bluuebunny/crossref_metadata_2025 huggingface dataset:
Improved Transcatheter aortic valve implantation for aortic regurgitation using a new-type stent: the first preclinical experience
Authors: Kan Tong , Gu Lan , Lu Hongjiang , Cao Junxiong , Zhu Zhijun , Wu Danning , Zhu Zhidong , Chen Xiang
Published: September 2020

Background

In this study, we sought to evaluate the feasibility of improved transcatheter aortic valve implantation (TAVI) in noncalcified aortic valve by using the novel concept of double-layer ChenValve prosthesis. TAVI was initially considered as an alternative treatment for high-risk patients with aortic stenosis. However, non noncalcified aortic valve disease was considered as a contraindication to TAVI.

Methods

ChenValve prosthesis, which consisted of a self-expanding Nitinol ring, a balloon-expandable cobalt-chromium alloy stent and a biological valve, was implanted at the desired position under fluoroscopic guidance in a transapical approach through a 20F sheath in 10 goats. Aortic angiography was performed to measure the diameter of the aotic annulus and assess the performance of the artificial valve. The ultrasound was used to evaluate the regurgitation or paravalvular leakage and trans-prosthetic vascular flow velocity postoperatively. The aortogram and transthoracic echocardiography were applied to observe whether the valve stent was implanted at the desired position.

Results

ChenValve prosthesis was successfully transppical implanted in all animals. The aortogram and transthoracic echocardiography performed immediately after implantation revealed that the valve stent was implanted at the desired position. There was no significant paravalvular leakage, obstruction of coronary artery ostia, stent malpositioning or dislodgement occurred.

Conclusions

This preliminary trial with the novel double-layer ChenValve prosthesis demonstrated the feasibility of improved TAVI in noncalcified aortic valve. The mechanism of Nitinol ring-guided locating the aortic sinus enables us to anatomically correct position the artifact valve. This improved strategy seems to make the TAVI process more safe and repeatable in noncalcified aortic valve.
Catheter ablation or surgical therapy in moderate-severe tricuspid regurgitation caused by long-standing persistent atrial fibrillation. Propensity score analysis
Authors: Wang Jiangang , Li Songnan , Ye Qing , Ma Xiaolong , Zhao Yichen , Han Jie , Li Yan , Zheng Shuai , Liu Kemin , He Meng , Yu Wen , Sun Junhui , Meng Xu
Published: September 2020

Background

This study aimed to describe the mid-term outcomes of different treatments in patients with atrial fibrillation caused tricuspid regurgitation.

Methods

A retrospective study of patients diagnosed as atrial fibrillation caused moderate-severe tricuspid regurgitation undergoing ablation (n = 411) were reviewed. The surgical cohort (n = 114) underwent surgical ablation and tricuspid valve repair; the catheter cohort (n = 279) was selected from those patients who had catheter ablation.

Results

The estimated actuarial 5-year survival rates were 96.8% (95% CI: 92.95–97.78) and 92.0% (95% CI: 85.26–95.78) in the catheter and surgical cohort, respectively. Tethering height was showed as independent risk factors for recurrent atrial fibrillation and tricuspid regurgitation in both cohorts. A matched group analysis using propensity-matched was conducted after categorizing total patients by tethering height < 6 mm and ≥ 6 mm. Kaplan–Meier analysis showed in patients with tethering height < 6 mm, there were no differences in survival from mortality, stroke, recurrent atrial fibrillation and tricuspid regurgitation between two groups. In patients with tethering height ≥ 6 mm, there were significantly higher cumulative incidence of stroke (95% CI, 0.047–0.849; P = 0.029), recurrent atrial fibrillation (95% CI, 0.357–09738; P = 0.039) and tricuspid regurgitation (95% CI, 0.359–0.981; P = 0.042) in catheter group.

Conclusions

Atrial fibrillation caused tricuspid regurgitation resulted in less leaflets coaptation, which risk the recurrence of atrial fibrillation and tricuspid regurgitation. Patients whose tethering height was less than 6 mm showed satisfying improvement in tricuspid regurgitation with the restoration of sinus rhythm after catheter ablation. However, in patients with severe leaflets tethering, the results favored surgical over catheter.
Open stented elephant trunk for complicated Stanford type B aortic dissection: a single-center experience
Authors: Tie Hongtao , Kong Lingwen , Tu Zhengjie , Chen Dan , Zheng Delai , Wu Qingchen , Li Qiang
Published: September 2020

Background

Open stented elephant trunk (SET) or SET with left subclavian artery (LSCA) to left common carotid artery (LCCA) bypass is proven to a potentially alternative treatment for complicated Stanford type B aortic dissection (TBAD). In the current study, we reported our experience with ten consecutive TBAD patients who underwent open SET.

Methods

Patients with complicated TBAD underwent open SET from May 2016 to November 2018 in our institution were included. Patients’ clinical data were obtained from the electronic medical record system, and long-term clinical outcomes were collected by telephone interviews or outpatient interviews.

Results

A total of ten patients with nine males and one female were included, and the average age was 47.3 (31–65) years. Increased D-dimer and fibrinogen degradation products were observed in all patients at admission, and two patients had renal insufficiency. The average postoperative mechanical ventilation time, length of stay in intensive care unit, and postoperative hospital length of stay were 46.9 (6.7–151.2) hours, 7.7 (4–17) days, and 15.7 (10–26) days. No postoperative death occurred. Acute kidney injury and other complications were observed, and they were recovered well when discharge. In long-term follow-up, computed tomography angiography indicated that aortas were completely well remodeled, and blood supply of the brachiocephalic trunks was normal without anastomotic complications. All patients lived well.

Conclusion

SET or SET with subclavian artery correction shows satisfactory clinical outcomes, and it could be considered as an alternative treatment. Well-designed, large-scale studies with long-term follow-up are still needed.
Reporting quality of systematic reviews with moxibustion
Authors: Tian Ran , Zhang Xuan , Li Si-Yao , Aixinjueluo Qi-Ying , Lam Wai Ching , Bian Zhao-Xiang
Published: September 2020

Background

Moxibustion is one of the major interventions of Chinese medicine (CM). The systematic reviews (SRs) are essential references for evaluating the efficacy and safety of moxibustion interventions. This study aimed to assess the reporting quality of these SRs, particularly whether necessary information related to moxibustion was adequately reported.

Methods

Seven databases (including four English and three Chinese databases) were systematically searched for SRs of moxibustion that were published up to 31 December 2019. The primary analysis was to assess their reporting quality based on 27-item of the Preferred Reporting Items for SRs and Meta-Analyses (PRISMA) and 14-item of moxibustion-related information designed according to CM theory and the STandards for Reporting Interventions in Clinical Trials Of Moxibustion (STRICTOM). Descriptive statistics were also used to analyze their baseline characteristics.

Results

A total of 97 SRs of moxibustion were identified from 2011 to 2019. For 27-item of PRISMA, except item 5, 8, 16 and 23, the remaining 23 items had the reporting compliances higher than 55%, of which 2 items (item 20 and 26) were fully reporting (100%). However, for moxibustion-related information, 69.1% (67/97) SRs did not provide the specific type of moxibustion, 39.2% (38/97) lacked details regarding the materials, procedure and technique used for moxibustion, 67.0% (65/97) did not report the selection criteria of acupoints for moxibustion, 28.9% (28/97) did not provide the number or duration of treatment sessions, 69.1% (67/97) did not provide any information about safety evaluation, and 94.8% (92/97) SRs did not report the treatment environment. For 51 (55.4%) of 92 SRs that included meta-analysis, it was impossible to assess whether meta-analysis had been properly conducted due to inadequate reporting of moxibustion interventions.

Conclusion

The reporting quality of SRs of moxibustion need further improvements in terms of adequate reporting of moxibustion interventions and of moxibustion-related rationales. Reporting guideline of “PRISMA extension for moxibustion interventions” should be developed thus to improve their quality.
Early detection of Niemann-pick disease type C with cataplexy and orexin levels: continuous observation with and without Miglustat
Authors: Imanishi A. , Kawazoe T. , Hamada Y. , Kumagai T. , Tsutsui K. , Sakai N. , Eto K. , Noguchi A. , Shimizu T. , Takahashi T. , Han G. , Mishima K. , Kanbayashi T. , Kondo H.
Published: September 2020

Study objectives

Niemann-Pick type C (NPC) is an autosomal recessive and congenital neurological disorder characterized by the accumulation of cholesterol and glycosphingolipids. Symptoms include hepatosplenomegaly, vertical supranuclear saccadic palsy, ataxia, dystonia, and dementia. Some cases frequently display narcolepsy-like symptoms, including cataplexy which was reported in 26% of all NPC patients and was more often recorded among late-infantile onset (50%) and juvenile onset (38%) patients. In this current study, we examined CSF orexin levels in the 10 patients of NPC with and without cataplexy, which supports previous findings.

Methods

Ten patients with NPC were included in the study (5 males and 5 females). NPC diagnosis was biochemically confirmed in all 10 patients, from which 8 patients with NPC1 gene were identified. We compared CSF orexin levels among NPC, narcoleptic and idiopathic hypersomnia patients.

Results

Six NPC patients with cataplexy had low or intermediate orexin levels. In 4 cases without cataplexy, their orexin levels were normal. In 5 cases with Miglustat treatment, their symptoms stabilized or improved. For cases without Miglustat treatment, their conditions worsened generally. The CSF orexin levels of NPC patients were significantly higher than those of patients with narcolepsy-cataplexy and lower than those of patients with idiopathic hypersomnia, which was considered as the control group with normal CSF orexin levels.

Discussion

Our study indicates that orexin level measurements can be an early alert of potential NPC. Low or intermediate orexin levels could further decrease due to reduction in the neuronal function in the orexin system, accelerating the patients’ NPC pathophysiology. However with Miglustat treatment, the orexin levels stabilized or improved, along with other general symptoms. Although the circuitry is unclear, this supports that orexin system is indeed involved in narcolepsy-cataplexy in NPC patients.

Conclusion

The NPC patients with cataplexy had low or intermediate orexin levels. In the cases without cataplexy, their orexin levels were normal. Our study suggests that orexin measurements can serve as an early alert for potential NPC; furthermore, they could be a marker of therapy monitoring during a treatment.
FadA promotes DNA damage and progression of Fusobacterium nucleatum-induced colorectal cancer through up-regulation of chk2
Authors: Guo Pin , Tian Zibin , Kong Xinjuan , Yang Lin , Shan Xinzhi , Dong Bingzi , Ding Xueli , Jing Xue , Jiang Chen , Jiang Na , Yu Yanan
Published: September 2020

Background

Globally, colorectal cancer (CRC) affects more than 1 million people each year. In addition to non-modifiable and other environmental risk factors,Fusobacterium nucleatuminfection has been linked to CRC recently. In this study, we explored mechanisms underlying the role ofFusobacterium nucleatuminfection in the progression of CRC in a mouse model.

Methods

C57BL/6 J-Adenomatous polyposis coli (APC) Min/J mice [APC (Min/+)] were treated withFusobacterium nucleatum(109 cfu/mL, 0.2 mL/time/day, i.g., 12 weeks), saline, or FadA knockout (FadA−/−)Fusobacterium nucleatum. The number, size, and weight of CRC tumors were determined in isolated tumor masses. The human CRC cell lines HCT29 and HT116 were treated with lentiviral vectors overexpressing chk2 or silencing β-catenin. DNA damage was determined by Comet assay and γH2AX immunofluorescence assay and flow cytometry. The mRNA expression of chk2 was determined by RT-qPCR. Protein expression of FadA, E-cadherin, β-catenin, and chk2 were determined by Western blot analysis.

Results

Fusobacterium nucleatumtreatment promoted DNA damage in CRC in APC (Min/+) mice.Fusobacterium nucleatumalso increased the number of CRC cells that were in the S phase of the cell cycle. FadA−/− reduced tumor number, size, and burden in vivo. FadA−/− also reduced DNA damage, cell proliferation, expression of E-cadherin and chk2, and cells in the S phase. Chk2 overexpression elevated DNA damage and tumor growth in APC (Min/+) mice.

Conclusions

In conclusion, this study provided evidence thatFusobacterium nucleatuminduced DNA damage and cell growth in CRC through FadA-dependent activation of the E-cadherin/β-catenin pathway, leading to up-regulation of chk2.
Preferences for breast cancer prevention among women with a BRCA1 or BRCA2 mutation
Authors: Mansfield Carol A. , Metcalfe Kelly A. , Snyder Carrie , Lindeman Geoffrey J. , Posner Joshua , Friedman Sue ,   Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer, Lynch Henry T. , Narod Steven A. , Evans D. Gareth , Liede Alexander
Published: September 2020

Background

Women with a BRCA1 or BRCA2 mutation have high lifetime risks of developing breast and ovarian cancer. The decision to embark on risk reduction strategies is a difficult and personal one. We surveyed an international group of women with BRCA mutations and measured choices and sequence of breast cancer risk reduction strategies.

Methods

Women with a BRCA1/2 mutation and no previous cancer diagnosis were recruited from the US, Canada, the UK, Australia, and from a national advocacy group. Using an online survey, we asked about cancer-risk reduction preferences including for one of two hypothetical medicines, randomly assigned, and women’s recommendations for a hypothetical woman (Susan, either a 25- or 36-year-old). Sunburst diagrams were generated to illustrate hierarchy of choices.

Results

Among 598 respondents, mean age was 40.9 years (range 25–55 years). Timing of the survey was 4.8 years (mean) after learning their positive test result and 33% had risk-reducing bilateral salpingo-oophorectomy (RRBSO) and bilateral mastectomy (RRBM), while 19% had RRBSO only and 16% had RRBM only. Although 30% said they would take a hypothetical medicine, 6% reported taking a medicine resembling tamoxifen. Respondents were 1.5 times more likely to select a hypothetical medicine for risk reduction when Susan was 25 than when Susan was 36. Women assigned to 36-year-old Susan were more likely to choose a medicine if they had a family member diagnosed with breast cancer and personal experience taking tamoxifen.

Conclusions

Women revealed a willingness to undergo surgeries to achieve largest reduction in breast cancer risk, although this would not be recommended for a younger woman in her 20s. The goal of achieving the highest degree of cancer risk reduction is the primary driver for women with BRCA1 or BRCA2 mutations in selecting an intervention and a sequence of interventions, regardless of whether it is non-surgical or surgical.
Effect of antiviral therapy on the outcomes of mechanically ventilated patients with herpes simplex virus detected in the respiratory tract: a systematic review and meta-analysis
Authors: Hagel Stefan , Scherag André , Schuierer Lukas , Hoffmann Reinhard , Luyt Charles-Edouard , Pletz Mathias W. , Kesselmeier Miriam , Weis Sebastian
Published: September 2020

Background

Herpes simplex virus (HSV) is frequently detected in the respiratory tract of mechanically ventilated patients. The aim of this study was to assess current evidence to determine whether antiviral therapy is associated with better outcomes in these patients.

Methods

MEDLINE, ISI Web of Science, Cochrane Database and ClinicalTrials.gov were searched from inception to 25 May 2020. All clinical studies investigating the effects of antiviral therapy on the outcome of mechanically ventilated ICU patients in whom HSV was detected in the respiratory tract were eligible for inclusion, regardless of study design, publication status or language. Titles and abstracts were reviewed independently by two authors. If the articles seemed eligible, full-text articles were reviewed and data extracted.

We performed a random-effects meta-analysis to estimate relative risks (RRs) with corresponding 95% confidence intervals (CIs). The primary endpoint was hospital all-cause mortality.

Results

Nine studies were included in the meta-analysis (one randomized controlled trial, eight cohort studies). Antiviral treatment was associated with lower hospital mortality (with antiviral treatment, 40.6% (189 out of 465 patients); without, 52.7% (193 out of 366 patients); RR 0.74 [0.64, 0.85]; eight studies, low quality of evidence). Furthermore, antiviral treatment was associated with lower 30-day mortality (RR 0.75 [0.59, 0.94]; three studies, very low quality of evidence). We did not observe evidence for differences in ICU mortality (RR 0.73 [0.51, 1.05]; three studies, very low quality of evidence).

Conclusions

This meta-analysis of the available data shows that antiviral therapy might result in lower hospital and 30-day all-cause mortality in mechanically ventilated ICU patients who are positive for HSV in the respiratory tract. However, this result must be interpreted with great caution due to the high risk of bias and limited number of patients. Large, well-designed randomized controlled clinical trials are urgently needed.

Trial registration

The study was registered in advance on International Prospective Register of Systematic Reviews (CRD42020180053).
Influence of overdistension/recruitment induced by high positive end-expiratory pressure on ventilation–perfusion matching assessed by electrical impedance tomography with saline bolus
Authors: He Huaiwu , Chi Yi , Long Yun , Yuan Siyi , Frerichs Inéz , Möller Knut , Fu Feng , Zhao Zhanqi
Published: September 2020

Background

High positive end-expiratory pressures (PEEP) may induce overdistension/recruitment and affect ventilation–perfusion matching (VQMatch) in mechanically ventilated patients. This study aimed to investigate the association between PEEP-induced lung overdistension/recruitment and VQMatch by electrical impedance tomography (EIT).

Methods

The study was conducted prospectively on 30 adult mechanically ventilated patients: 18/30 with ARDS and 12/30 with high risk for ARDS. EIT measurements were performed at zero end-expiratory pressures (ZEEP) and subsequently at high (12–15 cmH2O) PEEP. The number of overdistended pixels over the number of recruited pixels (O/R ratio) was calculated, and the patients were divided into low O/R (O/R ratio < 15%) and high O/R groups (O/R ratio ≥ 15%). The global inhomogeneity (GI) index was calculated to evaluate the ventilation distribution. Lung perfusion image was calculated from the EIT impedance–time curves caused by 10 ml 10% NaCl injection during a respiratory pause (> 8 s). DeadSpace%, Shunt%, and VQMatch% were calculated based on lung EIT perfusion and ventilation images.

Results

Increasing PEEP resulted in recruitment mainly in dorsal regions and overdistension mainly in ventral regions. ΔVQMatch% (VQMatch% at high PEEP minus that at ZEEP) was significantly correlated with recruited pixels (r = 0.468, P = 0.009), overdistended pixels (r = − 0.666, P < 0.001), O/R ratio (r = − 0.686, P < 0.001), and ΔSpO2 (r = 0.440, P = 0.015). Patients in the low O/R ratio group (14/30) had significantly higher Shunt% and lower VQMatch% than those in the high O/R ratio group (16/30) at ZEEP but not at high PEEP. Comparable DeadSpace% was found in both groups. A high PEEP caused a significant improvement of VQMatch%, DeadSpace%, Shunt%, and GI in the low O/R ratio group, but not in the high O/R ratio group. Using O/R ratio of 15% resulted in a sensitivity of 81% and a specificity of 100% for an increase of VQMatch% > 20% in response to high PEEP.

Conclusions

Change of ventilation–perfusion matching was associated with regional overdistention and recruitment induced by PEEP. A low O/R ratio induced by high PEEP might indicate a more homogeneous ventilation and improvement of VQMatch.

Trial registration

ClinicalTrials.gov, NCT04081155. Registered on 9 September 2019—retrospectively registered.
Efficacy of tocilizumab in patients with COVID-19 ARDS undergoing noninvasive ventilation
Authors: Menzella Francesco , Fontana Matteo , Salvarani Carlo , Massari Marco , Ruggiero Patrizia , Scelfo Chiara , Barbieri Chiara , Castagnetti Claudia , Catellani Chiara , Gibellini Giorgia , Falco Francesco , Ghidoni Giulia , Livrieri Francesco , Montanari Gloria , Casalini Eleonora , Piro Roberto , Mancuso Pamela , Ghidorsi Luca , Facciolongo Nicola
Published: September 2020

Background

The severity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is extremely variable, ranging from asymptomatic patients to those who develop severe acute respiratory distress syndrome (ARDS). As for now, there are still no really effective therapies for coronavirus disease 2019 (COVID-19). Some evidences suggest that tocilizumab (TCZ) may avoid the progression of severe COVID-19. The aim of this retrospective case-control study was to analyze the efficacy and safety of TCZ in patients with COVID-19 ARDS undergoing noninvasive mechanical ventilation (NIV).

Methods

Seventy-nine consecutive patients with severe COVID-19 pneumonia and worsening acute respiratory failure (ARF) were admitted to the Pulmonology Unit of Azienda USL of Reggio Emilia-IRCCS. All patients were inflamed (elevated CRP and IL-6 levels) and received NIV at admission according to the presence of a pO2/FiO2ratio ≤ 200 mmHg. The possibility of being treated with TCZ depended on the drug availability. The primary outcome was the in-hospital mortality rate. A secondary composite outcome of worsening was represented by the patients who died in the pulmonology unit or were intubated.

Results

Out of 79 patients, 41 were treated with TCZ. Twenty-eight patients received intravenous (IV) TCZ and 13 patients received subcutaneous (SC) TCZ. In-hospital overall mortality rate was 38% (30/79 patients). The probabilities of dying and being intubated during the follow-up using Kaplan-Meier method were significantly lower in total patients treated with TCZ compared to those of patients not treated with TCZ (log-rankpvalue = 0.006 and 0.036, respectively). However, using Cox multivariate analyses adjusted for age and Charlson comorbidity index only the association with the reduced risk of being intubated or dying maintained the significance (HR 0.44, 95%CI 0.22–0.89,p = 0.022). Two patients treated with TCZ developed cavitating lung lesions during the follow-up.

Conclusions

This study shows that TCZ treatment may be effective in COVID-19 patients with severe respiratory impairment receiving NIV. More data on safety are required. Randomized controlled trials are needed to confirm these results.
Fibroblasts direct differentiation of human breast epithelial progenitors
Authors: Morsing Mikkel , Kim Jiyoung , Villadsen René , Goldhammer Nadine , Jafari Abbas , Kassem Moustapha , Petersen Ole William , Rønnov-Jessen Lone
Published: September 2020

Background

Breast cancer arises within specific regions in the human breast referred to as the terminal duct lobular units (TDLUs). These are relatively dynamic structures characterized by sex hormone driven cyclic epithelial turnover. TDLUs consist of unique parenchymal entities embedded within a fibroblast-rich lobular stroma. Here, we established and characterized a new human breast lobular fibroblast cell line against its interlobular counterpart with a view to assessing the role of region-specific stromal cues in the control of TDLU dynamics.

Methods

Primary lobular and interlobular fibroblasts were transduced to express human telomerase reverse transcriptase (hTERT). Differentiation of the established cell lines along lobular and interlobular pathways was determined by immunocytochemical staining and genome-wide RNA sequencing. Their functional properties were further characterized by analysis of mesenchymal stem cell (MSC) differentiation repertoire in culture and in vivo. The cells’ physiological relevance for parenchymal differentiation was examined in heterotypic co-culture with fluorescence-activated cell sorting (FACS)-purified normal breast primary luminal or myoepithelial progenitors. The co-cultures were immunostained for quantitative assessment of epithelial branching morphogenesis, polarization, growth, and luminal epithelial maturation. In extension, myoepithelial progenitors were tested for luminal differentiation capacity in culture and in mouse xenografts. To unravel the significance of transforming growth factor-beta (TGF-β)-mediated crosstalk in TDLU-like morphogenesis and differentiation, fibroblasts were incubated with the TGF-β signaling inhibitor, SB431542, prior to heterotypic co-culture with luminal cells.

Results

hTERT immortalized fibroblast cell lines retained critical phenotypic traits in culture and linked to primary fibroblasts. Cell culture assays and transplantation to mice showed that the origin of fibroblasts determines TDLU-like and ductal-like differentiation of epithelial progenitors. Whereas lobular fibroblasts supported a high level of branching morphogenesis by luminal cells, interlobular fibroblasts supported ductal-like myoepithelial characteristics. TDLU-like morphogenesis, at least in part, relied on intact TGF-β signaling.

Conclusions

The significance of the most prominent cell type in normal breast stroma, the fibroblast, in directing epithelial differentiation is largely unknown. Through establishment of lobular and interlobular fibroblast cell lines, we here demonstrate that epithelial progenitors are submitted to stromal cues for site-specific differentiation. Our findings lend credence to considering stromal subtleties of crucial importance in the development of normal breast and, in turn, breast cancer.
Soluble EGFR, a hepatokine, and adipsin, an adipokine, are biomarkers correlated with distinct aspects of insulin resistance in type 2 diabetes subjects
Authors: Kyohara Mayu , Shirakawa Jun , Okuyama Tomoko , Togashi Yu , Inoue Ryota , Li Jinghe , Miyashita Daisuke , Terauchi Yasuo
Published: September 2020

Background

Insulin resistance can occur in all metabolic organs including the liver, adipose tissue, and skeletal muscles. Circulating soluble epidermal growth factor receptor (soluble EGFR) and adipsin levels are altered in obese diabetic mice and are possibly correlated with insulin resistance in both mice and humans. Here, we investigated the significance of soluble EGFR and adipsin as biomarkers for insulin resistance in Japanese subjects with type 2 diabetes.

Methods

We measured the soluble EGFR and adipsin levels in sera from 47 non-diabetic subjects and 106 subjects with type 2 diabetes using enzyme-linked immunosorbent assays (ELISAs) and analyzed the correlations between the soluble EGFR or adipsin levels and metabolic parameters in type 2 diabetes subjects. We also measured the gene expression levels of Egfr and Cfd (adipsin) in the liver, adipose tissue, and skeletal muscle in mice with/without obesity or diabetes.

Results

The soluble EGFR levels were correlated with the fasting blood glucose level (P = 0.010), HOMA-IR (P = 0.035), HbA1c level (P = 0.007), HDL-cholesterol level (P = 0.044), and FIB-4 index (P = 0.017) after adjustments for age, sex, and total cholesterol levels. These factors are known to be related to hepatic insulin resistance. The serum adipsin levels were correlated with BMI (P < 0.001), waist circumference (P < 0.001), fasting serum insulin level (P = 0.001), HOMA-IR (P = 0.009), CPR-index (P = 0.045), and FIB-4 index (P = 0.007) after adjustments for age, sex and eGFR levels. Abdominal adiposity leads to the potentiation of these factors. The expression of Egfr was abundant in the liver, while Cfd was predominantly expressed in adipose tissue in mice.

Conclusions

Soluble EGFR, a hepatokine, is correlated with insulin resistance in the liver, while adipsin, an adipokine, is associated with adipose insulin resistance.

Trial registration: UMIN Clinical Trials Registry (www.umin.ac.jp), UMIN000020474. Registered 8 January 2016.
Fusobacterium nucleatum infection correlates with two types of microsatellite alterations in colorectal cancer and triggers DNA damage
Authors: Okita Yoshiki , Koi Minoru , Takeda Koki , Ross Ryan , Mukherjee Bhramar , Koeppe Erika , Stoffel Elena M. , Galanko Joseph A. , McCoy Amber N. , Keku Temitope O. , Okugawa Yoshinaga , Kitajima Takahito , Toiyama Yuji , Martens Eric , Carethers John M.
Published: September 2020

Fusobacterium nucleatum (Fn) is frequently found in colorectal cancers (CRCs). High loads of Fn DNA are detected in CRC tissues with microsatellite instability-high (MSI-H), or with the CpG island hypermethylation phenotype (CIMP). Fn infection is also associated with the inflammatory tumor microenvironment of CRC. A subtype of CRC exhibits inflammation-associated microsatellite alterations (IAMA), which are characterized by microsatellite instability-low (MSI-L) and/or an elevated level of microsatellite alterations at selected tetra-nucleotide repeats (EMAST). Here we describe two independent CRC cohorts in which heavy or moderate loads of Fn DNA are associated with MSI-H and L/E CRC respectively. We also show evidence that Fn produces factors that induce γ-H2AX, a hallmark of DNA double strand breaks (DSBs), in the infected cells.
Biomechanical conditioning of the motor unit transitory force decrease following a reduction in stimulation rate
Authors: Rakoczy Joanna , Kryściak Katarzyna , Drzymała-Celichowska Hanna , Raikova Rositsa , Celichowski Jan
Published: September 2020

Background

The biomechanical background of the transitory force decrease following a sudden reduction in the stimulation frequency under selected experimental conditions was studied on fast resistant motor units (MUs) of rat medial gastrocnemius in order to better understand the mechanisms of changes in force transmission.

Methods

Firstly, MUs were stimulated with three-phase trains of stimuli (low–high–low frequency pattern) to identify patterns when the strongest force decrease (3–36.5%) following the middle high frequency stimulation was observed. Then, in the second part of experiments, the MUs which presented the largest force decrease in the last low-frequency phase were alternatively tested under one of five conditions to analyse the influence of biomechanical factors of the force decrease: (1) determine the influence of muscle stretch on amplitude of the force decrease, (2) determine the numbers of interpulse intervals necessary to evoke the studied phenomenon, (3) study the influence of coactivation of other MUs on the studied force decrease, (4) test the presence of the transitory force decrease at progressive changes in stimulation frequency, (5) and perform mathematical analysis of changes in twitch-shape responses to individual stimuli within a tetanus phase with the studied force decrease.

Results

Results indicated that (1) the force decrease was highest when the muscle passive stretch was optimal for the MU twitch (100 mN); (2) the middle high-frequency burst of stimuli composed of at least several pulses was able to evoke the force decrease; (3) the force decrease was eliminated by a coactivation of 10% or more MUs in the examined muscle; (4) the transitory force decrease occured also at the progressive decrease in stimulation frequency; and (5) a mathematical decomposition of contractions with the transitory force decrease into twitch-shape responses to individual stimuli revealed that the force decrease in question results from the decrease of twitch forces and a shortening in contraction time whereas further force restitution is related to the prolongation of relaxation.

Conclusions

High sensitivity to biomechanical conditioning indicates that the transitory force decrease is dependent on disturbances in the force transmission predominantly by collagen surrounding active muscle fibres.
Effect of dapsone alone and in combination with intracellular antibiotics against the biofilm form of B. burgdorferi
Authors: Horowitz Richard I. , Murali Krithika , Gaur Gauri , Freeman Phyllis R. , Sapi Eva
Published: September 2020

Objective

Lyme disease is a tick-borne, multisystemic disease caused by Borrelia burgdorferi. Standard treatments for early Lyme disease include short courses of oral antibiotics but relapses often occur after discontinuation of treatment. Several studies have suggested that ongoing symptoms may be due to a highly antibiotic resistant form of B. burgdorferi called biofilms. Our recent clinical study reported the successful use of an intracellular mycobacterium persister drug used in treating leprosy, diaminodiphenyl sulfone (dapsone), in combination therapy for the treatment of Lyme disease. In this in vitro study, we evaluated the effectiveness of dapsone individually and in combination with cefuroxime and/or other antibiotics with intracellular activity including doxycycline, rifampin, and azithromycin against Borrelia biofilm forms utilizing crystal violet biofilm mass, and dimethyl methylene blue glycosaminoglycan assays combined with Live/Dead fluorescent microscopy analyses.

Results

Dapsone, alone or in various combinations with doxycycline, rifampin and azithromycin produced a significant reduction in the mass and protective glycosaminoglycan layer and overall viability of B. burgdorferi biofilm forms. This in vitro study strongly suggests that dapsone combination therapy could represent a novel and effective treatment option against the biofilm form of B. burgdorferi.
Differential diagnostic value of total alpha-synuclein assay in the cerebrospinal fluid between Alzheimer’s disease and dementia with Lewy bodies from the prodromal stage
Authors: Bousiges Olivier , Philippi Nathalie , Lavaux Thomas , Perret-Liaudet Armand , Lachmann Ingolf , Schaeffer-Agalède Caroline , Anthony Pierre , Botzung Anne , Rauch Lucie , Jung Barbara , de Sousa Paulo Loureiro , Demuynck Catherine , Martin-Hunyadi Catherine , Cretin Benjamin , Blanc Frédéric
Published: September 2020

Background

Several studies have investigated the value of alpha-synuclein assay in the cerebrospinal fluid (CSF) of Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB) patients in the differential diagnosis of these two pathologies. However, very few studies have focused on this assay in AD and DLB patients at the MCI stage.

Methods

All patients were enrolled under a hospital clinical research protocol from the tertiary Memory Clinic (CM2R) of Alsace, France, by an experienced team of clinicians. A total of 166 patients were included in this study: 21 control subjects (CS), 51 patients with DLB at the prodromal stage (pro-DLB), 16 patients with DLB at the demented stage (DLB-d), 33 AD patients at the prodromal stage (pro-AD), 32 AD patients at the demented stage (AD-d), and 13 patients with mixed pathology (AD+DLB). CSF levels of total alpha-synuclein were assessed using a commercial enzyme-linked immunosorbent assay (ELISA) for alpha-synuclein (AJ Roboscreen). Alzheimer’s biomarkers (t-Tau, P-Tau, Aβ42, and Aβ40) were also measured.

Results

The alpha-synuclein assays showed a significant difference between the AD and DLB groups. Total alpha-synuclein levels were significantly higher in AD patients than in DLB patients. However, the ROC curves show a moderate discriminating power between AD and DLB (AUC = 0.78) which does not improve the discriminating power of the combination of Alzheimer biomarkers (AUC = 0.95 with or without alpha-synuclein). Interestingly, the levels appeared to be altered from the prodromal stage in both AD and DLB.

Conclusions

The modification of total alpha-synuclein levels in the CSF of patients occurs early, from the prodromal stage. The adding of alpha-synuclein total to the combination of Alzheimer’s biomarker does not improve the differential diagnosis between AD and DLB.

Trial registration

ClinicalTrials.gov, NCT01876459 (AlphaLewyMa)
Shedding light on the role of keratinocyte-derived extracellular vesicles on skin-homing cells
Authors: Nasiri Golara , Azarpira Negar , Alizadeh Aliakbar , Goshtasbi Sanaz , Tayebi Lobat
Published: September 2020

Extracellular vesicles (EVs) are secretory lipid membranes with the ability to regulate cellular functions by exchanging biological components between different cells. Resident skin cells such as keratinocytes, fibroblasts, melanocytes, and inflammatory cells can secrete different types of EVs depending on their biological state. These vesicles can influence the physiological properties and pathological processes of skin, such as pigmentation, cutaneous immunity, and wound healing. Since keratinocytes constitute the majority of skin cells, secreted EVs from these cells may alter the pathophysiological behavior of other skin cells. This paper reviews the contents of keratinocyte-derived EVs and their impact on fibroblasts, melanocytes, and immune cells to provide an insight for better understanding of the pathophysiological mechanisms of skin disorders and their use in related therapeutic approaches.
Microparticles derived from human erythropoietin mRNA-transfected mesenchymal stem cells inhibit epithelial-to-mesenchymal transition and ameliorate renal interstitial fibrosis
Authors: Lee Mirae , Kim Seok-hyung , Jhee Jong Hyun , Kim Tae Yeon , Choi Hoon Young , Kim Hyung Jong , Park Hyeong Cheon
Published: September 2020

Background

Renal tubulointerstitial fibrosis (TIF) plays an important role in the progression of chronic kidney disease (CKD) and its pathogenesis involves epithelial-to-mesenchymal transition (EMT) upon renal injury. Recombinant human erythropoietin (rhEPO) has been shown to display novel cytoprotective effects, in part by inhibiting transforming growth factor (TGF)-β1-induced EMT. Here, we evaluated the inhibitory effects of microparticles (MPs) derived from human EPO gene-transfected kidney mesenchymal stem cells (hEPO-KMSCs) against TGF-β1-induced EMT in Madin-Darby canine kidney (MDCK) cells and against TIF in mouse kidneys with unilateral ureteral obstruction (UUO).

Methods

EMT was induced in MDCK cells by treatment with TGF-β1 (5 ng/mL) for 48 h and then inhibited by co-treatment with rhEPO (100 IU/mL), mock gene-transfected KMSC-derived MPs (MOCK-MPs), or hEPO-KMSC-derived MPs (hEPO-MPs) for a further 48 h. UUO was induced in FVB/N mice, which were then treated with rhEPO (1000 IU/kg, intraperitoneally, every other day for 1 week), MOCK-MPs, or hEPO-MPs (80 μg, intravenously). Alpha-smooth muscle actin (α-SMA), fibronectin, and E-cadherin expression were evaluated in MDCK cells and kidney tissues, and the extent of TIF in UUO kidneys was assessed by immunohistochemical staining.

Results

TGF-β1 treatment significantly increased α-SMA and fibronectin expression in MDCK cells and decreased that of E-cadherin, while co-treatment with rhEPO, MOCK-MPs, or hEPO-MPs markedly attenuated these changes. In addition, rhEPO and hEPO-MP treatment effectively decreased phosphorylated Smad2 and Smad3, as well as phosphorylated p38 mitogen-activated protein kinase (MAPK) expression, suggesting that rhEPO and rhEPO-MPs can inhibit TGF-β1-induced EMT via both Smad and non-Smad pathways. rhEPO and hEPO-MP treatment also significantly attenuated the extent of renal TIF after 1 week of UUO compared to MOCK-MPs, with hEPO-MPs significantly reducing myofibroblast and F4/80+ macrophage infiltration as well as EMT marker expression in UUO renal tissues in a similar manner to rhEPO.

Conclusions

Our results demonstrate that hEPO-MPs modulate TGF-β1-induced EMT in MDCK cells via the Smad2, Smad3, and p38 MAPK pathways and significantly attenuated renal TIF in UUO kidneys.
Maternal sevoflurane exposure affects differentiation of hippocampal neural stem cells by regulating miR-410-3p and ATN1
Authors: Zhang Yi , Wu Ziyi , Li Xingyue , Wan Yuxiao , Zhang Yinong , Zhao Ping
Published: September 2020

Background

Currently, numerous animal studies have shown that exposure to commonly used general anesthetics during pregnancy may cause neurocognitive impairment in the offspring. Reportedly, exposure to sevoflurane during mid-trimester of pregnancy can inhibit proliferation of neural stem cells (NSCs) and lead to early apoptosis. Whether exposure to sevoflurane during pregnancy affects the differentiation of NSCs remains unclear.

Methods

In the present study, pregnant rats were exposed to 3% sevoflurane once for 2 h on gestational day 14 (G14) or 3 times for 2 h on G13, G14, and G15. Next, the differentiation of NSCs was measured using neuron marker β-tubulin III and astrocyte marker glial fibrillary acidic protein (GFAP) in fetal brain tissues 24 h and 72 h after anesthesia and in hippocampus on postnatal day 28. Primary cultured rat NSCs were exposed to 4.1% sevoflurane to explore the mechanism.

Results

The results showed that during mid-trimester, multiple exposures to sevoflurane can cause premature differentiation of NSCs in developing brains of offspring and lead to long-term neuron reduction and astrocyte proliferation in hippocampus. The data from the present study indicated that repeated exposure to sevoflurane downregulated atrophin-1 (ATN1) expression and caused early differentiation of NSCs. Overexpression of ATN1 via lentivirus transfection attenuated the influence of sevoflurane. Using dual luciferase assay, ATN1 was found to be a target gene of microRNA-410-3p (miR-410-3p). MiR-410-3p suppression via lentivirus transfection recovered the ATN1 expression and differentiation of NSCs.

Conclusions

The results from the present study demonstrated that repeated exposure to sevoflurane leads to early differentiation of NSCs and long-term effects via the miR-410-3p/ATN1 pathway.
Mesenchymal stem cell-derived extracellular vesicles alter disease outcomes via endorsement of macrophage polarization
Authors: Wang Jiangmei , Xia Jie , Huang Ruoqiong , Hu Yaoqin , Fan Jiajie , Shu Qiang , Xu Jianguo
Published: September 2020

Mesenchymal stem cells (MSCs) are adult stromal cells that reside in virtually all postnatal tissues. Due to their regenerative and immunomodulatory capacities, MSCs have attracted growing attention during the past two decades. MSC-derived extracellular vesicles (MSC-EVs) are able to duplicate the effects of their parental cells by transferring functional proteins and genetic materials to recipient cells without cell-to-cell contact. MSC-EVs also target macrophages, which play an essential role in innate immunity, adaptive immunity, and homeostasis. Recent studies have demonstrated that MSC-EVs reduce M1 polarization and/or promote M2 polarization in a variety of settings. In this review, we discuss the mechanisms of macrophage polarization and roles of MSC-EV-induced macrophage polarization in the outcomes of cardiovascular, pulmonary, digestive, renal, and central nervous system diseases. In conclusion, MSC-EVs may become a viable alternative to MSCs for the treatment of diseases in which inflammation and immunity play a critical role.
Fluorescent image-guided surgery in breast cancer by intravenous application of a quenched fluorescence activity-based probe for cysteine cathepsins in a syngeneic mouse model
Authors: Suurs Frans V. , Qiu Si-Qi , Yim Joshua J. , Schröder Carolien P. , Timmer-Bosscha Hetty , Bensen Eric S. , Santini John T. , de Vries Elisabeth G. E. , Bogyo Matthew , van Dam Gooitzen M.
Published: September 2020

Purpose

The reoperation rate for breast-conserving surgery is as high as 15–30% due to residual tumor in the surgical cavity after surgery. In vivo tumor-targeted optical molecular imaging may serve as a red-flag technique to improve intraoperative surgical margin assessment and to reduce reoperation rates. Cysteine cathepsins are overexpressed in most solid tumor types, including breast cancer. We developed a cathepsin-targeted, quenched fluorescent activity-based probe, VGT-309, and evaluated whether it could be used for tumor detection and image-guided surgery in syngeneic tumor-bearing mice.

Methods

Binding specificity of the developed probe was evaluated in vitro. Next, fluorescent imaging in BALB/c mice bearing a murine breast tumor was performed at different time points after VGT-309 administration. Biodistribution of VGT-309 after 24 h in tumor-bearing mice was compared to control mice. Image-guided surgery was performed at multiple time points tumors with different clinical fluorescent camera systems and followed by ex vivo analysis.

Results

The probe was specifically activated by cathepsins X, B/L, and S. Fluorescent imaging revealed an increased tumor-to-background contrast over time up to 15.1 24 h post probe injection. In addition, VGT-309 delineated tumor tissue during image-guided surgery with different optical fluorescent imaging camera systems.

Conclusion

These results indicate that optical fluorescent molecular imaging using the cathepsin-targeted probe, VGT-309, may improve intraoperative tumor detection, which could translate to more complete tumor resection when coupled with commercially available surgical tools and techniques.
[18F]MPPF and [18F]FDG μPET imaging in rats: impact of transport and restraint stress
Authors: Buchecker Verena , Waldron Ann-Marie , van Dijk R. Maarten , Koska Ines , Brendel Matthias , von Ungern-Sternberg Barbara , Lindner Simon , Gildehaus Franz Josef , Ziegler Sibylle , Bartenstein Peter , Potschka Heidrun
Published: September 2020

Background

Stress exposure can significantly affect serotonergic signaling with a particular impact on 5-HT1A receptor expression. Positron emission tomography (PET) provides opportunities for molecular imaging of alterations in 5-HT1A receptor binding following stress exposure. Considering the possible role of 5-HT1A receptors in stress coping mechanisms, respective imaging approaches are of particular interest.

Material and methods

For twelve consecutive days, Sprague Dawley rats were exposed to daily transport with a 1 h stay in a laboratory or daily transport plus 1 h restraint in a narrow tube. Following, animals were subjected to μPET imaging with 2′-methoxyphenyl-(N-2′-pyridinyl)-p-[18F]fluoro-benzamidoethylpiperazine ([18F]MPPF) and 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG). Behavioral and biochemical parameters were analyzed to obtain additional information.

Results

In rats with repeated transport, hippocampal [18F]MPPF binding exceeded that in the naive group, while no difference in [18F]FDG uptake was detected between the groups. A transient decline in body weight was observed in rats with transport or combined transport and restraint. Thereby, body weight development correlated with [18F]MPPF binding.

Conclusions

Mild-to-moderate stress associated with daily transport and exposure to a laboratory environment can trigger significant alterations in hippocampal binding of the 5-HT1A receptor ligand [18F]MPPF. This finding indicates that utmost care is necessary to control and report transport and associated handling procedures for animals used in μPET studies analyzing the serotonergic system in order to enhance the robustness of conclusions and allow replicability of findings. In view of earlier studies indicating that an increase in hippocampal 5-HT1A receptor expression may be associated with a resilience to stress, it would be of interest to further evaluate 5-HT1A receptor imaging approaches as a candidate biomarker for the vulnerability to stress.