bluuebunny/crossref_metadata_2025 huggingface dataset:
The hybrid governance of environmental transnational municipal networks: Lessons from 100 Resilient Cities
Authors: Nielsen Anne Bach , Papin Marielle
Published: July 2020

Transnational Municipal Networks (TMNs) are increasing in size, scope and number on the global arena. They reflect a tendency for city governments to coordinate environmental action through networked forms of governance. In this article, we argue that a new generation of TMNs has entered the global scene to help cities steer their efforts to handle environmental issues. In contrast to the characteristics of older TMNs as public, inclusive, and self-governed, new-generation TMNs are influenced by private actors, they are exclusive, and employ enforcement mechanisms to secure the fulfilment of network goals. To underline the diversity of TMNs and thus better understand urban networked governance, we present a case study of the 100 Resilient Cities initiative covering its conduct in 2013–2019. Looking at its actor composition and membership terms, we identify a hybrid nature different from the one described in earlier literature on European TMNs primarily. This subscription to a hybrid form of governance calls for a larger discussion on the implications of this shift in governance type and on the extent to which hybridisation implies a shift of power from the public to the private sphere.
Clonal hematopoiesis and non-hematologic disorders
Authors: Jaiswal Siddhartha
Published: July 2020

Clonal expansions of mutated hematopoietic cells, termed clonal hematopoiesis, are common in aging humans. One expected consequence of mutation-associated clonal hematopoiesis is an increased risk of hematologic cancers, which has now been shown in several studies. However, the hematopoietic stem cells that acquire these somatic mutations also give rise to mutated immune effector cells, such as monocytes, granulocytes, and lymphocytes. These effector cells can potentially influence many disease states, especially those with a chronic inflammatory component. Indeed, several studies have now shown that clonal hematopoiesis associates with increased risk of atherosclerotic cardiovascular disease. Emerging data also associate clonal hematopoiesis to other non-hematologic diseases. Here, we will review recent studies linking clonal hematopoiesis to altered immune function, inflammation, and non-malignant diseases of aging.
Clonal hematopoiesis in the inherited bone marrow failure syndromes
Authors: Tsai Frederick D , Lindsley R. Coleman
Published: July 2020

Inherited bone marrow failure syndromes (IBMFS) are characterized by ineffective hematopoiesis and increased risk of developing myeloid malignancy. The pathophysiologies of different IBMFS are variable, and can relate to defects in diverse biological processes, including DNA damage repair (Fanconi anemia), telomere maintenance (dyskeratosis congenita), and ribosome biogenesis (Diamond-Blackfan anemia, Shwachman-Diamond syndrome). Somatic mutations leading to clonal hematopoiesis have been described in IBMFS, but the distinct mechanisms by which mutations drive clonal advantage in each disease and their associations with leukemia risk are not well understood. Clinical observations and laboratory models of IBMFS suggest that the germline deficiencies establish a qualitatively impaired functional state at baseline. In this context, somatic alterations can promote clonal hematopoiesis by improving the competitive fitness of specific hematopoietic stem cell clones. Some somatic alterations relieve baseline fitness constraints by normalizing the underlying germline deficit through direct reversion or indirect compensation, while others do so by subverting senescence or tumor suppressor pathways. Clones with normalizing somatic mutations may have limited transformation potential due to retention of functionally intact fitness-sensing and tumor suppressor pathways, while those with mutations that impair cellular elimination may have increased risk of malignant transformation due to subversion of tumor suppressor pathways. Since clonal hematopoiesis is not deterministic of malignant transformation, rational surveillance strategies will thus depend on the ability to prospectively identify specific clones with increased leukemic potential. We describe a framework by which an understanding of the processes that promote clonal hematopoiesis in IBMFS may inform clinical surveillance strategies.
Clonal hematopoiesis and risk for hematologic malignancy
Authors: Warren Julia T , Link Daniel C
Published: July 2020

Clonal hematopoiesis is common in older persons and is associated with an increased risk of hematologic cancer. Here, we review studies establishing an association between clonal hematopoiesis and hematopoietic malignancy, discuss features of clonal hematopoiesis that are predictive of leukemic progression, and explore the role of hematopoietic stressors in the evolution of clonal hematopoiesis to acute myeloid leukemia or myelodysplastic syndrome. Clonal hematopoiesis due to point mutations or structural variants, such as copy number alterations, are associated with an approximately 10-fold increased risk of hematopoietic malignancy. Although the absolute risk of hematopoietic malignancy is low, certain features of clonal hematopoiesis may confer a higher risk of transformation, including the presence of TP53 or splicesome gene mutations, a variant allele fraction greater than 10%, the presence of multiple mutations, and altered red blood indices. Clonal hematopoiesis in the setting of peripheral blood cytopenias carries a very high risk of progression to a myeloid malignancy and merits close observation. There is emerging evidence to suggest the hematopoietic stressors contribute both to the development of clonal hematopoiesis and progression to hematopoietic malignancy. Specifically, there is evidence that genotoxic stress from chemotherapy or radiation therapy, ribosome biogenesis stress, and possibly inflammation may increase the risk of transformation from clonal hematopoiesis to a myeloid malignancy. Models that incorporate features of clonal hematopoiesis along with an assessment of hematopoietic stressors may eventually help predict and prevent the development of hematopoietic malignancies.
SLFN11 promotes stalled fork degradation that underlies the phenotype in Fanconi anemia cells
Authors: Okamoto Yusuke , Abe Masako , Mu Anfeng , Tempaku Yasuko , Rogers Colette B. , Mochizuki Ayako L. , Katsuki Yoko , Kanemaki Masato T. , Takaori-Kondo Akifumi , Sobeck Alexandra , Bielinsky Anja-Katrin , Takata Minoru
Published: July 2020

Fanconi anemia (FA) is a hereditary disorder caused by mutations in any 1 of 22 FA genes. The disease is characterized by hypersensitivity to interstrand crosslink (ICL) inducers such as mitomycin C (MMC). In addition to promoting ICL repair, FA proteins such as RAD51, BRCA2, or FANCD2 protect stalled replication forks from nucleolytic degradation during replication stress, which may have a profound impact on FA pathophysiology. Recent studies showed that expression of the putative DNA/RNA helicase SLFN11 in cancer cells correlates with cell death on chemotherapeutic treatment. However, the underlying mechanisms of SLFN11-mediated DNA damage sensitivity remain unclear. Because SLFN11 expression is high in hematopoietic stem cells, we hypothesized that SLFN11 depletion might ameliorate the phenotypes of FA cells. Here we report that SLFN11 knockdown in the FA patient-derived FANCD2-deficient PD20 cell line improved cell survival on treatment with ICL inducers. FANCD2−/−SLFN11−/− HAP1 cells also displayed phenotypic rescue, including reduced levels of MMC-induced chromosome breakage compared with FANCD2−/− cells. Importantly, we found that SLFN11 promotes extensive fork degradation in FANCD2−/− cells. The degradation process is mediated by the nucleases MRE11 or DNA2 and depends on the SLFN11 ATPase activity. This observation was accompanied by an increased RAD51 binding at stalled forks, consistent with the role of RAD51 antagonizing nuclease recruitment and subsequent fork degradation. Suppression of SLFN11 protects nascent DNA tracts even in wild-type cells. We conclude that SLFN11 destabilizes stalled replication forks, and this function may contribute to the attrition of hematopoietic stem cells in FA.
What is the future of immunotherapy in multiple myeloma?
Authors: Rasche Leo , Hudecek Michael , Einsele Hermann
Published: July 2020

The treatment of multiple myeloma (MM) is currently being redefined by humoral and cellular immunotherapies. For decades, there was limited belief in immune-based anti-MM therapy as a result of the moderate graft-versus-myeloma effect of allogeneic stem cell transplantation. Today, monoclonal antibodies comprise the new backbone of anti-MM therapy, and T-cell therapies targeting BCMA are emerging as the most potent single agents for MM treatment. Herein, we present our assessment of and vision for MM immunotherapy in the short and midterm.
The integrin-linked kinase is required for chemokine-triggered high-affinity conformation of the neutrophil β2-integrin LFA-1
Authors: Margraf Andreas , Germena Giulia , Drexler Hannes C. A. , Rossaint Jan , Ludwig Nadine , Prystaj Barbara , Mersmann Sina , Thomas Katharina , Block Helena , Gottschlich Wiebke , Liu Chang , Krenn Peter W. , Haller Hermann , Heitplatz Barbara , Meyer zu Brickwedde Marika , Moser Markus , Vestweber Dietmar , Zarbock Alexander
Published: July 2020

Neutrophil adhesion and extravasation into tissue at sites of injury or infection depend on binding of the integrin lymphocyte function–associated antigen 1 (LFA-1) to ICAM-1 expressed on activated endothelial cells. The activation-dependent conformational change of LFA-1 to the high-affinity conformation (H+) requires kindlin-3 binding to the β2-integrin cytoplasmic domain. Here we show that genetic deletion of the known kindlin interactor integrin-linked kinase (ILK) impaired neutrophil adhesion and extravasation in the cremaster muscle and in a clinically relevant model of renal ischemia reperfusion injury. Using in vitro microfluidic adhesion chambers and conformation-specific antibodies, we show that knockdown of ILK in HL-60 cells reduced the conformational change of β2-integrins to the H+ conformation. Mechanistically, we found that ILK was required for protein kinase C (PKC) membrane targeting and chemokine-induced upregulation of its kinase activity. Moreover, PKC-α deficiency also resulted in impaired leukocyte adhesion in bone marrow chimeric mice. Mass spectrometric and western blot analyses revealed stimulation- and ILK-dependent phosphorylation of kindlin-3 upon activation. In summary, our data indicate an important role of ILK in kindlin-3–dependent conformational activation of LFA-1.
Tissue factor pathway inhibitor is required for cerebrovascular development in mice
Authors: Maroney Susan A. , Westrick Randal J. , Cleuren Audrey C. , Martinez Nicholas D. , Siebert Amy E. , Zogg Mark , Ginsburg David , Weiler Hartmut , Mast Alan E.
Published: July 2020

Tissue factor pathway inhibitor (TFPI) inhibits proteases in the blood coagulation cascade that lead to the production of thrombin, including prothrombinase (factor Xa [FXa]/FVa), the catalytic complex that directly generates thrombin. Thus, TFPI and FV are directly linked in regulating the procoagulant response. Studies using knockout mice indicate that TFPI and FV are necessary for embryogenesis, but their contributions to vascular development are unclear. We performed extensive histological analyses of Tfpi−/− and Tfpi−/−F5−/− mouse embryos to investigate the importance of the interplay between TFPI and FV in regulating hemostasis and vascular development during embryogenesis. We observed normal tissue development throughout Tfpi−/− embryos, except in the central nervous system (CNS). The CNS displayed stunted brain growth, delayed development of the meninges, and severe vascular pathology characterized by the formation of glomeruloid bodies surrounding areas of cellular death, fibrin deposition, and hemorrhage. Removing FV from Tfpi−/− embryos completely ameliorated their brain pathology, suggesting that TFPI dampens FV-dependent procoagulant activity in a manner that modulates cerebrovascular development. Thus, we have identified a previously unrecognized role for TFPI activity within the CNS. This TFPI activity likely diminishes an effect of excess thrombin activity on signaling pathways that control cerebral vascular development.
TP53 mutations in myelodysplastic syndromes and secondary AML confer an immunosuppressive phenotype
Authors: Sallman David A. , McLemore Amy F. , Aldrich Amy L. , Komrokji Rami S. , McGraw Kathy L. , Dhawan Abhishek , Geyer Susan , Hou Hsin-An , Eksioglu Erika A. , Sullivan Amy , Warren Sarah , MacBeth Kyle J. , Meggendorfer Manja , Haferlach Torsten , Boettcher Steffen , Ebert Benjamin L. , Al Ali Najla H. , Lancet Jeffrey E. , Cleveland John L. , Padron Eric , List Alan F.
Published: July 2020

Somatic gene mutations are key determinants of outcome in patients with myelodysplastic syndromes (MDS) and secondary AML (sAML). In particular, patients with TP53 mutations represent a distinct molecular cohort with uniformly poor prognosis. The precise pathogenetic mechanisms underlying these inferior outcomes have not been delineated. In this study, we characterized the immunological features of the malignant clone and alterations in the immune microenvironment in patients with TP53-mutant and wild-type MDS or sAML. Notably, PDL1 expression is significantly increased in hematopoietic stem cells of patients with TP53 mutations, which is associated with MYC upregulation and marked downregulation of MYC’s negative regulator miR-34a, a p53 transcription target. Notably, patients with TP53 mutations display significantly reduced numbers of bone marrow–infiltrating OX40+ cytotoxic T cells and helper T cells, as well as decreased ICOS+ and 4-1BB+ natural killer cells. Further, highly immunosuppressive regulatory T cells (Tregs) (ie, ICOShigh/PD-1−) and myeloid-derived suppressor cells (PD-1low) are expanded in cases with TP53 mutations. Finally, a higher proportion of bone marrow–infiltrating ICOShigh/PD-1− Treg cells is a highly significant independent predictor of overall survival. We conclude that the microenvironment of TP53 mutant MDS and sAML has an immune-privileged, evasive phenotype that may be a primary driver of poor outcomes and submit that immunomodulatory therapeutic strategies may offer a benefit for this molecularly defined subpopulation.
A randomized phase 3 trial of zanubrutinib vs ibrutinib in symptomatic Waldenström macroglobulinemia: the ASPEN study
Authors: Tam Constantine S. , Opat Stephen , D'Sa Shirley , Jurczak Wojciech , Lee Hui-Peng , Cull Gavin , Owen Roger G. , Marlton Paula , Wahlin Björn E. , Sanz Ramón Garcia , McCarthy Helen , Mulligan Stephen , Tedeschi Alessandra , Castillo Jorge J. , Czyz Jaroslaw , Fernández de Larrea Carlos , Belada David , Libby Edward , Matous Jeffrey V. , Motta Marina , Siddiqi Tanya , Tani Monica , Trneny Marek , Minnema Monique C. , Buske Christian , Leblond Veronique , Trotman Judith , Chan Wai Y. , Schneider Jingjing , Ro Sunhee , Cohen Aileen , Huang Jane , Dimopoulos Meletios
Published: July 2020

Bruton tyrosine kinase (BTK) inhibition is an effective treatment approach for patients with Waldenström macroglobulinemia (WM). The phase 3 ASPEN study compared the efficacy and safety of ibrutinib, a first-generation BTK inhibitor, with zanubrutinib, a novel highly selective BTK inhibitor, in patients with WM. Patients with MYD88L265P disease were randomly assigned 1:1 to treatment with ibrutinib or zanubrutinib. The primary end point was the proportion of patients achieving a complete response (CR) or a very good partial response (VGPR) by independent review. Key secondary end points included major response rate (MRR), progression-free survival (PFS), duration of response (DOR), disease burden, and safety. A total of 201 patients were randomized, and 199 received ≥1 dose of study treatment. No patient achieved a CR. Twenty-nine (28%) zanubrutinib patients and 19 (19%) ibrutinib patients achieved a VGPR, a nonstatistically significant difference (P = .09). MRRs were 77% and 78%, respectively. Median DOR and PFS were not reached; 84% and 85% of ibrutinib and zanubrutinib patients were progression free at 18 months. Atrial fibrillation, contusion, diarrhea, peripheral edema, hemorrhage, muscle spasms, and pneumonia, as well as adverse events leading to treatment discontinuation, were less common among zanubrutinib recipients. Incidence of neutropenia was higher with zanubrutinib, although grade ≥3 infection rates were similar in both arms (1.2 and 1.1 events per 100 person-months). These results demonstrate that zanubrutinib and ibrutinib are highly effective in the treatment of WM, but zanubrutinib treatment was associated with a trend toward better response quality and less toxicity, particularly cardiovascular toxicity.
Bendamustine and rituximab as induction therapy in both transplant-eligible and -ineligible patients with mantle cell lymphoma
Authors: Villa Diego , Sehn Laurie H. , Savage Kerry J. , Toze Cynthia L. , Song Kevin , den Brok Wendie D. , Freeman Ciara L. , Scott David W. , Gerrie Alina S.
Published: July 2020

Rituximab-containing chemotherapy regimens constitute standard first-line therapy for mantle cell lymphoma (MCL). Since June 2013, 190 patients ≥18 years of age with MCL in British Columbia have been treated with bendamustine and rituximab (BR). The overall response rate to BR was 88% (54% complete response). Of these, 61 of 89 patients (69%) aged ≤65 years received autologous stem cell transplantation and 141 of 190 patients (74%) from the entire cohort received maintenance rituximab. Twenty-three patients (12%) had progressive disease, associated with high risk per the Mantle Cell Lymphoma International Prognostic Index (MIPI), Ki-67 ≥50%, and blastoid/pleomorphic histology. Outcomes were compared with a historical cohort of 248 patients treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP; January 2003 to May 2013). Treatment with BR was associated with significant improvements in progression-free survival (PFS), but not overall survival (OS), compared with R-CHOP in the whole cohort (3-year PFS, 66% BR vs 51% R-CHOP, P = .003; 3-year OS, 73% BR vs 66% R-CHOP, P = .054) and in those >65 years of age (3-year PFS, 56% BR vs 35% R-CHOP, P = .001; 3-year OS, 64% BR vs 55% R-CHOP, P = .063). Outcomes in transplanted patients were not statistically significantly different compared with R-CHOP (3-year PFS, 85% BR vs 76% R-CHOP, P = .135; 3-year OS, 90% BR vs 88% R-CHOP, P = .305), although in multivariate analyses, treatment with BR was associated with improved PFS (hazard ratio, 0.40 [95% confidence interval, 0.17-0.94]; P = .036) but not OS. BR is an effective first-line option for most patients with MCL, however, outcomes are suboptimal for those with high-risk features and further studies integrating novel agents are warranted.
RETRACTED ARTICLE: Contribution of
anthocyanin pathways to fruit flesh coloration in pitayas
Authors: Fan Ruiyi , Sun Qingming , Zeng Jiwu , Zhang Xinxin
Published: July 2020

Background

Color formation in Hylocereus
spp. (pitayas) has been ascribed to the accumulation of
betalains. However, several studies have reported the presence of anthocyanins
in pitaya fruit and their potential role in color formation has not yet been
explored. In this study, we profiled metabolome and transcriptome in fruit of
three cultivars with contrasting flesh colors (red, pink and white) to
investigate their nutritional quality and the mechanism of color formation
involving anthocyanins.

Results

Results revealed that pitaya fruit is enriched in amino acid, lipid,
carbohydrate, polyphenols, vitamin and other bioactive components with
significant variation among the three cultivars. Anthocyanins were detected in
the fruit flesh and accumulation levels of Cyanidin 3-glucoside, Cyanidin
3-rutinoside, Delphinidin 3-O-(6-O-malonyl)-beta-glucoside-3-O-beta-glucoside
and Delphinidin 3-O-beta-D-glucoside 5-O-(6-coumaroyl-beta-D-glucoside)
positively correlated with the reddish coloration. Transcriptome data showed
that the white cultivar tends to repress the anthocyanin biosynthetic pathway
and divert substrates to other competing pathways. This perfectly contrasted
with observations in the red cultivar. The pink cultivar however seems to keep a
balance between the anthocyanin biosynthetic pathway and the competing pathways.
We identified several active transcription factors of the MYB and bHLH families
which can be further investigated as potential regulators of the anthocyanin
biosynthetic genes.

Conclusions

Collectively, our results suggest that anthocyanins partly
contribute to color formation in pitaya fruit. Future studies aiming at
manipulating the biosynthetic pathways of anthocyanins and betalains will better
clarify the exact contribution of each pathway in color formation in pitayas.
This will facilitate efforts to improve pitaya fruit quality and appeal.
A colonic mass revealing a disseminated crystal storing histiocytosis secondary to indolent multiple myeloma: a case report with literature review
Authors: Contejean Adrien , Larousserie Frédérique , Bouscary Didier , Dohan Anthony , Deau-Fischer Bénédicte , Szwebel Tali-Anne , Dhooge Marion , Terris Benoit , Vignon Marguerite
Published: July 2020

Background

Crystal storing histiocytosis is a rare disorder associated with monoclonal gammopathy. In this disease, monoclonal heavy and light chains accumulate in the lysosome of macrophages, leading to histiocytic reaction in different organs. It is secondary to the presence of a small B-cell clone, responsible for monoclonal immunoglobulin production. Histological diagnosis is a challenge and differential diagnoses include fibroblastic and histiocytic neoplasm. Clinical manifestations depend on the involved organs, rarely including peritoneum or digestive tract.

Case presentation

We present a case of a 75-year-old with a medical history of colonic carcinoma. She presented with abdominal pain and inflammatory syndrome revealing a colonic mass. Hemicolectomy was performed. Initial diagnosis was fibroblastic tumour. The patient worsened, and diagnosis of a diffuse crystal storing histiocytosis was finally done. Haematological exploration found an indolent IgG-kappa multiple myeloma. The initial treatment with conventional chemotherapy did not permit an improvement of the patient condition. Immunotherapy with anti-CD38 monoclonal antibody (daratumumab) was proposed with a clinical and biological response.

Conclusion

This case report emphasizes the histopathological challenge of histiocytic tumours which may involve digestive track. It focuses on the concept of monoclonal gammopathy of clinical significance, which can have a large spectrum of manifestations.
Prevalence and risk factors of paradoxical tuberculosis associated immune reconstitution inflammatory syndrome among HIV-infected patients in Beijing, China
Authors: Xue Ming , Xie Ruming , Pang Yu , Yan Shuo , Du Yanni , Guan Chunshuang , Chen Budong
Published: July 2020

Background

In this study, we aimed to describe the prevalence, clinical presentation and risk factors of paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) cases in China.

Methods

We performed a descriptive analysis of demographic and clinical data of HIV/TB coinfected patients receiving ART at Beijing Ditan Hospital between January 2014 and October 2018.

Results

Of 199 patients included, 45 (22.6%) developed paradoxical TB-IRIS, and 19 (9.5%) TB-IRIS cases presented miliary TB. The pre-ART CD4 count lower than 50 cells/mm3 was found to be significantly associated with development of TB-IRIS. Similarly, patients with higher than 4-fold increase in CD4 cell count after antiretroviral therapy (ART) had significantly higher odds of having TB-IRIS. When patients aged 25–44 years were utilized as the control group, youths (< 25 years old) were more likely to have miliary TB. No significant difference was observed in the intervals from initiation of ART to IRIS presentation between miliary and non-miliary group.

Conclusions

In conclusion, our data demonstrate that approximate one quarter of patients coinfected with TB and HIV develop paradoxical TB-IRIS after initial of ART therapy in China. Lower baseline CD4 count and rapid increase in CD4 count are the major risk factors associated with the occurrence of paradoxical TB-IRIS.
Association studies of dopamine synthesis and metabolism genes with multiple phenotypes of heroin dependence
Authors: Li Yunxiao , Zhu Yongsheng , Lai Jianghua , Shi Xugang , Chen Yuanyuan , Zhang Jinyu , Wei Shuguang
Published: July 2020

Background

Heroin dependence is a complex disease with multiple phenotypes. Classification of heroin users into more homogeneous subgroups on the basis of these phenotypes could help to identify the involved genetic factors and precise treatments. This study aimed to identify the association between genetic polymorphisms of DA synthesis and metabolism genes, including tyrosine hydroxylase (TH), DOPA decarboxylase (DDC), solute carrier family 6 member 3 (SLC6A3) and DA beta-hydroxylase (DBH), with six important phenotypes of heroin dependence.

Methods

A total of 801 heroin dependent patients were recruited and fourteen potential functional single nucleotide polymorphisms (SNPs) were genotyped by SNaPshot. Associations between SNPs with six phenotypes were mainly assessed by binary logistic regression. Generalized multifactor dimensionality reduction was used to analyze the gene-by-gene and gene-by-environment interactions.

Results

We found that DBH rs1611114 TT genotype had a protective effect on memory impairment after heroin dependence (P = 0.002, OR = 0.610). We also found that the income-rs12666409-rs129915-rs1611114 interaction yielded the highest testing balance accuracy and cross-validation consistency for memory change after heroin dependence.

Conclusions

Our results suggest that the memory change after heroin dependence was a result of a combination of genetics and environment. This finding could lead to a better understanding of heroin dependence and further improve personalized treatment.
Ultrasound diagnosis and follow-up of a locked thumb metacarpophalangeal joint caused by radial sesamoid entrapment: a case report
Authors: Ahn Kyung-Sik , Choi In Cheul , Kang Chang Ho , Park Jong Woong
Published: July 2020

Background

A locked thumb metacarpophalangeal joint is a rare condition that presents as restricted joint motions with mild hyperextension deformity, usually after a relatively minor hyperextension injury. Owing to the limitations of radiographs, computed tomography is a useful diagnostic imaging modality for assessing sesamoid displacement. However, despite its convenience, ultrasound findings of the locked thumb have rarely been reported. Here, we report a case of a locked thumb metacarpophalangeal joint diagnosed and followed-up using ultrasound.

Case presentation

A 15-year-old boy with a locked thumb metacarpophalangeal joint presented to our hospital. On physical examination, the 1st metacarpophalangeal joint was found to be hyperextended, and active and passive flexions were not possible. While radiographs were inconclusive, ultrasound revealed radial sesamoid entrapment at the 1st metacarpophalangeal joint causing locking. After closed manual reduction, metacarpophalangeal motions recovered. Success of the reduction was also confirmable by ultrasound.

Conclusions

Ultrasound can be a feasible modality to diagnose a locked thumb metacarpophalangeal joint and immediately judge the success or failure of the reduction.
Experiential learning for children’s dental anxiety: a cluster randomized trial
Authors: Zhu Minmin , Yu Hongbing , Xie Bo , Li Hongwen , He Qian , Li Huimin , Su Jing , Li Xueqi
Published: July 2020

Background

Dental anxiety (DA) has an impact on the quality of dental treatment and may have long-lasting implications for children. A recent study introducing experiential learning (EL) into children’s oral health promotion resulted in better oral hygiene. The purpose of the study is to evaluate whether EL can reduce children’s DA.

Methods

In September 2018, we recruited 988 children aged 7–8 years from 24 classes to participate in a cluster-randomized trial. Classes were randomly assigned to EL (in which children received a lively presentation on oral health and participated in a role play in a simulated dental clinic in the classroom) or the Tell-Show-Do (TSD) group (in which children received a conventional TSD behavior management). The primary outcome was the prevalence of high DA after the procedure of pit and fissure sealant (PFS), assessed by a modified Children’s Fear Survey Schedule-Dental Subscale. Secondary outcomes were changes in blood pressures (BP) and pulse rates (PR) before and after the PFS procedure. The intervention effects were estimated by means of mixed effect models, which included covariates of gender and school (and baseline value for BP and PR only), and a random cluster effect.

Results

In 396 children of the EL group who received the PFS treatment, the prevalence of high DA (score ≥ 38) was 18.5%, compared with 24.3% in 391 children of the TSD group (OR = 0.65; 95% confidence interval, 0.46–0.93;P = 0.019). The increases in BP and PR after the PFS were also significantly less in the EL group.

Conclusion

School-based experiential learning intervention before a dental visit is feasible and effective in reducing children’s dental anxiety during PFS.

Trial registration

The trial was registered in Chinese Clinical Trial Registry on 5 January 2020 (No.:ChiCTR2000028878, retrospectively registered).
HOXA-AS2 promotes type I endometrial carcinoma via miRNA-302c-3p-mediated regulation of ZFX
Authors: Song Ning , Zhang Ying , Kong Fanfei , Yang Hui , Ma Xiaoxin
Published: July 2020

Background

HOXA cluster antisense RNA2 (HOXA-AS2), a long-chain non-coding RNA, plays an important role in the behavior of various malignant tumors. The roles of HOXA-AS2 in endometrial cancer remain unclear.

Methods

We test expression levels of HOXA-AS2, miRNA-302c-3p, the transcription factor zinc finger X-chromosomal protein (ZFX), and the chitinase-like protein YKL-40 in endometrial carcinoma by qRT-PCR and western blotting. Luciferase reporter and qRT-PCR assays were conducted to identify potential binding sites of HOXA-AS2 to miRNA-302c-3p. Cell cycle, migration and invasion ability of endometrial cancer cells were investigated using flow-cytometric analysis, CCK-8 and transwell assays, respectively.

Results

HOXA-AS2 levels were significantly increased in endometrial cancer specimens compared to normal endometrial specimens. Upregulated HOXA-AS2 promoted invasion and proliferation of type I endometrial cancer cells. HOXA-AS2 silenced miRNA-302c-3p by binding to it. MiRNA-302c-3p negatively regulates ZFX and YKL-40. Thus HOXA-AS2 promotes the development of type I endometrial cancer via miRNA-302c-3p-mediated regulation of ZFX.

Conclusions

These findings suggest that HOXA-AS2 can act as a new therapeutic target for type I endometrial cancer.
Measuring ventilation in different typologies of rural Gambian houses: a pilot experimental study
Authors: Knudsen Jakob B. , Pinder Margaret , Jatta Ebrima , Jawara Musa , Yousuf Mahamed A. , Søndergaard Amalie T. , Lindsay Steve W.
Published: July 2020

Background

African houses are frequently too hot and uncomfortable to use a bed net at night. Indoor thermal comfort is often evaluated by measuring temperature and humidity, ignoring ventilation. This study explored ways to measure ventilation in single-roomed rural Gambian houses during the malaria transmission season and evaluated building designs that could increase airflow at night and help keep the occupants comfortable.

Methods

Two identical mud-walled houses were constructed with a metal roof, three doors and closed eaves. Experiment 1 compared five methods for measuring ventilation in a building: (1) using a blower door, (2) increasing carbon dioxide (CO2) levels indoors using an artificial source of CO2 and then measuring the rate of gas decay, (3) using a similar approach with a natural source of CO2, (4) measuring the rise of CO2 when people enter a building and (5) using hot-wire anemometers. Experiment 2 used CO2 data loggers to compare ventilation in a reference metal-roofed house with closed eaves and badly-fitting doors with a similar house with (1) thatched roof and open eaves, (2) eaves tubes, (3) screened doors and (4) screened doors and windows.

Results

In experiment 1, CO2 data loggers placed indoors in two identical houses showed similar changes in airflow (p > 0.05) for all three methods recording either decreasing or increasing CO2. Blower doors were unable to measure airflow in houses with open eaves or screened windows and the anemometers broke down under field conditions. In experiment 2, open eaves in thatched houses, screened doors alone, and screened doors and windows increased indoor ventilation compared to the reference metal-roofed house with closed eaves and badly fitting doors (p < 0.05). Eaves tubes did not increase ventilation in comparison to the reference house.

Conclusion

CO2 data loggers proved to be a simple and efficient method for measuring ventilation in rural houses at night. Ventilation of metal-roofed houses can be improved by adding two screened doors and windows on opposite walls. Improved ventilation will result in increased thermal comfort making it more likely that people will sleep under a bed net.
“They look at us like junkies”: influences of drug use stigma on the healthcare engagement of people who inject drugs in New York City
Authors: Muncan Brandon , Walters Suzan M. , Ezell Jerel , Ompad Danielle C.
Published: July 2020

Background

People who inject drugs (PWID) are a medically and socially vulnerable population with a high incidence of overdose, mental illness, and infections like HIV and hepatitis C. Existing literature describes social and economic correlations to increased health risk, including stigma. Injection drug use stigma has been identified as a major contributor to healthcare disparities for PWID. However, data on this topic, particularly in terms of the interface between enacted, anticipated, and internalized stigma, is still limited. To fill this gap, we examined perspectives from PWID whose stigmatizing experiences impacted their views of the healthcare system and syringe service programs (SSPs) and influenced their decisions regarding future medical care.

Methods

Semi-structured interviews conducted with 32 self-identified PWID in New York City. Interviews were audio recorded and transcribed. Interview transcripts were coded using a grounded theory approach by three trained coders and key themes were identified as they emerged.

Results

A total of 25 participants (78.1%) reported at least one instance of stigma related to healthcare system engagement. Twenty-three participants (71.9%) reported some form of enacted stigma with healthcare, 19 participants (59.4%) described anticipated stigma with healthcare, and 20 participants (62.5%) reported positive experiences at SSPs. Participants attributed healthcare stigma to their drug injection use status and overwhelmingly felt distrustful of, and frustrated with, medical providers and other healthcare staff at hospitals and local clinics. PWID did not report internalized stigma, in part due to the availability of non-stigmatizing medical care at SSPs.

Conclusions

Stigmatizing experiences of PWID in formal healthcare settings contributed to negative attitudes toward seeking healthcare in the future. Many participants describe SSPs as accessible sites to receive high-quality medical care, which may curb the manifestation of internalized stigma derived from negative experiences in the broader healthcare system. Our findings align with those reported in the literature and reveal the potentially important role of SSPs. With the goal of limiting stigmatizing interactions and their consequences on PWID health, we recommend that future research include explorations of mechanisms by which PWID make decisions in stigmatizing healthcare settings, as well as improving medical care availability at SSPs.
A modular framework for the development of targeted Covid-19 blood transcript profiling panels
Authors: Rinchai Darawan , Syed Ahamed Kabeer Basirudeen , Toufiq Mohammed , Tatari-Calderone Zohreh , Deola Sara , Brummaier Tobias , Garand Mathieu , Branco Ricardo , Baldwin Nicole , Alfaki Mohamed , Altman Matthew C. , Ballestrero Alberto , Bassetti Matteo , Zoppoli Gabriele , De Maria Andrea , Tang Benjamin , Bedognetti Davide , Chaussabel Damien
Published: July 2020

Background

Covid-19 morbidity and mortality are associated with a dysregulated immune response. Tools are needed to enhance existing immune profiling capabilities in affected patients. Here we aimed to develop an approach to support the design of targeted blood transcriptome panels for profiling the immune response to SARS-CoV-2 infection.

Methods

We designed a pool of candidates based on a pre-existing and well-characterized repertoire of blood transcriptional modules. Available Covid-19 blood transcriptome data was also used to guide this process. Further selection steps relied on expert curation. Additionally, we developed several custom web applications to support the evaluation of candidates.

Results

As a proof of principle, we designed three targeted blood transcript panels, each with a different translational connotation: immunological relevance, therapeutic development relevance and SARS biology relevance.

Conclusion

Altogether the work presented here may contribute to the future expansion of immune profiling capabilities via targeted profiling of blood transcript abundance in Covid-19 patients.
Meta-analysis of mouse transcriptomic studies supports a context-dependent astrocyte reaction in acute CNS injury versus neurodegeneration
Authors: Das Sudeshna , Li Zhaozhi , Noori Ayush , Hyman Bradley T. , Serrano-Pozo Alberto
Published: July 2020

Background

Neuronal damage in acute CNS injuries and chronic neurodegenerative diseases is invariably accompanied by an astrocyte reaction in both mice and humans. However, whether and how the nature of the CNS insult—acute versus chronic—influences the astrocyte response, and whether astrocyte transcriptomic changes in these mouse models faithfully recapitulate the astrocyte reaction in human diseases remains to be elucidated. We hypothesized that astrocytes set off different transcriptomic programs in response to acute versus chronic insults, besides a shared “pan-injury” signature common to both types of conditions, and investigated the presence of these mouse astrocyte signatures in transcriptomic studies from human neurodegenerative diseases.

Methods

We performed a meta-analysis of 15 published astrocyte transcriptomic datasets from mouse models of acute injury (n = 6) and chronic neurodegeneration (n = 9) and identified pan-injury, acute, and chronic signatures, with both upregulated (UP) and downregulated (DOWN) genes. Next, we investigated these signatures in 7 transcriptomic datasets from various human neurodegenerative diseases.

Results

In mouse models, the number of UP/DOWN genes per signature was 64/21 for pan-injury and 109/79 for acute injury, whereas only 13/27 for chronic neurodegeneration. The pan-injury-UP signature was represented by the classic cytoskeletal hallmarks of astrocyte reaction (Gfap and Vim), plus extracellular matrix (i.e., Cd44, Lgals1, Lgals3, Timp1), and immune response (i.e., C3, Serping1, Fas, Stat1, Stat2, Stat3). The acute injury-UP signature was enriched in protein synthesis and degradation (both ubiquitin-proteasome and autophagy systems), intracellular trafficking, and anti-oxidant defense genes, whereas the acute injury-DOWN signature included genes that regulate chromatin structure and transcriptional activity, many of which are transcriptional repressors. The chronic neurodegeneration-UP signature was further enriched in astrocyte-secreted extracellular matrix proteins (Lama4, Cyr61, Thbs4), while the DOWN signature included relevant genes such as Agl (glycogenolysis), S1pr1 (immune modulation), and Sod2 (anti-oxidant). Only the pan-injury-UP mouse signature was clearly present in some human neurodegenerative transcriptomic datasets.

Conclusions

Acute and chronic CNS injuries lead to distinct astrocyte gene expression programs beyond their common astrocyte reaction signature. However, caution should be taken when extrapolating astrocyte transcriptomic findings from mouse models to human diseases.
Sirt6 inhibition delays the onset of experimental autoimmune encephalomyelitis by reducing dendritic cell migration
Authors: Ferrara Giovanni , Benzi Andrea , Sturla Laura , Marubbi Daniela , Frumento Davide , Spinelli Sonia , Abbotto Elena , Ivaldi Federico , von Holtey Maria , Murone Maximilien , Nencioni Alessio , Uccelli Antonio , Bruzzone Santina
Published: July 2020

Background

Experimental autoimmune encephalomyelitis (EAE) is the most common animal model of multiple sclerosis (MS), a neuroinflammatory and demyelinating disease characterized by multifocal perivascular infiltrates of immune cells. Although EAE is predominantly considered a T helper 1-driven autoimmune disease, mounting evidence suggests that activated dendritic cells (DC), which are the bridge between innate and adaptive immunity, also contribute to its pathogenesis. Sirtuin 6 (SIRT6), a NAD+-dependent deacetylase involved in genome maintenance and in metabolic homeostasis, regulates DC activation, and its pharmacological inhibition could, therefore, play a role in EAE development.

Methods

EAE was induced in female C57bl/6 mice by MOG35-55 injection. The effect of treatment with a small compound SIRT6 inhibitor, administered according to therapeutic and preventive protocols, was assessed by evaluating the clinical EAE score. SIRT6 inhibition was confirmed by Western blot analysis by assessing the acetylation of histone 3 lysine 9, a known SIRT6 substrate. The expression of DC activation and migration markers was evaluated by FACS in mouse lymph nodes. In addition, the expression of inflammatory and anti-inflammatory cytokines in the spinal cord were assessed by qPCR. T cell infiltration in spinal cords was evaluated by immunofluorescence imaging. The effect of Sirt6 inhibition on the migration of resting and activated bone marrow-derived dendritic cells was investigated in in vitro chemotaxis assays.

Results

Preventive pharmacological Sirt6 inhibition effectively delayed EAE disease onset through a novel regulatory mechanism, i.e., by reducing the representation of CXCR4-positive and of CXCR4/CCR7-double-positive DC in lymph nodes. The delay in EAE onset correlated with the early downregulation in the expression of CD40 on activated lymph node DC, with increased level of the anti-inflammatory cytokine IL-10, and with a reduced encephalitogenic T cell infiltration in the central nervous system. Consistent with the in vivo data, in vitro pharmacological Sirt6 inhibition in LPS-stimulated, bone marrow-derived DC reduced CCL19/CCL21- and SDF-1-induced DC migration.

Conclusions

Our findings indicate the ability of Sirt6 inhibition to impair DC migration, to downregulate pathogenic T cell inflammatory responses and to delay EAE onset. Therefore, Sirt6 might represent a valuable target for developing novel therapeutic agents for the treatment of early stages of MS, or of other autoimmune disorders.
Chronic extradural compression of spinal cord leads to syringomyelia in rat model
Authors: Ma Longbing , Yao Qingyu , Zhang Can , Li Mo , Cheng Lei , Jian Fengzeng
Published: July 2020

Background

Syringomyelia is a common spinal cord lesion. However, whether CSF blockage is linked to the formation and enlargement of syringomyelia is still controversial. The current model of syringomyelia needs modification to more closely mimic the clinical situation.

Methods

We placed cotton strips under the T13 lamina of 40 8-week-old rats and blocked CSF flow by extradural compression. After 4 and 8 weeks, MRI was performed to evaluate the morphology of syringomyelia and the ratio of spinal cord diameter to syrinx diameter calculated. Locomotor function was evaluated weekly. Spinal cord sections, staining and immunohistochemistry were performed 8 weeks after surgery, the ratio of the central canal to the spinal cord area was calculated, and ependymal cells were counted. In another experiment, we performed decompression surgery for 8 rats with induced syringomyelia at the 8th week after surgery. During the surgery, the cotton strip was completely removed without damaging the dura mater. Then, the rats received MRI imaging during the following weeks and were sacrificed for pathological examination at the end of the experiment.

Results

Syringomyelia formed in 82.5% (33/40) of rats at the 8-week follow-up. The Basso, Beattie and Bresnahan (BBB) scores of rats in the experimental group decreased from 21.0±0.0 to 18.0 ±3.9 in the first week after operation but returned to normal in later weeks. The BBB score indicated that the locomotor deficit caused by compression is temporary and can spontaneously recover. MRI showed that the syrinx is located in the center of the spinal cord, which is very similar to the most common syringomyelia in humans. The ratio of the central canal to the spinal cord area reached (2.9 ± 2.0) × 10−2, while that of the sham group was (5.4 ± 1.5) × 10−4. The number of ependymal cells lining the central canal was significantly increased (101.9 ±  39.6 vs 54.5 ± 3.4). There was no syrinx or proliferative inflammatory cells in the spinal cord parenchyma. After decompression, the syringomyelia size decreased in 50% (4/8) of the rats and increased in another 50% (4/8).

Conclusion

Extradural blockade of CSF flow can induce syringomyelia in rats. Temporary locomotor deficit occurred in some rats. This reproducible rat model of syringomyelia, which mimics syringomyelia in humans, can provide a good model for the study of disease mechanisms and therapies.
A robust spectral angle index for remotely assessing soybean canopy chlorophyll content in different growing stages
Authors: Yue Jibo , Feng Haikuan , Tian Qingjiu , Zhou Chengquan
Published: July 2020

Background

Timely and accurate estimates of canopy chlorophyll (Chl) a and b content are crucial for crop growth monitoring and agricultural management. Crop canopy reflectance depends on many factors, which can be divided into the following categories: (i) leaf effects (e.g., leaf pigments), (ii) canopy effects (e.g., Leaf Area Index [LAI]), and (iii) soil background reflectance (e.g., soil reflectance). The estimation of leaf variables, such as Chl contents, from reflectance at the canopy scale is usually less accurate than that at the leaf scale. In this study, we propose a Visible and Near-infrared (NIR) Angle Index (VNAI) to estimate the Chl content of soybean canopy, and soybean canopy Chl maps are produced using visible and NIR unmanned aerial vehicle (UAV) remote sensing images. The VNAI is insensitive to LAI and can be used for the multi-stage estimation of crop canopy Chl content.

Results

Eleven previously used vegetation indices (VIs) (e.g., Pigment-specific Normalized Difference Index) were selected for performance comparison. The results showed that (i) most previously used Chl VIs were significantly correlated with LAI, and the proposed VNAI was more sensitive to Chl content than LAI; (ii) the VNAI-based estimates of Chl content were more accurate than those based on the other investigated VIs using (1) simulated, (2) real (field), and (3) real (UAV) datasets.

Conclusions

Most previously used Chl VIs were significantly correlated with LAI whereas the proposed VNAI was more sensitive to Chl content than to LAI, indicating that the VNAI may be more strongly correlated with Chl content than these previously used VIs. Multi-stage estimations of the Chl content of cropland obtained using the VNAI and broadband remote sensing images may help to obtain Chl maps with high temporal and spatial resolution.