bluuebunny/crossref_metadata_2025 huggingface dataset:
Prognostic nutritional index is an independent prognostic factor for older patients aged ≥ 85 years treated by gastric endoscopic submucosal dissection
Authors: Toya Yosuke , Endo Masaki , Akasaka Risaburo , Morishita Toshifumi , Yanai Shunichi , Nakamura Shotaro , Eizuka Makoto , Sugimoto Ryo , Uesugi Noriyuki , Sugai Tamotsu , Matsumoto Takayuki
Published: August 2021

Background

Clinical outcomes and prognostic factors for survival after endoscopic submucosal dissection (ESD) in older patients aged ≥ 85 years with early gastric cancer (EGC) are not well defined. The aim of this study was to investigate the clinical outcomes and prognostic factors for survival after ESD in older patients aged ≥ 85 years with EGC.

Methods

Clinical outcomes of 70 patients aged ≥ 85 years with EGC treated with ESD were evaluated retrospectively. Prognostic factors for overall survival (OS) were analyzed with the Kaplan–Meier method and a Cox proportional hazards model.

Results

During the follow-up period, 33 patients died from any cause, none of whom died from gastric cancer. OS probability after 3 years was 90.0%. Univariate analyses revealed that a neutrophil/lymphocyte ratio ≥ 2.6, a prognostic nutritional index (PNI) < 42.5 and low serum albumin value (< 3.5 g/dl) were associated with poor OS. Cox multivariate analysis revealed low PNI (< 42.5) to be an independent prognostic factor associated with OS (hazard ratio; 3.40, 95% confidence interval; 1.47–7.86,P = 0.004).

Conclusions

PNI may be a useful parameter for making the decision to perform ESD for older patients aged ≥ 85 years with EGC.
Anti-proteinase 3 antineutrophil cytoplasmic antibody reflects disease activity and predicts the response to steroid therapy in ulcerative colitis
Authors: Aoyama Yuki , Inaba Tomoki , Takahashi Sakuma , Yasuhara Hisae , Hiraoka Sakiko , Morimoto Takeshi , Colvin Hugh Shunsuke , Wato Masaki , Ando Midori , Nakamura Satoko , Mizobuchi Koichi , Okada Hiroyuki
Published: August 2021

Background

Serum anti-proteinase 3 antineutrophil cytoplasmic antibody (PR3-ANCA) is a disease-specific antibody against granulomatosis with polyangiitis. PR3-ANCA is a useful serological marker for disease severity in ulcerative colitis (UC). The purpose of this study was to investigate whether PR3-ANCA levels could also predict the success of induction therapy and to compare its performance against other markers, including serum CRP and fecal hemoglobin.

Methods

This was a multicenter retrospective study. In total, 159 patients with active-phase UC underwent colonoscopy. Disease activity was measured using the Mayo endoscopic subscore (MES). PR3-ANCA positivity and the response to induction therapy, either 5-aminosalicylic acid or steroid, were assessed. PR3-ANCA, CRP, and fecal hemoglobin were measured during the active phase, and during clinical remission.

Results

Eighty-five (53.5%) of 159 patients with active UC were positive for PR3-ANCA. PR3-ANCA titers were significantly higher in the group of patients with MES 3 compared to patients with MES 1 (P = 0.002) or MES 2 (P = 0.035). Steroid therapy was administered to 56 patients with a median partial Mayo score of 7 (5–9), which is equivalent to moderate-to-severe disease activity. PR3-ANCA positivity of non-responders to steroid therapy was significantly higher than that of responders (71.9% vs, 41.7%, P = 0.030), whereas CRP and fecal hemoglobin were not predictive of steroid response. Multivariate analysis demonstrated that PR3-ANCA positivity was associated with non-response to steroid therapy (odds ratio 5.19; 95% confidence interval, 1.54–17.5; P = 0.008). Of the 37 patients treated to clinical remission who were also positive for PR3-ANCA during the active phase, 27 had an MES of ≥ 1, and 10 patients had an MES of 0. In clinical remission, the proportion of patients with MES 0 in 17 patients whose PR3-ANCA became negative was significantly higher than that in 20 patients whose PR3-ANCA remained positive (47.1% vs. 10.0%, P = 0.023).

Conclusions

PR3-ANCA not only serves as a marker of disease activity, but also predicts the failure of steroid therapy in moderate-to-severe UC.

Trial registration: This study was retrospectively registered in the UMIN Clinical Trials Registry System (000039174) on January 16, 2020.
Aerodynamic characteristics in upper airways among orthodontic patients and its association with adenoid nasopharyngeal ratios in lateral cephalograms
Authors: Feng Xin , Chen Yicheng , Cai Weihua , Lie Stein Atle , Hellén-Halme Kristina , Shi Xie-Qi
Published: August 2021

Background

Adenoid hypertrophy among orthodontic patients may be detected in lateral cephalograms. The study investigates the aerodynamic characteristics within the upper airway (UA) by means of computational fluid dynamics (CFD) simulation. Furthermore, airflow features are compared between subgroups according to the adenoidal nasopharyngeal (AN) ratios.

Methods

This retrospective study included thirty-five patients aged 9–15 years having both lateral cephalogram and cone beam computed tomography (CBCT) imaging that covered the UA region. The cases were divided into two subgroups according to the AN ratios measured on the lateral cephalograms: Group 1 with an AN ratio < 0.6 and Group 2 with an AN ratio ≥ 0.6. Based on the CBCT images, segmented UA models were created and the aerodynamic characteristics at inspiration and expiration were simulated by the CFD method for the two groups. The studied aerodynamic parameters were pressure drop (ΔP), maximum midsagittal velocity (Vms), maximum wall shear stress (Pws), and minimum wall static pressure (Pw).

Results

The maximum Vms exhibits nearly 30% increases in Group 2 at both inspiration (p = 0.013) and expiration (p = 0.045) compared to Group 1. For the other aerodynamic parameters such as ΔP, the maximum Pws, and minimum Pw, no significant difference is found between the two groups.

Conclusions

The maximum Vms seems to be the most sensitive aerodynamic parameter for the groups of cases. An AN ratio of more than 0.6 measured on a lateral cephalogram may associate with a noticeably increased maximum Vms, which could assist clinicians in estimating the airflow features in the UA.
Geographic disparities in Saskatchewan prostate cancer incidence and its association with physician density: analysis using Bayesian models
Authors: Andkhoie Mustafa , Szafron Michael
Published: August 2021

Background

Saskatchewan has one of the highest incidence of prostate cancer (PCa) in Canada. This study assesses if geographic factors in Saskatchewan, including location of where patients live and physician density are affecting the PCa incidence. First, the objective of this study is to estimate the PCa standardized incidence ratio (SIRs) in Saskatchewan stratified by PCa risk-level. Second, this study identifies clusters of higher than and lower than expected PCa SIRs in Saskatchewan. Lastly, this study identifies the association (if any) between family physician density and estimated PCa SIRs in Saskatchewan.

Methods

First, using Global Moran’s I, Local Moran’s I, and the Kuldorff’s Spatial Scan Statistic, the study identifies clusters of PCa stratified by risk-levels. Then this study estimates the SIRs of PCa and its association with family physician density in Saskatchewan using the Besag, York, and Mollie (BYM) Bayesian method.

Results

Higher than expected clusters of crude estimated SIR for metastatic PCa were identified in north-east Saskatchewan and lower than expected clusters were identified in south-east Saskatchewan. Areas in north-west Saskatchewan have lower than expected crude estimated SIRs for both intermediate-risk and low-risk PCa. Family physician density was negatively associated with SIRs of metastatic PCa (IRR: 0.935 [CrI: 0.880 to 0.998]) and SIRs of high-risk PCa (IRR: 0.927 [CrI: 0.880 to 0.975]).

Conclusions

This study identifies the geographical disparities in risk-stratified PCa incidence in Saskatchewan. The study identifies areas with a lower family physician density have a higher-than-expected incidences of metastatic and high-risk PCa. Hence policies to increase the number of physicians should ensure an equitable geographic distribution of primary care physicians to support early detection of diseases, including PCa.
A case report: pseudoxanthoma elasticum diagnosed based on ocular angioid streaks and the curative effect of Conbercept treatment
Authors: Cui Chaoxiong , Zhou Zhanyu , Zhang Yi , Sun Ding
Published: August 2021

Background

This article is a case report of pseudoxanthoma elasticum (PXE) which was diagnosed based on significant angioid streaks (AS) with choroidal neovascularization (CNV) and regain normal visual function by intravitreal injection with Conbercept.

Case presentation

A 51-year-old woman was referred to the Ophthalmology Department of Qingdao Municipal Hospital (Qingdao, China) on September 14, 2020 for metamorphopsia and loss of vision in the left eye in the preceding three days. Past history: high myopia for more than 30 years, best corrected visual acuity (BCVA) of both eyes was 1.0 (5 m Standard Logarithm Visual Acuity chart in decimal notations), hypertension for six years, and cerebral infarction two years ago, no history of ocular trauma or surgeries or similar patients in family was documented. We used methods for observation, including fundus examination, optical coherence tomography (OCT), fluorescein angiography combined with indocyanine green angiography (FFA + ICGA). Due to her symptoms and manifestations, along with the appearance of her neck skin, which resembled ‘chicken skin’, we speculated that she should be further examined at the Department of Dermatology by tissue paraffin section and molecular pathology analyses, and the diagnosis of PXE was then confirmed. After intravitreal injection with Conbercept (10 mg/ml, 0.2 ml, Chengdu Kanghong Biotechnologies Co., Ltd.; Chengdu, Sichuan, China) she regained her BCVA.

Conclusions

This patient regained her best corrected visual acuity through intravitreal injection with Conbercept. To the best of our knowledge, no publications are available on cases in which a vision loss and the normal visual function can be reverted by intravitreal injection with Conbercept. Although PXE is a disease with low incidence and thus no effective cure established, targeted symptomatic treatment can effectively retard the disease progression and improve visual function, such as intravitreal injection with Conbercept.
Health ambassadors in the workplace: a health promotion intervention mobilizing middle managers and RE-AIM evaluation of outcomes
Authors: Greenberg Keren L. , Donchin Milka , Leiter Elisheva , Zwas Donna R.
Published: August 2021

Background

The workplace provides an ideal setting for health promotion, as adults spend most of their day at work. Middle managers hold a strategic position to lead workplace health promotion. This study evaluates the outcomes of an intensive intervention training middle managers to promote health in the workplace.

Methods

A workshop was designed and conducted to train female middle management employees to construct, implement, and evaluate a health promotion program in their workplace. Semi-structured interviews were carried out post-intervention to assess workplace health promotion outcomes according to the RE-AIM framework, and identify variables contributing to success. Additionally, questionnaires were distributed pre and post-program assessing personal health and self-efficacy changes.

Results

Eighteen participants from 13 government offices, who serve 19,560 employees, completed the training course. Nine workplaces had workplace health promotion programs in progress 12 months after the course had ended, of which 8 made health promotion changes in organizational policy. Workplace RE-AIM scores showed that 8 workplaces were high or partial performers, and 5 were low or non-performers. Factors that increased the likelihood of successful interventions included management support, steering committee, comprehensive programming, conducting a needs assessment and flexibility in program implementation in the presence of challenges. Post course, participants reported increased health knowledge related to workplace health promotion (p < 0.001), and increased health promotion self-efficacy (p < 0.05).

Conclusions

Training and continued guidance of middle managers resulted in the design and successful implementation of workplace health promotion interventions. A RE-AIM based assessment was found to be an effective method for evaluating multi-content workplace health promotion programs.

Registered at ClinicalTrials.gov, https://www.clinicaltrials.gov, registration number:

NCT03295136, registration date: 24/09/2017.
Paradoxical effects of cigarette smoke and COPD on SARS-CoV-2 infection and disease
Authors: Tomchaney M. , Contoli M. , Mayo J. , Baraldo S. , Li S. , Cabel C. R. , Bull D. A. , Lick S. , Malo J. , Knoper S. , Kim S. S. , Tram J. , Rojas-Quintero J. , Kraft M. , Ledford J. G. , Tesfaigzi Y. , Martinez F. D. , Thorne C. A. , Kheradmand F. , Campos S. K. , Papi A. , Polverino F.
Published: August 2021

Background

How cigarette smoke (CS) and chronic obstructive pulmonary disease (COPD) affect severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection and severity is controversial. We investigated the effects of COPD and CS on the expression of SARS-CoV-2 entry receptor ACE2 in vivo in COPD patients and controls and in CS-exposed mice, and the effects of CS on SARS-CoV-2 infection in human bronchial epithelial cells in vitro.

Methods

We quantified: (1) pulmonary ACE2 protein levels by immunostaining and ELISA, and both ACE2 and/or TMPRSS2 mRNA levels by RT-qPCR in two independent human cohorts; and (2) pulmonary ACE2 protein levels by immunostaining and ELISA in C57BL/6 WT mice exposed to air or CS for up to 6 months. The effects of CS exposure on SARS-CoV-2 infection were evaluated after in vitro infection of Calu-3 cells and differentiated human bronchial epithelial cells (HBECs), respectively.

Results

ACE2 protein and mRNA levels were decreased in peripheral airways from COPD patients versus controls but similar in central airways. Mice exposed to CS had decreased ACE2 protein levels in their bronchial and alveolar epithelia versus air-exposed mice. CS treatment decreased viral replication in Calu-3 cells, as determined by immunofluorescence staining for replicative double-stranded RNA (dsRNA) and western blot for viral N protein. Acute CS exposure decreased in vitro SARS-CoV-2 replication in HBECs, as determined by plaque assay and RT-qPCR.

Conclusions

ACE2 levels were decreased in both bronchial and alveolar epithelial cells from COPD patients versus controls, and from CS-exposed versus air-exposed mice. CS-pre-exposure potently inhibited SARS-CoV-2 replication in vitro. These findings urge to investigate further the controversial effects of CS and COPD on SARS-CoV-2 infection.
Lung "holes" after cryobiopsy: a case report
Authors: Piro Roberto , Taddei Sofia , Fontana Matteo , Scelfo Chiara , Casalini Eleonora , Facciolongo Nicola
Published: August 2021

Background

Transbronchial lung cryobiopsy is a safe technique increasingly used in the study of lung diseases. Until now, only a case of pneumatocele was described but this interesting condition is probably underestimated because CT scan is routinely not performed after transbronchial lung cryobiopsies.

Case presentation

We report a case of a woman presenting two pneumatoceles after lung cryobiopsies performed for the study of an interstitial lung disease. The finding was obtained with a CT scan performed because of the appearance of hemoptysis, four days after the biopsies.

Conclusions

Small cavitations could develop after cryobiopsies in the absence of an active infection. Studies that prospectively perform CT scan of the chest in patients who have undergone these samplings could be useful to know the incidence of iatrogenic lesions.
The Elk1/MMP-9 axis regulates E-cadherin and occludin in ventilator-induced lung injury
Authors: Tao Zhao , Jie Yan , Mingru Zhang , Changping Gu , Fan Yang , Haifeng Wu , Yuelan Wang
Published: August 2021

Background

Ventilator-induced lung injury (VILI) is a common complication in the treatment of respiratory diseases with high morbidity and mortality. ETS-domain containing protein (Elk1) and Matrix metalloproteinase (MMP) 9 are involved in VILI, but the roles have not been fully elucidated. This study examined the mechanisms of the activation of MMP-9 and Elk1 regulating barrier function in VILI in vitro and in vivo.

Methods

For the in vitro study, Mouse lung epithelial cells (MLE-12) were pre-treated with Elk1 siRNA or MMP-9 siRNA for 48 h prior to cyclic stretch at 20% for 4 h. For the in vivo study, C57BL/6 mice were pre-treated with Elk1 siRNA or MMP-9 siRNA for 72 h prior to 4 h of mechanical ventilation. The expressions of Elk1, MMP-9, Tissue inhibitor of metalloproteinase 1 (TIMP-1), E-cadherin, and occludin were measured by Western blotting. The intracellular distribution of E-cadherin and occludin was shown by immunofluorescence. The degree of pulmonary edema and lung injury were evaluated by Hematoxylin–eosin (HE) staining, lung injury scores, Wet/Dry (W/D) weight ratio, total cell counts, and Evans blue dye.

Results

20% cyclic stretch and high tidal volume increases the expressions of Elk1, MMP-9, and TIMP-1, increases the ratio of MMP-9/TIMP-1, decreases the E-cadherin and occludin level. Elk1 siRNA or MMP-9 siRNA reverses the degradations of E-cadherin, occludin, and the ratio of MMP-9/TIMP-1 caused by cyclic stretch. Elk1 siRNA decreases the MMP-9 level with or not 20% cyclic stretch and high tidal volume.

Conclusions

The results demonstrate mechanical stretch damages the tight junctions and aggravates the permeability in VILI, Elk1 plays an important role in affecting the tight junctions and permeability by regulating the balance of MMP-9 and TIMP-1, thus indicating the therapeutic potential of Elk1 to treat VILI.
Entomological baseline data collection and power analyses in preparation of a mosquito swarm-killing intervention in south-western Burkina Faso
Authors: Niang Abdoulaye , Sawadogo Simon P. , Millogo Abdoul A. , Akpodiete Nwamaka O. , Dabiré Roch K. , Tripet Frederic , Diabaté Abdoulaye
Published: August 2021

Background

Insecticides are currently the main tools used to reduce the transmission of malaria; therefore, the development of resistance to insecticides in malaria vectors is of major concern for malaria control. The resistance level to pyrethroids is particularly high in the Western region of Burkina Faso and may affect the efficacy of insecticidal bed nets and indoor residual spraying. Adult mosquito swarming and other nocturnal behaviours exhibit spatial and temporal patterns that suggest potential vulnerability to targeted space spraying with effective insecticides. Indeed, targeted space-spraying against adult mosquito swarms has been used to crash mosquito populations and disrupt malaria transmission.

Methods

Prior to impact assessment of swarm killing, a baseline data collection was conducted from June to November 2016 in 10 villages divided into two areas in western Burkina Faso. The data considered both ecological and demographic characteristics to monitor the key entomological parameters.

Results

The mean number of swarms observed was 35 per village, ranging from 25 to 70 swarms according to the village. Female density in both areas varied significantly as a function of the village and the period of collection. The human biting rate was significantly affected by the period of collection and depended upon whether the collection was carried out indoors or outdoors. Averages of parity rate were high in both areas for all periods of collection, ranging from 60 to 90%. These values ranged from 80 to 100% for inseminated females. Sporozoite rates ranged between 1.6 and 7.2% depending upon the village. The molecular identification of resting and swarming mosquitoes showed the presence of the three major malaria vectors in Burkina Faso, but in different proportions for each village.

Conclusions

The distribution of the potential swarm markers and swarms in villages suggested that swarms are clustered across space, making intervention easier. Power simulations showed that the direct sampling of swarms provides the highest statistical power, thereby reducing the number of villages needed for a trial.
Cardiac amyloidosis screening using a relative apical sparing pattern in patients with left ventricular hypertrophy
Authors: Nakao Yasuhisa , Saito Makoto , Inoue Katsuji , Higaki Rieko , Yokomoto Yuki , Ogimoto Akiyoshi , Suzuki Moeko , Kawakami Hideo , Hiasa Go , Okayama Hideki , Ikeda Shuntaro , Yamaguchi Osamu
Published: August 2021

Background

Cardiac amyloidosis (CA) mimics left ventricular hypertrophy (LVH). It is treatable, but its prognosis is poor. A simple screening tool for CA would be valuable. CA is more precisely diagnosed with echocardiographic deformation parameters (e.g., relative apical sparing pattern [RASP]) than with conventional parameters. We aimed to 1) investigate incremental benefits of echocardiographic deformation parameters over established parameters for CA screening; 2) determine the resultant risk score for CA screening; and 3) externally validate the score in LVH patients.

Methods

We retrospectively studied 295 consecutive non-ischemic LVH patients who underwent detailed diagnostic tests. CA was diagnosed with biopsy or99mTc-PYP scintigraphy. The base model comprised age (≥65 years [men], ≥70 years [women]), low voltage on the electrocardiogram, and posterior wall thickness ≥ 14 mm in reference to the literature. The incremental benefit of each binarized echocardiographic parameter over the base model was assessed using receiver operating characteristic curve analysis and comparisons of the area under the curve (AUC).

Results

Fifty-four (18%) patients had CA. RASP showed the most incremental benefit for CA screening over the base model. After conducting multiple logistic regression analysis for CA screening using four variables (RASP and base model components), a score was determined (range, 0–4 points). The score demonstrated adequate discrimination ability for CA (AUC = 0.86). This result was confirmed in another validation cohort (178 patients, AUC = 0.88).

Conclusions

We developed a score incorporating RASP for CA screening. This score is potentially useful in the risk stratification and management of LVH patients.
Efficacy of radiotherapy for gastric bleeding associated with advanced gastric cancer
Authors: Lee Joongyo , Byun Hwa Kyung , Koom Woong Sub , Lee Yong Chan , Seong Jinsil
Published: August 2021

Background

Gastric bleeding negatively impacts the quality of life of patients with unresectable advanced gastric cancer and is frequently lethal. We investigated the efficacy of RT for palliation of gastric bleeding from gastric cancer and identified an optimal radiotherapy (RT) strategy.

Methods

The study analyzed 57 patients submitted to palliative RT for gastric bleeding associated with gastric cancer between January 2009 and February 2019. Changes in hemoglobin (Hb) levels were analyzed based on measurements taken before and immediately, 1 month, and 2 months after RT. Re-bleeding after RT was identified as either Hb level dropping to < 7.0 g/dL or the administration of a blood transfusion after RT.

Results

The median biologically effective dose (α/β = 10) was 37.5 Gy (range 23.6–58.5). The most common regimen was 25 Gy in five fractions. The mean Hb levels before, immediately after, 1 month, and 2 months after RT (6.6, 9.7, 10.3, and 9.7 g/dL, respectively) were significantly higher than that before RT (all p < 0.001). No significant differences in re-bleeding rates were observed according to total dose, fractional dose, and fraction number. Gastric tumor response evaluated by computed tomography within 2 months after RT showed partial responses were more frequent in patients achieving bleeding control (25.0% vs. 10.8%, p = 0.023) and overall survival was significantly improved for bleeding control within 3 months after RT (median, 15.4 vs. 10.0 weeks, p = 0.048).

Conclusions

RT was an effective modality for gastric bleeding control in gastric cancer, which can be achieved with a short course scheme with five fractions.
iGlioSub: an integrative transcriptomic and epigenomic classifier for glioblastoma molecular subtypes
Authors: Ensenyat-Mendez Miquel , Íñiguez-Muñoz Sandra , Sesé Borja , Marzese Diego M.
Published: August 2021

Background

Glioblastoma (GBM) is the most aggressive and prevalent primary brain tumor, with a median survival of 15 months. Advancements in multi-omics profiling combined with computational algorithms have unraveled the existence of three GBM molecular subtypes (Classical, Mesenchymal, and Proneural) with clinical relevance. However, due to the costs of high-throughput profiling techniques, GBM molecular subtyping is not currently employed in clinical settings.

Methods

Using Random Forest and Nearest Shrunken Centroid algorithms, we constructed transcriptomic, epigenomic, and integrative GBM subtype-specific classifiers. We included gene expression and DNA methylation (DNAm) profiles from 304 GBM patients profiled in the Cancer Genome Atlas (TCGA), the Human Glioblastoma Cell Culture resource (HGCC), and other publicly available databases.

Results

The integrative Glioblastoma Subtype (iGlioSub) classifier shows better performance (mean AUC = 95.9%) stratifying patients than gene expression (mean AUC = 91.9%) and DNAm-based classifiers (AUC = 93.6%). Also, to expand the understanding of the molecular differences between the GBM subtypes, this study shows that each subtype presents unique DNAm patterns and gene pathway activation.

Conclusions

The iGlioSub classifier provides the basis to design cost-effective strategies to stratify GBM patients in routine pathology laboratories for clinical trials, which will significantly accelerate the discovery of more efficient GBM subtype-specific treatment approaches.
Synthetic lethality and synergetic effect: the effective strategies for therapy of IDH-mutated cancers
Authors: Yao Kun , Liu Hua , Yin Jiajun , Yuan Jianmin , Tao Hong
Published: August 2021

Mutant isocitrate dehydrogenase 1/2 (mIDH1/2) gain a novel function for the conversion of α-ketoglutarate (α-KG) to oncometabolite R-2-hydroxyglutarate (R-2-HG). Two molecular entities namely enasidenib (AG-221) and ivosidenib (AG-120) targeting mIDH2 and mIDH1 respectively, have already been approved by FDA for the treatment of relapsed/refractory acute myeloid leukemia (R/R AML). However, the low responses, drug-related adverse effects, and most significantly, the clinically-acquired resistance of AG-221 and AG-120 has shown great influence on their clinical application. Therefore, searching for novel therapeutic strategies to enhance tumor sensitivity, reduce drug-related side effects, and overcome drug resistance have opened a new research field for defeating IDH-mutated cancers. As the effective methods, synthetic lethal interactions and synergetic therapies are extensively investigated in recent years for the cure of different cancers. In this review, the molecules displaying synergetic effects with mIDH1/2 inhibitors, as well as the targets showing relevant synthetic lethal interactions with mIDH1/2 are described emphatically. On these foundations, we discuss the opportunities and challenges for translating these strategies into clinic to combat the defects of existing IDH inhibitors.
GATA1-induced upregulation of LINC01503 promotes carboplatin resistance in ovarian carcinoma by upregulating PD-L1 via sponging miR-766-5p
Authors: Li Yao , Zhai Yan , Chen Yuxuan
Published: August 2021

Background

Ovarian Carcinoma (OCa) is a high-mortality malignancy derived from female reproductive system. Increasing evidence has identified long non-coding RNAs (lncRNAs) as important regulators in OCa chemoresistance. In this study, we intended to explore the role of LINC01503 in OCa resistance to carboplatin (CBP).

Methods

Gene expression was measured by reverse transcription-quantitative PCR (RT-qPCR) in OCa cells. Western blot was adopted to detect protein levels of GATA1, PD-L1, E-cadherin, N-cadherin, Vimentin, Bcl-2, Bax, cleaved caspase-3. To assess the effects of LINC01503 on the resistance of OCa cells to CBP, Cell Counting Kit-8 (CCK-8), colony formation, Transwell, and flow cytometry experiments were performed to evaluate half-maximal inhibitory concentration (IC50), cell viability, migrative and invasive ability, as well as cell apoptosis. Dual-luciferase reporter assay was employed to assess the associations between the genes.

Results

LINC01503 was upregulated in CBP-resistant OCa cells. LINC01503 knockdown reduced CBP resistance in OCa cells. Besides, GATA-binding protein 1 (GATA1) activated LINC01503 transcription in CBP-resistant OCa cells. MiR-766-5p was lowly expressed in CBP-resistant cells and confirmed as a target for LINC01503. In addition, miR-766-5p overexpression increased CBP sensitivity in OCa cells. PD-L1 was verified as the target of miR-766-5p. Besides, LINC01503 upregulated PD-L1 level by regulating miR-766-5p. Furthermore, rescue experiments showed that PD-L1 overexpression abrogated the inhibited impacts of blocking LINC01503 on CBP resistance in OCa cells.

Conclusion

GATA1-induced LINC01503 expedited CBP resistance in OCa cells via the miR-766-5p/PD-L1 axis, providing a new target for improving the efficacy of OCa chemotherapy.

Graphical Abstract
Accelerated first-in-human clinical trial of EIDD-2801/MK-4482 (molnupiravir), a ribonucleoside analog with potent antiviral activity against SARS-CoV-2
Authors: Holman Wendy , Holman Wayne , McIntosh Stacy , Painter Wendy , Painter George , Bush Jim , Cohen Oren
Published: August 2021

A recently published article described the safety, tolerability, and pharmacokinetic profile of molnupiravir (Painter et al. 2021), a novel antiviral agent with potent activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19). Here, we report an unprecedented collaboration between sponsor, contract research organization (CRO), and regulatory authorities that enabled accelerated generation of these phase I data, including administration of the first-in-human (FIH) dose of molnupiravir within 5 days of receiving regulatory approval in the United Kingdom (UK). Single and multiple ascending dose (SAD and MAD, respectively) cohorts were dosed in randomized, double-blind, and placebo-controlled fashion, with a 6:2 active-to-placebo ratio in each cohort. A food-effect (FE) cohort included 10 subjects who were randomized to receive drug in the fasted or fed state followed by the fed or fasted state to complete a fed and fasted sequence for each subject. Dose escalation decisions were accelerated and MAD cohorts were initiated prior to completion of all SAD cohorts with the provision that the total daily dose in a MAD cohort would not exceed a dose proven to be safe and well-tolerated in a SAD cohort. Dosing in healthy volunteers was completed for eight single ascending dose (SAD) cohorts, seven multiple ascending dose (MAD) cohorts, and one food-effect (FE) cohort within approximately 16 weeks of initial protocol submission to the Research Ethics Committee (REC) and Medicines and Healthcare products Regulatory Agency (MHRA). Working to standard industry timelines, the FIH study would have taken approximately 46 weeks to complete and 33 weeks to enable phase 2 dosing. Data from this study supported submission of a phase 2/3 clinical trial protocol to the US Food and Drug Administration (FDA) within 8 weeks of initial protocol submission, with FDA comments permitting phase 2 study initiation within two additional weeks. In the setting of a global pandemic, this model of collaboration allows for accelerated generation of clinical data compared to standard processes, without compromising safety.
Recreational behaviour, risk perceptions, and protective practices against ticks: a cross-sectional comparative study before and during the lockdown enforced by the COVID-19 pandemic in Romania
Authors: Borșan Silvia-Diana , Trif Sabina Ramona , Mihalca Andrei Daniel
Published: August 2021

Background

Gaining insight into the risk perceptions and the knowledge evolution of the public about emerging or changing health risks is vital for the improvement of health promotion activities. Currently, scientific evidence regarding the attitudes of the Romanian public towards ticks is scanty. This study aimed to identify how the lockdown enforced by the COVID-19 pandemic in Romania impacted the recreational behaviour, risk perceptions, and protective practices of the Romanian population regarding ticks.

Methods

A cross-sectional, nationwide web-based questionnaire was designed and distributed via social media to evaluate if, and how, the COVID-19 lockdown impacted the behaviour of the Romanian public concerning ticks. The survey was available online from 6 May until 15 May 2020, which marked the last day of the travel ban in Romania. The collected data were processed by applying both uni- and multivariate methods.

Results

Respondents reported a higher frequency of finding ticks on themselves and their dogs during the lockdown. Bathing/showering and checking the body for ticks were the two most used protective behaviours both before and during the lockdown. Nevertheless, an overall lower usage rate of protective measures was registered during the lockdown. Almost all dog owners used a form of ectoparasite control for their dogs, and only three stopped due to lockdown-associated reasons. Respondent characteristics that were found to be positively associated with risk perceptions were being female and living in peri-urban/suburban/rural environments.

Conclusions

Despite spending less time outdoors during the lockdown, more respondents reported finding ticks on themselves or their dogs. Changes in the preferences for recreational locations, rates of protective practices usage, amount of time spent in specific areas, or tick seasonal activity might have contributed to this outcome. Concerning risk groups, men of all ages, senior citizens, and rural inhabitants should be targeted by the relevant Romanian authorities when promoting local or nationwide tick awareness campaigns.

Graphical abstract
Age-related alteration in characteristics, function, and transcription features of ADSCs
Authors: Li Keya , Shi Guiying , Lei Xuepei , Huang Yiying , Li Xinyue , Bai Lin , Qin Chuan
Published: August 2021

Background and objectives

Adipose tissue-derived stem cells (ADSCs) autologous transplantation has been a promising strategy for aging-related disorders. However, the relationship between ADSCs senescence and organismal aging has not been clearly established. Therefore, we aimed at evaluating senescence properties of ADSCs from different age donors and to verify the influence of organismal aging on the proliferation and function of ADSCs in vitro, providing the theoretical basis for the clinical application of autologous ADSCs transplantation.

Methods and results

The ADSCs were obtained from 1-month-old and 20-month-old mice. The cells characteristics, functions, gene expression levels, apoptosis proportion, cell cycle, SA-β-gal staining, and transcription features were evaluated. Compared to ADSCs from 1-month-old mice, ADSCs from 20-month-old mice exhibited some senescence-associated changes, including inhibited abilities to proliferate. Moreover, differentiation abilities, cell surface markers, and cytokines secreting differed between 1M and 20M ADSCs. SA-β-Gal staining did not reveal differences between the two donor groups, while cells exhibited more remarkable age-related changes through continuous passages. Based on transcriptome analysis and further detection, the CCL7-CCL2-CCR2 axis is the most probable mechanism for the differences.

Conclusions

ADSCs from old donors have some age-related alterations. The CCL7-CCL2-CCR2 axis is a potential target for gene therapy to reduce the harmful effects of ADSCs from old donors. To improve on autologous transplantation, we would recommend that ADSCs should be cryopreserved in youth with a minimum number of passages or block CCL7-CCL2-CCR2 to abolish the effects of age-related alterations in ADSCs through the Chemokine signaling pathway.
Linking common human diseases to their phenotypes; development of a resource for human phenomics
Authors: Kafkas Şenay , Althubaiti Sara , Gkoutos Georgios V. , Hoehndorf Robert , Schofield Paul N.
Published: August 2021

Background

In recent years a large volume of clinical genomics data has become available due to rapid advances in sequencing technologies. Efficient exploitation of this genomics data requires linkage to patient phenotype profiles. Current resources providing disease-phenotype associations are not comprehensive, and they often do not have broad coverage of the disease terminologies, particularly ICD-10, which is still the primary terminology used in clinical settings.

Methods

We developed two approaches to gather disease-phenotype associations. First, we used a text mining method that utilizes semantic relations in phenotype ontologies, and applies statistical methods to extract associations between diseases in ICD-10 and phenotype ontology classes from the literature. Second, we developed a semi-automatic way to collect ICD-10–phenotype associations from existing resources containing known relationships.

Results

We generated four datasets. Two of them are independent datasets linking diseases to their phenotypes based on text mining and semi-automatic strategies. The remaining two datasets are generated from these datasets and cover a subset of ICD-10 classes of common diseases contained in UK Biobank. We extensively validated our text mined and semi-automatically curated datasets by: comparing them against an expert-curated validation dataset containing disease–phenotype associations, measuring their similarity to disease–phenotype associations found in public databases, and assessing how well they could be used to recover gene–disease associations using phenotype similarity.

Conclusion

We find that our text mining method can produce phenotype annotations of diseases that are correct but often too general to have significant information content, or too specific to accurately reflect the typical manifestations of the sporadic disease. On the other hand, the datasets generated from integrating multiple knowledgebases are more complete (i.e., cover more of the required phenotype annotations for a given disease). We make all data freely available at 10.5281/zenodo.4726713.
Sex correction improves the accuracy of clinical dopamine transporter imaging
Authors: Honkanen Emma A. , Noponen Tommi , Hirvilammi Risto , Lindholm Kari , Parkkola Riitta , Joutsa Juho , Varrone Andrea , Kaasinen Valtteri
Published: August 2021

Background

In clinical diagnostic imaging, dopamine transporter (DAT) SPECT scans are commonly evaluated using automated semiquantitative analysis software. Age correction is routinely implemented, but usually no sex correction of DAT binding is performed. Since there are sex differences in presynaptic dopaminergic function, we investigated the effect of DAT sex correction in a sample of healthy volunteers who underwent brain [123I]-FP-CIT SPECT.

Methods

Forty healthy elderly individuals (21 men and 19 women) underwent brain [123I]-FP-CIT SPECT, and each subject was examined clinically for motor and non-motor parkinsonian symptoms and signs. Regional specific DAT binding ratios (SBR = [ROI-occ]/occ) were calculated using age correction, and the results were compared to those in normal databases with and without sex correction. The level of regional abnormality was set at 2 standard deviations below the mean values of the reference databases.

Results

In the analysis without sex correction, compared to the mean ratio of the reference database, ten healthy individuals (8 men and 2 women) had abnormally low DAT binding ratios, and four individuals (3 men and 1 woman) had borderline low DAT binding ratios in at least one striatal region. When sex correction was implemented, the ratio of one individual was abnormal, and the ratio of one individual was borderline (both males). There were no clinically significant differences in motor or non-motor symptoms between healthy volunteers with abnormal and normal binding.

Conclusions

A considerable number of elderly healthy male subjects can be interpreted to be dopaminergically abnormal if no sex correction of DAT binding is performed. Sex differences in striatal dopaminergic function should be taken into account when DAT imaging is used to assist clinical diagnostics in patients with suspected neurological disorders.
Complex factors and educational tools for social change and empowerment for severely marginalized Nepalese women working in hospitality and tourism
Authors: Deagon Jay R. , Ham Miriam , Hillman Wendy
Published: August 2021

Educated and skilled women are active change agents. This paper focuses on informal hospitality education as a tool for social change and empowerment for severely marginalized Nepalese women. Studied over 18 months, a small group of women cooking for a boutique local and international tourist market in Kathmandu participated in cookery skills training. The Australian educator/researchers focused on the educational experience to uptake and retention of cookery skills and technical language. As a result of the educational intervention, changes in personal attributes and perceptions of inherent sociocultural gender roles/caste emerged. Participation in the cookery skills training program contributed partially as a catalyst that improved confidence, communication skills and exposed to the women pathways toward self-sustainability, emancipation and empowerment within an often-hostile working environment for women from severely disadvantaged backgrounds in Nepal.
Investigation and analysis of groundwater-derived damage to the Shahe ancient bridge site in Xi’an, China
Authors: Cao Jing , Mai Bingjie , Chen Hua , Li Yuhu , Wang Juanli
Published: August 2021

Earthen cultural ruins and their subsurface environments act as carriers or support for aboveground cultural heritage artefacts, and groundwater has been identified as the most important factor accelerating the destruction of ruins. In this paper, a wooden structure on the site of the Xianyang Shahe ancient bridge is taken as the research object. Through geotechnical surveys and site sample analyses, the relationship between the environment and cause of damage at the site is explored. Fluctuations in groundwater level are found to affect the movement of water and salt, thereby accelerating deterioration and allowing microbes and other soil inhabitants and plants to erode the ruins. Furthermore, strong correlations are revealed between the stratigraphy of the area and both ruin status and sample analysis results. Geotechnical investigation data are used to predict the effects of various damaging factors on long-term preservation and the underlying mechanisms and to propose feasible, long-term countermeasures for preservation studies.
Towards building a Cathodoluminescence (CL) database for pigments: characterization of white pigments
Authors: Palamara E. , Das P. P. , Nicolopoulos S. , Tormo Cifuentes L. , Kouloumpi E. , Terlixi A. , Zacharias N.
Published: August 2021

Paintings and painted surfaces are considered to be extremely complex due to their multitude of materials and thus form the basis for particularly intricate Cultural Heritage studies. The combination of Scanning Electron Microscopy (SEM) with Cathodoluminescence (CL) can serve as a powerful tool for the identification of individual pigments. SEM/CL has the potential of identifying both organic and inorganic pigments and can focus on a micrometer or even nanometer scale. The combination with Energy Dispersive Spectrometry (EDS) allows for robust, cross-checked, elemental and mineralogical characterization of pigments. In order to apply SEM/CL in a routine-based way for the identification of pigments, it is necessary to have a robust, open-access database of characteristic CL spectra of pigments. A large project has been undertaken to create such a database, focusing primarily at the pigments, both organic and inorganic, which were most commonly used from antiquity until today. In the present paper, the CL characterization of common white pigments is presented. White pigments were selected, due to their significance and frequency of use, since they were also present on the ground layers or mixed with other pigments in most of the painting layers. More specifically, the CL spectra of samples in pure form of calcite, kaolinite, lead white, zinc oxide, barium sulfate, lithopone and titanium white are presented. In all cases, the CL spectra present characteristic bands, which allow for a secure identification of the pigments. In order to facilitate comparison with other databases, EDS and RAMAN spectra are also presented. Additionally, the effect of weathering on the CL spectra was evaluated, by comparison to naturally and artificially aged samples and to pigments identified on areas of two paintings, of the 19th and 20th c., respectively. Finally, the effect of binding media was also studied, using combination of pigments with four common media: egg yolk, linseed, walnut and poppy oil. Overall, both weathering and binding media appear to cause minor differences in the occurring spectra, without preventing the identification of pigments.
α-Farnesene production from lipid by engineered Yarrowia lipolytica
Authors: Liu Yinghang , Wang Zhaoxuan , Cui Zhiyong , Qi Qingsheng , Hou Jin
Published: August 2021

Producing high value-added products from waste lipid feedstock by microbial cell factory has great advantages to minimize the pollution as well as improve the economic value of wasted oils and fats. Yarrowia lipolytica is a non-conventional oleaginous yeast and can grow on a variety of hydrophobic substrates. In this study, we explored its ability to synthesize α-farnesene, an important sesquiterpene, using lipid feedstock. Based on the α-farnesene production strain, we constructed previously, we identified that Erg12 was the key limiting factor to further increase the α-farnesene production. The α-farnesene production was improved by 35.8% through increasing the copy number of ERG12 and FSERG20 on oleic acid substrate. Expression of heterologous VHb further improved α-farnesene production by 12.7%. Combining metabolic engineering with the optimization of fermentation conditions, the α-farnesene titer and yield reached 10.2 g/L and 0.1 g/g oleic acid, respectively, in fed-batch cultivation. The α-farnesene synthesis ability on waste cooking oil and other edible oils were also explored. Compared with using glucose as carbon source, using lipid substrates obtained higher α-farnesene yield and titer, but lower by-products accumulation, demonstrating the advantage of Y. lipolytica to synthesize high value-added products using lipid feedstock.