER2-positive breast cancer, high expression of NRG1 was associated to poor response to trastuzumab, but not in combination with pertuzumab.
Vesseg
Authors: Murray Jacob M. , Pfeffer Phillip , Seifert Robert , Hermann Alexander , Handke Jessica , Kummer Laura , Janssen Henrike , Weigand Markus A. , Schlemmer Heinz-Peter , Larmann Jan , Kleesiek Jens 
Published: August 2021

Objective:
Manual plaque segmentation in microscopy images is a time-consuming process in atherosclerosis research and potentially subject to unacceptable user-to-user variability and observer bias. We address this by releasing Vesseg a tool that includes state-of-the-art deep learning models for atherosclerotic plaque segmentation.

Approach and Results:

Vesseg is a containerized, extensible, open-source, and user-oriented tool. It includes 2 models, trained and tested on 1089 hematoxylin-eosin stained mouse model atherosclerotic brachiocephalic artery sections. The models were compared to 3 human raters. Vesseg can be accessed at
https://vesseg
.online or downloaded. The models show mean Soerensen-Dice scores of 0.91±0.15 for plaque and 0.97±0.08 for lumen pixels. The mean accuracy is 0.98±0.05. Vesseg is already in active use, generating time savings of >10 minutes per slide.

Conclusions:
Vesseg brings state-of-the-art deep learning methods to atherosclerosis research, providing drastic time savings, while allowing for continuous improvement of models and the underlying pipeline.