bluuebunny/crossref_metadata_2025 huggingface dataset:
The Biological and Clinical Consequences of RNA Splicing Factor U2AF1 Mutation in Myeloid Malignancies
Authors: Zhao Yangjing , Cai Weili , Hua Ye , Yang Xiaochen , Zhou Jingdong
Published: September 2022

Mutations of spliceosome genes have been frequently identified in myeloid malignancies with the large-scale application of advanced sequencing technology. U2 small nuclear RNA auxiliary factor 1 (U2AF1), an essential component of U2AF heterodimer, plays a pivotal role in the pre-mRNA splicing processes to generate functional mRNAs. Over the past few decades, the mutation landscape of U2AF1 (most frequently involved S34 and Q157 hotspots) has been drawn in multiple cancers, particularly in myeloid malignancies. As a recognized early driver of myelodysplastic syndromes (MDSs), U2AF1 mutates most frequently in MDS, followed by acute myeloid leukemia (AML) and myeloproliferative neoplasms (MPNs). Here, for the first time, we summarize the research progress of U2AF1 mutations in myeloid malignancies, including the correlations between U2AF1 mutations with clinical and genetic characteristics, prognosis, and the leukemic transformation of patients. We also summarize the adverse effects of U2AF1 mutations on hematopoietic function, and the alterations in downstream alternative gene splicing and biological pathways, thus providing comprehensive insights into the roles of U2AF1 mutations in the myeloid malignancy pathogenesis. U2AF1 mutations are expected to be potential novel molecular markers for myeloid malignancies, especially for risk stratification, prognosis assessment, and a therapeutic target of MDS patients.
Investigation of Microbial Translocation, TLR and VDR Gene Polymorphisms, and Recurrence Risk in Stage III Colorectal Cancer Patients
Authors: Messaritakis Ippokratis , Koulouridi Asimina , Boukla Eleni , Sfakianaki Maria , Vogiatzoglou Konstantinos , Karagianni Michaela , Gouvas Nikolaos , Tsiaoussis John , Xynos Evangelos , Athanasakis Elias , Mavroudis Dimitrios , Tzardi Maria , Souglakos John
Published: September 2022

Gut microbial dysbiosis and microbial passage into the peripheral blood leads to colorectal cancer (CRC) and disease progression. Toll-like (TLR) and vitamin D (VDR) receptors play important role in the immune modulation and polymorphisms that may increase CRC risk and death rates. The aim of the current study was to demonstrate the prognostic value of microbial DNA fragments in the blood of stage III CRC patients and correlate such microbial detection to TLR/VDR polymorphisms. Peripheral blood was collected from 132 patients for the detection of microbial DNA fragments, and TLR/VDR gene polymorphisms. In the detection of various microbial DNA fragments, TLR and VDR polymorphisms was significantly higher compared to healthy group. Homozygous individuals of either TLR or VDR polymorphisms had significantly higher detection rates of microbial DNA fragments. Mutational and MSI status were significantly correlated with TLR9 and VDR polymorphisms. Significantly shorter disease-free survival was associated with patients with BRAF mutated tumors and ApaI polymorphisms, whereas shorter overall survival was associated with the detection of C. albicans. The detection of B. fragilis, as demonstrated by the multivariate analysis, is an independent poor prognostic factor for shorter disease-free survival. TLR/VDR genetic variants were significantly correlated with the detection of microbial fragments in the blood, and this in turn is significantly associated with tumorigenesis and disease progression.
Appropriate Lymph Node Dissection Sites for Cancer in the Body and Tail of the Pancreas: A Multicenter Retrospective Study
Authors: Tanaka Kimitaka , Kimura Yasutoshi , Hayashi Tsuyoshi , Ambo Yoshiyasu , Yoshida Makoto , Umemoto Kazufumi , Murakami Takeshi , Asano Toshimichi , Nakamura Toru , Hirano Satoshi
Published: September 2022

Distal pancreatectomy (DP) with lymphadenectomy is the standard surgery for pancreatic body–tail cancer. However, the optimal lymph node (LN) dissection area for DP remains controversial. Thus, we evaluated the frequency and patterns of LN metastasis based on the tumor site. In this multicenter retrospective study, we examined 235 patients who underwent DP for pancreatic cancer. Tumor sites were classified as confined to the pancreatic body (Pb) or pancreatic tail (Pt). The efficacy index (EI) was calculated by multiplying the frequency of metastasis to each LN station by the five-year survival rate of patients with metastasis to that station. LN metastasis occurred in 132/235 (56.2%) of the patients. Patients with Pb tumors showed no metastasis to the splenic hilum LN. Distal splenic artery LNs and anterosuperior/posterior common hepatic artery LNs did not benefit from dissection for Pb and Pt tumors, respectively. In multivariate analysis, splenic artery LN metastasis was identified as an independent predictor of poor overall survival in patients with pancreatic body–tail cancer. In conclusion, differences in metastatic LN sites were evident in pancreatic body–tail cancers confined to the Pb or Pt. Spleen-preserving pancreatectomy might be feasible for Pb cancer.
Prognostic Potential of the Baseline Pan-Immune-Inflammation Value and Neutrophil/Lymphocyte Ratio in Stage I to III Melanoma Patients
Authors: Gambichler Thilo , Stang Andreas , Mansour Rita , Scheel Christina H. , Nick Celine , Abu Rached Nessr , Becker Jürgen C. , Susok Laura
Published: September 2022

Prognostic biomarkers derived from complete blood count (CBC) have received marked interest as an indirect measure of the inflammatory pressure in cancers such as metastatic melanoma. Here, we evaluated the novel pan-immune-inflammation value (PIV) and the frequently assessed neutrophil/lymphocyte ratio (NLR) in a large cohort of patients with cutaneous melanoma (CM) without distant metastases (stages I to III). PIV and NLR were calculated at CM diagnosis. Healthy controls were also included. We used the Kaplan–Meier method to estimate crude survival probabilities and used Cox proportional hazards regression for multiple adjustment of hazard ratios. We observed that higher PIV (HR: 1.72, 95% CI 1.14 to 2.58 and HR: 1.696, 95% CI 1.029 to 2.795, respectively) and NLR (HR: 1.70, 95% CI 1.10 to 2.62) values were associated with CM relapse and CM-specific death in the crude analysis. However, when adjusting for potential confounders, in particular age and tumor thickness, the total effect of PIV and NLR on CM-relapse-free (HR: 1.28, 95% CI 0.83 to 1.98 and HR: 1.26, 95% CI 0.80 to 1.98, respectively) and CM-specific survival (HR: 1.36, 95% CI 0.80 to 2.30 and HR: 1.37, 95% CI 0.80 to 2.33, respectively) was substantially reduced. However, both PIV and NLR were positively correlated with age and tumor thickness, which are important independent predictors for CM relapse and CM-specific death. In conclusion, in stage I to III CM patients PIV as well as NLR appear to be confounded by age and tumor thickness and probably have no potential to further improve the prediction of survival of stage I to III CM patients beyond standard prognostic factors.
Malignant Pleural Mesothelioma: Current Understanding of the Immune Microenvironment and Treatments of a Rare Disease
Authors: Tedesco John , Jaradeh Mark , Vigneswaran Wickii T.
Published: September 2022

Malignant pleural mesothelioma is a rare disease with an annual incidence of around 3000 cases a year in the United States. Most cases are caused by asbestos exposure, with a latency period of up to 40 years. Pleural mesothelioma is an aggressive disease process with overall survival of roughly 6–12 months after the time of diagnosis. It is divided into three subtypes: epithelioid, mixed type, and sarcomatoid type, with the epithelioid subtype having the best overall survival. Often, the treatment is multimodality with surgery, chemotherapy, and radiation. The survival benefit is improved but remains marginal. New treatment options involving targeted immune therapies appear to offer some promise. The tumor microenvironment is the ecosystem within the tumor that interacts and influences the host immune system. Understanding this complex interaction and how the host immune system is involved in the progression of the disease process is important to define and guide potential treatment options for this devastating and rare disease.
Music Therapy as a Form of Nonpharmacologic Pain Modulation in Patients with Cancer: A Systematic Review of the Current Literature
Authors: Rennie Christopher , Irvine Dylan S. , Huang Evan , Huang Jeffrey
Published: September 2022

Aims and Objectives: To consolidate and summarize the current literature surrounding the use of music therapy as an effective noninvasive adjunct to conventional cancer therapy, especially as a low-risk alternative for pain management and anesthetic use in cancer patients. Background: Current studies have proposed that music therapy may be effective as a noninvasive adjunct to conventional cancer therapy in managing numerous outcomes in cancer patients. However, the findings of these investigations have not been consolidated and analyzed on a large scale. Therefore, focusing a systematic review on the effects of music therapy as an adjunct to conventional cancer therapy would give a better understanding of which intervention approaches are associated with better clinical outcomes for cancer patients. Design: A systematic review. Methods: A review of randomized controlled trials to evaluate the effectiveness of music therapy in physical, cognitive, and psychosocial outcomes for cancer patients alone or in conjunction with standard therapy was implemented. We conducted searches using the PubMed/MEDLINE, CINAHL, and Cochrane Library databases for all articles meeting the search criteria up until the time of article extraction in May, 2022. Only studies published in English were included. Two reviewers independently extracted data on participant and intervention characteristics. The main outcome variables included pain, anxiety, quality of life, mood, sleep disorders, fatigue, heart rate, blood pressure, respiratory rate, and oxygen saturation. Results: Of the 202 initially identified articles, 25 randomized controlled trials met the inclusion criteria for evaluation. Of the 25 studies, 23 (92.0%) reported statistically and clinically significant improvements across the outcome variables. Two of the studies (8.00%) found no significant positive effect from music therapy in any of the aforementioned outcomes variables. Conclusion: Music therapy, both as a standalone treatment and when used in conjunction with other pharmacologic and nonpharmacologic modalities, has a generally beneficial effect across several physiologic and psychosocial aspects of cancer.
Circulating Tumor DNA-Based Disease Monitoring of Patients with Locally Advanced Esophageal Cancer
Authors: Hofste Lisa S. M. , Geerlings Maartje J. , von Rhein Daniel , Tolmeijer Sofie H. , Weiss Marjan M. , Gilissen Christian , Hofste Tom , Garms Linda M. , Janssen Marcel J. R. , Rütten Heidi , Rosman Camiel , van der Post Rachel S. , Klarenbeek Bastiaan R. , Ligtenberg Marjolijn J. L.
Published: September 2022

Patients diagnosed with locally advanced esophageal cancer are often treated with neoadjuvant chemoradiotherapy followed by surgery. This study explored whether detection of circulating tumor DNA (ctDNA) in plasma can be used to predict residual disease during treatment. Diagnostic tissue biopsies from patients with esophageal cancer receiving neoadjuvant chemoradiotherapy and surgery were analyzed for tumor-specific mutations. These tumor-informed mutations were used to measure the presence of ctDNA in serially collected plasma samples using hybrid capture-based sequencing. Plasma samples were obtained before chemoradiotherapy, and prior to surgery. The association between ctDNA detection and progression-free and overall survival was measured. Before chemoradiotherapy, ctDNA was detected in 56% (44/78) of patients and detection was associated with tumor stage and volume (p = 0.05, Fisher exact and p = 0.02, Mann-Whitney, respectively). After chemoradiotherapy, ctDNA was detected in 10% (8/78) of patients. This preoperative detection of ctDNA was independently associated with recurrent disease (hazard ratio 2.8, 95% confidence interval 1.1–6.8, p = 0.03, multivariable Cox-regression) and worse overall survival (hazard ratio 2.9, 95% confidence interval 1.2–7.1, p = 0.02, multivariable Cox-regression).Ultradeep sequencing-based detection of ctDNA in preoperative plasma of patients with locally advanced esophageal cancer may help to assess which patients have a high risk of recurrence after neoadjuvant chemoradiotherapy and surgery.
Acupuncture for Managing Cancer-Related Fatigue in Breast Cancer Patients: A Systematic Review and Meta-Analysis
Authors: Choi Tae-Young , Ang Lin , Jun Ji Hee , Alraek Terje , Birch Stephen , Lu Weidong , Lee Myeong Soo
Published: September 2022

Breast cancer (BC) is the most common cancer in women and is a serious threat to women’s health. Cancer-related fatigue (CRF) is a distressing symptom in BC patients during and after chemotherapy or radiation therapy that severely affects quality of life (QoL). AT is widely used for fatigue management. However, the effect of AT on CRF is still uncertain. This study aimed to evaluate the efficacy and safety of AT in the management of CRF in patients with BC. Eleven databases were searched through June 2022. Two researchers independently performed the database search, study selection, data extraction, and risk of bias assessment. Study selection was performed based on predefined Participants, Intervention, Comparators, Outcomes, Study design (PICOS) criteria, and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed when reporting the results. A meta-analysis was performed according to the Cochrane systematic review method using RevMan 5.3. A total of 12 studies including a total of 1084 participants were included. The results showed that AT had a beneficial effect compared with sham AT (n = 256, SMD = −0.26, 95% CI [−0.51, −0.01], p = 0.04, I2 = 0%) and a long-term effect on fatigue score (n = 209, MD = −0.32, 95% CI [–0.59, −0.04], p = 0.02, I2 = 0%). Meta-analysis showed that AT had a beneficial effect compared with usual care (UC) on fatigue scores (n = 238, SMD = −0.39, 95% CI [−0.66 to −0.12], p = 0.005, I2 = 0%). Of the 12 articles, 3 articles were judged as having a low risk of bias in all domains and hence were of high quality. No serious adverse effects were identified. AT is an effective and safe treatment for CRF, and AT is more effective than sham AT or UC or wait-list control (WLC). Nevertheless, the methodological quality of most of these studies was low, and the included studies/sample sizes were small, so the ability to derive decisive implications was limited. Further research is needed to confirm these findings.
MYCN Impact on High-Risk Neuroblastoma: From Diagnosis and Prognosis to Targeted Treatment
Authors: Bartolucci Damiano , Montemurro Luca , Raieli Salvatore , Lampis Silvia , Pession Andrea , Hrelia Patrizia , Tonelli Roberto
Published: September 2022

Among childhood cancers, neuroblastoma is the most diffuse solid tumor and the deadliest in children. While to date, the pathology has become progressively manageable with a significant increase in 5-year survival for its less aggressive form, high-risk neuroblastoma (HR-NB) remains a major issue with poor outcome and little survivability of patients. The staging system has also been improved to better fit patient needs and to administer therapies in a more focused manner in consideration of pathology features. New and improved therapies have been developed; nevertheless, low efficacy and high toxicity remain a staple feature of current high-risk neuroblastoma treatment. For this reason, more specific procedures are required, and new therapeutic targets are also needed for a precise medicine approach. In this scenario, MYCN is certainly one of the most interesting targets. Indeed, MYCN is one of the most relevant hallmarks of HR-NB, and many studies has been carried out in recent years to discover potent and specific inhibitors to block its activities and any related oncogenic function. N-Myc protein has been considered an undruggable target for a long time. Thus, many new indirect and direct approaches have been discovered and preclinically evaluated for the interaction with MYCN and its pathways; a few of the most promising approaches are nearing clinical application for the investigation in HR-NB.
Surgical Resection Is Superior to TACE in the Treatment of HCC in a Well Selected Cohort of BCLC-B Elderly Patients—A Retrospective Observational Study
Authors: Brozzetti Stefania , D’Alterio Chiara , Bini Simone , Antimi Jessica , Rocco Bianca , Fassari Alessia , Lucatelli Pierleone , Nardis Piergiorgio , Di Martino Michele , De Sanctis Giuseppe Maria , Corona Mario , Bagni Oreste , Cortesi Enrico , Bezzi Mario , Catalano Carlo
Published: September 2022

Hepatocellular carcinoma (HCC) usually develops in cirrhotic liver, with high recurrence rates. However, considering its increasing detection in non-cirrhotic liver, the choice of treatment assumes particular relevance. This study aimed to investigate outcomes of patients among BCLC stages and enrolled for surgical resection (SR) according to a more complex evaluation, to establish its safety and efficacy. A total of 186 selected HCC patients (median age 73.2 yrs), submitted to SR between January 2005 and January 2021, were retrospectively analyzed. Of which, 166 were staged 0, A, B according to the BCLC system, while 20 with a single large tumor (>5 cm) were classified as stage AB. No perioperative mortality was recorded; complications occurred in 48 (25.80%) patients, and all but two were Clavien–Dindo grade I–II. Median follow-up was 9.2 years. Subsequently, 162 recurrent patients (87,1%) were selected for new treatments. Comparable overall survival rates (OS) were observed at 1, 3, 5, and 10 years in 0, A, B and AB stages (p = 0.2). Eventually, the BCLC-B group was matched to 40 BCLC-B patients treated (2015-2021) with TACE. Significant differences in baseline characteristics (p <0.0001) and in OS were observed at 1 and 3 years (p <0.0001); a significant difference was also observed in oncological outcomes, in terms of the absence, residual, or relapse of disease (p <0.05). Surgery might be a valid treatment in HCC for patients affected by chronic liver disease in a condition of compensation, up to BCLC-B stage. Surgical indication for liver resection in case of HCC should be extensively revised.
Astragaloside IV Inhibits the Proliferation of Human Uterine Leiomyomas by Targeting IDO1
Authors: Qiu Tiantian , Li Donghua , Liu Yu , Ren Hui , Yang Xuan , Luo Wenting
Published: September 2022

Astragaloside IV (AS-IV) is a chemical found in traditional Chinese medicine called Astragalus membranaceus (Fisch.) Bunge that has antitumor properties. However, the roles and mechanisms of AS-IV in uterine leiomyomas (ULMs) are unclear. The immunosuppressive enzyme indoleamine-2,3-dioxygenase-1 (IDO1) is involved in tumor formation. IDO1 is a new and reliable prognostic indicator for several cancers. In this work, AS-IV was applied to ULM cells in various concentrations. CCK-8, immunofluorescence, and flow cytometry were used to examine the proliferation and apoptosis of ULM cells caused by AS-IV. After lentiviral vector transduction with IDO1 short hairpin RNA (shRNA), the knockdown and overexpression of IDO1 were stable in ULM cells. To verify the antitumor effect of AS-IV in vivo, we established a rat model of uterine leiomyoma. HE staining, Masson staining, and transmission electron microscopy were used to observe pathological changes in the uterus, and the levels of serum sex hormones were measured by radio immune assay (RIA). The levels of CD3+T, CD4+T, and CD25+ Foxp3+Treg in rat peripheral blood were detected by flow cytometry. Western blotting and immunohistochemistry were used to examine protein expression. We found that AS-IV dramatically increased the apoptotic rate of ULM cells and reduced viability in a time- and dosage-dependent manner. After sh-IDO1 lentiviral transfection, we discovered that knocking down IDO1 reversed the effects of AS-IV on ULM cell proliferation and autophagy. We also found that AS-IV can effectively inhibit the growth of ULMs in vivo. AS-IV may promote apoptosis and autophagy in ULMs by activating PTEN/PI3K/AKT signaling through inhibition of IDO1. These findings imply that AS-IV exerts antifibroid effects, and the underlying mechanism may be IDO1, which is involved in proliferation, apoptosis, and autophagy.
Development and Validation of a Predictive Model for Toxicity of Neoadjuvant Chemoradiotherapy in Rectal Cancer in the CAO/ARO/AIO-04 Phase III Trial
Authors: Diefenhardt Markus , Martin Daniel , Ludmir Ethan B. , Fleischmann Maximilian , Hofheinz Ralf-Dieter , Ghadimi Michael , Kosmala Rebekka , Polat Bülent , Friede Tim , Minsky Bruce D. , Rödel Claus , Fokas Emmanouil
Published: September 2022

Background: There is a lack of predictive models to identify patients at risk of high neoadjuvant chemoradiotherapy (CRT)-related acute toxicity in rectal cancer. Patient and Methods: The CAO/ARO/AIO-04 trial was divided into a development (n = 831) and a validation (n = 405) cohort. Using a best subset selection approach, predictive models for grade 3–4 acute toxicity were calculated including clinicopathologic characteristics, pretreatment blood parameters, and baseline results of quality-of-life questionnaires and evaluated using the area under the ROC curve. The final model was internally and externally validated. Results: In the development cohort, 155 patients developed grade 3–4 toxicities due to CRT. In the final evaluation, 15 parameters were included in the logistic regression models using best-subset selection. BMI, gender, and emotional functioning remained significant for predicting toxicity, with a discrimination ability adjusted for overfitting of AUC 0.687. The odds of experiencing high-grade toxicity were 3.8 times higher in the intermediate and 6.4 times higher in the high-risk group (p < 0.001). Rates of toxicity (p = 0.001) and low treatment adherence (p = 0.007) remained significantly different in the validation cohort, whereas discrimination ability was not significantly worse (DeLong test 0.09). Conclusion: We developed and validated a predictive model for toxicity using gender, BMI, and emotional functioning. Such a model could help identify patients at risk for treatment-related high-grade toxicity to assist in treatment guidance and patient participation in shared decision making.
Endoscopic Predictors of Neoplastic Lesions in Inflammatory Bowel Diseases Patients Undergoing Chromoendoscopy
Authors: Lolli Elisabetta , De Cristofaro Elena , Marafini Irene , Troncone Edoardo , Neri Benedetto , Zorzi Francesca , Biancone Livia , Calabrese Emma , Monteleone Giovanni
Published: September 2022

Dye-based chromoendoscopy (DCE) with targeted biopsies is recommended for surveillance of patients with long-standing inflammatory bowel diseases (IBD), but endoscopic features that predict dysplasia are not fully clarified. We here aimed at identifying predictive factors of dysplastic/neoplastic lesions in IBD patients undergoing DCE. Two-hundred-and-nineteen patients were consecutively and prospectively enrolled from October 2019 to March 2022. One-hundred-and-forty-five out of 219 patients underwent DCE, and 148 lesions were detected in 79/145 (54%) patients. Thirty-nine lesions (26%) were dysplastic and one of them contained a CRC. Among these lesions, 7 (17.9%) had Kudo pit pattern I-II and 32 (82.1%) had a neoplastic pit pattern (Kudo III-IV). Multivariate analysis showed that neoplastic lesions Kudo III-IV (OR: 5.8, 95% CI: 2.3–14.6; p = 0.0002), lesion’s size (OR 1.16, 95% CI: 1.06–1.26; p = 0.0009), and polypoid lesions according to Paris Classification (OR 7.4, 95% CI: 2.7–20.2; p = 0.0001) were independent predictors of dysplasia. A cut-off of lesion’s size > 7 mm was identified as the best predictor of dysplasia. Among such features, Kudo pit pattern III-IV had the highest sensitivity and specificity to predict dysplasia (79% and 80%, respectively). Lesions with all three endoscopic features had a sensitivity of 90% and specificity of 100% to predict dysplasia. In contrast, non-polypoid lesions were inversely associated with dysplasia (OR 0.13, 95% CI: 0.05–0.36; p = 0.0001). These findings indicate that, in IBD patients, DCE-evidenced polypoid lesions with Kudo pit pattern III-IV and size > 7 mm are frequently dysplastic.
Identification of a Biomarker Combination for Survival Stratification in pStage II/III Gastric Cancer after Curative Resection
Authors: Hashimoto Itaru , Kimura Yayoi , Oue Naohide , Hiroshima Yukihiko , Aoyama Toru , Rino Yasushi , Yokose Tomoyuki , Yasui Wataru , Miyagi Yohei , Oshima Takashi
Published: September 2022

Background: We sought to identify an optimal combination of survival risk stratification markers in patients with pathological (p) stage II/III gastric cancer (GC) after curative resection. Methods: We measured the expression levels of 127 genes in pStage II/III GC tissues of two patient cohorts by quantitative polymerase chain reaction (qPCR) and the expression of 1756 proteins between two prognosis (good and poor) groups by proteomic analysis to identify candidate survival stratification markers. Further, immunohistochemistry (IHC) using tumor microarrays (TMAs) in another cohort of patients was performed to identify an optimal biomarker combination for survival stratification in GC patients. Results: secreted protein acidic and rich in cysteine (SPARC), erb-b2 receptor tyrosine kinase 2 (ERBB2), inhibin subunit beta A (INHBA), matrix metallopeptidase-11 (MMP11), tumor protein p53 (TP53), and platelet-derived growth factor receptor-beta (PDGFRB) were identified as candidate biomarkers from qPCR analysis, and SPARC and galectin-10 were obtained from the proteomic analysis. The combination of PDGFRB, INHBA, MMP11, and galectin-10 was identified as the optimal combination of survival risk stratification markers. Conclusions: A combination of four proteins in GC tissues may serve as useful survival risk stratification markers in patients with pStage II/III GC following curative resection. Our results may facilitate future multicenter prospective clinical trials.
Combined Focused Next-Generation Sequencing Assays to Guide Precision Oncology in Solid Tumors: A Retrospective Analysis from an Institutional Molecular Tumor Board
Authors: Tarawneh Thomas S. , Rodepeter Fiona R. , Teply-Szymanski Julia , Ross Petra , Koch Vera , Thölken Clemens , Schäfer Jonas A. , Gremke Niklas , Mack Hildegard I. D. , Gold Judith , Riera-Knorrenschild Jorge , Wilhelm Christian , Rinke Anja , Middeke Martin , Klemmer Andreas , Romey Marcel , Hattesohl Akira , Jesinghaus Moritz , Görg Christian , Figiel Jens , Chung Ho-Ryun , Wündisch Thomas , Neubauer Andreas , Denkert Carsten , Mack Elisabeth K. M.
Published: September 2022

Background: Increasing knowledge of cancer biology and an expanding spectrum of molecularly targeted therapies provide the basis for precision oncology. Despite extensive gene diagnostics, previous reports indicate that less than 10% of patients benefit from this concept. Methods: We retrospectively analyzed all patients referred to our center’s Molecular Tumor Board (MTB) from 2018 to 2021. Molecular testing by next-generation sequencing (NGS) included a 67-gene panel for the detection of short-sequence variants and copy-number alterations, a 53- or 137-gene fusion panel and an ultra-low-coverage whole-genome sequencing for the detection of additional copy-number alterations outside the panel’s target regions. Immunohistochemistry for microsatellite instability and PD-L1 expression complemented NGS. Results: A total of 109 patients were referred to the MTB. In all, 78 patients received therapeutic proposals (70 based on NGS) and 33 were treated accordingly. Evaluable patients treated with MTB-recommended therapy (n = 30) had significantly longer progression-free survival than patients treated with other therapies (n = 17) (4.3 vs. 1.9 months, p = 0.0094). Seven patients treated with off-label regimens experienced major clinical benefits. Conclusion: The combined focused sequencing assays detected targetable alterations in the majority of patients. Patient benefits appeared to lie in the same range as with large-scale sequencing approaches.
Increased KV2.1 Channel Clustering Underlies the Reduction of Delayed Rectifier K+ Currents in Hippocampal Neurons of the Tg2576 Alzheimer’s Disease Mouse
Authors: Piccialli Ilaria , Sisalli Maria José , de Rosa Valeria , Boscia Francesca , Tedeschi Valentina , Secondo Agnese , Pannaccione Anna
Published: September 2022

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by the progressive deterioration of cognitive functions. Cortical and hippocampal hyperexcitability intervenes in the pathological derangement of brain activity leading to cognitive decline. As key regulators of neuronal excitability, the voltage-gated K+ channels (KV) might play a crucial role in the AD pathophysiology. Among them, the KV2.1 channel, the main α subunit mediating the delayed rectifier K+ currents (IDR) and controlling the intrinsic excitability of pyramidal neurons, has been poorly examined in AD. In the present study, we investigated the KV2.1 protein expression and activity in hippocampal neurons from the Tg2576 mouse, a widely used transgenic model of AD. To this aim we performed whole-cell patch-clamp recordings, Western blotting, and immunofluorescence analyses. Our Western blotting results reveal that KV2.1 was overexpressed in the hippocampus of 3-month-old Tg2576 mice and in primary hippocampal neurons from Tg2576 mouse embryos compared with the WT counterparts. Electrophysiological experiments unveiled that the whole IDR were reduced in the Tg2576 primary neurons compared with the WT neurons, and that this reduction was due to the loss of the KV2.1 current component. Moreover, we found that the reduction of the KV2.1-mediated currents was due to increased channel clustering, and that glutamate, a stimulus inducing KV2.1 declustering, was able to restore the IDR to levels comparable to those of the WT neurons. These findings add new information about the dysregulation of ionic homeostasis in the Tg2576 AD mouse model and identify KV2.1 as a possible player in the AD-related alterations of neuronal excitability.
Targeting Gastric Cancer Stem Cells to Enhance Treatment Response
Authors: Rao Xionghui , Zhang Chaojun , Luo Huixing , Zhang Jianbao , Zhuang Zhehong , Liang Zhihao , Wu Xiaobin
Published: September 2022

Gastric cancer (GC) was the fourth deadliest cancer in the world in 2020, and about 770,000 people died from GC that year. The death of patients with GC is mainly caused by the metastasis, recurrence, and chemotherapy resistance of GC cells. The cancer stem cell theory defines cancer stem cells (CSCs) as a key factor in the metastasis, recurrence, and chemotherapy resistance of cancer. It considers targeting gastric cancer stem cells (GCSCs) to be an effective method for the treatment of GC. For GCSCs, genes or noncoding RNAs are important regulatory factors. Many experimental studies have found that some drugs can target the stemness of gastric cancer by regulating these genes or noncoding RNAs, which may bring new directions for the clinical treatment of gastric cancer. Therefore, this review mainly discusses related genes or noncoding RNAs in GCSCs and drugs that target its stemness, thereby providing some information for the treatment of GC.
H2A-H2B Histone Dimer Plasticity and Its Functional Implications
Authors: Kniazeva Anastasiia S. , Armeev Grigoriy A. , Shaytan Alexey K.
Published: September 2022

The protein core of the nucleosome is composed of an H3-H4 histone tetramer and two H2A-H2B histone dimers. The tetramer organizes the central 60 DNA bp, while H2A-H2B dimers lock the flanking DNA segments. Being positioned at the sides of the nucleosome, H2A-H2B dimers stabilize the overall structure of the nucleosome and modulate its dynamics, such as DNA unwrapping, sliding, etc. Such modulation at the epigenetic level is achieved through post-translational modifications and the incorporation of histone variants. However, the detailed connection between the sequence of H2A-H2B histones and their structure, dynamics and implications for nucleosome functioning remains elusive. In this work, we present a detailed study of H2A-H2B dimer dynamics in the free form and in the context of nucleosomes via atomistic molecular dynamics simulations (based on X. laevis histones). We supplement simulation results by comparative analysis of information in the structural databases. Particularly, we describe a major dynamical mode corresponding to the bending movement of the longest H2A and H2B α-helices. This overall bending dynamics of the H2A-H2B dimer were found to be modulated by its interactions with DNA, H3-H4 tetramer, the presence of DNA twist-defects with nucleosomal DNA and the amino acid sequence of histones. Taken together, our results shed new light on the dynamical mechanisms of nucleosome functioning, such as nucleosome sliding, DNA-unwrapping and their epigenetic modulation.
Inhibition of BRD4 Promotes Pexophagy by Increasing ROS and ATM Activation
Authors: Kim Yong Hwan , Jo Doo Sin , Park Na Yeon , Bae Ji-Eun , Kim Joon Bum , Lee Ha Jung , Kim So Hyun , Kim Seong Hyun , Lee Sunwoo , Son Mikyung , Park Kyuhee , Jeong Kwiwan , Yeom Eunbyul , Cho Dong-Hyung
Published: September 2022

Although autophagy regulates the quality and quantity of cellular compartments, the regulatory mechanisms underlying peroxisomal autophagy (pexophagy) remain largely unknown. In this study, we identified several BRD4 inhibitors, including molibresib, a novel pexophagy inducer, via chemical library screening. Treatment with molibresib promotes loss of peroxisomes selectively, but not mitochondria, ER, or Golgi apparatus in HeLa cells. Consistently, depletion of BRD4 expression also induced pexophagy in RPE cells. In addition, the inhibition of BRD4 by molibresib increased autophagic degradation of peroxisome ATG7-dependency. We further found that molibresib produced reactive oxygen species (ROS), which potentiates ATM activation. Inhibition of ROS or ATM suppressed the loss of peroxisomes in molibresib-treated cells. Taken together, our data suggest that inhibition of BRD4 promotes pexophagy by increasing ROS and ATM activation.
Mesenchymal Stem Cell Sheet Centrifuge-Assisted Layering Augments Pro-Regenerative Cytokine Production
Authors: Bou-Ghannam Sophia , Kim Kyungsook , Kondo Makoto , Grainger David W. , Okano Teruo
Published: September 2022

A focal advantage of cell sheet technology has been as a scaffold-free three-dimensional (3D) cell delivery platform capable of sustained cell engraftment, survival, and reparative function. Recent evidence demonstrates that the intrinsic cell sheet 3D tissue-like microenvironment stimulates mesenchymal stem cell (MSC) paracrine factor production. In this capacity, cell sheets not only function as 3D cell delivery platforms, but also prime MSC therapeutic paracrine capacity. This study introduces a “cell sheet multilayering by centrifugation” strategy to non-invasively augment MSC paracrine factor production. Cell sheets fabricated by temperature-mediated harvest were first centrifuged as single layers using optimized conditions of rotational speed and time. Centrifugation enhanced cell physical and biochemical interactions related to intercellular communication and matrix interactions within the single cell sheet, upregulating MSC gene expression of connexin 43, integrin β1, and laminin α5. Single cell sheet centrifugation triggered MSC functional enhancement, secreting higher concentrations of pro-regenerative cytokines vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), and interleukin-10 (IL-10). Subsequent cell sheet stacking, and centrifugation generated cohesive, bilayer MSC sheets within 2 h, which could not be accomplished within 24 h by conventional layering methods. Conventional layering led to H1F-1α upregulation and increased cell death, indicating a hypoxic thickness limitation to this approach. Comparing centrifuged single and bilayer cell sheets revealed that layering increased VEGF production 10-fold, attributed to intercellular interactions at the layered sheet interface. The “MSC sheet multilayering by centrifugation” strategy described herein generates a 3D MSC-delivery platform with boosted therapeutic factor production capacity.
mTORC1 Activity in Psoriatic Lesions Is Mediated by Aberrant Regulation through the Tuberous Sclerosis Complex
Authors: Ferreri Antonio , Lang Victoria , Kaufmann Roland , Buerger Claudia
Published: September 2022

In the basal, proliferative layer of healthy skin, the mTOR complex 1 (mTORC1) is activated, thus regulating proliferation while preventing differentiation. When cells leave the proliferative, basal compartment, mTORC1 signaling is turned off, which allows differentiation. Under inflammatory conditions, this switch is hijacked by cytokines and prevents proper differentiation. It is currently unknown how mTORC1 is regulated to mediate these effects on keratinocyte differentiation. In other tissues, mTORC1 activity is controlled through various pathways via the tuberous sclerosis complex (TSC). Thus, we investigated whether the TS complex is regulated by proinflammatory cytokines and contributes to the pathogenesis of psoriasis. TNF-α as well as IL-1β induced the phosphorylation of TSC2, especially on S939 via the PI3-K/AKT and MAPK pathway. Surprisingly, increased TSC2 phosphorylation could not be detected in psoriasis patients. Instead, TSC2 was strongly downregulated in lesional psoriatic skin compared to non-lesional skin of the same patients or healthy skin. In vitro inflammatory cytokines induced dissociation of TSC2 from the lysosome, followed by destabilization of the TS complex and degradation. Thus, we assume that in psoriasis, inflammatory cytokines induce strong TSC2 phosphorylation, which in turn leads to its degradation. Consequently, chronic mTORC1 activity impairs ordered keratinocyte differentiation and contributes to the phenotypical changes seen in the psoriatic epidermis.
Identification of Seven Key Structural Genes in the Anthocyanin Biosynthesis Pathway in Sepals of Hydrangea macrophylla
Authors: Qi Hui , Zhang Gaitian , Chu Zhiyun , Liu Chun , Yuan Suxia
Published: September 2022

Under specific cultivation conditions, the sepal color of Hydrangea macrophylla (H. macrophylla) changes from red to blue due to the complexation of aluminum ions (Al3+), delphinidin 3-glucoside, and copigments. However, this phenomenon cannot occur in all cultivars despite the presence of sufficient Al3+ and copigments. To explore the mechanism of sepal bluing in H. macrophylla, there is an urgent need to study the molecular regulation of the anthocyanin biosynthesis pathway. However, the key structural genes, other than CHS, regulating anthocyanin biosynthesis in the sepals of H. macrophylla have not been identified. In this study, based on full-length transcriptome data from H.macrophylla ‘Bailmer’, the key structural genes regulating anthocyanin biosynthesis in the sepals of H. macrophylla were isolated and investigated. Ultimately, seven key structural genes, HmCHS1, HmCHI, HmF3H1, HmF3′H1, HmF3′5′H, HmDFR2, and HmANS3, were demonstrated to show high expression levels in colored sepals. The expression levels of these seven genes increased gradually with the development of sepals and were highest in the full-bloom stage. The trend of gene expression was consistent with the trend of anthocyanin contents. It was concluded that the seven selected genes were involved in anthocyanin biosynthesis in the sepals of H. macrophylla. The full-length sequence data have been deposited into the NCBI Sequence Read Archive (SRA) with accession number PRJNA849710. This study lays a good foundation for the further elucidation of the molecular mechanism of sepal coloration in H. macrophylla.
Full-Length Transcriptome Sequencing Combined with RNA-Seq to Analyze Genes Related to Terpenoid Biosynthesis in Cinnamomum burmannii
Authors: Guo Siyuan , Liang Jiahao , Deng Zhiwei , Lu Ziqing , Fu Minghui , Su Jianyu
Published: September 2022

Cinnamomum burmannii is a cinnamomum plant rich in natural D-borneol. Natural D-borneol is a bicycle monoterpenoid compound widely used in the food, pharmaceutical, and cosmetic industries. Therefore, analyzing the biosynthesis mechanism of natural D-borneol in C. burmannii at the molecular level is helpful for directional breeding in the future and further development and utilization of C. burmannii and its related gene resources. In our study, 76 genes related to terpene metabolism were analyzed through third-generation sequencing and second-generation sequencing. Of these genes, 57 were associated with the synthesis of the terpenoid skeleton, and 19 belonged to terpenoid synthase, including four monoterpenoid synthases, seven sesquiterpenoid synthases, and eight diterpenoid synthases. Two genes in diterpenoid synthase were differentially expressed in high D-borneol and low D-borneol plants. It was speculated that these two genes might be related to D-borneol synthesis. How these two genes participate in the synthesis of D-borneol needs further study.
Immunostimulatory Activities of Theobromine on Macrophages via the Activation of MAPK and NF-κB Signaling Pathways
Authors: Lee Hee-Weon , Choi In-Wook , Ha Sang Keun
Published: September 2022

Theobromine is mainly found in plant foods, such as tea; the primary source of theobromine is the seeds of the Theobroma cacao tree. Theobromine is an alkaloid belonging to the methylxanthine class of drugs, and it is similar to theophylline and caffeine. Theobromine is known for its efficacy and role in health and disorder prevention. We evaluated the effects of theobromine on macrophage function, including the phosphorylation of mitogen-activated protein kinases (MAPKs) and nuclear factor-kappa B (NF-κB). Theobromine significantly stimulated the production of nitric oxide (NO) and prostaglandin E2 through immune responses, which relate to the increased expression of inducible nitric oxide synthase and cyclooxygenase-2. Additionally, theobromine increased the production of inflammatory cytokines, including tumor necrosis factor-α and interleukin-6 in macrophages. Additionally, theobromine induced the translocation and activity of NF-κB in a concentration-dependent manner. Consistent with these results, the phosphorylation level of MAPKs was increased in theobromine-stimulated macrophages. Collectively, these data revealed that theobromine acts as an immune response stimulator via the NF-κB and MAPKs signaling pathways. Thus, theobromine might have protective effects against inflammatory disorders.
Plasma-Sprayed Hydroxyapatite Coatings and Their Biological Properties
Authors: Kowalski Szymon , Gonciarz Weronika , Belka Radosław , Góral Anna , Chmiela Magdalena , Lechowicz Łukasz , Kaca Wiesław , Żórawski Wojciech
Published: September 2022

Air plasma spraying (APS) is a common method of producing hydroxyapatite (HA) coatings for alloprosthetic implants. Modification of HA spraying potentially may diminish the risk of inflammation and local infection during bone implantation. Titanium implants were HA coated with different deposition process parameters. HA powder was deposited using APS with axial powder injection at three different distances (100, 120, and 140 mm). The surface morphology of each implant was examined and the direct contact cytotoxicity of each HA coating was evaluated according to norm ISO 10993 5:2009. The response of monocytes to HA was assessed via the activation of transcription nuclear factor. All coatings had a lamellar structure. HA sprayed at a distance of 120 mm showed the highest roughness and little phase change. The analysis of the results of the conducted research showed that plasma-spraying distance during the HA coating process had a negligible impact on biocompatibility. The results obtained for a distance of 120 mm showed a slight increase in the biological properties tested. Moreover, HA coatings sprayed at different distances were not cytotoxic and did not stimulate the NF-kB. Bare titanium was less susceptible to colonization by Staphylococcus aureus than HA-coated surfaces. HA constitutes a potentially good, low-cost, non-cytotoxic material for joint prostheses.
Fault Diagnosis of Check Valve Based on KPLS Optimal Feature Selection and Kernel Extreme Learning Machine
Authors: Yuan Xuyi , Fan Yugang , Zhou Chengjiang , Wang Xiaodong , Zhang Guanghui
Published: September 2022

The check valve is the core part of high-pressure diaphragm pumps. It has complex operation conditions and has difficulty characterizing fault states completely with its single feature. Therefore, a fault signal diagnosis model based on the kernel extreme learning machine (KELM) was constructed to diagnose the check valve. The model adopts a multi-feature extraction method and reduces dimensionality through kernel partial least squares (KPLS). Firstly, we divided the check valve vibration signal into several non-overlapping samples. Then, we extracted 16 time-domain features, 13 frequency-domain features, 16 wavelet packet energy features, and energy entropy features from each sample to construct a multi-feature set characterizing the operation state of the check valve. Next, we used the KPLS method to optimize the 45 dimension multi-feature data and employed the processed feature set to establish a KELM fault diagnosis model. Experiments showed that the method based on KPLS optimal feature selection could fully characterize the operating state of the equipment with an accuracy rate of 96.88%. This result indicates the high accuracy and effectiveness of the multi-feature set constructed with the KELM fault diagnosis model.
Effect of the Surface States of 1Cr18Ni9Ti Stainless Steel on Mn-Based Brazing Alloy Wetting
Authors: Zhang Chenghao , Chen Huize , Yang Weipeng , Zhang Qinlian , Yang Bo , Hu Yazhen , Li Chun , Gao Dejun , Si Xiaoqing , Qi Junlei , Cao Jian
Published: September 2022

The wetting properties of the brazing filler on the substrates play an important role in achieving a reliable joint. In this work, the wetting behaviour of the Mn-based brazing alloy on the surface of 1Cr18Ni9Ti stainless steel is investigated. First, surface treatment was adopted to prepare four different surface states on the stainless steel, including polished, acid treatment, nickel coating, and sandblasting. The surface morphology with nickel coating shows micro-and nano-scale protrusions, forming a uniform 3D Ni layer. The surface roughness of substrates increases after sandblasting treatment. It is found that the wetting angle of brazing alloy on the Ni coated substrates decreases noticeably. After sandblasting, the high roughness speeds up the wetting spread of the brazing alloy at the initial stage. The effect of heating temperature and holding time is also studied systematically. With the increase in holding time, the height of the melting brazing alloy decreases slightly on the sample surfaces. Based on the characterization of the joint section, the Ni layer dissolves into the melting brazing alloy. The diffusion and dissolving are indicated between the brazing alloy and substrates, forming a reliable bond.