bluuebunny/crossref_metadata_2025_split huggingface dataset:
CEBPγ facilitates lamellipodia formation and cancer cell migration through CERS6 upregulation
Authors: Shi Hanxiao , Niimi Atsuko , Takeuchi Toshiyuki , Shiogama Kazuya , Mizutani Yasuyoshi , Kajino Taisuke , Inada Kenichi , Hase Tetsunari , Hatta Takahiro , Shibata Hirofumi , Fukui Takayuki , Chen‐Yoshikawa Toyofumi Fengshi , Nagano Kazuki , Murate Takashi , Kawamoto Yoshiyuki , Tomida Shuta , Takahashi Takashi , Suzuki Motoshi 
Published: May 2021

AbstractCeramide synthase 6 (CERS6) promotes lung cancer metastasis by stimulating cancer cell migration. To examine the underlying mechanisms, we performed luciferase analysis of the CERS6 promoter region and identified the Y‐box as a cis‐acting element. As a parallel analysis of database records for 149 non–small‐cell lung cancer (NSCLC) cancer patients, we screened for trans‐acting factors with an expression level showing a correlation with CERS6 expression. Among the candidates noted, silencing of either CCAAT enhancer‐binding protein γ (CEBPγ) or Y‐box binding protein 1 (YBX1) reduced the CERS6 expression level. Following knockdown, CEBPγ and YBX1 were found to be independently associated with reductions in ceramide‐dependent lamellipodia formation as well as migration activity, while only CEBPγ may have induced CERS6 expression through specific binding to the Y‐box. The mRNA expression levels of CERS6, CEBPγ, and YBX1 were positively correlated with adenocarcinoma invasiveness. YBX1 expression was observed in all 20 examined clinical lung cancer specimens, while 6 of those showed a staining pattern similar to that of CERS6. The present findings suggest promotion of lung cancer migration by possible involvement of the transcription factors CEBPγ and YBX1.
5‐Aminolevulinic acid/sodium ferrous citrate enhanced the antitumor effects of programmed cell death‐ligand 1 blockade by regulation of exhausted T cell metabolism in a melanoma model
Authors: Hu Xin , Que Weitao , Hirano Hiroshi , Wang Zhidan , Nozawa Naoko , Ishii Takuya , Ishizuka Masahiro , Ito Hidenori , Takahashi Kiwamu , Nakajima Motowo , Tanaka Tohru , Zhu Ping , Guo Wen‐Zhi , Li Xiao‐Kang 
Published: May 2021

AbstractMitochondria are key cytoplasmic organelles. Their activation is critical for the generation of T cell proliferation and cytotoxicity. Exhausted tumor‐infiltrating T cells show a decreased mitochondrial function and mass. 5‐Aminolevulinic acid (5‐ALA), a natural amino acid that is only produced in the mitochondria, has been shown to influence metabolic functions. We hypothesized that 5‐ALA with sodium ferrous citrate (SFC) might provide metabolic support for tumor‐infiltrating T cells. In a mouse melanoma model, we found that 5‐ALA/SFC with a programmed cell death‐ligand 1 (PD‐L1) blocking Ab synergized tumor regression. After treatment with 5‐ALA/SFC and anti‐PD‐L1 Ab, tumor infiltrating lymphocytes (TILs) were not only competent for the production of cytolytic particles and cytokines (granzyme B, interleukin‐2, and γ‐interferon) but also showed enhanced Ki‐67 activity (a proliferation marker). The number of activated T cells (PD‐1+Tim‐3−) was also significantly increased. Furthermore, we found that 5‐ALA/SFC activated the mitochondrial functions, including the oxygen consumption rate, ATP level, and complex V expression. The mRNA levels of Nrf‐2, HO‐1, Sirt‐1, and PGC‐1α and the protein levels of Sirt‐1 were upregulated by treatment with 5‐ALA/SFC. Taken together, our findings revealed that 5‐ALA/SFC could be a key metabolic regulator in exhausted T cell metabolism and suggested that 5‐ALA/SFC might synergize with anti‐PD‐1/PD‐L1 therapy to boost the intratumoral efficacy of tumor‐specific T cells. Our study not only revealed a new aspect of immune metabolism, but also paved the way to develop a strategy for combined anti‐PD‐1/PD‐L1 cancer immunotherapy.
Clonal evidence for the development of neuroblastoma with extensive copy‐neutral loss of heterozygosity arising in a mature teratoma
Authors: Ono Rintaro , Ueno Hiroo , Yoshida Kenichi , Takahashi Satoko , Yoshihara Hiroki , Nozaki Taiki , Suzuki Koyu , Nakazawa Atsuko , Saiki Ryunosuke , Seki Masafumi , Takita Junko , Ogawa Seishi , Manabe Atsushi , Hasegawa Daisuke 
Published: May 2021

AbstractMature teratomas are usually benign tumors that rarely undergo malignant transformation. We report an advanced neuroblastoma arising in a mature teratoma of the ovary. Whole‐exome sequencing identified extensive copy‐neutral loss of heterozygosity (LOH) in both neuroblastoma and teratoma elements, suggesting that the neuroblastoma evolved from the teratoma. In addition, several truncating germline heterozygous variants in tumor suppressor genes, including RBL2 and FBXW12, became homozygous as a result of LOH. Collectively, we speculate that extensive LOH in teratoma cells may force heterozygous germline variants to become homozygous, which, in turn, may contribute to the development of neuroblastoma with the acquisition of additional chromosomal changes.
Casp8 acts through A20 to inhibit PD‐L1 expression: The mechanism and its implication in immunotherapy
Authors: Zou Jiahuan , Xia Hongwei , Zhang Chenliang , Xu Huanji , Tang Qiulin , Zhu Gongmin , Li Jielang , Bi Feng 
Published: May 2021

AbstractImmunotherapy targeting the PD‐L1/PD‐1 pathway is a novel type of clinical cancer treatment, but only small subsets of patients can benefit from it because of multiple factors. PD‐L1/PD‐1 expression is a biomarker for predicting the efficacy of anti‐PD‐L1/PD‐1 therapy, which highlights the importance of understanding the regulatory mechanisms of PD‐L1 expression in cancer cells. Casp8 is an apical caspase protease involved in mediating cell apoptosis, but it also has multiple nonapoptotic functions. Casp8 mutations are associated with increased risks of cancer, and low expression of Casp8 is closely connected with poor prognosis in patients with cancer. In addition, mutations of Casp8 in lymphocytes also lead to human immunodeficiency, thereby causing dysfunction of the innate immune system, but the roles of Casp8 in antitumor immunity remain unclear. Here, we found that knocking down Casp8 in mouse melanoma cells promoted tumor progression in an immune system–dependent manner. Mechanistically, Casp8 induced PD‐L1 degradation by upregulating TNFAIP3 (A20) expression, a ubiquitin‐editing enzyme that results in PD‐L1 ubiquitination. In addition, compared with Casp8fl/fl mice, mice with conditional deletion of Casp8 in natural killer (NK) cells (Ncr1iCre/+Casp8fl/fl mice) showed a decreased frequency of IFN‐γ+ and CD107a+ NK cells but an increased frequency of PD‐1+ and CTLA‐4+ NK cells. Melanoma cells with Casp8 knocked down exhibited sensitivity to anti‐PD‐1 or anti‐CTLA‐4 antibody treatments, particularly in Ncr1iCre/+Casp8fl/fl mice. Together, the results indicate that Casp8 induces PD‐L1 degradation by upregulating A20 expression and that decreased Casp8 expression is a potential biomarker for predicting the sensitivity to anti‐PD‐L1/PD‐1 immunotherapy.
Serum and urine free light chains measurements in patients with systemic sclerosis: novel biomarkers for disease activity
Authors: Gigante Antonietta , Pellicano Chiara , Leodori Giorgia , Napodano Cecilia , Vantaggio Lorenzo , Gulli Francesca , Marino Mariapaola , Visentini Marcella , Rosato Edoardo , Basile Umberto 
Published: May 2021

Summary
Circulating free light chains (FLCs), considered biomarkers of B cell activity, are frequently elevated in patients affected by systemic inflammatory autoimmune diseases. As the systemic sclerosis (SSc) clinical course can be variable, this study is aimed at evaluating FLCs levels in affected individuals as biomarkers of disease activity. We assessed FLC levels in serum and urine of 72 SSc patients and 30 healthy controls (HC). Results were analyzed in comparison with overall clinical and laboratory findings, disease activity index (DAI) and disease severity scale (DSS). SSc patients displayed increased levels of κ and λ FLC in serum significantly higher than HC (p = 0.0001) alongside the mean values of free κ/λ ratio and κ + λ sum (p = 0.0001). SSc patients showed increased free κ in urine with a κ/λ higher than HC (p = 0.0001). SSc patients with increased κ + λ in serum showed that erythro-sedimentation rate (p = 0.034), C-reactive protein (p = 0.003), DAI (p = 0.024) and DSS (p = 0.015) were higher if compared to SSc patients with normal levels of FLC. A positive linear correlation was found between serum levels of free κ and DAI (r = 0.29, p = 0.014). In addition, SSc patients with increased free κ in urine had higher DAI (p = 0.048) than SSc patients with normal κ levels. Our results strengthen the role of serum FLC as useful biomarker in clinical practice to early diagnosis and monitor disease activity, showing for the first time that also urine FLC levels correlated with disease activity in SSc patients.
Increased interdigitation zone visibility on optical coherence tomography following systemic fibroblast growth factor receptor 1‐3 tyrosine kinase inhibitor anticancer therapy
Authors: Charng Jason , Attia Mary S. , Arunachalam Sukanya , Lam Wei‐Sen , Creaney Jenette , Muruganandan Sanjeevan , Read Catherine , Millward Michael , Spiro Jon , Chakera Aron , Lee Y. C. Gary , Nowak Anna K. , Chen Fred K. 
Published: May 2021

AbstractBackgroundTo describe ocular adverse events and retinal changes during fibroblast growth factor receptor (FGFR) inhibitor (AZD4547) anticancer therapy.MethodsThis is a sub‐study examining ocular adverse effects from AZD4547 therapy (single‐centre, open‐label, single arm phase II clinical trial). Comprehensive ocular examinations were performed 3 weekly in 24 patients. Macular optical coherence tomography (OCT) scan (300 × 250) was obtained at each visit and OCT parameters [central 1 mm retinal thickness (CRT) and total macular volume in central 6 mm] extracted. OCT scans were subdivided into outer (ELM to RPE) and inner (ELM to ILM) layers to compare outer and inner retinal changes.ResultsIn 24 patients, AZD4547 was associated with eyelash elongation (n = 5, 21%) and punctate corneal erosion (n = 2, 8%). One patient developed clinically significant posterior capsular opacification during the study. OCT data were available in 23 patients, retinal changes ranged from an asymptomatic increased visibility of the interdigitation zone (IDZ) (n = 10, 43%) to multilobular subretinal fluid pockets (n = 5, 22%), which was associated with mild visual acuity loss. In a subset of patients (n = 9) with pre‐AZD4547 dosing OCT baseline, CRT increased by mean (SD) of 9 (4) μm in those with IDZ change only compared with 64 (38) μm in those with other retinal changes. Retinal changes tended to be bilateral, self‐limiting and improved over time without medical intervention.ConclusionsThe ocular signs and symptoms did not result in dose cessation. Posteriorly, FGFR inhibition leads to outer retinal changes ranging from increased visibility of IDZ to distinct, multiple fluid pockets.
Characteristics, natural evolution and surgical treatment outcomes of unilateral laryngeal paralysis versus ankylosis: A longitudinal cohort study
Authors: Lisan Quentin , Couineau Florent , Laccourreye Ollivier 
Published: May 2021

AbstractAimsAlthough unilateral laryngeal immobility (ULI) can results from paralysis or ankylosis of the cricoarytenoid joint, no comparative study exists to date. Aim of this study was to compare clinical features, aetiologies, spontaneous recovery and evolution after surgical treatment of ULI according to its mechanism.MethodologyLongitudinal observational cohort study between 1992 and 2017 in a tertiary care referral centre and university teaching hospital. All adult patients with isolated ULI were included. Presenting symptoms and demographic data were recorded at baseline. During follow‐up, natural recovery and, if a surgical treatment was performed, treatment failure rate were noted.Results994 patients were included, 56.4% of male and with a mean age of 58 years. Overall, 91% had paralysis and 9% had ankylosis. Dysphonia was the main symptom in both groups (>96%). Dyspnoea was more frequent in patients with ankylosis (26.1% vs 4.2% in those with paralysis) whereas dysphagia was more frequent in those with paralysis (31.1% vs 20% in those with ankylosis). With a mean follow‐up of 2.3 years (±5.1), spontaneous recovery did not differ according to ULI’s aetiology (hazard ratio 1.43, 95% confidence interval 0.85‐2.40). Overall, 37.1% underwent a surgical treatment, and paralysis was associated with a lower odd of treatment failure (hazard ratio 0.27, 95% confidence interval 0.10‐0.70) over a mean follow‐up of 3.1 years (±4.1).ConclusionULI resulting from paralysis or ankylosis differ in their symptoms and responses to surgical treatment, whereas natural evolution was similar.
Patterns of positive patch test reactions to formaldehyde and formaldehyde releasers at the Finnish Institute of Occupational Health from 2007 to 2020
Authors: Aalto‐Korte Kristiina , Pesonen Maria 
Published: May 2021

AbstractBackgroundFormaldehyde is an important contact sensitizer. Formaldehyde releasing substances induce positive reactions in formaldehyde‐allergic patients, but there are also reactions independent of formaldehyde allergy. In an earlier study, stronger formaldehyde reactions led to more positive reactions to quaternium‐15.ObjectivesTo analyze patterns of positive patch test reactions to formaldehyde and different formaldehyde releasers.MethodsPatch test files of 1497 patients investigated during the period November 2007–August 2020 were retrospectively reviewed for positive reactions to formaldehyde and its releasers. During the study period, almost all (≥99.3%) patients were tested with a formaldehyde dilution series and six formaldehyde releasers.ResultsNinety‐three patients tested positive to formaldehyde; 80% of these had positive reactions to at least one formaldehyde releaser, most often benzylhemiformal. There were only nine independent contact allergies to formaldehyde releasers. There were only two reactions to 2‐bromo‐2‐nitropropane‐1,3‐diol and they occurred in formaldehyde‐negative patients. In patients with extreme (+++) reactions to formaldehyde, concomitant positive reactions to any of the other 11 investigated formaldehyde releasers were more common than in patients with milder formaldehyde reactions.ConclusionsStrong formaldehyde reactions were associated with positive reactions to formaldehyde releasers.
Complete mesocolic excision versus conventional surgery for colon cancer: A systematic review and meta‐analysis
Authors: Crane Jasmine , Hamed Mazin , Borucki Joseph P. , El‐Hadi Ahmed , Shaikh Irshad , Stearns Adam T 
Published: May 2021

AbstractAimComplete mesocolic excision (CME) lacks consistent data advocating operative superiority compared to conventional surgery for colon cancer. We performed a systematic review and meta‐analysis, analysing population characteristics and perioperative, pathological and oncological outcomes.MethodsD3 extended lymphadenectomy dissection was considered comparable to CME, and D2 and D1 dissection to be comparable to conventional surgery. Outcomes reviewed included lymph node yield, R1 resection, overall complications, overall survival and disease‐free survival.ResultsIn all, 3039 citations were identified; 148 studies underwent full‐text reviews and 31 matched inclusion criteria: total cohort 26 640 patients (13 830 CME/D3 vs. 12 810 conventional). Overall 3‐ and 5‐year survival was higher in the CME/D3 group compared with conventional surgery: relative risk (RR) 0.69 (95% CI 0.51–0.93, P = 0.016) and RR 0.78 (95% CI 0.64–0.95, P = 0.011) respectively. Five‐year disease‐free survival also demonstrated CME/D3 superiority (RR 0.67, 95% CI 0.52–0.86, P < 0.001), with similar findings at 1 and 3 years. There were no statistically significant differences between the CME/D3 and conventional group in overall complications (RR 1.06, 95% CI 0.97–1.14, P = 0.483) or anastomotic leak (RR 1.02, 95% CI 0.81–1.29, P = 0.647).ConclusionsMeta‐analysis suggests CME/D3 may have a better overall and disease‐free survival compared to conventional surgery, with no difference in perioperative complications. Quality of evidence regarding survival is low, and randomized control trials are required to strengthen the evidence base.
The identification of biophysical parameters which reflect skin status following mechanical and chemical insults
Authors: Jayabal Hemalatha , Bates‐Jensen Barbara M. , Abiakam Nkemjika S. , Worsley Peter R. , Bader Dan L. 
Published: May 2021

AbstractBackgroundSkin is constantly exposed to mechanical and chemical insults, in the form of prolonged loading, overhydration or exposure to irritants. An array of non‐invasive biophysical tools has been adopted to monitor the changes in skin response. The present study aims to identify a set of robust parameters sensitive to mechanical and chemical challenges to skin integrity.Materials and methodsEleven healthy participants were recruited to evaluate the skin response following mechanical loading, tape stripping, overhydration and chemical irritation. Forearm skin responses were recorded at baseline and at three time points following the insult. Measurements included transepidermal water loss, sub‐epidermal moisture, erythema and laser Doppler imaging. Thresholds were informed by basal values, and the sensitivity of parameters to detect skin changes was evaluated.ResultsHigh degree of variability in skin response was observed with selected biophysical parameters, such as sub‐epidermal moisture, laser Doppler imaging and erythema, even in the absence of an applied insult. Temporal skin response revealed distinct response profiles during each evoked insult. Indeed, the sensitivity of the biophysical parameters was influenced by the threshold values and time point of measurement. Some statistically significant correlations were determined between the biophysical parameters.ConclusionThe study revealed that thresholds derived from single biophysical parameters were limited in detecting skin changes following insults. A complementary evaluation using combined parameters has the potential to provide a more sensitive assessment. Further research is required to identify robust biophysical parameters, to aid the early detection of skin damage in clinical settings.
Dexmedetomidine combined with midazolam infusion guided by bispectral index during bronchoscopy
Authors: Zhang Qiudi , Zhou Jun , He Qian , Guan Shuhong , Qiu Hui , Xu Xiong , Xu Qianqian , Dai Pei , Dong Dingjiao , Wang Xuemin , Zhang Sujuan 
Published: May 2021

AbstractBackgroundConscious sedation guided by bispectral index (BIS) during bronchoscopy has been proved to be a feasible approach. This study aimed to investigate the safety and efficacy of dexmedetomidine combined with midazolam for undergoing conscious sedation during bronchoscopy.MethodsThe trial was registered prior to patient enrollment at the Chinese Clinical Trial Registry. Patients were randomized into DEX group (dexmedetomidine combined with midazolam) and FEN group (fentanyl combined with midazolam). Bronchoscopy was performed under awake sedation titrated to a BIS level of 60–80. The primary endpoint was the incidence of hypoxia, the secondary endpoint was the incidence of bradycardia and hypotension, effect of sedation including satisfaction degree (VAS) of the operators and patients and patients’ willingness to undergo bronchoscopy again.ResultsA total of 222 cases in DEX group and 211 cases in FEN group completed the study. The incidence of hypoxia and tachycardia in DEX group was lower than that in FEN group (8.1% vs 14.7%, 10.4% vs 19.0%,p < 0.05), and the incidence of hypotension and bradycardia in DEX group was higher than that in FEN group (6.8% vs 0, 15.3% vs 8.1%,p < 0.05). Midazolam dosage was significantly lower in the DEX group than in the FEN group, and the duration of surgery was significantly longer in the DEX group. The differences in intraoperative discomfort of VAS score, satisfaction VAS score, and willingness rate to undergo bronchoscopy again were not statistically significant between the two groups. In addition, the proportion of “procedural interference by patient movement” in DEX group was higher than that in FEN group.ConclusionsThe conscious sedation regimen of dexmedetomidine combined with midazolam monitored by BIS is considered to be safe and effective during bronchoscopy. The occurrence of hypoxia and tachycardia was less, and the fluctuation of blood pressure and heart rate was mild, but the proportion of bradycardia in dexmedetomidine group was higher than that in fentanyl combined with midazolam group.
A randomized, double‐blind, placebo‐ and positive‐controlled crossover study of the effects of durlobactam on cardiac repolarization in healthy subjects
Authors: O’Donnell John , Maloney Kathleen , Steidler Melissa , Morrison Royce , Isaacs Robin 
Published: May 2021

AbstractDurlobactam (formerly ETX2514) is a diazabicyclooctane β‐lactamase inhibitor that inhibits class A, C, and D β‐lactamases. Sulbactam combined with durlobactam has in vitro and in vivo activity against Acinetobacter baumannii including carbapenem‐ and colistin‐resistant isolates and is being developed for treating serious infections due to A. baumannii. The effect of a single supratherapeutic dose of durlobactam on the heart rate corrected QT interval (QTc) was evaluated in healthy subjects in a placebo‐ and active‐controlled, single‐infusion, three‐way crossover study. Subjects were randomized to 1 of 6 sequences that included a single 3‐h i.v. infusion of durlobactam 4 g (supratherapeutic dose), a single 3‐h i.v. infusion of placebo, and a single 3‐h i.v. infusion of placebo plus a single oral dose of moxifloxacin 400 mg given open‐label at the end of the i.v. infusion. In each treatment period, Holter electrocardiogram (ECG) measurements were obtained from predose through 24 h post‐start of infusion. For the primary ECG end point, placebo‐corrected change‐from‐baseline corrected QT Fridericia’s formula (ΔΔQTcF), no significant change was observed with durlobactam. A concentration‐QT analysis demonstrated no significant effect of durlobactam on ECG parameters, including QT interval prolongation. Thus, durlobactam has a low risk for prolonging the QT interval and is unlikely to produce any proarrhythmic effects.