bluuebunny/crossref_metadata_2025 huggingface dataset:
Intramuscular injection of skeletal muscle derived extracellular matrix mitigates denervation atrophy after sciatic nerve transection
Authors: Schilling Benjamin K , Baker Jocelyn S , Komatsu Chiaki , Marra Kacey G
Published: September 2021

Peripheral nerve injury and the associated muscle atrophy has an estimated annual healthcare burden of $150 billion dollars in the United States. When considering the total annual health-related spending of $3.5 trillion, these pathologies alone occupy about 4.3%. The prevalence of these ailments is rooted, at least in part, in the lack of specific preventative therapies that can be administered to muscle while it remains in the denervated state. To address this, skeletal muscle-derived ECM (skECM) was injected directly in denervated muscle with postoperative analysis performed at 20 weeks, including gait analysis, force production, cytokine quantification, and histological analysis. skECM was shown to be superior against non-injected muscle controls showing no difference in contraction force to uninjured muscle at 20 weeks. Cytokines IL-1β, IL-18, and IFNγ appeared to mediate regeneration with statistical regression implicating these cytokines as strong predictors of muscle contraction, showing significant linear correlation.
Acute severe poisoning with disinfectant in senior aged patient-case report and overview of literature considering age influence on treatment decision in alcohol-based intoxications
Authors: Pereska Zanina , Simonovska Natasha , Babulovska Aleksandra , Berat-Huseini Afrodita , Naumoski Kiril , Kostadinoski Kristin
Published: September 2021

We present our experiences in the first case of severe suicidal poisoning with 70% ethanol-disinfectant in North Macedonia, in an elderly patient with immunocompromising comorbidities. A 66-year-old unconscious woman was admitted at our clinic, with a history of seropositive rheumatoid arthritis treated with methotrexate. She was in a coma, without signs of serotonin syndrome, recurrent episodes of cardio-respiratory insufficiency under supportive treatment without invasive ventilation, metabolic acidosis, increased D-dimer 3254 ng/mL. The toxicology screening confirmed low benzodiazepines levels and alcoholaemia of 526 mg/dL (5.26 g/L), due to ingestion of 70% ethanol. Considering the decreased biotransformation in the elderly, immunocompromising comorbidities, reports of fatal outcome in poisoned elderly patients with disinfectants under standard fluids supportive protocol, haemodialysis was initiated, with registered associated hypercoagulability which resulted in complete stabilization after 48 h of admission. Treatment protocols of poisoning with ethanol-based disinfectant in the elderly should consider timely performing haemodialysis at lower alcoholaemia levels than recommended.
Kruppel-like factor 4 upregulates the resistance to apoptosis induced by tumor necrosis factor α in synovial fibroblasts with rheumatoid arthritis
Authors: Ni Chenghong , Zeng Shiyi , Zhang Chen , Lao Kehan , Wang Jifeng , Wang Weiwei , Mo Xuanrong , Luo Xinjing
Published: September 2021

Objective

The objective is to examine the effect of tumor necrosis factor α (TNFα) on apoptosis and proliferation of rheumatoid arthritis synovial fibroblasts (RASFs) and to elucidate the regulatory roles of Kruppel-like factor 4 (KLF4) in TNFα-induced RASF apoptosis.

Methods

Changes in cell proliferation were measured using an 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di- phenytetrazoliumromide (MTT) assay, and changes in cell apoptosis were detected by flow cytometry and Hoechst 33258 staining. Changes in the apoptosis-related protein caspase-3 and the apoptosis-related genes bcl-2/bax were measured by western blot and real-time PCR, respectively

Results

TNFα stimulation increased cell proliferation ( p < 0.05), decreased cell apoptosis ( p < 0.05), declined caspase-3 expression ( p < 0.05), and upregulated bcl-2/bax level ( p < 0.05) in RASFs. KLF4 gene silencing decreased cell proliferation ( p < 0.05), increased cell apoptosis ( p < 0.05), upregulated caspase-3 expression ( p < 0.05), and downregulated bcl-2/bax level ( p < 0.05) induced by TNFα in RASFs.

Conclusions

TNFα caused a decrease in RASF apoptosis, and KLF4 promoted resistance to TNFα-induced apoptosis and cell proliferation.
The Impact of COVID-19 Lockdown on Diabetes Complication and Diabetes Management in People With Diabetes in Indonesia
Authors: Kshanti Ida Ayu , Epriliawati Marina , Mokoagow Muhammad Ikhsan , Nasarudin Jerry , Magfira Nadya
Published: September 2021

Aims: As the country with the seventh largest number of People with Diabetes (PWD) in the world, the Coronavirus disease 2019 (COVID-19) pandemic, and the Large Social Scale Restriction (LSSR) policy taken by the Indonesian government to reduce the number of COVID-19 transmissions is estimated to interfere diabetes management and will increase the incidence of diabetes complications. This study aims to determine the difficulties of diabetes management and its impact on diabetes morbidity during the COVID-19 pandemic in Indonesia. Methods: This study is a cross-sectional study using a national scale web survey. This research was conducted in Indonesia enrolling 1124 PWD aged 18 years or older. Diabetes complications are defined as self-assessed incidence of hypoglycemia, or Diabetic Foot Ulcer (DFU), or hospital admission experienced by PWD in Indonesia during the COVID-19 pandemic. The correlation between diabetes management difficulties and diabetes-related complications was measured using a modified cox regression test. Results: Diabetes management difficulties were experienced by 69.8% of PWD in Indonesia. The difficulties include attending diabetes consultation 30.1%, access to diabetes medication 12.4%, checking blood glucose levels 9.5%, controlling diet 23.8%, and performing regular exercise 36.5%. Diabetes-related complications occurred in 24.6% of subjects. Those who had diabetes management difficulties during the COVID-19 pandemic are prone to have diabetes complications by 1.4 times greater (PR: 1.41, 95% CI: 1.09-1.83) than those who did not. Conclusion: The COVID-19 pandemic and LSSR have impact on diabetes management and diabetes-related complications as assessed by PWD in Indonesia.
Concept Analysis and Proposed Definition of Community Health Center
Authors: Nagel Daniel A. , Keeping-Burke Lisa , Shamputa Isdore Chola
Published: September 2021

Background: Community health centers (CHCs) have been used for delivery of health services since the 1920s and originally were intended to provide care to underserved populations. CHCs have become an integral part of healthcare systems in many countries; however, the term CHC is used synonymously with other concepts and there is no clear definition for CHC. The purpose of our concept analysis was to determine how CHCs are described in the literature and to develop a concept definition for CHC. Methods: Informed by the 8-step process described by Walker and Avant, we searched for literature spanning disciplines within health, business, and policy. We used a systematic review process to identify a range of peer-reviewed articles that help illustrate the attributes, antecedents, and consequences of CHCs. A total of 102 articles from 7 databases were included in our concept analysis. Results: We distinguished 6 attributes of a CHC: primary care; accessibility; preventative care; defined population; health promotion; and comprehensive and integrated care. About 4 antecedents fundamental to a CHC included: secure funding; vision and support; adequate human resources; and governance structure. Consequences of CHCs are improved health outcomes, efficiency, and cost-effective provision of healthcare services. Conclusions: Our concept analysis revealed core characteristics of CHCs that assisted us in synthesizing a concept definition for CHC. These characteristics and our proposed definition will help provide clarity on the concept of CHC to benefit evaluation, research, and policy development of CHCs.
Interrater Reliability of the Prone Apprehension Relocation Test
Authors: Watchmaker Lauren E. , Hetzel Scott J. , Sink Ernest L. , Spiker Andrea M.
Published: September 2021

Background:

The Prone Apprehension Relocation Test (PART) augments existing radiographic measures and clinical provocative maneuvers in diagnosing hip instability. One measure of the potential clinical utility of the PART depends on the reproducibility of test results by evaluating providers including physicians, licensed athletic trainers, and physical therapists.

Purpose:

To determine the interrater reliability of the PART among health care providers.

Study Design:

Cohort study (diagnosis); Level of evidence, 3.

Methods:

We retrospectively identified patients in our institution’s hip preservation registry who presented between September 2017 and June 2019 for evaluation of hip pain. Patients included in the study had the PART performed by a single physician as well as 1 of 12 physician extenders (a licensed athletic trainer or a physical therapist). The providers were blinded to the findings of the other examining professional. Interrater reliability was assessed using the Cohen κ (≥0.75 was considered excellent; between 0.75 and 0.40, moderate; and ≤0.40, poor).

Results:

A total of 96 patients (190 hips) were included in this study (61 women and 35 men, average age 32 ± 12.1 years). A total of 23 hips had a positive PART from both examiners. Interrater reliability was excellent between health care professionals for the PART when evaluating the right hip (κ = 0.80), left hip (κ = 0.82), and when combining the results for left and right (κ = 0.81). A subanalysis of patients with a positive PART from both raters demonstrated that 19 of the 23 hips had a lateral center-edge angle >25°.

Conclusion:

Our study demonstrated excellent interrater reliability of the PART, supporting its use in the physical evaluation of painful hips.
Inhibitory immune checkpoints PDCD-1 and LAG-3 hypermethylation may reduce the risk of colorectal cancer
Authors: Zhang Yuanyuan , zhang Lei , Sun Hongru , Liu Ying , Xu Jing , Huang Hao , Fu Jinming , Zhang Ding , Tian Tian , Zhao Yashuang , Wang Guiyu
Published: September 2021

Background

Changes in DNA methylation of immunosuppressive checkpoints may impact express and consequently affect antigen processing and presentation by tumor cells and facilitates evasion of immunosurveillance and lead to colorectal cancer (CRC). This study is to investigate the effect of PDCD-1, LAG-3 methylation statuses in peripheral blood leukocytes on CRC risk.

Methods

GSE51032 dataset from Gene Expression Omnibus comprised of 166 CRC patients and 424 normal samples was used to identify significantly differentially methylated CpG sites of the two genes. A case–control study with 390 CRC patients and 397 cancer-free controls was carried out to validate the relationship between the methylation levels of the two genes and CRC susceptibility and then estimated their interactions with environmental factors on CRC risk.

Results

In the GSE51032 dataset, cg06291111 (PDCD-1) and cg10191002 (LAG-3) were screened as the candidate CpG sites for the following study. There were significant associations between hypermethylation of PDCD-1 and LAG-3 and lower risk of CRC (ORadj = 0.322, 95% CI 0.197–0.528; ORadj = 0.666, 95% CI 0.446–0.5996, respectively). Moreover, the results in case–control study showed similar trend, that hypermethylation of PDCD-1 and LAG-3 were associated with lower CRC risk (ORadj = 0.448, 95% CI 0.322–0.622; ORadj = 0.417, 95% CI 0.301–0.578, respectively). A synergistic interaction between LAG-3 hypermethylation and intake of eggs on CRC risk was observed. There were combination effects between hypermethylation of PDCD-1 and LAG-3 and environmental factors on CRC risk.

Conclusions

PDCD-1 and LAG-3 may potentially serve as blood-based predictive biomarkers for CRC risk.
ncDLRES: a novel method for non-coding RNAs family prediction based on dynamic LSTM and ResNet
Authors: Wang Linyu , Zhong Xiaodan , Wang Shuo , Liu Yuanning
Published: September 2021

Background

Studies have proven that the same family of non-coding RNAs (ncRNAs) have similar functions, so predicting the ncRNAs family is helpful to the research of ncRNAs functions. The existing calculation methods mainly fall into two categories: the first type is to predict ncRNAs family by learning the features of sequence or secondary structure, and the other type is to predict ncRNAs family by the alignment among homologs sequences. In the first type, some methods predict ncRNAs family by learning predicted secondary structure features. The inaccuracy of predicted secondary structure may cause the low accuracy of those methods. Different from that, ncRFP directly learning the features of ncRNA sequences to predict ncRNAs family. Although ncRFP simplifies the prediction process and improves the performance, there is room for improvement in ncRFP performance due to the incomplete features of its input data. In the secondary type, the homologous sequence alignment method can achieve the highest performance at present. However, due to the need for consensus secondary structure annotation of ncRNA sequences, and the helplessness for modeling pseudoknots, the use of the method is limited.

Results

In this paper, a novel method “ncDLRES”, which according to learning the sequence features, is proposed to predict the family of ncRNAs based on Dynamic LSTM (Long Short-term Memory) and ResNet (Residual Neural Network).

Conclusions

ncDLRES extracts the features of ncRNA sequences based on Dynamic LSTM and then classifies them by ResNet. Compared with the homologous sequence alignment method, ncDLRES reduces the data requirement and expands the application scope. By comparing with the first type of methods, the performance of ncDLRES is greatly improved.
Elevated transcription of transposable elements is accompanied by het-siRNA-driven de novo DNA methylation in grapevine embryogenic callus
Authors: Lizamore Darrell , Bicknell Ross , Winefield Chris
Published: September 2021

Background

Somatic variation is a valuable source of trait diversity in clonally propagated crops. In grapevine, which has been clonally propagated worldwide for centuries, important phenotypes such as white berry colour are the result of genetic changes caused by transposable elements. Additionally, epiallele formation may play a role in determining geo-specific (‘terroir’) differences in grapes and thus ultimately in wine. This genomic plasticity might be co-opted for crop improvement via somatic embryogenesis, but that depends on a species-specific understanding of the epigenetic regulation of transposable element (TE) expression and silencing in these cultures. For this reason, we used whole-genome bisulphite sequencing, mRNA sequencing and small RNA sequencing to study the epigenetic status and expression of TEs in embryogenic callus, in comparison with leaf tissue.

Results

We found that compared with leaf tissue, grapevine embryogenic callus cultures accumulate relatively high genome-wide CHH methylation, particularly across heterochromatic regions. This de novo methylation is associated with an abundance of transcripts from highly replicated TE families, as well as corresponding 24 nt heterochromatic siRNAs. Methylation in the TE-specific CHG context was relatively low over TEs located within genes, and the expression of TE loci within genes was highly correlated with the expression of those genes.

Conclusions

This multi-‘omics analysis of grapevine embryogenic callus in comparison with leaf tissues reveals a high level of genome-wide transcription of TEs accompanied by RNA-dependent DNA methylation of these sequences in trans. This provides insight into the genomic conditions underlying somaclonal variation and epiallele formation in plants regenerated from embryogenic cultures, which is an important consideration when using these tissues for plant propagation and genetic improvement.
Effects of mulberry leaf silage on antioxidant and immunomodulatory activity and rumen bacterial community of lambs
Authors: Wang Bing , Luo Hailing
Published: September 2021

Background

Rumen is a natural fermentation system and the microorganisms inside can effectively utilize plant bioresource and interact with host metabolism. Here, analysis of rumen microbiome, together with animal performance and serum metabolism in a lamb model were performed to identify the potential use of mulberry leaf silage (MS) to replace alfalfa silage (AS) as a new functional feed resource and to mining the novel specific mulberry leaf associated rumen bacteria interact with host metabolism.

Results

The lambs fed with MS diet showed improved antioxidant capacity and immune function compared to those fed AS diet. The MS diet significantly altered rumen microbiota α- and β-diversity and taxonomic composition. Microbial analysis revealed that Bifidobacterium, Lactobacillus and Schwartzia were enhanced, and Ruminococcaceae UCG-010 and Lachnospiraceae_XPB1014_group were down-regulated in the rumen of MS group. A strong association was also found between these rumen microbial taxa and host antioxidant and immunomodulatory capacity.

Conclusion

These findings indicated that mulberry leaf silage can be a high-quality feed source or bioactive pharmaceutical that is responsible for ruminant’s health benefits. The modified rumen microbial community by mulberry leaf silage were associated with the enhanced antioxidant capacity and immunomodulatory of lambs.
Esophageal metastasis of renal cell carcinoma resected by endoscopic submucosal dissection: a case report
Authors: Ohnita Ken , Higashi Shuntaro , Hirai Satoshi , Kuwahara Ai , Kakigao Kana , Nakashiki Suguru , Inoue Kenichiro , Kurohama Hirokazu , Nakashima Masahiro , Nakao Kazuhiko
Published: September 2021

Background

Esophageal metastasis of renal cell carcinoma (RCC) is extremely rare. We have described herein a case of a 59-year-old man with esophageal metastasis of RCC that was endoscopically resected.

Case presentation

The case was a 59-year-old man who had undergone left nephrectomy for renal clear cell carcinoma 17 years ago and splenectomy for splenic metastasis 3 years ago. Esophagogastroduodenoscopy (EGD) performed 9 years ago revealed a small reddish elevated lesion with a smooth surface in the middle esophagus; this lesion increased in size 4 years ago. However, no biopsy was performed. The lesion continued to grow in size and was found to have become nodular during the present observation. Biopsy revealed clear cell carcinoma. Endoscopic ultrasound (EUS) revealed that the lesion had not invaded the submucosa, and contrast-enhanced computed tomography did not reveal any other metastasis. The lesion was successfully removed en bloc via endoscopic submucosal dissection (ESD). Pathologically, the tumor was detected in the subepithelium with focal infiltration of the muscularis mucosa. It consisted of monotonous cells with small nuclei and a clear cytoplasm. Immunohistological findings indicated that the tumor was a metastasis of RCC. The lateral and vertical margins were noted to be free.

Conclusions

We have presented herein a case of esophageal metastasis of RCC that had progressed over 9 years and was then resected en bloc through endoscopic submucosal dissection.
Cecal epidermoid cyst: a neonatal case with clinicopathological consideration
Authors: Na Joo-Young , Kim Soo-Hong , Lee Narae
Published: September 2021

Background

Only 10 cases of cecal epidermoid cyst (CEC) have been reported in the literature. Furthermore, its pathogenesis remains unclear. We report a rare case of congenital CEC in neonate, and discuss its clinicopathological findings.

Case presentation

A cystic lesion was incidentally identified in the retroperitoneal area of the abdominal right lower quadrant during a routine prenatal ultrasonography (US), prompting an ileocolectomy 3 days after birth. This congenital cyst was composed of mucosal lining cells and submucosal connective tissues, and the inner lining mucosa was composed of stratified squamous epithelium and focally mucin-producing ciliated epithelium. Based on the macroscopic and microscopic findings, the cystic lesion was diagnosed as a congenital cecal epidermoid cyst.

Conclusions

The management of a fetal abdominal mass should be tailored individually, considering that epidermoid cysts can occur in the cecum during the perinatal period. We report the clinicopathological findings in this case, including its possible pathogenesis.
Expansion of targetable sites for the ribonucleoprotein-based CRISPR/Cas9 system in the silkworm Bombyx mori
Authors: Zou Yun-long , Ye Ai-jun , Liu Shuo , Wu Wen-tao , Xu Li-feng , Dai Fang-yin , Tong Xiao-ling
Published: September 2021

Background

With the emergence of CRISPR/Cas9 technology, multiple gene editing procedures became available for the silkworm. Although binary transgene-based methods have been widely used to generate mutants, delivery of the CRISPR/Cas9 system via DNA-free ribonucleoproteins offers several advantages. However, the T7 promoter that is widely used in the ribonucleoprotein-based method for production of sgRNAs in vitro requires a 5′ GG motif for efficient initiation. The resulting transcripts bear a 5′ GG motif, which significantly constrains the number of targetable sites in the silkworm genome.

Results

In this study, we used the T7 promoter to add two supernumerary G residues to the 5′ end of conventional (perfectly matched) 20-nucleotide sgRNA targeting sequences. We then asked if sgRNAs with this structure can generate mutations even if the genomic target does not contain corresponding GG residues. As expected, 5′ GG mismatches depress the mutagenic activity of sgRNAs, and a single 5′ G mismatch has a relatively minor effect. However, tests involving six sgRNAs targeting two genes show that the mismatches do not eliminate mutagenesis in vivo, and the efficiencies remain at useable levels. One sgRNA with a 5′ GG mismatch at its target performed mutagenesis more efficiently than a conventional sgRNA with 5′ matched GG residues at a second target within the same gene. Mutations generated by sgRNAs with 5′ GG mismatches are also heritable. We successfully obtained null mutants with detectable phenotypes from sib-mated mosaics after one generation.

Conclusions

In summary, our method improves the utility and flexibility of the ribonucleoprotein-based CRISPR/Cas9 system in silkworm.
The determinants of burnout and professional turnover intentions among Canadian physicians: application of the job demands-resources model
Authors: Chênevert Denis , Kilroy Steven , Johnson Kevin , Fournier Pierre-Luc
Published: September 2021

Background

Burnout among physicians is growing at an exponential rate and many are leaving the profession. Nevertheless, the specific antecedents and intermediary stages involved in predicting their professional turnover intentions are not fully clear.

Purpose

We apply the Job Demands-Resources model and investigate an innovative model which predicts physician burnout and its ultimate consequences on professional turnover intentions.

Methodology/approach

Structural equation modeling was used on cross-sectional survey data from a sample of 407 Canadian physicians.

Results/conclusions

Job demands (work stress, work overload, and work-family conflict) and job resources (patient recognition and meaning at work) influence intention to leave the profession through a two stage health-impairment and motivational process related to health problems and professional commitment, respectively.

Practical implications

This study identifies key job resources and job demands which predict physician burnout and professional turnover intentions thereby pinpointing which levers managers can use improve their health and retain them in the profession.
USP39 promotes malignant proliferation and angiogenesis of renal cell carcinoma by inhibiting VEGF-A165b alternative splicing via regulating SRSF1 and SRPK1
Authors: Pan Xiu-wu , Xu Da , Chen Wen-jin , Chen Jia-xin , Chen Wei-jie , Ye Jian-qing , Gan Si-shun , Zhou Wang , Song Xu , Shi Lei , Cui Xin-gang
Published: September 2021

Background

The benefit of targeted therapy for renal cell carcinoma (RCC) is largely crippled by drug resistance. Rapid disease progression and poor prognosis occur in patients with drug resistance. New treatments demand prompt exploration for clinical therapies. Ubiquitin-specific peptidase 39 (USP39) serves as the pro-tumor factor in several previous studies of other malignant tumors. To investigate the function and mechanism of USP39 in promoting malignant proliferation and angiogenesis of RCC.

Methods

We applied ONCOMINE database to analyze the correlation between USP39 expression level and the clinical characteristics of RCC. USP39 knockdown or overexpression plasmids were transfected into 786-O and ACHN cells. The HUVEC received cell supernatants of 786-O and ACHN cells with knockdown or overexpression USP39.The effect of USP39 on RCC was evaluated by MTT assay, cell cycle analysis, colony formation assay and tubule formation assay. The interaction between USP39 and VEGF-A alternative splicing was assessed by affinity purification and mass spectrometry, co-immunoprecipitation and Western blot assays.

Results

The mRNA expression level of USP39 in RCC was significantly higher than that in normal renal tissue (P < 0.001), and negatively correlated with the survival rate of RCC patients (P < 0.01). Silencing of USP39 in 786-O and ACHN cells inhibited cell proliferation and colony formation, and induced S phase arrest. USP39 overexpression significantly increased the number of tubules (P < 0.05) and branches (P < 0.01) formed by HUVEC cells, and USP39 knockdown produced an opposite effect (P < 0.05). The USP39 (101–565) fragment directly mediated its binding to SRSF1 and SRPK1, and promoted the phosphorylation of SRSF1 to regulate VEGF-A alternative splicing. USP39 knockdown upregulated the expression of VEGF-A165b, and USP39 overexpression downregulated the expression of VEGF-A165b significantly (both P < 0.05).

Conclusion

USP39 acted as a pro-tumor factor by motivating the malignant biological processes of RCC, probably through inhibiting VEGF-A165b alternative splicing and regulating SRSF1 and SRPK1. USP39 may prove to be a potential therapeutic target for RCC.

Graphic abstract
Therapy of spinal cord injury by zinc modified gold nanoclusters via immune-suppressing strategies
Authors: Lin Sen , Li Dan , Zhou Zipeng , Xu Chang , Mei Xifan , Tian He
Published: September 2021

Background

Spinal cord injury (SCI) is damage to the central nervous system (CNS) that causes devastating complications from chronic pain to breathing problems. Unfortunately, few effective and safe treatments are known to relieve the damages of SCI. Nanomedicines are used for the treatment of SCI with relatively few side effects, but only depending on the delivery of additional drugs, which increase complexity to the treatment. Considering the urgent need for saving SCI patients, it is important to develop promising nanobiotechnology for relieving their pains.

Methods

The clinical survey was used to investigate SCI patients, thereafter the therapy plan was designed. The receiver-operating characteristics (ROC) curves of the prediction model were built to find symptoms after SCI. The treatment plan (i.e. immunosuppressive strategy) was designed by manufacturing therapies based on gold nanoclusters (AuNCs). The response of the immune cells (macrophages) was studied accordingly. The western blot, reactive oxygen species (ROS) activity assay, enzyme-linked immunosorbent assay (ELISA), quantitative real-time PCR (RT-qPCR), and immunochemical staining were used for evaluation of the in vivo and in vitro therapeutic effects.

Results

We found increased monocytes/macrophages (M/Ms) levels in 114 SCI subjects (44.7% with severe SCI complications) by the clinical survey. Additionally, the enhanced macrophage level was found to be closely related to the walking disorder after SCI. Since macrophages were central effector cells of the immune system, we assumed that the immune-suppressing strategies could be used for SCI therapy. Thereafter, AuNCs were stabilized by dihydrolipoic acid (DHLA) enantiomers (including DL-DHLA, R-DHLA; A racemic mixture (R and S) was denoted as DL; R and S refer to Rectus and Sinister), obtaining DL-DHLA-AuNCs and R-DHLA-AuNCs, respectively. In addition, zinc-modified DL-DHLA and R-DHLA stabilized AuNCs (i.e., DL-DHLA-AuNCs-Zn and R-DHLA-AuNCs-Zn) were investigated. Among these AuNCs, R-DHLA-AuNCs-Zn showed the most remarkable therapeutic effect for promoting the polarization of pro-inflammatory macrophages and reducing neuronal ROS-induced apoptosis and inflammation in vitro and in vivo; the lesion size was decreased and the survival rate of ventral neurons is higher.

Conclusions

R-DHLA-AuNCs-Zn have comprehensive therapeutic capabilities, especially the immune-suppressing effects for the therapy of SCI, which is promising to relieve the pain or even recover SCI for the patients.

Graphical abstract
Molecularly engineered carrier-free co-delivery nanoassembly for self-sensitized photothermal cancer therapy
Authors: Shan Xinzhu , Zhang Xuanbo , Wang Chen , Zhao Zhiqiang , Zhang Shenwu , Wang Yuequan , Sun Bingjun , Luo Cong , He Zhonggui
Published: September 2021

Background

Photothermal therapy (PTT) has been extensively investigated as a tumor-localizing therapeutic modality for neoplastic disorders. However, the hyperthermia effect of PTT is greatly restricted by the thermoresistance of tumor cells. Particularly, the compensatory expression of heat shock protein 90 (HSP90) has been found to significantly accelerate the thermal tolerance of tumor cells. Thus, a combination of HSP90 inhibitor and photothermal photosensitizer is expected to significantly enhance antitumor efficacy of PTT through hyperthermia sensitization. However, it remains challenging to precisely co-deliver two or more drugs into tumors.

Methods

A carrier-free co-delivery nanoassembly of gambogic acid (GA, a HSP90 inhibitor) and DiR is ingeniously fabricated based on a facile and precise molecular co-assembly technique. The assembly mechanisms, photothermal conversion efficiency, laser-triggered drug release, cellular uptake, synergistic cytotoxicity of the nanoassembly are investigated in vitro. Furthermore, the pharmacokinetics, biodistribution and self-enhanced PTT efficacy were explored in vivo.

Results

The nanoassembly presents multiple advantages throughout the whole drug delivery process, including carrier-free fabrication with good reproducibility, high drug co-loading efficiency with convenient dose adjustment, synchronous co-delivery of DiR and GA with long systemic circulation, as well as self-tracing tumor accumulation with efficient photothermal conversion. As expected, HSP90 inhibition-augmented PTT is observed in a 4T1 tumor BALB/c mice xenograft model.

Conclusion

Our study provides a novel and facile dual-drug co-assembly strategy for self-sensitized cancer therapy.

Graphic abstract
Vaso-occlusive crisis in sickle cell disease: a vicious cycle of secondary events
Authors: Jang Tim , Poplawska Maria , Cimpeanu Emanuela , Mo George , Dutta Dibyendu , Lim Seah H.
Published: September 2021

Painful vaso-occlusive crisis (VOC) remains the most common reason for presenting to the Emergency Department and hospitalization in patients with sickle cell disease (SCD). Although two new agents have been approved by the Food and Drug Administration for treating SCD, they both target to reduce the frequency of VOC. Results from studies investigating various approaches to treat and shorten VOC have so far been generally disappointing. In this paper, we will summarize the complex pathophysiology and downstream events of VOC and discuss the likely reasons for the disappointing results using monotherapy. We will put forward the rationale for exploring some of the currently available agents to either protect erythrocytes un-involved in the hemoglobin polymerization process from sickling induced by the secondary events, or a multipronged combination approach that targets the complex downstream pathways of VOC.
A novel immune subtype classification of ER-positive, PR-negative and HER2-negative breast cancer based on the genomic and transcriptomic landscape
Authors: Xie Peiling , An Rui , Yu Shibo , He Jianjun , Zhang Huimin
Published: September 2021

Background

The diversity and plasticity behind ER+/PR−/HER2− breast cancer have not been widely explored. It is essential to identify heterogeneous microenvironment phenotypes and investigate specific genomic events driving the formation of these phenotypes.

Methods

Based on the immune-related gene expression profiles of 411 ER+/PR−/HER2− breast cancers in the METABRIC cohort, we used consensus clustering to identify heterogeneous immune subtypes and assessed their reproducibility in an independent meta-cohort including 135 patients collected from GEO database. We further analyzed the differences of cellular and molecular characteristics, and potential immune escape mechanism among immune subtypes. In addition, we constructed a transcriptional trajectory to visualize the distribution of individual patient.

Results

Our analysis identified and validated five reproducible immune subtypes with distinct cellular and molecular characteristics, potential immune escape mechanisms, genomic drivers, as well as clinical outcomes. An immune-cold subtype, with the least amount of lymphocyte infiltration, had a poorer prognosis. By contrast, an immune-hot subtype, which demonstrated the highest infiltration of CD8+ T cells, DCs and NK cells, and elevated IFN-γ response, had a comparatively favorable prognosis. Other subtypes showed more diverse gene expression and immune infiltration patterns with distinct clinical outcomes. Finally, our analysis revealed a complex immune landscape consisting of both discrete cluster and continuous spectrum.

Conclusion

Overall, this study revealed five heterogeneous immune subtypes among ER+/PR–/HER2− breast cancer, also provided important implications for clinical translations.
Tauroursodeoxycholic acid alleviates secondary injury in spinal cord injury mice by reducing oxidative stress, apoptosis, and inflammatory response
Authors: Hou Yonghui , Luan Jiyao , Huang Taida , Deng Tiancheng , Li Xing , Xiao Zhifeng , Zhan Jiheng , Luo Dan , Hou Yu , Xu Liangliang , Lin Dingkun
Published: September 2021

Background

Tauroursodeoxycholic acid (TUDCA) is a hydrophilic bile acid derivative, which has been demonstrated to have neuroprotective effects in different neurological disease models. However, the effect and underlying mechanism of TUDCA on spinal cord injury (SCI) have not been fully elucidated. This study aims to investigate the protective effects of TUDCA in the SCI mouse model and the related mechanism involved.

Methods

The primary cortical neurons were isolated from E16.5 C57BL/6 mouse embryos. To evaluate the effect of TUDCA on axon degeneration induced by oxidative stress in vitro, the cortical neurons were treated with H2O2 with or without TUDCA added and immunostained with Tuj1. Mice were randomly divided into sham, SCI, and SCI+TUDCA groups. SCI model was induced using a pneumatic impact device at T9-T10 level of the vertebra. TUDCA (200 mg/kg) or an equal volume of saline was intragastrically administrated daily post-injury for 14 days.

Results

We found that TUDCA attenuated axon degeneration induced by H2O2 treatment and protected primary cortical neurons from oxidative stress in vitro. In vivo, TUDCA treatment significantly reduced tissue injury, oxidative stress, inflammatory response, and apoptosis and promoted axon regeneration and remyelination in the lesion site of the spinal cord of SCI mice. The functional recovery test revealed that TUDCA treatment significantly ameliorated the recovery of limb function.

Conclusions

TUDCA treatment can alleviate secondary injury and promote functional recovery by reducing oxidative stress, inflammatory response, and apoptosis induced by primary injury, and promote axon regeneration and remyelination, which could be used as a potential therapy for human SCI recovery.
Preparing for and responding to sexual and reproductive health in disaster settings: evidence from Fiji and Tonga
Authors: Beek Kristen , Drysdale Robyn , Kusen Matthew , Dawson Angela
Published: September 2021

Background

Pacific Island countries are vulnerable to disasters, including cyclones and earthquakes. Disaster preparedness is key to a well-coordinated response to preventing sexual violence and assisting survivors, reducing the transmission of HIV and other STIs, and preventing excess maternal and neonatal mortality and morbidity. This study aimed to identify the capacity development activities undertaken as part of the SPRINT program in Fiji and Tonga and how these enabled the sexual and reproductive health (SRH) response to Tropical Cyclones Winston and Gita.

Methods

This descriptive qualitative study was informed by a framework designed to assess public health emergency response capacity across various levels (systems, organisational, and individual) and two phases of the disaster management cycle (preparedness and response). Eight key informants were recruited purposively to include diverse individuals from relevant organisations and interviewed by telephone, Zoom, Skype and email. Template analysis was used to examine the data.

Findings

Differences in the country contexts were highlighted. The existing program of training in Tonga, investment from the International Planned Parenthood Federation (IPPF) Humanitarian Hub, the status of the Tonga Family Health Association as the key player in the delivery of SRH, together with its long experience of delivering contract work in short time-frames and strong relationship with the Ministry of Health (MoH) facilitated a relatively smooth and rapid response. In contrast, there had been limited capacity development work in Fiji prior to Winston, requiring training to be rapidly delivered during the immediate response to the cyclone with the support of surge staff from IPPF. In Fiji, the response was initially hampered by a lack of clarity concerning stakeholder roles and coordination, but linkages were quickly built to enable a response. Participants highlighted the importance of personal relationships, individuals’ and organisations' motivation to respond, and strong rapport with the community to deliver SRH.

Discussion

This study highlights the need for comprehensive activities at multiple levels within a country and across the Pacific region to build capacity for a SRH response. While the SPRINT initiative has been implemented across several regions to improve organisational and national capacity preparedness, training for communities can be strengthened. This research outlines the importance of formalising partnerships and regular meetings and training to ensure the currency of coordination efforts in readiness for activation. However, work is needed to further institutionalise SRH in emergencies in national policy and accountability mechanisms.
Risky business: COVAX and the financialization of global vaccine equity
Authors: Stein Felix
Published: September 2021

Background

During the first year and a half of the COVID-19 pandemic, COVAX has been the world’s most prominent effort to ensure equitable access to SARS-CoV-2 vaccines. Launched as part of the Access to COVID-19 Tools Accelerator (Act-A) in June 2020, COVAX suggested to serve as a vaccine buyers’ and distribution club for countries around the world. It also aimed to support the pharmaceutical industry in speeding up and broadening vaccine development. While COVAX has recently come under critique for failing to bring about global vaccine equity, influential politicians and public health advocates insist that future iterations of it will improve pandemic preparedness. So far COVAX’s role in the ongoing financialization of global health, i.e. in the rise of financial concepts, motives, practices and institutions has not been analyzed.

Methods

This article describes and critically assesses COVAX’s financial logics, i.e. the concepts, arguments and financing flows on which COVAX relies. It is based on a review of over 109 COVAX related reports, ten in-depth interviews with global health experts working either in or with COVAX, as well as participant observation in 18 webinars and online meetings concerned with global pandemic financing, between September 2020 and August 2021.

Results

The article finds that COVAX expands the scale and scope of financial instruments in global health governance, and that this is done by conflating different understandings of risk. Specifically, COVAX conflates public health risk and corporate financial risk, leading it to privilege concerns of pharmaceutical companies over those of most participating countries – especially low and lower-middle income countries (LICs and LMICs). COVAX thus drives the financialization of global health and ends up constituting a risk itself - that of perpetuating the downsides of financialization (e.g. heightened inequality, secrecy, complexity in governance, an ineffective and slow use of aid), whilst insufficiently realising its potential benefits (pandemic risk reduction, increased public access to emergency funding, indirect price control over essential goods and services).

Conclusion

Future iterations of vaccine buyers’ and distribution clubs as well as public vaccine development efforts should work towards reducing all aspects of public health risk rather than privileging its corporate financial aspects. This will include reassessing the interplay of aid and corporate subsidies in global health.
The feasibility of a dose painting procedure to treat prostate cancer based on mpMR images and hierarchical clustering
Authors: Rezaeijo Seyed Masoud , Hashemi Bijan , Mofid Bahram , Bakhshandeh Mohsen , Mahdavi Arash , Hashemi Mohammad Saber
Published: September 2021

Background

We aimed to assess the feasibility of a dose painting (DP) procedure, known as simultaneous integrated boost intensity modulated radiation Therapy (SIB-IMRT), for treating prostate cancer with dominant intraprostatic lesions (DILs) based on multi-parametric magnetic resonance (mpMR) images and hierarchical clustering with a machine learning technique.

Methods

The mpMR images of 120 patients were used to create hierarchical clustering and draw a dendrogram. Three clusters were selected for performing agglomerative clustering. Then, the DIL acquired from the mpMR images of 20 patients were categorized into three groups to have them treated with a DP procedure being composed of three planning target volumes (PTVs) determined as PTV1, PTV2, and PTV3 in treatment plans. The DP procedure was carried out on the patients wherein a total dose of 80, 85 and 91 Gy were delivered to the PTV1, PTV2, and PTV3, respectively. Dosimetric and radiobiologic parameters [Tumor Control Probability (TCP) and Normal Tissue Complication Probability (NTCP)] of the DP procedure were compared with those of the conventional IMRT and Three-Dimensional Conformal Radiation Therapy (3DCRT) procedures carried out on another group of 20 patients. A post-treatment follow-up was also made four months after the radiotherapy procedures.

Results

All the dosimetric variables and the NTCPs of the organs at risks (OARs) revealed no significant difference between the DP and IMRT procedures. Regarding the TCP of three investigated PTVs, significant differences were observed between the DP versus IMRT and also DP versus 3DCRT procedures. At post-treatment follow-up, the DIL volumes and apparent diffusion coefficient (ADC) values in the DP group differed significantly (p-value < 0.001) from those of the IMRT. However, the whole prostate ADC and prostate-specific antigen (PSA) indicated no significant difference (p-value > 0.05) between the DP versus IMRT.

Conclusions

The results of this comprehensive clinical trial illustrated the feasibility of our DP procedure for treating prostate cancer based on mpMR images validated with acquired patients’ dosimetric and radiobiologic assessment and their follow-ups. This study confirms significant potential of the proposed DP procedure as a promising treatment planning to achieve effective dose escalation and treatment for prostate cancer.

Trial registration: IRCT20181006041257N1; Iranian Registry of Clinical Trials, Registered: 23 October 2019,https://en.irct.ir/trial/34305.
The correlation between the labrum size and the labral tear in asymptomatic volunteers and symptomatic patients
Authors: Gao Guanying , Fu Qiang , Wu Ruiqi , Liu Rongge , Ao Yingfang , Xu Yan
Published: September 2021

Background

Some studies have proved that labrum size is associated with symptoms in patients with hip labral tear. The correlation between the labrum size and the labral tear in asymptomatic volunteers and symptomatic patients is still uncertain.

Methods

The volunteers with no history of pain, injury, or surgery were recruited from the community. Patients who were diagnosed with labral tear and underwent hip arthroscopic surgery in this period in our hospital were also included. The length and height of the acetabular hip labrum were measured at three separate anatomic sites through magnetic resonance imaging (MRI) along the acetabular rim: lateral, anterior, and anteroinferior.

Results

A total of 70 volunteers (125 hips) and 70 patients (70 hips) were included in this study. Sixty-six (52.8%) hips had labral tears in all 125 hips of volunteers. The lateral labral length of volunteers with labral tears was significantly larger than those without labral tears (P < .05). In 14 volunteers with unilateral labral tears, length of lateral, anterior, and anteroinferior labrum in the side with tear were significantly larger than normal on the other side. The anterior labral height of volunteers was significantly larger than that of patients (P < .05).

Conclusions

In conclusion, asymptomatic volunteers with larger length of lateral, anterior, and anteroinferior labrum are more prone to present with labral tears. Symptomatic patients with labral tears exhibited thinner anterior labrum. Further studies are warranted to explore the mechanisms of labral tears in asymptomatic people and validate the use of labral size as a guide to differential diagnosis and treatment.