bluuebunny/crossref_metadata_2025 huggingface dataset:
Hypofibrinogenemia with preserved hemostasis and protection from thrombosis in mice with an Fga truncation mutation
Authors: Hur Woosuk S. , Paul David S. , Bouck Emma G. , Negrón Oscar A. , Mwiza Jean-Marie , Poole Lauren G. , Cline-Fedewa Holly M. , Clark Emily G. , Juang Lih Jiin , Leung Jerry , Kastrup Christian J. , Ugarova Tatiana P. , Wolberg Alisa S. , Luyendyk James P. , Bergmeier Wolfgang , Flick Matthew J.
Published: December 2021

Genetic variants within the fibrinogen Aα chain encoding the αC-region commonly result in hypodysfibrinogenemia in patients. However, the (patho)physiological consequences and underlying mechanisms of such mutations remain undefined. Here, we generated Fga270 mice carrying a premature termination codon within the Fga gene at residue 271. The Fga270 mutation was compatible with Mendelian inheritance for offspring of heterozygous crosses. Adult Fga270/270 mice were hypofibrinogenemic with ∼10% plasma fibrinogen levels relative to FgaWT/WT mice, linked to 90% reduction in hepatic Fga messenger RNA (mRNA) because of nonsense-mediated decay of the mutant mRNA. Fga270/270 mice had preserved hemostatic potential in vitro and in vivo in models of tail bleeding and laser-induced saphenous vein injury, whereas Fga−/− mice had continuous bleeding. Platelets from FgaWT/WT and Fga270/270 mice displayed comparable initial aggregation following adenosine 5′-diphosphate stimulation, but Fga270/270 platelets quickly disaggregated. Despite ∼10% plasma fibrinogen, the fibrinogen level in Fga270/270 platelets was ∼30% of FgaWT/WT platelets with a compensatory increase in fibronectin. Notably, Fga270/270 mice showed complete protection from thrombosis in the inferior vena cava stasis model. In a model of Staphylococcus aureus peritonitis, Fga270/270 mice supported local, fibrinogen-mediated bacterial clearance and host survival comparable to FgaWT/WT, unlike Fga−/− mice. Decreasing the normal fibrinogen levels to ∼10% with small interfering RNA in mice also provided significant protection from venous thrombosis without compromising hemostatic potential and antimicrobial function. These findings both reveal novel molecular mechanisms underpinning fibrinogen αC-region truncation mutations and highlight the concept that selective fibrinogen reduction may be efficacious for limiting thrombosis while preserving hemostatic and immune protective functions.
OTC intron 4 variations mediate pathogenic splicing patterns caused by the c.386G>A mutation in humans and spfash mice, and govern susceptibility to RNA-based therapies
Authors: Sacchetto Claudia , Peretto Laura , Baralle Francisco , Maestri Iva , Tassi Francesca , Bernardi Francesco , van de Graaf Stan F. J. , Pagani Franco , Pinotti Mirko , Balestra Dario
Published: December 2021

Background

Aberrant splicing is a common outcome in the presence of exonic or intronic variants that might hamper the intricate network of interactions defining an exon in a specific gene context. Therefore, the evaluation of the functional, and potentially pathological, role of nucleotide changes remains one of the major challenges in the modern genomic era. This aspect has also to be taken into account during the pre-clinical evaluation of innovative therapeutic approaches in animal models of human diseases. This is of particular relevance when developing therapeutics acting on splicing, an intriguing and expanding research area for several disorders. Here, we addressed species-specific splicing mechanisms triggered by the OTC c.386G>A mutation, relatively frequent in humans, leading to Ornithine TransCarbamylase Deficiency (OTCD) in patients and spfash mice, and its differential susceptibility to RNA therapeutics based on engineered U1snRNA.

Methods

Creation and co-expression of engineered U1snRNAs with human and mouse minigenes, either wild-type or harbouring different nucleotide changes, in human (HepG2) and mouse (Hepa1-6) hepatoma cells followed by analysis of splicing pattern. RNA pulldown studies to evaluate binding of specific splicing factors.

Results

Comparative nucleotide analysis suggested a role for the intronic +10-11 nucleotides, and pull-down assays showed that they confer preferential binding to the TIA1 splicing factor in the mouse context, where TIA1 overexpression further increases correct splicing. Consistently, the splicing profile of the human minigene with mouse +10-11 nucleotides overlapped that of mouse minigene, and restored responsiveness to TIA1 overexpression and to compensatory U1snRNA. Swapping the human +10-11 nucleotides into the mouse context had opposite effects.

Moreover, the interplay between the authentic and the adjacent cryptic 5′ss in the human OTC dictates pathogenic mechanisms of several OTCD-causing 5′ss mutations, and only the c.386+5G>A change, abrogating the cryptic 5′ss, was rescuable by engineered U1snRNA.

Conclusions

Subtle intronic variations explain species-specific OTC splicing patterns driven by the c.386G>A mutation, and the responsiveness to engineered U1snRNAs, which suggests careful elucidation of molecular mechanisms before proposing translation of tailored therapeutics from animal models to humans.
A novel biplanar medial opening-wedge high tibial osteotomy: the Z-shaped technique. A case series at 7.2 years follow-up
Authors: Presutti Marcello , Goderecci Remo , Palumbo Pietro , Giannetti Alessio , Mazzoleni Manuel Giovanni , Randelli Filippo Maria Nicola , Angelozzi Massimo , Calvisi Vittorio , Fidanza Andrea
Published: December 2021

Background

High tibial osteotomy (HTO) provides reliable and good long-term results, if performed with correct indications, but different techniques and types of fixation have been described. The purpose of this study is to present a novel modified biplanar medial opening-wedge (MOW) HTO technique where the osteotomies are performed in a Z-shaped fashion, and to present the medium-term clinical and radiographic results.

Materials and methods

We present a case series of 75 patients (80 knees) with mean age of 45.8 years, affected by isolated medial knee osteoarthritis and symptomatic varus knee malalignment, who underwent novel biplanar Z-shaped MOWHTO. Clinical and radiological outcomes were collected, retrospectively before surgery and at median follow-up of 7.2 years (95% CI 5.6–9.2 months) after surgery. Clinical results and satisfaction were assessed by visual analog scale (VAS), Western Ontario and McMaster University Osteoarthritis Index (WOMAC), and Likert scale. Radiological assessment involved the evaluation of the medial proximal tibial angle (MPTA), tibial slope (TS), Caton–Deschamps index, and knee osteoarthritis grade according to Ahlbäck classification. Pre- and postoperative results were compared using the two-tailed t-test or Wilcoxon’s test of independent samples for paired data or nonparametric analog. P < 0.05 was considered significant.

Results

At medium-term follow-up, Z-shaped MOWHTO showed a survival rate of 95 ± 1.7% with failure occurring in four knees due to symptom recurrence and osteoarthritis progression. No perioperative complications were observed (intraarticular fracture, delayed union or nonunion, and neurological injury). Mean bone healing time was 12 weeks. Clinical scores showed significant improvement at last follow-up and a good grade of satisfaction. MPTA increased significantly, while Caton–Deschamps index decreased significantly. No significant TS increase was found.

Conclusions

Modified biplanar Z-shaped MOWHTO is a safe and reliable technique that offers satisfactory clinical and radiological medium-term outcomes with low knee arthroplasty conversion rate. The unique three-dimensional geometrical conformation potentially provides a favorable environment for bone healing, increased anteroposterior and rotational stability, and safer opening-wedge loading force application with low lateral hinge fracture risk.

Level of evidence

Level IV, retrospective observational case series study.

Trial registration The study protocol was approved by the Internal Review Board of our Institution (authorization number 54/2019, 20 November 2019).
Identification and validation of a regulatory mutation upstream of the BMP2 gene associated with carcass length in pigs
Authors: Li Jing , Peng Song , Zhong Liepeng , Zhou Lisheng , Yan Guorong , Xiao Shijun , Ma Junwu , Huang Lusheng
Published: December 2021

Background

Carcass length is very important for body size and meat production for swine, thus understanding the genetic mechanisms that underly this trait is of great significance in genetic improvement programs for pigs. Although many quantitative trait loci (QTL) have been detected in pigs, very few have been fine-mapped to the level of the causal mutations. The aim of this study was to identify potential causal single nucleotide polymorphisms (SNPs) for carcass length by integrating a genome-wide association study (GWAS) and functional assays.

Results

Here, we present a GWAS in a commercial Duroc × (Landrace × Yorkshire) (DLY) population that reveals a prominent association signal (P = 4.49E−07) on pig chromosome 17 for carcass length, which was further validated in two other DLY populations. Within the detected 1 Mb region, the BMP2 gene stood out as the most likely causal candidate because of its functions in bone growth and development. Whole-genome gene expression studies showed that the BMP2 gene was differentially expressed in the cartilage tissues of pigs with extreme carcass length. Then, we genotyped an additional 267 SNPs in 500 selected DLY pigs, followed by further whole-genome SNP imputation, combined with deep genome resequencing data on multiple pig breeds. Reassociation analyses using genotyped and imputed SNP data revealed that the rs320706814 SNP, located approximately 123 kb upstream of the BMP2 gene, was the strongest candidate causal mutation, with a large association with carcass length, with a ~ 4.2 cm difference in length across all three DLY populations (N = 1501; P = 3.66E−29). This SNP segregated in all parental lines of the DLY (Duroc, Large White and Landrace) and was also associated with a significant effect on body length in 299 pure Yorkshire pigs (P = 9.2E−4), which indicates that it has a major value for commercial breeding. Functional assays showed that this SNP is likely located within an enhancer and may affect the binding affinity of transcription factors, thereby regulating BMP2 gene expression.

Conclusions

Taken together, these results suggest that the rs320706814 SNP on pig chromosome 17 is a putative causal mutation for carcass length in the widely used DLY pigs and has great value in breeding for body size in pigs.
Comparative transcriptome and metabolome analysis reveal glutathione metabolic network and functional genes underlying blue and red-light mediation in maize seedling leaf
Authors: Liu Tiedong , Zhang Xiwen
Published: December 2021

Background

Light quality severely affects biosynthesis and metabolism-associated process of glutathione. However, the role of specific light is still unclear on the glutathione metabolism. In this article, comparatively transcriptome and metabolome methods are used to fully understand the blue and red-light conditions working on the glutathione metabolism in maize seedling leaf.

Results

There are 20 differently expressed genes and 4 differently expressed metabolites in KEGG pathway of glutathione metabolism. Among them, 12 genes belong to the glutathione S-transferase family, 3 genes belong to the ascorbate peroxidase gene family and 2 genes belong to the ribonucleoside-diphosphate reductase gene family. Three genes, G6PD, SPDS1, and GPX1 belong to the gene family of glucose 6-phosphate dehydrogenase, spermidine synthase, and glutathione peroxidase, respectively. Four differently expressed metabolites are identified. Three of them, Glutathione disulfide, Glutathione, and l-γ-Glutamyl-L-amino acid are decreased while L-Glutamate is increased. In addition, Through PPI analysis, two annotated genes gst16 and DAAT, and 3 unidentified genes 100381533, pco105094 and umc2770, identified as RPP13-like3, BCAT-like1and GMPS, were obtained. By the analysis of protein sequence and PPI network, we predict that pco105094 and umc2770 were involved in the GSSG-GSH and AsA-GSH cycle in the network of glutathione metabolism.

Conclusions

Compared to red light, blue light remarkably changed the transcription signal transduction and metabolism of glutathione metabolism. Differently expressed genes and metabolic mapped to the glutathione metabolism signaling pathways. In total, we obtained three unidentified genes, and two of them were predicted in current glutathione metabolism network. This result will contribute to the research of glutathione metabolism of maize.
Comparison of different embolic particles for superior rectal arterial embolization of chronic hemorrhoidal bleeding: gelfoam versus microparticle
Authors: Wang Xuemin , Sheng Yuguo , Wang Zhu , Wang Wenming , Xia Fengfei , Zhao Mengpeng , Han Xinqiang
Published: December 2021

Background

Whether different embolic particles with comparable diameter lead to similar beneficial effects in endovascular embolization of hemorrhoidal disease remains to be established. We sought to evaluate the efficacy and safety of different types of agents for superior rectal arterial embolization (SRAE) in patients with bleeding hemorrhoids.

Methods

Patients with recurrent episodes of internal hemorrhoidal bleeding and chronic anemia treated by SRAE in three tertiary hospitals between March 2017 and June 2020 were retrospectively evaluated. The patients were divided into two study groups based on the embolic materials: embolization with coils (2–3 mm) + gelfoam particles at 350–560 μm (Group A, n = 23), embolization with coils (2–3 mm) + microparticles at 300–500 μm (Group B, n = 18). The technical success, preliminary clinical efficacy (percentage of patients without hematochezia), postoperative complications and short-term follow-up outcomes were analysed.

Results

A total of 41 patients (27 males) with symptomatic hemorrhoids were included in the study, mean age was 47 ± 12 years (range 25–72). 39% (16) patients with grade II hemorrhoids while 61% (25) patients with grade III. The technical success rate of the embolization procedure was 100%, and the preliminary clinical efficacy (87.0% vs 88.9%) showed no significant difference between the 2 groups (p = 0.098). No patients reported post-procedural and short-term serious complications, such as infection, intestinal ischemia or massive hemorrhage during the follow-up period (range 6–15 months).

Conclusions

Both gelfoam particles and microparticles with comparable diameter in the endovascular treatment of hemorrhoidal bleeding demonstrated similarly good short-term efficacy and safety profile.
Three-step operation for esophago-left bronchial fistula with respiratory failure after esophagectomy: a case report with literature review
Authors: Sato Yuta , Tanaka Yoshihiro , Suetsugu Tomonari , Takaha Ritsuki , Ojio Hidenori , Hatanaka Yuji , Imai Takeharu , Okumura Naoki , Matsuhashi Nobuhisa , Takahashi Takao , Kato Hisakazu , Yoshida Kazuhiro
Published: December 2021

Background

The development of esophago-bronchial fistula after esophagectomy and reconstruction using a posterior mediastinal gastric tube remains a rare complication associated with a high rate of mortality.

Case presentation

A 63-year-old man with esophageal cancer underwent a thoracoscopic esophagectomy with two-field lymph node dissection and reconstruction via a gastric tube through the posterior mediastinal route. Postoperatively, the patient developed extensive pyothorax in the right lung due to port site bleeding and hematoma infection. Four months after surgery, he developed an esophago-left bronchial fistula due to ischemia of the cervical esophagus and severe reflux esophagitis at the site of the anastomosis. Because of respiratory failure due to the esophago-bronchial fistula and the history of extensive right pyothorax, right thoracotomy and left one-lung ventilation were thought to be impossible, so we decided to perform the surgery in three-step systematically. First, we inserted a decompression catheter and feeding tube into the gastric tube as a gastrostomy and expected neovascularization to develop from the wall of the gastric tube through the anastomosis after this procedure. Second, 14 months after esophagectomy, we constructed an esophagostomy after confirming blood flow in the distal side of the cervical esophagus via gastric tube using intraoperative indocyanine green-guided blood flow evaluation. In the final step, we closed the esophagostomy and performed a cervical esophago-jejunal anastomosis to restore esophageal continuity using a pedicle jejunum in a Roux-en-Y anastomosis via a subcutaneous route.

Conclusion

This three-step operation can be an effective procedure for patients with esophago-left bronchial fistula after esophagectomy, especially those with respiratory failure and difficulty in undergoing right thoracotomy with left one-lung ventilation.
Initial experience with novel CGRP-receptor inhibitor therapy in Migraine in the United Arab Emirates: a retrospective observational study
Authors: Dinh Bui Bao Khanh , Aziz Waseem Hamed , Terruzzi Alessandro , Krieger Derk Wolfgang
Published: December 2021

Background

Erenumab is a calcitonin gene-related peptide (CGRP)-receptor antibody inhibiting CGRP function. CGRP is prominently involved in the pathophysiology of migraine through nociceptive modulation in the trigeminovascular system. This study aims to explore the treatment effect of erenumab in a real-life setting.

Methods

In this retrospective observational study, we analyzed the data of 91 patients with migraine receiving at least three consecutive monthly injections of erenumab and followed up for 3–12 months. The primary objective was to describe the reduction in monthly migraine days throughout the follow-up period. To identify patients who responded to treatment, we analyzed the association between different patient characteristics and their treatment outcomes.

Results

Seventy-three patients (80.2%) responded to erenumab treatment, defined as ≥50% reduction of migraine days per month, across all migraine types. It was noted that ethnicity (p-value = 0.015) and older age (p-value = 0.035) were associated with clinically relevant improvement of symptoms. Middle Eastern ethnicity was related to less improvement of symptoms while Europeans were more likely to benefit from erenumab therapy (odds ratio: 12.788, p = 0.037). Patients aged from 31 to 40 and 41–65 years benefited most from erenumab treatment with a response rate of 77.8 and 89.9%, respectively, also confirmed by logistic regression (p = 0.047). Neither gender nor dose increase of erenumab showed association with the reported clinically relevant improvement of the symptoms. An association between clinically relevant improvement of headaches and the type of migraine was also noted. Around 87.9% of patients with episodic migraine responded to treatment, followed by 84.1% of chronic migraine patients and 50% of medication overuse headache patients. Medication overuse headache showed a lower probability of therapy success with erenumab (odds ratio: 0.126, p = 0.039). An improvement of headaches was eminent in patients who received 140 mg erenumab monthly (2 × 70 mg injections) and patients who had one injection every two weeks.

Conclusions

Erenumab is a novel preventive treatment for all migraine types. Clinically relevant improvement of headaches and reduction of monthly migraine days were demonstrated in patients that continued the treatment course. In real-life, a substantial number of patients suspended therapy early, reasons for which need further investigation.
Persistent hyperglycemia is a useful glycemic pattern to predict stroke mortality: a systematic review and meta-analysis
Authors: Hou Duanlu , Zhong Ping , Ye Xiaofei , Wu Danhong
Published: December 2021

Background

Glycemic patterns have been reported to be prognostic factors for stroke; however, this remains to be further evaluated. This meta-analysis aimed to evaluate the usefulness of glycemic patterns such as persistent hyperglycemia (PH) including short duration and long duration PH (SPH; LPH), admission hyperglycemia (AH), short-duration hyperglycemia (SH), and persistent normoglycemia (PN) in predicting stroke prognosis using published results.

Methods

Major scientific databases including but are not limited to PubMed, EMBASE, Web of Science, Ovid, CNKI (Chinese National Knowledge Infrastructure), and Clinicaltrials.gov were searched till 1st March 2021 for clinical trials on the correlation between glycemic patterns and stroke outcomes. The primary outcome was defined as short-term (1- or 3-month) post-stroke mortality, and the secondary outcome was post-stroke hemorrhage at 6 months.

Results

Ten studies involving 3584 individuals were included in the final analysis. In subgroup analyses, PH patients with no history of diabetes had increased post-stroke mortality (odds ratio [OR]: 4.80, 95% CI: 3.06–7.54) than patients with no PH; and patients with glucose levels > 140 mg/dl had greater mortality (OR: 5.12, 95% CI: 3.21–8.18) than those with glucose levels < 140 mg/dl; compared with AH patients, PH patients had increased short-term mortality (OR: 0.31, 95% CI: 0.16–0.60). In the prediction of stroke mortality among patients without diabetes, SPH (OR: 0.28, 95%CI: 0.12–0.69) seemed to be more related to increased mortality than LPH (OR: 0.35, 95% CI: 0.14–-0.90).

Conclusions

PH, especially SPH, could predict increased post-stroke mortality in non-diabetic patients. The rank of individual glycemic patterns in predicting stroke mortality in non-diabetic patients was SPH > LPH > AH > PN.
A qualitative focus group study concerning perceptions and experiences of Nigerian mothers on stillbirths
Authors: Milton R. , Alkali F. I. , Modibbo F. , Sanders J. , Mukaddas A. S. , Kassim A. , Sa’ad F. H. , Tukur F. M. , Pell B. , Hood K. , Ghazal P. , Iregbu K. C.
Published: December 2021

Objective

To explore the experiences and perceptions of stillbirth among mothers from a tertiary medical centre in Kano, Northern Nigeria.

Design

Qualitative, interpretative.

Setting

Tertiary healthcare facility, Murtala Muhammad Specialist Hospital (MMSH), Kano, Northern Nigeria.

Sample

Mothers who had given birth to a liveborn baby at the MMSH in the prior 6 months (n = 31). In order to capture the experiences and perception of stillbirth within this cohort we approached mothers who had in a previous pregnancy experienced a stillbirth. Of the 31 who attended 16 had a previous stillbirth.

Methods

Semi-structured Focus Group Discussions, consisting of open-ended questions about stillbirth, beliefs, experiences and influences were held in MMSH, conducted over 1 day.

Results

Our findings highlight that this is a resource-poor tertiary facility serving an ever-growing population, increasing strain on the hospital and healthcare workers. Many of the participants highlighted needing permission from certain family members before accessing healthcare or medical treatment. We identified that mothers generally have knowledge on self-care during pregnancy, yet certain societal factors prevented that from being their priority. Judgement and blame was a common theme, yet a complex area entwined with traditions, superstitions and the pressure to procreate with many mothers described being made to feel useless and worthless if they did not birth a live baby.

Conclusions

As access to healthcare becomes easier, there are certain traditions, family and social dynamics and beliefs which conflict with scientific knowledge and act as a major barrier to uptake of healthcare services. The findings highlight the need for investment in maternity care, appropriate health education and public enlightenment; they will help inform appropriate interventions aimed at reducing stigma around stillbirth and aide in educating mothers about the importance of appropriate health seeking behaviour. Stillbirths are occurring in this area of the world unnecessarily, globally there has been extensive research conducted on stillbirth prevention. This research has highlighted some of the areas which can be tackled by modifying existing successful interventions to work towards reducing preventable stillbirths.
Anemia among pregnant women in internally displaced camps in Mogadishu, Somalia: a cross-sectional study on prevalence, severity and associated risk factors
Authors: Ahmed Ramla Hussein , Yussuf Asha Abdirahman , Ali Asma Abdikarin , Iyow Sowdo Nuur , Abdulahi Maryan , Mohamed Lul Mohamud , Mohamud Mohamed Hayir Tahlil
Published: December 2021

Background

Anemia in pregnancy is a serious global public health problem in most developing countries and a major cause of maternal morbidity and mortality. Somalia which already had very high maternal mortality ratio of 829 per 100,000 live births, pregnant women in internally displaced camps (IDPs) remain at most exposed. The aim of the study was to determine the prevalence, severity and associated risk factors of anemia among pregnant women in internally displaced camps in Mogadishu, Somalia.

Methods

A community based cross-sectional study was conducted among 383 households in the most IDP settled districts in Mogadishu. Every pregnant mother in these sampled households who was voluntarily consented was targeted. A sample of blood was also taken by pricking the fingertip and inserted into hemoglobin meter. Those with Hb < 11 g/dl from hemoglobin meter had been taken another sample of 3 cc blood and put into EDTA tube for CBC analysis to identify the type of anemia. Data on risk factors were collected using structured pretested questionnaire via an interview. Collected data was coded and entered in SPSS- Version 22 for analysis. Descriptive analysis, bivariate chi-square and multivariate logistic regression were done.

Results

The overall prevalence of anemia among study participants was 44.4% (95%CI: 39.5-49.3%), where severe and moderate anemia were 11.8 and 47.0% respectively. In addition all anaemic cases were microcytic hypochromic anemia. Young maternal age, low Family income, fewer/zero parity, being at third or second trimesters, lack of ANC attendance during pregnancy, lack of iron supplementation during pregnancy, taking tea immediately after meal during pregnancy, lower/zero frequency of daily meat and vegetables consumption during pregnancy were associated risk factors of anemia.

Conclusion

The anemia prevalence from this study was severe public health problem. Several factors were found to be associated with anemia during pregnancy. Measures has to be taken to curb the problem by including them mass iron supplementation and health education towards identified risk factors.
Identification of immune subtypes of Ph-neg B-ALL with ferroptosis related genes and the potential implementation of Sorafenib
Authors: Hong Yang , Zhang Ling , Tian Xiaopeng , Xiang Xin , Yu Yan , Zeng Zhao , Cao Yaqing , Chen Suning , Sun Aining
Published: December 2021

Background

The clinical outcome of Philadelphia chromosome-negative B cell acute lymphoblastic leukemia (Ph-neg B-ALL) varies considerably from one person to another after clinical treatment due to lack of targeted therapies and leukemia’s heterogeneity. Ferroptosis is a recently discovered programmed cell death strongly correlated with cancers. Nevertheless, few related studies have reported its significance in acute lymphoblastic leukemia.

Methods

Herein, we collected clinical data of 80 Ph-neg B-ALL patients diagnosed in our center and performed RNA-seq with their initial bone marrow fluid samples. Throughout unsupervised machine learning K-means clustering with 24 ferroptosis related genes (FRGs), the clustered patients were parted into three variant risk groups and were performed with bioinformatics analysis.

Results

As a result, we discovered significant heterogeneity of both immune microenvironment and genomic variance. Furthermore, the immune check point inhibitors response and potential implementation of Sorafenib in Ph-neg B-ALL was also analyzed in our cohort. Lastly, one prognostic model based on 8 FRGs was developed to evaluate the risk of Ph-neg B-ALL patients.

Conclusion

Jointly, our study proved the crucial role of ferroptosis in Ph-neg B-ALL and Sorafenib is likely to improve the survival of high-risk Ph-neg B-ALL patients.
Sickness absence and disability pension among injured working-aged pedestrians - a population-based Swedish register study
Authors: Kjeldgård Linnea , Stigson Helena , Klingegård Maria , Alexanderson Kristina , Friberg Emilie
Published: December 2021

Background

The knowledge is scarce about sickness absence (SA) and disability pension (DP) among pedestrians injured in a traffic-related accident, including falls. Thus, the aim was to explore the frequencies of types of accidents and injuries and their association with SA and DP among working-aged individuals.

Methods

A nationwide register-based study, including all individuals aged 16-64 and living in Sweden, who in 2010 had in- or specialized outpatient healthcare after a new traffic-related accident as a pedestrian. Information on age, sex, sociodemographics, SA, DP, type of accident, injury type, and injured body region was used. Frequencies of pedestrians with no SA or DP, with ongoing SA or full-time DP already at the time of the accident, and with a new SA spell >14 days in connection to the accident were analyzed. Crude and adjusted odds ratios (ORs) with 95% confidence intervals (CIs) for new SA were estimated by logistic regression.

Results

In total, 5576 pedestrians received healthcare due to a traffic-related accident (of which 75% were falls, with half of the falls related to snow and ice). At the time of the accident, 7.5% were already on SA and 10.8% on full-time DP, while 20% started a new SA spell. The most common types of injuries were fractures (45%) and external injuries (30%). The body region most frequently injured was the lower leg, ankle, foot, and other (in total 26%). Older individuals had a higher OR for new SA compared with younger (OR 1.91; 95% CI 1.44-2.53, for ages: 45-54 vs. 25-34). The injury type with the highest OR for new SA, compared with the reference group external injuries, was fractures (9.58; 7.39-12.43). The injured body region with the highest OR for new SA, compared with the reference group head, face, and neck, was lower leg, ankle, foot, and other (4.52; 2.78-7.36).

Conclusions

In this explorative nationwide study of the working-aged pedestrians injured in traffic-related accidents including falls, one fifth started a new SA spell >14 days. Fractures, internal injuries, collisions with motor vehicle, and falls related to snow and ice had the strongest associations with new SA.
“The Real Cost” Smokeless campaign: changes in beliefs about smokeless tobacco among rural boys, a longitudinal randomized controlled field trial
Authors: Farrelly Matthew C. , Taylor Nathaniel H. , Nonnemaker James M. , Smith Alexandria A. , Delahanty Janine C. , Zhao Xiaoquan
Published: December 2021

Background

The prevalence of current smokeless tobacco (SLT) use in 2019 among high school students was 4.8%, and the overall rate of SLT use was higher among high school boys (7.5%) than girls (1.8%). The U.S. Food and Drug Administration (FDA) launched “The Real Cost” Smokeless media campaign in April 2016 to educate rural youth about the dangers of SLT use. In this study, we evaluate the effectiveness of “The Real Cost” Smokeless campaign.

Methods

We use a 3-year (Jan 2016 – Dec 2018) randomized controlled longitudinal field trial that consists of a baseline survey of boys and a parent/guardian and four follow-up surveys of the boys. The cohort includes 2200 boys who were 11 to 16 years old at baseline and lived in the rural segments of 30 media markets (15 treatment markets and 15 control). “The Real Cost” Smokeless campaign targets boys who are 12 to 17 years old in 35 media markets. It focuses primarily on graphic depictions of cosmetic and long-term health consequences of SLT use. The key outcome measures include beliefs and attitudes toward SLT that are targeted (explicitly or implicitly) by campaign messages.

Results

Using multivariate difference-in-difference analysis (conducted in 2019 and 2020), we found that agreement with 4 of the 11 explicit campaign-targeted belief and attitude measures increased significantly from baseline to post-campaign launch among boys 14 to 16 years old in treatment vs. control markets. Agreement did not increase for boys 11–13 years old in treatment vs. control markets and only increased for one targeted message for the overall sample.

Conclusions

These findings suggest that “The Real Cost” Smokeless campaign influenced beliefs and attitudes among older boys in campaign markets and that a campaign focused on health consequences of tobacco use can be targeted to rural boys, influence beliefs about SLT use, and potentially prevent SLT use.
Value of willingness to pay for a QALY gained in Iran; a modified chained-approach
Authors: Jahanbin Seyedeh-Fariba , Yusefzadeh Hasan , Nabilou Bahram , Alinia Cyrus
Published: December 2021

Background

Due to the lack of a constant Willingness to Pay per one additional Quality Adjusted Life Years gained based on the preferences of Iran’s general public, the cost-effectiveness of health system interventions is unclear and making it challenging to apply economic evaluation to health resources priority setting.

Methods

We have measured this cost-effectiveness threshold with the participation of 2854 individuals from five provinces, each representing an income quintile, using a modified Time Trade-Off-based Chained-Approach. In this online-based empirical survey, to extract the health utility value, participants were randomly assigned to one of two green (21121) and yellow (22222) health scenarios designed based on the earlier validated EQ-5D-3L questionnaire.

Results

Across the two health state versions, mean values for one QALY gain (rounded) ranged from $6740-$7400 and $6480-$7120, respectively, for aggregate and trimmed models, which are equivalent to 1.35-1.18 times of the GDP per capita. Log-linear Multivariate OLS regression analysis confirmed that respondents were more likely to pay if their income, disutility, and education level were higher than their counterparts.

Conclusions

In the health system of Iran, any intervention that is with the incremental cost-effectiveness ratio, equal to and less than 7402.12 USD, will be considered cost-effective.
LEA motifs promote desiccation tolerance in vivo
Authors: Hibshman Jonathan D. , Goldstein Bob
Published: December 2021

Background

Cells and organisms typically cannot survive in the absence of water. However, some animals including nematodes, tardigrades, rotifers, and some arthropods are able to survive near-complete desiccation. One class of proteins known to play a role in desiccation tolerance is the late embryogenesis abundant (LEA) proteins. These largely disordered proteins protect plants and animals from desiccation. A multitude of studies have characterized stress-protective capabilities of LEA proteins in vitro and in heterologous systems. However, the extent to which LEA proteins exhibit such functions in vivo, in their native contexts in animals, is unclear. Furthermore, little is known about the distribution of LEA proteins in multicellular organisms or tissue-specific requirements in conferring stress protection. Here, we used the nematodeC. elegansas a model to study the endogenous function of an LEA protein in an animal.

Results

We created a null mutant ofC. elegansLEA-1, as well as endogenous fluorescent reporters of the protein. LEA-1 mutant animals formed defective dauer larvae at high temperature. We confirmed thatC. eleganslacking LEA-1 are sensitive to desiccation. LEA-1 mutants were also sensitive to heat and osmotic stress and were prone to protein aggregation. During desiccation, LEA-1 expression increased and became more widespread throughout the body. LEA-1 was required at high levels in body wall muscle for animals to survive desiccation and osmotic stress, but expression in body wall muscle alone was not sufficient for stress resistance, indicating a likely requirement in multiple tissues. We identified minimal motifs withinC. elegansLEA-1 that were sufficient to increase desiccation survival ofE. coli. To test whether such motifs are central to LEA-1’s in vivo functions, we then replaced the sequence oflea-1with these minimal motifs and found thatC. elegansdauer larvae formed normally and survived osmotic stress and mild desiccation at the same levels as worms with the full-length protein.

Conclusions

Our results provide insights into the endogenous functions and expression dynamics of an LEA protein in a multicellular animal. The results show that LEA-1 buffers animals from a broad range of stresses. Our identification of LEA motifs that can function in both bacteria and in a multicellular organism in vivo suggests the possibility of engineering LEA-1-derived peptides for optimized desiccation protection.
Influence of prefoldin subunit 4 on the tolerance of Kluyveromyces marxianus to lignocellulosic biomass-derived inhibitors
Authors: Zhang Nini , Shang Yingying , Wang Feier , Wang Dongmei , Hong Jiong
Published: December 2021

Background

Kluyveromyces marxianusis a potentially excellent host for microbial cell factories using lignocellulosic biomass, due to its thermotolerance, high growth rate, and wide substrate spectrum. However, its tolerance to inhibitors derived from lignocellulosic biomass pretreatment needs to be improved. The prefoldin complex assists the folding of cytoskeleton which relates to the stress tolerance, moreover, several subunits of prefoldin have been verified to be involved in gene expression regulation. With the presence of inhibitors, the expression of a gene coding the subunit 4 of prefoldin (KmPFD4), a possible transcription factor, was significantly changed. Therefore,KmPFD4was selected to evaluate its functions in inhibitors tolerance.

Results

In this study, the disruption of the prefoldin subunit 4 gene (KmPFD4) led to increased concentration of intracellular reactive oxygen species (ROS) and disturbed the assembly of actin and tubulin in the presence of inhibitors, resulting in reduced inhibitor tolerance. Nuclear localization of KmPFD4 indicated that it could regulate gene expression. Transcriptomic analysis showed that upregulated gene expression related to ROS elimination, ATP production, and NAD+synthesis, which is a response to the presence of inhibitors, disappeared inKmPFD4-disrupted cells. Thus,KmPFD4impacts inhibitor tolerance by maintaining integration of the cytoskeleton and directly or indirectly affecting the expression of genes in response to inhibitors. Finally, overexpression ofKmPFD4enhanced ethanol fermentation with a 46.27% improvement in productivity in presence of the inhibitors.

Conclusion

This study demonstrated thatKmPFD4plays a positive role in the inhibitor tolerance and can be applied for the development of inhibitor-tolerant platform strains.
C1QTNF6 promotes oral squamous cell carcinoma by enhancing proliferation and inhibiting apoptosis
Authors: Song Xiaobin , Li Longjie , Shi Liang , Liu Xinyu , Qu Xun , Wei Fengcai , Wang Ketao
Published: December 2021

Background

C1QTNF6 (CTRP6), a member of the CTRP family, has recently been implied to play a role in the tumorigenesis of for a variety of cancer types. However, the role of C1QTNF6 in oral squamous cell carcinoma (OSCC) and its potential molecular remains unclear.

Methods

C1QTNF6 expression was detected by qRT-PCR and western blot analysis. Lentiviral vectors were constructed to knockdown C1QTNF6 in CaL27 and SCC-9 human OSCC cell lines. Cell viability, cell cycle and cell apoptosis analyses were performed by MTT assay, PI/Annexin V staining, and flow cytometry. The effect of C1QTNF6 knockdown on in vivo tumorigenicity of OSCC cells in vivo was evaluated using nude mouse xenograft tumor model. Downstream signaling mechanisms were identified by microarray and Ingenuity Pathway Analysis.

Results

Immunohistochemistry of OSCC tissue and data from TCGA demonstrate that C1QTNF6 was overexpressed in OSCC tissues, and that cellular proliferation was significantly decreased after C1QTNF6 was knockdown in CaL27 and SCC-9 cell lines. Knockdown of C1QTNF6 also resulted in cell cycle arrest at the G2/M phase and enhanced cell apoptosis in in CaL27 and SCC-9 cell lines. Furthermore, knockdown of C1QTNF6 in Cal-27 cells inhibited tumor growth of OSCC in vivo. Microarray analysis revealed that C1QTNF6 silencing resulted in significant alterations of gene expression, with the Acute Phase Response signaling pathway significantly activated following C1QTNF6 silencing.

Conclusions

These results suggest that C1QTNF6 plays an important role in promoting OSCC tumorigenesis, which indicates that C1QTNF6 may comprise a promising therapeutic target for OSCC treatment.
ITGB1-DT/ARNTL2 axis may be a novel biomarker in lung adenocarcinoma: a bioinformatics analysis and experimental validation
Authors: Qiu Bai-Quan , Lin Xia-Hui , Lai Song-Qing , Lu Feng , Lin Kun , Long Xiang , Zhu Shu-Qiang , Zou Hua-Xi , Xu Jian-Jun , Liu Ji-Chun , Wu Yong-Bing
Published: December 2021

Background

Lung cancer is one of the most lethal malignant tumors that endangers human health. Lung adenocarcinoma (LUAD) has increased dramatically in recent decades, accounting for nearly 40% of all lung cancer cases. Increasing evidence points to the importance of the competitive endogenous RNA (ceRNA) intrinsic mechanism in various human cancers. However, behavioral characteristics of the ceRNA network in lung adenocarcinoma need further study.

Methods

Groups based on SLC2A1 expression were used in this study to identify associated ceRNA networks and potential prognostic markers in lung adenocarcinoma. The Cancer Genome Atlas (TCGA) database was used to obtain the patients' lncRNA, miRNA, and mRNA expression profiles, as well as clinical data. Informatics techniques were used to investigate the effect of hub genes on prognosis. The Cox regression analyses were performed to evaluate the prognostic effect of hub genes. The methylation, GSEA, and immune infiltration analyses were utilized to explore the potential mechanisms of the hub gene. The CCK-8, transwell, and colony formation assays were performed to detect the proliferation and invasion of lung cancer cells.

Results

We eventually identified the ITGB1-DT/ARNTL2 axis as an independent fact may promote lung adenocarcinoma progression. Furthermore, methylation analysis revealed that hypo-methylation may cause the dysregulated ITGB1-DT/ARNTL2 axis, and immune infiltration analysis revealed that the ITGB1-DT/ARNTL2 axis may affect the immune microenvironment and the progression of lung adenocarcinoma. The CCK-8, transwell, and colonu formation assays suggested that ITGB1-DT/ARNTL2 promotes the progression of lung adenocarcinoma. And hsa-miR-30b-3p reversed the ITGB1/ARNTL2-mediated oncogenic processes.

Conclusion

Our study identified the ITGB1-DT/ARNTL2 axis as a novel prognostic biomarker affects the prognosis of lung adenocarcinoma.
Comprehensive analysis of pyroptosis regulators and tumor immune microenvironment in clear cell renal cell carcinoma
Authors: Zhang Yan , Chen Xianwu , Fu Qinghe , Wang Feifan , Zhou Xuejian , Xiang Jiayong , He Ning , Hu Zhenghui , Jin Xiaodong
Published: December 2021

Background

Increasing evidence has indicated that pyroptosis could regulate the tumor immune microenvironment (TIME) to affect the tumor development. As a highly immunogenic tumor, clear cell renal cell carcinoma (ccRCC) can benefit from immunotherapy, but related research on pyroptosis in the TIME of ccRCC is still deficient.

Methods

Available data derived from TCGA and GEO databases were analyzed to identify the different expression profiles of pyroptosis in ccRCC and normal tissues, and the correlation of pyroptosis regulators with TIME was evaluated in ccRCC.

Results

According to consensus clustering analysis, two differential expression levels of subtypes were identified to affect patient prognosis, and were related to histological tumor stage and grade. Immune cells were calculated by the CIBERSORT algorithm. Higher infiltrated levels of B cells naive, T cells CD4 memory resting, NK cells resting, monocytes, macrophages were observed in Cluster 1, while higher infiltrated levels of CD8+ T cells, T follicular helper cells, and Tregs were observed in Cluster 2. Gene set enrichment analysis indicated that Cluster 2 was enriched in multiple immune-related pathways, including the JAK-STAT signaling pathway. Moreover, overexpression of eight immune checkpoints was related to ccRCC development, especially in Cluster 2. As four potentially key pyroptosis regulators, AIM2, CASP5, NOD2, and GZMB were confirmed to be upregulated in ccRCC by RT-qPCR analysis and further verified by the HPA database. Further pan-cancer analysis suggested that these four pyroptosis regulators were differentially expressed and related to the TIME in multiple cancers.

Conclusion

The present study provided a comprehensive view of pyroptosis regulators in the TIME of ccRCC, which may provide potential value for immunotherapy.
Identification of crucial genes of pyrimidine metabolism as biomarkers for gastric cancer prognosis
Authors: Wu Zhengxin , Tan Jinshui , Zhuang Yifan , Zhong Mengya , Xiong Yubo , Ma Jingsong , Yang Yan , Gao Zhi , Zhao Jiabao , Ye Zhijian , Zhou Huiwen , Zhu Yuekun , Lu Haijie , Hong Xuehui
Published: December 2021

Background

Metabolic reprogramming has been reported in various kinds of cancers and is related to clinical prognosis, but the prognostic role of pyrimidine metabolism in gastric cancer (GC) remains unclear.

Methods

Here, we employed DEG analysis to detect the differentially expressed genes (DEGs) in pyrimidine metabolic signaling pathway and used univariate Cox analysis, Lasso-penalizes Cox regression analysis, Kaplan–Meier survival analysis, univariate and multivariate Cox regression analysis to explore their prognostic roles in GC. The DEGs were experimentally validated in GC cells and clinical samples by quantitative real-time PCR.

Results

Through DEG analysis, we found NT5E, DPYS and UPP1 these three genes are highly expressed in GC. This conclusion has also been verified in GC cells and clinical samples. A prognostic risk model was established according to these three DEGs by Univariate Cox analysis and Lasso-penalizes Cox regression analysis. Kaplan–Meier survival analysis suggested that patient cohorts with high risk score undertook a lower overall survival rate than those with low risk score. Stratified survival analysis, Univariate and multivariate Cox regression analysis of this model confirmed that it is a reliable and independent clinical factor. Therefore, we made nomograms to visually depict the survival rate of GC patients according to some important clinical factors including our risk model.

Conclusion

In a word, our research found that pyrimidine metabolism is dysregulated in GC and established a prognostic model of GC based on genes differentially expressed in pyrimidine metabolism.