bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical insights into the three-dimensional anatomy of cheek teeth in alpacas based on micro-computed tomography - Part 2: Maxillary cheek teeth
Authors: Proost Kirsten , Boone Matthieu N. , Josipovic Ivàn , Pardon Bart , Chiers Koen , Vlaminck Lieven
Published: January 2022

Background

Scientific knowledge regarding alpaca dentistry is relatively limited despite its clinical implications. The present gap in available supportive data leads to limited treatment options for dental pathology in alpacas in comparison to other species. The main goal of this study was to gain novel insights into the general and pulp morphology of maxillary cheek teeth to allow development of more advanced treatment strategies in the future. Also, the risk of causing pulp exposure when floating maxillary cheek teeth was of particular interest. Concurent research focusing on the anatomy of mandibular cheek teeth has been performed accordingly. The results obtained in mandibular teeth are expected to be non-extrapolatable because of the structural differences between mandibular and maxillary teeth.

Results

Pulp morphology of maxillary cheek teeth showed great variation. A common pulp chamber was identified in 46/83 (55.4%) teeth with a mean dental age of 2 years and 7 months (± 2 years and 5 months). Pulpal segmentation was more commonly observed in teeth of increasing age. Full columnar segmentation was seen in 33/69 teeth (47.8%), whereas within-column segmentation was observed in 36/83 teeth (43.4%). Age and degree of segmentation of the pulpal tissue varied greatly according to Triadan position. Physical contact between roots of adjacent teeth was found in the majority of examined molars (range 82–94%) which resulted in morphological adaptations at the level of the root tips. The measured sub-occlusal dentinal thickness was as low as 0.46 mm above pulp horn 2 in a 14 years and 11 months old Triadan 09, emphasizing the risk of pulp exposure attributed to dental floating.

Conclusion

This study offers an objective description of age-dependent maxillary cheek teeth pulp morphology in alpacas. Current findings are of great value to provide a basis for the development of tooth-saving techniques as a treatment for dental disease in this species. Observed physical contact between the roots of different examined molars may be a facilitating factor in the spread of apical infection in chronically diseased cases. Finally, a conservative approach regarding dental floating is recommended in order to avoid iatrogenic damage to pulp tissue.
Canine transmissible venereal tumour established in immunodeficient mice reprograms the gene expression profiles associated with a favourable tumour microenvironment to enable cancer malignancy
Authors: Ke Chiao-Hsu , Tomiyasu Hirotaka , Lin Yu-Ling , Huang Wei-Hsiang , Huang Hsiao-Hsuan , Chiang Hsin-Chien , Lin Chen-Si
Published: January 2022

Background

Canine transmissible venereal tumours (CTVTs) can cross the major histocompatibility complex barrier to spread among dogs. In addition to the transmissibility within canids, CTVTs are also known as a suitable model for investigating the tumour–host immunity interaction because dogs live with humans and experience the same environmental risk factors for tumourigenesis. Moreover, outbred dogs are more appropriate than inbred mice models for simulating the diversity of human cancer development. This study built a new model of CTVTs, known as MCTVTs, to further probe the shaping effects of immune stress on tumour development. For xenotransplantation, CTVTs were first injected and developed in immunodeficient mice (NOD.CB17-Prkdcscid/NcrCrl), defined as XCTVTs. The XCTVTs harvested from NOD/SCID mice were then inoculated and grown in beagles and named mouse xenotransplantation of CTVTs (MCTVTs).

Results

After the inoculation of CTVTs and MCTVTs into immune-competent beagle dogs separately, MCTVTs grew faster and metastasized more frequently than CTVTs did. Gene expression profiles in CTVTs and MCTVTs were analysed by cDNA microarray to reveal that MCTVTs expressed many tumour-promoting genes involved in chronic inflammation, chemotaxis, extracellular space modification, NF-kappa B pathways, and focal adhesion. Furthermore, several well-known tumour-associated biomarkers which could predict tumour progression were overexpressed in MCTVTs.

Conclusions

This study demonstrated that defective host immunity can result in gene instability and enable transcriptome reprogramming within tumour cells. Fast tumour growth in beagle dogs and overexpression of tumour-associated biomarkers were found in a CTVT strain previously established in immunodeficient mice. In addition, dysregulated interaction of chronic inflammation, chemotaxis, and extracellular space modification were revealed to imply the possibly exacerbating mechanisms in the microenvironments of these tumours. In summary, this study offers a potential method to facilitate tumour progression and provide a niche for discovering tumour-associated biomarkers in cancer research.
Toxoplasma gondii infection in pet cats and their owners in northeastern China:an important public health concern
Authors: Li Xin-Tong , Wang Lu , Ding Yuan , Sun Wu-Wen
Published: January 2022

Background

Limited information about Toxoplasma gondii infection in pet cats and their owners is available in China.

Methods

In this study, blood samples were randomly collected from 306 pet cats and 397 corresponding pet owners in Jilin province, northeastern China. Sera from the pet cats and the pet owners were tested for anti-T. gondii antibodies using an modified agglutination test (MAT) and an enzyme-linked immunosorbent assay (ELISA), respectively. Moreover, the risk factors for T. gondii infection in pet cats and corresponding pet owners were explored.

Result

In total, 62 sera out of 306 examined pet cats (20.3%) and 18.1% (72/397) pet cat owners were seropositive for T. gondii, respectively. The results of statistical analysis showed that both pet cats and their owners from rural area had significantly higher T. gondii seroprevalence than those from urban area (p < 0.001). Moreover, owners of pet cas who have the knowledge of zoonotic protozoan diseases had a significantly lower T. gondii seroprevalence than those without the knowledge of zoonotic protozoan diseases (p < 0.001).

Conclusions

The present results revealed that the seroprevalence of T. gondii infection are widespread in pet cats and their owners in Jilin province, northeastern China. Residence area and understanding knowledge of zoonotic protozoan diseases are considered to be raleted to the T. gondii infection. Hence, it is necessary to highlight the dangers and protection methods of zoonotic protozoan diseases caused by pet cats, especially in rural area.
SCUBE3 downregulation modulates hepatocellular carcinoma by inhibiting CCNE1 via TGFβ/PI3K/AKT/GSK3β pathway
Authors: Xu Pan , Luo Aoran , Xiong Chuan , Ren Hong , Yan Liang , Luo Qiang
Published: January 2022

Objectives

We aimed to verify the role of signal peptide-CUB-EGF-like domain-containing protein3 (SCUBE3) in the hepatocellular carcinoma (HCC) progression.

Methods

The role of SCUBE3 in HCC cell proliferation, apoptosis, and cell cycle in vitro were detected using MTT assay, colony formation assay, 5-ethynyl-2´-deoxyuridine assay (EDU), Celigo cell counting assay, Caspase3/7 activity assay, and flow cytometry. The effect of SCUBE3 on HCC cell proliferation in vivo was inspected by a xenograft tumour model in nude mice. The related mechanisms were further studied.

Results

The level of SCUBE3 was upregulated in HCC tissues and cell lines. Knockdown of SCUBE3 inhibited proliferation, promoted apoptosis, and induced cell cycle arrest in HCC cell lines in vitro and in vivo. Screening of cell cycle-related proteins revealed that CCNL2, CDK6, CCNE1, and CCND1 exhibited a significantly different expression profile. We found that SCUBE3 may promote the proliferation of HCC cells by regulating CCNE1 expression. The pathway enrichment analysis showed that the TGFβ signalling pathway and the PI3K/AKT signalling pathway were significantly altered. Co-immunoprecipitation results showed that SCUBE3 binds to the TGFβRII receptor. SCUBE3 knockdown inhibited the PI3K/AKT signalling pathway and the phosphorylation of GSK3β to inhibit its kinase activity.

Conclusions

SCUBE3 promotes HCC development by regulating CCNE1 via TGFβ/PI3K/AKT/GSK3β pathway. In addition, SCUBE3 may be a new molecular target for the clinical diagnosis and treatment of HCC.
circCDYL2 promotes trastuzumab resistance via sustaining HER2 downstream signaling in breast cancer
Authors: Ling Yun , Liang Gehao , Lin Qun , Fang Xiaolin , Luo Qing , Cen Yinghuan , Mehrpour Maryam , Hamai Ahmed , Liu Zihao , Shi Yu , Li Juanmei , Lin Wanyi , Jia Shijie , Yang Wenqian , Liu Qiang , Song Erwei , Li Jun , Gong Chang
Published: January 2022

Background

Approximate 25% HER2-positive (HER2+) breast cancer (BC) patients treated with trastuzumab recurred rapidly. However, the mechanisms underlying trastuzumab resistance remained largely unclear.

Methods

Trastuzumab-resistant associated circRNAs were identified by circRNAs high-throughput screen and qRT-PCR in HER2+ breast cancer tissues with different trastuzumab response. The biological roles of trastuzumab-resistant associated circRNAs were detected by cell vitality assay, colony formation assay, Edu assay, patient-derived xenograft (PDX) models and orthotopic animal models. For mechanisms research, the co-immunoprecipitation, Western blot, immunofluorescence, and pull down assays confirmed the relevant mechanisms of circRNA and binding proteins.

Results

We identified a circRNA circCDYL2, which was overexpressed in trastuzumab-resistant patients, which conferred trastuzumab resistance in breast cancer cells in vitro and in vivo. Mechanically, circCDYL2 stabilized GRB7 by preventing its ubiquitination degradation and enhanced its interaction with FAK, which thus sustained the activities of downstream AKT and ERK1/2. Trastuzumab-resistance of HER2+ BC cells with high circCDYL2 could be reversed by FAK or GRB7 inhibitor. Clinically, HER2+ BC patients with high levels of circCDYL2 developed rapid recurrence and had shorter disease-free survival (DFS) and overall survival (OS) following anti-HER2 therapy compared to those with low circCDYL2.

Conclusions

circCDYL2-GRB7-FAK complex plays a critical role in maintaining HER2 signaling, which contributes to trastuzumab resistance and circCDYL2 is a potential biomarker for trastuzumab-resistance in HER2+ BC patients.
Dysbiosis of vaginal microbiota associated with persistent high-risk human papilloma virus infection
Authors: Mei Ling , Wang Tao , Chen Yueyue , Wei Dongmei , Zhang Yueting , Cui Tao , Meng Jian , Zhang Xiaoli , Liu Yuqing , Ding Lisha , Niu Xiaoyu
Published: January 2022

Background

The status of vaginal microbiota in persistent high-risk human papilloma virus (HR-HPV) infection is unclear. The present work aimed to identify the vaginal microbiota of persistent HPV infection and explore the possible underlying microbiota factors.

Methods

A total of 100 women were recruited in this study, of which 28 presented HR-HPV persistent infection (P group), 30 showed clearance of any subtype of HR-HPV (C group), and 42 had no history of any HR-HPV infection (NC group). The vaginal microbiota and the community structure of the three groups were compared based on the 16S rRNA sequencing of the V3–V4 region. The microbiota diversity and differential analysis were carried out to detect the potential factors associated with HR-HPV infection.

Results

P and C groups showed an increase of Firmicutes and Actinobacteriota but a decrease in Proteobacteria compared to the NC group. The Chao1 index indicated that the microbial richness of the NC group was greater than C group (P < 0.05).The principal co-ordinate analysis(PCoA) revealed differences between the NC and P/C groups.The linear discriminant analysis effect size (LEfSe) method indicated that Proteobacteria phylum was significantly different in the mean relative abundance in the NC group,but the P and C groups did not show such indicative taxa. The Wilcox rank-sum test indicated that the Bifidobacterium (P = 0.002) and Lactobacillus (P = 0.005) of the C group were in a high mean relative abundance compared to the NC group.

Conclusions

The persistent HR-HPV infection is associated with dysbiosis of the vaginal microbiota. Microbiome regulation with Bifidobacteria and Lactobacillus may affect the clearance of HPV.
Increased expression of six-large extracellular vesicle-derived miRNAs signature for nonvalvular atrial fibrillation
Authors: Siwaponanan Panjaree , Kaewkumdee Pontawee , Phromawan Wilasinee , Udompunturak Suthipol , Chomanee Nusara , Udol Kamol , Pattanapanyasat Kovit , Krittayaphong Rungroj
Published: January 2022

Backgrounds

Non-valvular atrial fibrillation (AF) is the most common type of cardiac arrhythmia. AF is caused by electrophysiological abnormalities and alteration of atrial tissues, which leads to the generation of abnormal electrical impulses. Extracellular vesicles (EVs) are membrane-bound vesicles released by all cell types. Large EVs (lEVs) are secreted by the outward budding of the plasma membrane during cell activation or cell stress. lEVs are thought to act as vehicles for miRNAs to modulate cardiovascular function, and to be involved in the pathophysiology of cardiovascular diseases (CVDs), including AF. This study identified lEV-miRNAs that were differentially expressed between AF patients and non-AF controls.

Methods

lEVs were isolated by differential centrifugation and characterized by Nanoparticle Tracking Analysis (NTA), Transmission Electron Microscopy (TEM), flow cytometry and Western blot analysis. For the discovery phase, 12 AF patients and 12 non-AF controls were enrolled to determine lEV-miRNA profile using quantitative reverse transcription polymerase chain reaction array. The candidate miRNAs were confirmed their expression in a validation cohort using droplet digital PCR (30 AF, 30 controls). Bioinformatics analysis was used to predict their target genes and functional pathways.

Results

TEM, NTA and flow cytometry demonstrated that lEVs presented as cup shape vesicles with a size ranging from 100 to 1000 nm. AF patients had significantly higher levels of lEVs at the size of 101–200 nm than non-AF controls. Western blot analysis was used to confirm EV markers and showed the high level of cardiomyocyte expression (Caveolin-3) in lEVs from AF patients. Nineteen miRNAs were significantly higher (> twofold, p < 0.05) in AF patients compared to non-AF controls. Six highly expressed miRNAs (miR-106b-3p, miR-590-5p, miR-339-3p, miR-378-3p, miR-328-3p, and miR-532-3p) were selected to confirm their expression. Logistic regression analysis showed that increases in the levels of these 6 highly expressed miRNAs associated with AF. The possible functional roles of these lEV-miRNAs may involve in arrhythmogenesis, cell apoptosis, cell proliferation, oxygen hemostasis, and structural remodeling in AF.

Conclusion

Increased expression of six lEV-miRNAs reflects the pathophysiology of AF that may provide fundamental knowledge to develop the novel biomarkers for diagnosis or monitoring the patients with the high risk of AF.
The exit of axons and glial membrane from the developing Drosophila retina requires integrins
Authors: Ren Qian , Rao Yong
Published: January 2022

Coordinated development of neurons and glia is essential for the establishment of neuronal circuits during embryonic development. In the developingDrosophilavisual system, photoreceptor (R cell) axons and wrapping glial (WG) membrane extend from the eye disc through the optic stalk into the optic lobe. Extensive studies have identified a number of genes that control the establishment of R-cell axonal projection pattern in the optic lobe. The molecular mechanisms directing the exit of R-cell axons and WG membrane from the eye disc, however, remain unknown. In this study, we show that integrins are required in R cells for the extension of R-cell axons and WG membrane from the eye disc into the optic stalk. Knockdown of integrins in R cells but not WG caused the stalling of both R-cell axons and WG membrane in the eye disc. Interfering with the function of Rhea (i.e. theDrosophilaortholog of vertebrate talin and a key player of integrin-mediated adhesion), caused an identical stalling phenotype. These results support a key role for integrins on R-cell axons in directing R-cell axons and WG membrane to exit the eye disc.
Long non-coding RNA lncC11orf54-1 modulates neuroinflammatory responses by activating NF-κB signaling during meningitic Escherichia coli infection
Authors: Xu Bojie , Yang Ruicheng , Yang Bo , Li Liang , Chen Jiaqi , Fu Jiyang , Qu Xinyi , Huo Dong , Tan Chen , Chen Huanchun , Peng Zhong , Wang Xiangru
Published: January 2022

Escherichia coli is the most common gram-negative pathogenic bacterium causing meningitis. It penetrates the blood–brain barrier (BBB) and activates nuclear factor kappa B (NF-κB) signaling, which are vital events leading to the development of meningitis. Long non-coding RNAs (lncRNAs) have been implicated in regulating neuroinflammatory signaling, and our previous study showed that E. coli can induce differential expression of lncRNAs, including lncC11orf54-1, in human brain microvascular endothelial cells (hBMECs). The hBMECs constitute the structural and functional basis for the BBB, however, it is unclear whether lncRNAs are involved in the regulation of inflammatory responses of hBMECs during meningitic E. coli infection. In this study, we characterized an abundantly expressed lncRNA, lncC11orf54-1, which was degraded by translocated coilin to produce mgU2-19 and mgU2-30 in hBMECs during E. coli infection. Functionally, lncC11orf54-1-originated non-coding RNA mgU2-30 interacted with interleukin-1 receptor-associated kinase 1 (IRAK1) to induce its oligomerization and autophosphorylation, thus promoting the activation of NF-κB signaling and facilitating the production of pro-inflammatory cytokines. In summary, our study uncovers the involvement of lncC11orf54-1 in IRAK1–NF-κB signaling, and it functions as a positive regulator of inflammatory responses in meningitic E. coli-induced neuroinflammation, which may be a valuable therapeutic and diagnostic target for bacterial meningitis.
High efficacy and safety of CD38 and BCMA bispecific CAR-T in relapsed or refractory multiple myeloma
Authors: Tang Yuanyan , Yin Haisen , Zhao Xinying , Jin Dan , Liang Yan , Xiong Tao , Li Lu , Tang Wen , Zhang Jiangzhao , Liu Min , Yu Zhuojun , Liu Huimin , Zang Sibin , Huang Zhiping
Published: January 2022

Background

B-cell maturation antigen (BCMA) chimeric antigen receptor T (CAR-T) cell therapy has obtained promising results in relapsed or refractory multiple myeloma (R/R MM), while some patients do not response, or relapse in short term after treatment. Combining with anti-CD38 might solve the problem of targeting BCMA alone. We aimed to assess the efficacy and safety of BCMA and CD38 (BCMA-CD38) bispecific CAR-T cells in R/R MM patients.

Methods

We did a single-center, single-arm clinical study at the Second Affiliated Hospital of Yangtze University in China. Patients meeting with the inclusion criteria were administered with fludarabine and cyclophosphamide before CAR-T cells infusion. Response and adverse events were assessed after infusion. This study was registered with the Chinese Clinical Trial Registration Center (ChiCTR1900026286).

Results

First, we found BCMA-CD38 CAR-T cells exhibited enhanced killing effect on BCMA+CD38+ cells in vitro, compared to BCMA CAR-T and CD38 CAR-T cells. We further demonstrated its anti-tumor activity in vivo. Then, we enrolled 16 R/R MM patients for safety and efficacy analyses. Of the 16 evaluable patients, 14 (87.5%) respond to the treatment, including 13 stringent complete response (sCR) and one partial response (PR), while two patients did not respond. At a median follow-up of 11.5 months, of the 13 patients who achieved sCR, 76.9% (10/13) did not relapse or progress during follow-up. Relapse occurred in 3 patients (Patient 2, 3 and 4) after achieving sCR. In sum, four patients died, of which one died of hemophagocytic lymphohistiocytosis syndrome secondary to severe cytokine release syndrome (CRS) and three died of disease progression or relapse. The 1-year progression-free survival rates was 68.8%. The 1-year overall survival rate was 75.0%. Extramedullary lesions were eliminated in 62.5% (5/8) patients. The most common symptoms after CAR-T infusion were cytopenia (16, 100%), fever (10, 62.5%), fatigue (8, 50.0%) and myalgias (8, 50.0%). Twelve patients (75.0%) were observed with various grades of CRS, of which five patients (31.3%) got serious CRS (Grade ≥ 3). The CAR+ cell expansion levels were associated with the severity of CRS. Transient clonal isotype switch was observed after CAR-T infusion.

Conclusion

Our results confirm that BCMA-CD38 CAR-T cells therapy is feasible in treating R/R MM patients, with high response rate, low recurrence rate and manageable CRS, which will be a promising treatment option for R/R MM.

Trial registration

ChiCTR1900026286, registered on September 29, 2019, retrospectively registered, URL: https://www.chictr.org.cn/showproj.aspx?proj=43805
Effect of different conditioning methods of traditional Chinese health exercise on lung function in healthy middle-aged and elderly people: study protocol for a randomized controlled trial
Authors: Li Wenlong , Song Yapei , Xiang Qiuping , Wang Xinlei , Wei Xiaoyun , Fan Tonggang
Published: January 2022

Background

Lung function is highly age-dependent as it decreases in varying degrees with age, even in healthy people. Decreased lung function results in less elastic lung tissue, reduced chest wall compliance, reduced area for gas exchange, and even a variety of chronic diseases. Traditional Chinese health exercise (TCHE) has three components: “breath regulation,” “body regulation,” and “heart regulation,” which play an important role in the improvement of lung function. However, which component has the most significant effect on lung functioning remains unclear. Therefore, depending on the modality of conditioning, TCHEs will be divided into three exercise intervention groups: breath regulation group, body regulation group, and heart regulation group, in order to explore the magnitude of the effect of the different modalities of conditioning on the improvement of lung function.

Methods

The prospective, parallel, single-blind, randomized controlled trial will evaluate the effects of different conditioning methods of TCHE on lung function in middle-aged and elderly people. The study subjects are healthy middle-aged and elderly adults, who will be randomly divided into the “breath regulation group,” “body regulation group,” “heart regulation group,” and “control group.” The control group will receive health education. Health education and exercise intervention in the three intervention groups will be provided for 6 months, 5 times a week, with each session lasting 60 min. The outcomes of interest include changes in the pulmonary function tests measured at baseline and 3 and 6 months after the beginning of the intervention. The primary outcome is the forced vital capacity (FVC), while the secondary outcomes include forced expiratory volume in 1 s (FEV1), FVC/FEV1 ratio, vital capacity (VC), and maximal voluntary ventilation (MVV).

Discussion

This study will assess the effects of different conditioning methods of TCHE on lung function in middle-aged and elderly people. The final findings of this study will validate the effectiveness and safety of TCHE on lung function interventions in middle-aged and elderly people.

Trial registration

China Clinical Trial Registry ChiCTR2100052687. Registered on November 3, 2021
Hematological malignancies in systemic lupus erythematosus: clinical characteristics, risk factors, and prognosis—a case-control study
Authors: Zhang Yuqi , Li Wei , Zhang Panpan , Guo Jinyan , Sun Jinlei , Lu Jiameng , Liu Shengyun
Published: January 2022

Background

Systemic lupus erythematosus (SLE) is a chronic and complex multi-system autoimmune disorder. Higher risks of hematological malignancies (HM) were observed in SLE patients, which was associated with higher mortality. The mechanism and risk factors of HM oncogenesis in SLE patients are still under investigation. The aim of this study was to explore clinical characteristics, risk factors, and prognosis of SLE patients with or without HM in the Chinese population.

Methods

A retrospective, case-controlled study was conducted in 72 SLE patients between January 2013 and December 2020. Clinical and laboratory data were collected and compared between the two groups of patients with HM and those without HM. Logistic regression analysis was performed to determine risk factors of HM oncogenesis. The survival rate was estimated by Kaplan-Meier methods and Cox proportional hazards regression analysis.

Results

Among 72 SLE patients in this study, fifteen complicated with HM and 57 without HM were identified. The incidence rate of HM was approximately 0.24% with elevated standardized incidence ratios of lymphoma and leukemia (27.559 and 12.708, respectively). Patients with HM were older when diagnosed with SLE, with a higher frequency of infection and splenomegaly, lower levels of hemoglobin and high-density lipoprotein compared with those without HM. Fewer patients with HM expressed positive anti-dsDNA antibody (26.7% vs 66.7%, P = 0.005) or received hydroxychloroquine treatment (40.0% vs 86.0%, P = 0.001). Older age at SLE diagnosis (OR=1.122, 95% CI: 1.037–1.214) was regarded as an independent risk factor of HM oncogenesis. Female (RR= 0.219, 95% CI: 0.070–0.681) and hydroxychloroquine (RR= 0.281, 95% CI: 0.094–0.845) were protective factors of mortality in SLE patients.

Conclusions

SLE patients with an older age are at an increased risk of HM carcinogenesis. The prognosis of male patients with SLE tends to be poorer whether complicated with HM. The association of antinuclear antibody spectrum, medication, and HM oncogenesis in SLE needs further investigation.
Hydroxychloroquine administration exacerbates acute kidney injury complicated by lupus nephritis
Authors: An Ning , Yang Chen , Wu Hong-Luan , Guo Yun , Huang Xi-Jie , Huang Tong-Sheng , Wu Zhi-Hong , Xue Jing , Chen Rui-Hong , Li Zhi-Hang , Pan Qing-Jun , Liu Hua-Feng
Published: January 2022

Background

Hydroxychloroquine (HCQ) has been recommended as a basic treatment for lupus nephritis (LN) during this decade based on its ability to improve LN-related renal immune-mediated inflammatory lesions. As a classical lysosomal inhibitor, HCQ may inhibit lysosomal degradation and disrupt protective autophagy in proximal tubular epithelial cells (PTECs). Therefore, the final renal effects of HCQ on LN need to be clarified.

Method

HCQ was administered on spontaneous female MRL/lpr LN mice with severe proteinuria daily for 4 weeks. Moreover, the MRL/lpr mice with proteinuric LN were subjected to cisplatin-induced or unilateral ischemia/reperfusion (I/R)-induced acute kidney injury (AKI) after 2 weeks of HCQ preadministration.

Results

As expected, HCQ treatment increased the survival ratio and downregulated the levels of serum creatinine in the mice with LN, ameliorated renal lesions, and inhibited renal interstitial inflammation. Unexpectedly, HCQ preadministration significantly increased susceptibility to and delayed the recovery of AKI complicated by LN, as demonstrated by an increase in PTEC apoptosis and expression of the tubular injury marker KIM-1 as well as the retardation of PTEC replenishment. HCQ preadministration suppressed the proliferation of PTECs by arresting cells in G1/S phase and upregulated the expression of cell cycle inhibitors. Furthermore, HCQ preadministration disrupted the PTEC autophagy-lysosomal pathway and accelerated PTEC senescence.

Conclusion

HCQ treatment may increase susceptibility and delay the recovery of AKI complicated by LN despite its ability to improve LN-related renal immune-mediated inflammatory lesions. The probable mechanism involves accelerated apoptosis and inhibited proliferation of PTECs via autophagy-lysosomal pathway disruption and senescence promotion.
Performance of an automated ultrasound device in identifying and tracing the heart in porcine cardiac arrest
Authors: Olszynski Paul , Marshall Rory A. , Olver T. Dylan , Oleniuk Trevor , Auser Cameron , Wilson Tracy , Atkinson Paul , Woods Rob
Published: January 2022

Background

While intra-arrest echocardiography can be used to guide and monitor chest compression quality, it is not currently feasible on the scene of out-of-hospital cardiac arrests. Rapid and automated sonographic localization of the heart may provide first-responders guidance to an optimal area of compression without requiring them to interpret ultrasound images. In this proof-of-concept porcine study, we sought to describe the performance of an automated ultrasound device in correctly identifying and tracing the borders of the heart in three distinct states: pre-arrest, arrest, and late arrest.

Methods

An automated ultrasound device (bladder scanner) was placed on the chests of 7 swine, along the left sternal border (4th–8th intercostal spaces). Scanner-generated images were recorded for each space during pre-arrest, arrest, and finally late arrest. 828 images of the LV and LV outflow tract were randomized and 150 (50/state) selected for analysis. Scanner tracings of the heart were then digitally obscured to facilitate tracing by expert reviewers who were blinded to the physiologic state. Reviewer tracings were compared to bladder scanner tracings; with concordance between these images determined via Sørensen–Dice index (SDI).

Results

When compared to human reviewers, the bladder scanner was able to identify and trace the borders during cardiac arrest. The bladder scanner performed best at the time of arrest (SDI 0.900 ± 0.059). As resuscitation efforts continued and time from initial arrest increased, the scanner’s performance decreased dramatically (SDI 0.597 ± 0.241 in late arrest).

Conclusion

An automated ultrasound device (bladder scanner) reliably traced porcine hearts during cardiac arrest. It is possible a device could be developed to indicate where compressions should be performed without requiring the operator to interpret ultrasound images. Further investigation into rapid, automated, sonographic localization of the heart to identify the area of compression in out-of-hospital cardiac arrest is warranted.
Response from Varani et al. to “Comment on ‘the IS6 family, a clinically important group of insertion sequences including IS26’ by Ruth M. Hall”
Authors: Varani Alessandro , He Susu , Siguier Patricia , Ross Karen , Chandler Michael
Published: January 2022

The IS6 family of insertion sequences is a large but coherent group which was originally named to avoid confusion between a number of identical or nearly identical IS that were identified at about the same time and given different names (IS15D, IS26, IS46, IS140, IS160, IS176). The underlying common mechanistic feature of all IS6 family members which have been investigated is that they appear to transpose by replicative transposition and form pseudo compound transposons with the flanking IS in direct repeat and in which associated genes are simply transferred to the target replicon and lost from the donor.

In the accompanying letter Hall raises a number of very serious and wide-ranging criticisms of our recent review article concerning the IS6 family of insertion sequences. She clearly feels that we have undervalued her work and that we question or ignore certain of her in vivo results. This impression is almost certainly the result of the standard of proof we generally apply to mechanistic aspects of transposition where we think it important to identify transposition intermediates including the types of synaptic, strand cleavage and strand transfer complexes involved.
Acute worsening of native lung fibrosis after single lung transplantation for pulmonary fibrosis: two case reports
Authors: Goletto Tiphaine , Decaux Sixtine , Bunel Vincent , Weisenburger Gaëlle , Messika Jonathan , Najem Samer , Medraoui Chahine , Godet Cendrine , Debray Marie Pierre , Lortat-Jacob Brice , Mordant Pierre , Castier Yves , Bouadma Lila , Borie Raphael , Mal Hervé
Published: January 2022

Background

In patients receiving single lung transplantation for idiopathic pulmonary fibrosis, worsening of fibrosis of the native lung is usually progressive over time, with no significant effects on gas exchange.

Case presentation

Here, we describe the cases of two Caucasian male recipients of single lung transplants for idiopathic pulmonary fibrosis, 65 and 62 years of age, who exhibited acute worsening of lung fibrosis after an episode of serious viral infection (cytomegalovirus primo-infection in one case and COVID-19 in the other). In both cases, along with opacification of the native lung over several days, the patients presented acute respiratory failure that required the use of high-flow nasal oxygen therapy. Eventually, hypoxemic respiratory failure resolved, but with rapid progression of fibrosis of the native lung.

Conclusion

We conclude that acute worsening of fibrosis on the native lung secondary to a severe viral infection should be added to the list of potential complications developing on the native lung after single lung transplantation for idiopathic pulmonary fibrosis.
How deep is your model? Network topology selection from a model validation perspective
Authors: Nowaczyk Nikolai , Kienitz Jörg , Acar Sarp Kaya , Liang Qian
Published: January 2022

Deep learning is a powerful tool, which is becoming increasingly popular in financial modeling. However, model validation requirements such as SR 11-7 pose a significant obstacle to the deployment of neural networks in a bank’s production system. Their typically high number of (hyper-)parameters poses a particular challenge to model selection, benchmarking and documentation. We present a simple grid based method together with an open source implementation and show how this pragmatically satisfies model validation requirements. We illustrate the method by learning the option pricing formula in the Black–Scholes and the Heston model.
Plasmatic MMP9 released from tumor-infiltrating neutrophils is predictive for bevacizumab efficacy in glioblastoma patients: an AVAglio ancillary study
Authors: Jiguet-Jiglaire Carine , Boissonneau Sebastien , Denicolai Emilie , Hein Victoria , Lasseur Romain , Garcia Josep , Romain Sylvie , Appay Romain , Graillon Thomas , Mason Warren , Carpentier Antoine F. , Brandes Alba A. , Ouafik L.’Houcine , Wick Wolfgang , Baaziz Ania , Gigan Julien P. , Argüello Rafael J. , Figarella-Branger Dominique , Chinot Olivier , Tabouret Emeline
Published: January 2022

We previously identified matrix metalloproteinase 2 (MMP2) and MMP9 plasma levels as candidate biomarkers of bevacizumab activity in patients with recurrent glioblastoma. The aim of this study was to assess the predictive value of MMP2 and MMP9 in a randomized phase III trial in patients with newly diagnosed glioblastoma and to explore their tumor source. In this post hoc analysis of the AVAglio trial (AVAGlio/NCT00943826), plasma samples from 577 patients (bevacizumab, n = 283; placebo, n = 294) were analyzed for plasma MMP9 and MMP2 levels by enzyme-linked immunosorbent assay. A prospective local cohort of 38 patients with newly diagnosed glioblastoma was developed for analysis of tumor characteristics by magnetic resonance imaging and measurement of plasma and tumor levels of MMP9 and MMP2. In this AVAglio study, MMP9, but not MMP2, was correlated with bevacizumab efficacy. Patients with low MMP9 derived a significant 5.2-month overall survival (OS) benefit with bevacizumab (HR 0.51, 95% CI 0.34–0.76, p = 0.0009; median 13.6 vs. 18.8 months). In multivariate analysis, a significant interaction was seen between treatment and MMP9 (p = 0.03) for OS. In the local cohort, we showed that preoperative MMP9 plasma levels decreased after tumor resection and were correlated with tumor levels of MMP9 mRNA (p = 0.03). However, plasma MMP9 was not correlated with tumor size, invasive pattern, or angiogenesis. Using immunohistochemistry, we showed that MMP9 was expressed by inflammatory cells but not by tumor cells. After cell sorting, we showed that MMP9 was expressed by CD45+ immune cells. Finally, using flow cytometry, we showed that MMP9 was expressed by tumor-infiltrating neutrophils. In conclusion, circulating MMP9 is predictive of bevacizumab efficacy and is released by tumor-infiltrating neutrophils.
Suicidal ideation, self-injury, aggressive behavior and substance use during intensive trauma-focused treatment with exposure-based components in adolescent and young adult PTSD patients
Authors: Fischer Anne , Rosner Rita , Renneberg Babette , Steil Regina
Published: January 2022

Background

Multiple traumata such as child sexual and/or physical abuse often result in complex psychopathologies and a range of associated dysfunctional behaviors. Although evidence-based interventions exist, some therapists are concerned that trauma-focused psychotherapy with exposure-based elements may lead to the deterioration of associated dysfunctional behaviors in adolescents and young adults. Therefore, we examined the course of suicidal ideation, self-injury, aggressive behavior and substance use in a group of abuse-related posttraumatic stress disorder (PTSD) patients during phase-based, trauma-focused PTSD treatment.

Methods

Daily assessments from a randomized controlled trial (RCT) of Developmentally adapted Cognitive Processing Therapy (D-CPT) were analyzed to test for differences in the stated dysfunctional behaviors between the four treatment phases. We conducted multilevel modeling and repeated measure ANOVAs.

Results

We did not find any significant differences between the treatment phases concerning the stated dysfunctional behaviors, either at the level of urge or at the level of actual actions. On the contrary, in some primary outcomes (self-injury, aggressive behavior), as well as secondary outcomes (distress caused by trauma, joy), we observed significant improvements.

Discussion

Overall, during D-CPT, adolescents and young adults showed no deterioration in dysfunctional behaviors, while even showing improvements in some, suggesting that trauma-focused treatment preceded by skills building was not deleterious to this population. Hence, the dissemination of effective interventions such as D-CPT should be fostered, whilst the concerns of the therapists regarding exposure-based components need to be addressed during appropriate training. Nevertheless, further studies with momentary assessment, extended measurement methods, a control group and larger sample sizes are needed to confirm our preliminary findings.

Trial registration

The trial was registered at the German Clinical Trial Registry (GCTR), DRKS00004787, 18 March 2013, https://www.drks.de/DRKS00004787.
Parathyroid hormone promotes maxillary expansion and reduces relapse in the repeated activation maxillary expansion rat model by regulating Wnt/β-catenin pathway
Authors: Xu Mengting , Li Yuan , Feng Xiaoxia , Zheng Wei , Zhao Zhihe , Li Yu
Published: January 2022

Background

Constricted maxillary bone is a common skeletal deformity, which may lead to crowding and posterior crossbite. Mid-palatal suture expansion is often used to increase the maxillary width, but its skeletal effects are limited and tend to relapse, even with prolonged retention. We hypothesized that parathyroid hormone (PTH) may reduce the relapse of maxillary expansion.

Methods

We established a novel rat maxillary expansion model using palatal tubes with an insertable “W”-shaped spring which can be repeatedly activated. A total of 32 male healthy Wistar rats were randomly divided into six groups: the control group, the PTH group, the expansion group, the expansion + PTH group, the expansion + relapse group and the expansion + PTH + relapse group. All animals in the first 4 groups were killed after 10 days and the 2 relapse groups were killed after 15 days. The maxillary arch widths and histological staining were used to assess the expansion and relapse effects. The immunohistochemical staining, micro-CT, RT-qPCR and Western blot were used to evaluate the bone remodeling during expansion.

Results

The suture width was increased by the expansion device, and the repeated activation maxillary expansion rat model showed better expansion effects than the conventional model. PTH significantly promoted the expansion width and reduced the relapse ratio. Meanwhile, in the expansion + PTH group, histological and immunohistochemical staining showed that osteoblasts, osteoclasts, new cartilage and osteoid were significantly increased, micro-CT showed increased bone mass, and PCR and Western blot results confirmed up-regulation of RANKL, β-catenin, type II collagen and OCN.

Conclusion

The novel repeated activation maxillary expansion rat model has better effects than the conventional model. PTH enhances the maxillary expansion and reduces its relapse by regulating Wnt/β-catenin and RANKL pathways. PTH administration may serve as an adjunctive therapy in addition to mechanical expansion for treatment of maxillary constriction.
Experiences of violence in daily life among adults in California: a population-representative survey
Authors: Wintemute Garen J. , Aubel Amanda J. , Pallin Rocco , Schleimer Julia P. , Kravitz-Wirtz Nicole
Published: January 2022

Background

Research on violence exposure emphasizes discrete acute events such as direct and witnessed victimization. Little is known about the broad range of experiences of violence (EVs) in daily life. This study assesses the prevalence and patterns of distribution of 6 EVs in an adult general population.

Methods

California state-representative survey administered online (English and Spanish), July 14–27, 2020. Adult (age ≥ 18 years) California resident members of the Ipsos KnowledgePanel were eligible to participate. Two EVs concerned community environments: (1) the occurrence of gunshots and shootings in the neighborhood and (2) encounters with sidewalk memorials where violent deaths occurred. Four concerned social networks: direct personal knowledge of individuals who (1) had purposefully been shot by someone else or (2) had purposefully shot themselves, and direct personal knowledge of individuals whom respondents perceived to be at risk of violence, either (3) to another person or (4) to themselves. Main outcome measures, expressed as weighted percentages with 95% confidence intervals (CIs), were the prevalence and extent (or dose) of each EV and of EVs in combination and associations between EVs and respondents’ sociodemographic characteristics and firearm ownership status.

Results

Of 2870 respondents (57% completion rate), 52.3% (95% CI 49.5–55.0%) were female; mean [SD] age was 47.9 [16.9] years. Nearly two-thirds (64.6%, 95% CI 61.9–67.3%) reported at least 1 EV; 11.4% (95% CI 9.7–13.2%) reported 3 or more. Gender was not associated with the prevalence of any experience. Non-owners of firearms who lived with owners reported more extensive EVs through social networks than did firearm owners or non-owners in households without firearms. Knowledge of people who had been shot by others was most common among Black respondents, 31.0% (95% CI 20.9–43.3%) of whom knew 2 or more such persons. Knowledge of people who had shot themselves was greatest among respondents aged ≥ 60 years, but knowledge of persons perceived to be at risk of violence to themselves was greatest among respondents aged 18–29 years.

Conclusions and relevance

Experiences of violence in daily life are widespread. They occur in sociodemographic patterns that differ from those for direct victimization and suggest new opportunities for research and intervention.
Increasing NADPH impairs fungal H2O2 resistance by perturbing transcriptional regulation of peroxiredoxin
Authors: Li Jingyi , Sun Yanwei , Liu Feiyun , Zhou Yao , Yan Yunfeng , Zhou Zhemin , Wang Ping , Zhou Shengmin
Published: January 2022

NADPH provides the reducing power for decomposition of reactive oxygen species (ROS), making it an indispensable part during ROS defense. It remains uncertain, however, if living cells respond to the ROS challenge with an elevated intracellular NADPH level or a more complex NADPH-mediated manner. Herein, we employed a model fungus Aspergillus nidulans to probe this issue. A conditional expression of glucose-6-phosphate dehydrogenase (G6PD)-strain was constructed to manipulate intracellular NADPH levels. As expected, turning down the cellular NADPH concentration drastically lowered the ROS response of the strain; it was interesting to note that increasing NADPH levels also impaired fungal H2O2 resistance. Further analysis showed that excess NADPH promoted the assembly of the CCAAT-binding factor AnCF, which in turn suppressed NapA, a transcriptional activator of PrxA (the key NADPH-dependent ROS scavenger), leading to low antioxidant ability. In natural cell response to oxidative stress, we noticed that the intracellular NADPH level fluctuated “down then up” in the presence of H2O2. This might be the result of a co-action of the PrxA-dependent NADPH consumption and NADPH-dependent feedback of G6PD. The fluctuation of NADPH is well correlated to the formation of AnCF assembly and expression of NapA, thus modulating the ROS defense. Our research elucidated how A. nidulans precisely controls NADPH levels for ROS defense.

Graphical Abstract
Liquefaction hazard assessment and ground failure probability analysis in the Kathmandu Valley of Nepal
Authors: Subedi Mandip , Acharya Indra Prasad
Published: January 2022

During the 2015 Gorkha Earthquake (Mw7.8), extensive soil liquefaction was observed across the Kathmandu Valley. As a densely populated urban settlement, the assessment of liquefaction potential of the valley is crucial especially for ensuring the safety of engineering structures. In this study, we use borehole data including SPT-N values of 410 locations in the valley to assess the susceptibility, hazard, and risk of liquefaction of the valley soil considering three likely-to-recur scenario earthquakes. Some of the existing and frequently used analysis and computation methods are employed for the assessments, and the obtained results are presented in the form of liquefaction hazard maps indicating factor of safety, liquefaction potential index, and probability of ground failure (PG). The assessment results reveal that most of the areas have medium to very high liquefaction susceptibility, and that the central and southern parts of the valley are more susceptible to liquefaction and are at greater risk of liquefaction damage than the northern parts. The assessment outcomes are validated with the field manifestations during the 2015 Gorkha Earthquake. The target SPT-N values (Nimproved) at potentially liquefiable areas are determined using back analysis to ascertain no liquefaction during the aforesaid three scenario earthquakes.