bluuebunny/crossref_metadata_2025 huggingface dataset:
COL11A1 as an novel biomarker for breast cancer with machine learning and immunohistochemistry validation
Authors: Shi Wenjie , Chen Zhilin , Liu Hui , Miao Chen , Feng Ruifa , Wang Guilin , Chen Guoping , Chen Zhitong , Fan Pingming , Pang Weiyi , Li Chen
Published: October 2022

Machine learning (ML) algorithms were used to identify a novel biological target for breast cancer and explored its relationship with the tumor microenvironment (TME) and patient prognosis. The edgR package identified hub genes associated with overall survival (OS) and prognosis, which were validated using public datasets. Of 149 up-regulated genes identified in tumor tissues, three ML algorithms identified COL11A1 as a hub gene. COL11A1was highly expressed in breast cancer samples and associated with a poor prognosis, and positively correlated with a stromal score (r=0.49, p<0.001) and the ESTIMATE score (r=0.29, p<0.001) in the TME. Furthermore, COL11A1 negatively correlated with B cells, CD4 and CD8 cells, but positively associated with cancer-associated fibroblasts. Forty-three related immune-regulation genes associated with COL11A1 were identified, and a five-gene immune regulation signature was built. Compared with clinical factors, this gene signature was an independent risk factor for prognosis (HR=2.591, 95%CI 1.831–3.668, p=7.7e-08). A nomogram combining the gene signature with clinical variables, showed better predictive performance (C-index=0.776). The model correction prediction curve showed little bias from the ideal curve. COL11A1 is a potential therapeutic target in breast cancer and may be involved in the tumor immune infiltration; its high expression is strongly associated with poor prognosis.
Nucleic acid-sensing toll-like receptors: Important players in Sjögren’s syndrome
Authors: Alexopoulou Lena
Published: October 2022

Sjögren’s syndrome (SS) is a chronic systemic autoimmune disease that affects the salivary and lacrimal glands, as well as other organ systems like the lungs, kidneys and nervous system. SS can occur alone or in combination with another autoimmune disease, such as systemic lupus erythematosus (SLE) or rheumatoid arthritis. The etiology of SS is unknown but recent studies have revealed the implication of the activation of innate immune receptors, including Toll-like receptors (TLRs), mainly through the detection of endogenous nucleic acids, in the pathogenesis of systemic autoimmune diseases. Studies on SS mouse models suggest that TLRs and especially TLR7 that detects single-stranded RNA of microbial or endogenous origin can drive the development of SS and findings in SS patients corroborate those in mouse models. In this review, we will give an overview of the function and signaling of nucleic acid-sensing TLRs, the interplay of TLR7 with TLR8 and TLR9 in the context of autoimmunity, summarize the evidence for the critical role of TLR7 in the pathogenesis of SS and present a possible connection between SARS-CoV-2 and SS.
Diagnostic accuracy of dermoscopy for onychomycosis: A systematic review
Authors: Lim Sophie Soyeon , Hui Laura , Ohn Jungyoon , Cho Youngjoo , Oh Choon Chiat , Mun Je-Ho
Published: October 2022

Background

Dermoscopy is a non-invasive adjuvant diagnostic tool that allows clinicians to visualize microscopic features of cutaneous disorders. Recent studies have demonstrated that dermoscopy can be used to diagnose onychomycosis. We performed this systematic review to identify the characteristic dermoscopic features of onychomycosis and understand their diagnostic utility.

Methods

We searched the Medline, Embase, Scopus, and Cochrane databases from conception until May 2021. Studies on the dermoscopic features of onychomycosis were screened. The exclusion criteria were as follows: fewer than 5 cases of onychomycosis, review articles, and studies including onychomycosis cases that were not mycologically verified. Studies on fungal melanonychia were analyzed separately. We adhered to the MOOSE guidelines. Independent data extraction was performed. Data were pooled using a random effects model to account for study heterogeneity. The primary outcome was the diagnostic accuracy of the dermoscopic features of onychomycosis. This was determined by pooling the sensitivity and specificity values of the dermoscopic features identified during the systematic review using the DerSimonian-Laird method. Meta-DiSc version 1.4 and Review Manager 5.4.1 were used to calculate these values.

Results

We analyzed 19 articles on 1693 cases of onychomycosis and 5 articles on 148 cases of fungal melanonychia. Commonly reported dermoscopic features of onychomycosis were spikes or spiked pattern (509, 30.1%), jagged or spiked edges or jagged edge with spikes (188, 11.1%), jagged proximal edge (175, 10.3%), subungual hyperkeratosis (131, 7.7%), ruins appearance, aspect or pattern (573, 33.8%), and longitudinal striae (929, 54.9%). Commonly reported features of fungal melanonychia included multicolor (101, 68.2%), non-longitudinal homogenous pigmentation (75, 50.7%) and longitudinal white or yellow streaks (52, 31.5%).

Conclusion

This study highlights the commonly identified dermoscopic features of onychomycosis. Recognizing such characteristic dermoscopic features of onychomycosis can assist clinicians diagnose onychomycosis by the bedside.
A novel T4- and λ-based receptor binding protein family for bacteriophage therapy host range engineering
Authors: Magaziner Samuel J. , Salmond George P. C.
Published: October 2022

Widespread multidrug antimicrobial resistance in emerging pathogens has led to a renewed interest in phage therapy as an alternative or supplement to traditional small molecule drugs. The primary limiting factors of phage therapy deployment rest in the narrow host range specificity of phage as well as a poor understanding of many phages’ unintended downstream effects on host physiology and microbiota as well as on adverse pathogen evolution. Consequently, this has made assembling well-defined and safe “phage-cocktails” of solely naturally occurring phages labor- and time-intensive. To increase the speed, efficacy, and safety of therapeutic deployment, there is exceptional interest in modulating the host ranges of well-characterized lytic phages (e.g., T4 and T7) by using synthetic strategies to the swap phage tail components, the receptor binding proteins (RBPs) key for host specificity. Here we identify the RBP of the Citrobacter rodentium temperate phage ΦNP as ORF6. Through bioinformatic and phylogenetic assays, we demonstrate this RBP to be closely related to the known RBPs of T4 and λ. Further investigation reveals a novel, greater than 200 members RBP family with phages targeting several notable human pathogens, including Klebsiella pneumoniae, Escherichia coli O157:H7, Salmonella spp., and Shigella spp. With well characterized lytic members, this RBP family represents an ideal candidate for use in synthetic strategies for expanding therapeutic phage host ranges.
Geminicoccus flavidas sp. nov. and Geminicoccus harenae sp. nov., two IAA-producing novel rare bacterial species inhabiting desert biological soil crusts
Authors: Jiang Zhu-Ming , Deng Yang , Han Xue-Fei , Su Jing , Wang Hao , Yu Li-Yan , Zhang Yu-Qin
Published: October 2022

Two Gram-staining negative strains (CPCC 101082T and CPCC 101083T) were isolated from biological sandy soil crusts samples collected from Badain Jaran desert, China. Both isolates were heterotrophic phototroph, could produce indole-3-acetic acid. The 16S rRNA gene sequences of these two strains were closely related to the members of the family Geminicoccaceae, showing high similarities with Geminicoccus roseus DSM 18922T (96.9%) and Arboricoccus pini B29T1T (90.1%), respectively. In phylogenetic tree based on 16S rRNA gene sequences, strain CPCC 101082T and CPCC 101083T formed a robust distinct clade with Geminicoccus roseus DSM 18922T within the family Geminicoccaceae, which indicated that these two isolates could be classified into the genus Geminicoccus. The growth of strain CPCC 101082T occurred at 15–42°C and pH 4.0–10.0 (optima at 28–37°C and pH 6.0–8.0). The growth of strain CPCC 101083T occurred at 4–45°C and pH 4.0–10.0 (optima at 25–30°C and pH 6.0–8.0). The major cellular fatty acids of CPCC 101082T and CPCC 101083T contained C18:1ω7c/C18:1ω6c, cyclo-C19:0ω8c, and C16:0. Q-10 was detected as the sole respiratory quinone. Diphosphatidylglycerol, phosphatidylglycerol, phosphatidylcholine, phosphatidylethanolamine, an unidentified phospholipid and an unidentified aminolipid were tested in the polar lipids profile. The genomes of the two isolates were characterized as about 5.9 Mbp in size with the G + C content of nearly 68%. The IAA-producing encoding genes were predicated in both genomes. The values of average nucleotide identity were 80.6, 81.2 and 92.4% based on a pairwise comparison of the genomes of strains CPCC 101082T and CPCC 101083T and Geminicoccus roseus DSM 18922T, respectively. On the basis of the genotypic, chemotaxonomic and phenotypic characteristics, the strains CPCC 101082T (=NBRC 113513T = KCTC 62853T) and CPCC 101083T (=NBRC 113514T = KCTC 62854T) are proposed to represent two novel species of the genus Geminicoccus with the names Geminicoccus flavidas sp. nov. and Geminicoccus harenae sp. nov.
The large plasmid carried class 1 integrons mediated multidrug resistance of foodborne Salmonella Indiana
Authors: Wang Xuefeng , Wang Tian , Guo Mengjiao , Zhang Chengcheng , Bo Zongyi , Wu Yantao , Chao Guoxiang
Published: October 2022

Salmonella enterica serovar Indiana (S. Indiana) has aroused widespread concern as an important zoonotic pathogen. The molecular mechanism of multidrug resistance (MDR) in S. Indiana is not known and should be assessed. We aim to investigate the molecular mechanism of MDR and the importance of large plasmids carried class 1 integrons in the MDR of foodborne S. Indiana. Class 1 integrons in 48 S. Indiana isolates and 200 isolates of 7 other Salmonella serotypes were detected by polymerase chain reaction (PCR). To analyze the antimicrobial resistance genes (ARGs) of two S. Indiana isolates, designated S. Indiana 15 and S. Indiana 222, next-generation sequencing (NGS) was performed, and the resulting sequences were compared with the complete nucleotide sequences of S. Indiana D90 and S. Indiana C629. Comparative functional analysis was conducted between the intI1 (1,014 bp) of S. Indiana 222 and the intI1 (699 bp) of S. Indiana 15. Plasmid conjugation transfer analysis was performed to analyze the horizontal gene transfer of the integrons-related resistance genes with integron-positive and integron-negative Salmonella isolates. 64.58% of S. Indiana isolates carried class 1 integrons, which was significantly higher than that of other Salmonella serotypes (p < 0.001). The NGS results showed that the S. Indiana 15 and S. Indiana 222 isolates carried a large plasmid with a class 1 integron and multiple ARGs, similar to S. Indiana D90 and S. Indiana C629. Two integrases found in S. Indiana isolates belong to class 1 integrases and could integrate resistance genes into specific integration sites of the integrons. The conjugation frequency of intI1 (1,014 bp) was 6.08 × 10−5, which was significantly higher than that of intI1 (699 bp) (p < 0.01). The large plasmids carrying a class 1 integron and the number of ARGs were strongly correlated (p < 0.001). The conjugation frequency of integron-positive S. Indiana recipient isolates was significantly higher than that of integron-negative recipient isolates (p < 0.05). S. Indiana containing large plasmids carrying a class 1 integron more easily captured resistance genes from other bacteria (S. Enteritidis and S. Derby), which could be an important cause of the emerging pandemic of MDR clones.

Graphical abstract

S. Indiana containing large plasmids carrying a class 1 integron more easily captured resistance genes from other bacteria (S. Enteritidis and S. Derby), which could be an important cause of the emerging pandemic of MDR clones.
Polygenic hazard score modified the relationship between hippocampal subfield atrophy and episodic memory in older adults
Authors: Xu Jingjing , Guan Xiaojun , Wen Jiaqi , Zhang Minming , Xu Xiaojun ,   for the Alzheimer’s Disease Neuroimaging Initiative
Published: October 2022

Background

Understanding genetic influences on Alzheimer’s disease (AD) may improve early identification. Polygenic hazard score (PHS) is associated with the age of AD onset and cognitive decline. It interacts with other risk factors, but the nature of such combined effects remains poorly understood.

Materials and methods

We examined the effect of genetic risk and hippocampal atrophy pattern on episodic memory in a sample of older adults ranging from cognitively normal to those diagnosed with AD using structural MRI. Participants included 51 memory unimpaired normal control (NC), 69 mild cognitive impairment (MCI), and 43 AD adults enrolled in the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Hierarchical linear regression analyses examined the main and interaction effects of hippocampal subfield volumes and PHS, indicating genetic risk for AD, on a validated episodic memory composite score. Diagnosis-stratified models further assessed the role of PHS.

Results

Polygenic hazard score moderated the relationship between right fimbria/hippocampus volume ratio and episodic memory, such that patients with high PHS and lower volume ratio had lower episodic memory composite scores [ΔF = 6.730,p= 0.011, ΔR2= 0.059]. This effect was also found among individuals with MCI [ΔF = 4.519,p= 0.038, ΔR2= 0.050]. In contrast, no interaction effects were present for those NC or AD individuals. A follow-up mediation analysis also indicated that the right fimbria/hippocampus volume ratio might mediate the link between PHS and episodic memory performance in the MCI group, whereas no mediation effects were present for those NC or AD individuals.

Conclusion

These findings suggest that the interaction between AD genetic risk and hippocampal subfield volume ratio increases memory impairment among older adults. Also, the results highlighted a potential pathway in which genetic risk affects memory by degrading hippocampal subfield volume ratio in cognitive decline subjects.
Early-stage differentiation between Alzheimer’s disease and frontotemporal lobe degeneration: Clinical, neuropsychology, and neuroimaging features
Authors: Li Pan , Quan Wei , Wang Zengguang , Liu Ying , Cai Hao , Chen Yuan , Wang Yan , Zhang Miao , Tian Zhiyan , Zhang Huihong , Zhou Yuying
Published: October 2022

Background

Alzheimer’s disease (AD) and frontotemporal lobar degeneration (FTLD) are the two most common forms of neurodegenerative dementia. Although both of them have well-established diagnostic criteria, achieving early diagnosis remains challenging. Here, we aimed to make the differential diagnosis of AD and FTLD from clinical, neuropsychological, and neuroimaging features.

Materials and methods

In this retrospective study, we selected 95 patients with PET-CT defined AD and 106 patients with PET-CT/biomarker-defined FTLD. We performed structured chart examination to collect clinical data and ascertain clinical features. A series of neuropsychological scales were used to assess the neuropsychological characteristics of patients. Automatic tissue segmentation of brain by Dr. Brain tool was used to collect multi-parameter volumetric measurements from different brain areas. All patients’ structural neuroimage data were analyzed to obtain brain structure and white matter hyperintensities (WMH) quantitative data.

Results

The prevalence of vascular disease associated factors was higher in AD patients than that in FTLD group. 56.84% of patients with AD carried at least one APOE ε4 allele, which is much high than that in FTLD patients. The first symptoms of AD patients were mostly cognitive impairment rather than behavioral abnormalities. In contrast, behavioral abnormalities were the prominent early manifestations of FTLD, and few patients may be accompanied by memory impairment and motor symptoms. In direct comparison, patients with AD had slightly more posterior lesions and less frontal atrophy, whereas patients with FTLD had more frontotemporal atrophy and less posterior lesions. The WMH burden of AD was significantly higher, especially in cortical areas, while the WMH burden of FTLD was higher in periventricular areas.

Conclusion

These results indicate that dynamic evaluation of cognitive function, behavioral and psychological symptoms, and multimodal neuroimaging are helpful for the early diagnosis and differentiation between AD and FTLD.
Morphology of the murine choroid plexus: Attachment regions and spatial relation to the subarachnoid space
Authors: Greiner Theresa , Manzhula Katerina , Baumann Louise , Kaddatz Hannes , Runge Jens , Keiler Jonas , Kipp Markus , Joost Sarah
Published: October 2022

The choroid plexus has recently been identified as a possible migration route for peripheral immune cells into the central nervous system. For future investigation of this route, profound knowledge of the morphology of the murine choroid plexus is a prerequisite. We here present a detailed morphological description of the murine choroid plexus, its attachment regions as well as its spatial relation to the subarachnoid space. We used micro-computed tomography of immersion-contrasted fixated brains to generate three-dimensional models of the ventricle system and the choroid plexus and aligned micro-computed tomography-based sections with histological paraffin-embedded sections after immunohistochemical labeling of the basal lamina and choroid plexus epithelium marker proteins (laminin and aquaporin 1). The murine choroid plexus is located in all four ventricles and is attached to the brain parenchyma in narrow attachment regions with a specific morphology in each ventricle. While in the lateral and fourth ventricle, the attachment site is formed by thin tissue bridges, the choroid plexus attachment in the third ventricle has a more complex V-like shape. In all ventricles, the choroid plexus is in close spatial relationship with the subarachnoid space that extends from the brain surface along physiologic openings toward the choroid plexus. In summary, we here provide a description of the morphology of the murine ventricle system and choroid plexus, the attachment regions of the choroid plexus and its connection to the subarachnoid space, as well as a three-dimensional model of the ventricles, the choroid plexus, and the subarachnoid space to facilitate a spatial understanding of these complex structures.
Association between serum sodium and in-hospital mortality among critically ill patients with spontaneous subarachnoid hemorrhage
Authors: Jin Dongcai , Jin Shaofeng , Liu Bingyang , Ding Yi , Zhou Fen , Jin Yuhong
Published: October 2022

Objective

The aim of this study was to retrospectively explore the relationship between serum sodium and in-hospital mortality and related factors in critically ill patients with spontaneous subarachnoid hemorrhage (SAH).

Methods

Data were collected from the Medical Information Mart for Intensive Care IV database. Restricted cubic splines were used to explore the relationship between serum sodium and in-hospital mortality. Receiver operating characteristic analysis was used to calculate the optimal cutoff value of sodium fluctuation, and decision curve analysis was plotted to show the net benefit of different models containing serum sodium.

Results

A total of 295 patients with spontaneous SAH were included in the retrospective analysis. The level of sodium on ICU admission and minimum sodium in the ICU had a statistically significant non-linear relationship with in-hospital mortality (non-linear P-value < 0.05, total P-value < 0.001). Serum sodium on ICU admission, minimum serum sodium during ICU, and sodium fluctuation were independently associated with in-hospital mortality with odds ratios being 1.23 (95% confidence interval (CI): 1.04–1.45, P = 0.013), 1.35 (95% CI: 1.18-1.55, P < 0.001), and 1.07 (95% CI: 1.00–1.14, P = 0.047), respectively. The optimal cutoff point was 8.5 mmol/L to identify in-hospital death of patients with spontaneous SAH with sodium fluctuation, with an AUC of 0.659 (95% CI 0.573-0.744).

Conclusion

Among patients with spontaneous SAH, we found a J-shaped association between serum sodium on ICU admission and minimum sodium values during ICU with in-hospital mortality. Sodium fluctuation above 8.5 mmol/L was independently associated with in-hospital mortality. These results require being tested in prospective trials.
Patient's care bundle benefits to prevent stroke associated pneumonia: A meta-analysis with trial sequential analysis
Authors: Guo Feng , Fan Qiao , Liu Xiaoli , Sun Donghai
Published: October 2022

Background

Patient's care bundle has been found to have a beneficial effect on refractory diseases, but the preventive effect of this strategy on stroke-associated pneumonia (SAP) remains unclear. The purpose of this meta-analysis was to determine the role of the patient's care bundle in the prevention of SAP.

Methods

A systematic search was conducted in five electronic databases to identify randomized controlled trials (RCTs) published before January 31, 2022. The incidence of SAP and aspiration and the length of hospital stay were assessed. Random pair-wise meta-analysis was conducted using Review Manager 5.4, and trial sequential analysis (TSA) was also performed.

Results

Twenty eligible RCTs involving 1916 patients were included for data analysis. Pooled results suggested that patient's care bundle was associated with significantly lower incidence of SAP (risk ratio [RR], 0.37; 95% CI, 0.29–0.46; p < 0.001; I2 = 0%) and aspiration (RR, 0.23; 95% CI, 0.15–0.35; p < 0.001; I2 = 0%). Meanwhile, patient's care bundle also significantly shortened the length of hospital stay for general patients (mean difference [MD], −3.10; 95% CI, −3.83 to −2.37; p < 0.001; I2 = 16%) and the length of intensive care unit (ICU) stay for patients with severe stoke (MD, −4.85; 95% CI, −5.86−3.84; p < 0.001; I2 = 0%). Results of TSA confirmed that none of the findings could be significantly reversed by future studies.

Conclusions

The patient's care bundle effectively prevents the occurrence of SAP and aspiration and shortens the hospital stay of stroke patients. However, it is necessary to design more high-quality studies to further validate our findings and investigate their applicability in other geographical regions.
Persistent “MRI-negative” lupus myelitis-disease presentation, immunological profile and outcome
Authors: Das Shambaditya , Ray Biman Kanti , Chakraborty Arka Prava , Banerjee Abhirup , Pandit Alak , Das Gautam , Dubey Souvik
Published: October 2022

Introduction

Myelitis is the least common neuropsychiatric manifestation in systemic lupus erythematosus (SLE). Magnetic resonance imaging (MRI)-negative myelitis is even rarer. Here, we present the largest cohort of MRI-negative lupus myelitis cases to assess their clinical and immunological profiles and outcome.

Method

A single-center, observational study conducted over a period of 5 years (2017–2021) was undertaken to evaluate patients with MRI-negative lupus myelitis for the epidemiological, clinical, immunological, and radiological features at baseline and followed up at monthly intervals for a year, and the outcomes were documented. Among the 22 patients that presented with MRI-negative myelopathy (clinical features suggestive of myelopathy without signal changes on spinal-cord MRI [3Tesla], performed serially at the time of presentation and 7 days, 6 weeks, and 3 months after the onset of symptoms), 8 patients had SLE and were included as the study population.

Results

In 8 of 22 patients presenting with MRI-negative myelopathy, the etiology was SLE. MRI-negative lupus myelitis had a female preponderance (male: female ratio, 1:7). Mean age at onset of myelopathy was 30.0 ± 8.93 years, reaching nadir at 4.9 ± 4.39 weeks (Median, 3.0; range, 1.25–9.75). Clinically, cervical cord involvement was observed in 75% of patients, and 62.5% had selective tract involvement. The mean double stranded deoxyribonucleic acid, C3, and C4 titers at onset of myelopathy were 376.0 ± 342.88 IU/ml (median, 247.0), 46.1 ± 17.98 mg/dL (median, 47.5), and 7.3 ± 3.55 mg/dL (median, 9.0), respectively, with high SLE disease activity index 2,000 score of 20.6 ± 5.9. Anti-ribosomal P protein, anti-Smith antibody, and anti-ribonuclear protein positivity was observed in 87.5, 75, and 75% of the patients, respectively. On follow-up, improvement of myelopathic features with no or minimal deficit was observed in 5 of the 8 patients (62.5%). None of the patients had recurrence or new neurological deficit over 1-year follow-up.

Conclusion

Persistently “MRI-negative” lupus myelitis presents with white matter dysfunction, often with selective tract involvement, in light of high disease activity, which follows a monophasic course with good responsiveness to immunosuppressive therapy. A meticulous clinical evaluation and a low index of suspicion can greatly aid in the diagnosis of this rare clinical condition in lupus.
Membrane lipid rafts are required for AMPA receptor tyrosine phosphorylation
Authors: Hayashi Takashi
Published: October 2022

Membrane lipid rafts are sphingolipids and cholesterol-enriched membrane microdomains, which form a center for the interaction or assembly of palmitoylated signaling molecules, including Src family non-receptor type protein tyrosine kinases. Lipid rafts abundantly exist in neurons and function in the maintenance of synapses. Excitatory synaptic strength is largely controlled by the surface expression of α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors in the mammalian brain. AMPA receptor endocytosis from the synaptic surface is regulated by phosphorylation of the GluA2 subunit at tyrosine 876 by Src family kinases. Here, I revealed that tyrosine phosphorylated GluA2 is concentrated in the lipid rafts fraction. Furthermore, stimulation-induced upregulation of GluA2 tyrosine phosphorylation is disrupted by the treatment of neurons with a cholesterol-depleting compound, filipin III. These results indicate the importance of lipid rafts as enzymatic reactive sites for AMPA receptor tyrosine phosphorylation and subsequent AMPA receptor internalization from the synaptic surface.
Vitamin C intake potentially lowers total cholesterol to improve endothelial function in diabetic patients at increased risk of cardiovascular disease: A systematic review of randomized controlled trials
Authors: Dludla Phiwayinkosi V. , Nkambule Bongani B. , Nyambuya Tawanda M. , Ziqubu Khanyisani , Mabhida Sihle E. , Mxinwa Vuyolwethu , Mokgalaboni Kabelo , Ndevahoma Fransina , Hanser Sidney , Mazibuko-Mbeje Sithandiwe E. , Basson Albertus K. , Sabbatinelli Jacopo , Tiano Luca
Published: October 2022

Background

Vitamin C is one of the most consumed dietary compounds and contains abundant antioxidant properties that could be essential in improving metabolic function. Thus, the current systematic review analyzed evidence on the beneficial effects of vitamin C intake on cardiovascular disease (CVD)-related outcomes in patients with diabetes or metabolic syndrome.

Methods

To identify relevant randomized control trials (RCTs), a systematic search was run using prominent search engines like PubMed and Google Scholar, from beginning up to March 2022. The modified Black and Downs checklist was used to assess the quality of evidence.

Results

Findings summarized in the current review favor the beneficial effects of vitamin C intake on improving basic metabolic parameters and lowering total cholesterol levels to reduce CVD-risk in subjects with type 2 diabetes or related metabolic diseases. Moreover, vitamin C intake could also reduce the predominant markers of inflammation and oxidative stress like C-reactive protein, interleukin-6, and malondialdehyde. Importantly, these positive outcomes were consistent with improved endothelial function or increased blood flow in these subjects. Predominantly effective doses were 1,000 mg/daily for 4 weeks up to 12 months. The included RCTs presented with the high quality of evidence.

Conclusion

Clinical evidence on the beneficial effects of vitamin C intake or its impact on improving prominent markers of inflammation and oxidative stress in patients with diabetes is still limited. Thus, more RCTs are required to solidify these findings, which is essential to better manage diabetic patients at increased risk of developing CVD.
Case report: Metastatic urothelial cancer with an exceptional response to immunotherapy and comprehensive understanding of the tumor and the tumor microenvironment
Authors: Sternberg Cora N. , Shin Nara , Chernyshov Konstantin , Calabro Fabio , Cerbone Linda , Procopio Giuseppe , Miheecheva Natalia , Sagaradze Georgy , Zaichikova Alisa , Samarina Naira , Boyko Alexandra , Brown Jessica H. , Yunusova Leysan , Guevara Daniela , Manohar Jyothi , Sigouros Michael , Al Assaad Majd , Elemento Olivier , Mosquera Juan Miguel
Published: October 2022

Although immune checkpoint inhibitors (ICIs) are increasingly used as second-line treatments for urothelial cancer (UC), only a small proportion of patients respond. Therefore, understanding the mechanisms of response to ICIs is critical to improve clinical outcomes for UC patients. The tumor microenvironment (TME) is recognized as a key player in tumor progression and the response to certain anti-cancer treatments. This study aims to investigate the mechanism of response using integrated genomic and transcriptomic profiling of a UC patient who was part of the KEYNOTE-045 trial and showed an exceptional response to pembrolizumab. Diagnosed in 2014 and receiving first-line chemotherapy without success, the patient took part in the KEYNOTE-045 trial for 2 years. She showed dramatic improvement and has now been free of disease for over 6 years. Recently described by Bagaev et al., the Molecular Functional (MF) Portrait was utilized to dissect genomic and transcriptomic features of the patient’s tumor and TME. The patient’s tumor was characterized as Immune Desert, which is suggestive of a non-inflamed microenvironment. Integrated whole-exome sequencing (WES) and RNA sequencing (RNA-seq) analysis identified an ATM mutation and high TMB level (33.9 mut/mb), which are both positive biomarkers for ICI response. Analysis further revealed the presence of the APOBEC complex, indicating the potential for use of APOBEC signatures as predictive biomarkers for immunotherapy response. Overall, comprehensive characterization of the patient’s tumor and TME with the MF Portrait revealed important insights that could potentially be hypothesis generating to identify clinically useful biomarkers and improve treatment for UC patients.
Noncoding RNA-mediated regulation of pyroptotic cell death in cancer
Authors: Wang Man , Zhang Yuan , Chang Wenguang , Zhang Lei , Syrigos Konstantinos N. , Li Peifeng
Published: October 2022

Pyroptosis is a newly discovered form of programmed cell death, which is manifested by DNA fragmentation, cell swelling, cell membrane rupture and leakage of cell contents. Previous studies have demonstrated that pyroptosis is tightly associated with the initiation and development of various cancers, whereas the molecular mechanisms underlying pyroptosis remain obscure. Noncoding RNAs (ncRNAs) are a type of heterogeneous transcripts that are broadly expressed in mammalian cells. Owing to their potency of regulating gene expression, ncRNAs play essential roles in physiological and pathological processes. NcRNAs are increasingly acknowledged as important regulators of the pyroptosis process. Importantly, the crosstalk between ncRNAs and pyroptosis affects various hallmarks of cancer, including cell growth, survival, metastasis and therapeutic resistance. The study of the involvement of pyroptosis-associated ncRNAs in cancer pathobiology has become a hot area in recent years, while there are limited reviews on this topic. Herein, we provide an overview of the complicated roles of ncRNAs, mainly including microRNAs (miRNAs), long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs), in modulating pyroptosis, with a focus on the underlying mechanisms of the ncRNA-pyroptosis axis in cancer pathogenesis. Finally, we discuss the potential applications and challenges of exploiting pyroptosis-regulating ncRNAs as molecular biomarkers and therapeutic targets in cancer.
Immune marker expression of irradiated mesothelioma cell lines
Authors: Chang Faith , Keam Synat , Hoang Tracy Seymour , Creaney Jenette , Gill Suki , Nowak Anna K. , Ebert Martin , Cook Alistair M.
Published: October 2022

Background

Though immune checkpoint inhibition has recently shown encouraging clinical efficacy in mesothelioma, most patients do not respond. Combining immune checkpoint inhibition with radiotherapy presents an attractive option for improving treatment responses owing to the various immunomodulatory effects of radiation on tumors. However, the ideal dosing and scheduling of combined treatment remains elusive, as it is poorly studied in mesothelioma. The present study characterizes the dose- and time-dependent changes to expression of various immune markers and cytokines important to antitumor responses following irradiation of mesothelioma cell lines.

Methods

Two murine (AB1, AE17) and two human (BYE, JU77) mesothelioma cell lines were treated with titrated gamma-radiation doses (1-8 Gy) and the expression of MHC class-I, MHC class-II and PD-L1 was measured over a series of post-irradiation timepoints (1-72 hours) by flow cytometry. Levels of cytokines IL-1α, IL-1β, IL-6, IL-10, IL-12p70, IL-17A, IL-23, IL-27, MCP-1, IFN-β, IFN-γ, TNF-α, and GM-CSF were measured by multiplex immunoassay in murine cell lines following 8 Gy radiation.

Results

Following irradiation, a dose-dependent upregulation of MHC-I and PD-L1 was observed on three of the four cell lines studied to varying extents. For all cell lines, the increase in marker expression was most pronounced 72 hours after radiation. At this timepoint, increases in levels of cytokines IFN-β, MCP-1 and IL-6 were observed following irradiation with 8 Gy in AB1 but not AE17, reflecting patterns in marker expression.

Conclusions

Overall, this study establishes the dose- and time-dependent changes in immune marker expression of commonly studied mesothelioma cell lines following radiation and will inform future study into optimal dosing and scheduling of combined radiotherapy and immune checkpoint inhibition for mesothelioma.
Immunometabolism in the tumor microenvironment and its related research progress
Authors: Zhang Ziheng , Hu Yajun , Chen Yuefeng , Chen Zhuoneng , Zhu Yexin , Chen Mingmin , Xia Jichu , Sun Yixuan , Xu Wenfang
Published: October 2022

The tumor immune microenvironment has been a research hot spot in recent years. The cytokines and metabolites in the microenvironment can promote the occurrence and development of tumor in various ways and help tumor cells get rid of the surveillance of the immune system and complete immune escape. Many studies have shown that the existence of tumor microenvironment is an important reason for the failure of immunotherapy. The impact of the tumor microenvironment on tumor is a systematic study. The current research on this aspect may be only the tip of the iceberg, and a relative lack of integrity, may be related to the heterogeneity of tumor. This review mainly discusses the current status of glucose metabolism and lipid metabolism in the tumor microenvironment, including the phenotype of glucose metabolism and lipid metabolism in the microenvironment; the effects of these metabolic methods and their metabolites on three important immune cells Impact: regulatory T cells (Tregs), tumor-associated macrophages (TAM), natural killer cells (NK cells); and the impact of metabolism in the targeted microenvironment on immunotherapy. At the end of this article,the potential relationship between Ferroptosis and the tumor microenvironment in recent years is also briefly described.
Development and validation of prognostic models for colon adenocarcinoma based on combined immune-and metabolism-related genes
Authors: Jiang Hui-zhong , Yang Bing , Jiang Ya-li , Liu Xun , Chen Da-lin , Long Feng-xi , Yang Zhu , Tang Dong-xin
Published: October 2022

Background

The heterogeneity of tumor tissue is one of the reasons for the poor effect of tumor treatment, which is mainly affected by the tumor immune microenvironment and metabolic reprogramming. But more research is needed to find out how the tumor microenvironment (TME) and metabolic features of colon adenocarcinoma (COAD) are related.

Methods

We obtained the transcriptomic and clinical data information of COAD patients from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Consensus clustering analysis was used to identify different molecular subtypes, identify differentially expressed genes (DEGs) associated with immune-and metabolism-related genes (IMRGs) prognosis. Univariate and multivariable Cox regression analysis and Lasso regression analysis were applied to construct the prognostic models based on the IMRG risk score. The correlations between risk scores and TME, immune cell infiltration, and immune checkpoint genes were investigated. Lastly, potential appropriate drugs related to the risk score were screened by drug sensitivity analysis.

Results

By consensus clustering analysis, we identified two distinct molecular subtypes. It was also found that the multilayered IMRG subtypes were associated with the patient’s clinicopathological characteristics, prognosis, and TME cell infiltration characteristics. Meanwhile, a prognostic model based on the risk score of IMRGs was constructed and its predictive power was verified internally and externally. Clinicopathological analysis and nomogram give it better clinical guidance. The IMRG risk score plays a key role in immune microenvironment infiltration. Patients in the high-risk groups of microsatellite instability (MSI) and tumor mutational burden (TMB) were found to, although with poor prognosis, actively respond to immunotherapy. Furthermore, IMRG risk scores were significantly associated with immune checkpoint gene expression. The potential drug sensitivity study helps come up with and choose a chemotherapy treatment plan.

Conclusion

Our comprehensive analysis of IMRG signatures revealed a broad range of regulatory mechanisms affecting the tumor immune microenvironment (TIME), immune landscape, clinicopathological features, and prognosis. And to explore the potential drugs for immunotherapy. It will help to better understand the molecular mechanisms of COAD and provide new directions for disease treatment.
Blood-based biomarkers for immune-based therapy in advanced HCC: Promising but a long way to go
Authors: Sung Pil Soo , Lee Isaac Kise , Roh Pu Reun , Kang Min Woo , Ahn Jaegyoon , Yoon Seung Kew
Published: October 2022

The introduction of immune checkpoint inhibitors (ICIs) represents a key shift in the management strategy for patients with hepatocellular carcinoma (HCC). However, there is a paucity of predictive biomarkers that facilitate the identification of patients that would respond to ICI therapy. Although several researchers have attempted to resolve the issue, the data is insufficient to alter daily clinical practice. The use of minimally invasive procedures to obtain patient-derived specimen, such as using blood-based samples, is increasingly preferred. Circulating tumor DNA (ctDNA) can be isolated from the blood of cancer patients, and liquid biopsies can provide sufficient material to enable ongoing monitoring of HCC. This is particularly significant for patients for whom surgery is not indicated, including those with advanced HCC. In this review, we summarize the current state of understanding of blood-based biomarkers for ICI-based therapy in advanced HCC, which is promising despite there is still a long way to go.
Identification of CD8+ T cell infiltration-related genes and their prognostic values in cervical cancer
Authors: Shen Xiaopeng , Wang Chunguang , Li Meng , Wang Sufen , Zhao Yun , Liu Zhongxian , Zhu Guoping
Published: October 2022

Cervical cancer is a female-specific cancer with relatively high morbidity and mortality. As known to all, immune cell infiltrations in the cancer microenvironment are closely related to the cancer diagnosis and prognosis. Here we revealed that the CD8+ T cell infiltration was significantly upregulated in cervical cancer versus normal cervix uteri samples. Through univariate and multivariate cox analyses, we discovered that the CD8+ T cell infiltration was the only independent beneficial factor for the prognosis of cervical cancer. To explore the genes associated with the CD8+ T cell infiltration in cervical cancer, we performed the WGCNA analysis on the differentially expressed genes (DEGs) of cervical cancer versus normal cervix uteri tissues. As a result, 231 DEGs were found to be associated with CD8+ T cell infiltration in cervical cancer. Subsequently, with the Cytoscape analysis, we identified 105 hub genes out of the 231 DEGs. To further explore the genes that might be responsible for the prognosis of cervical cancer, we performed a univariate cox analysis followed by a LASSO assay on the 105 hub genes and located four genes (IGSF6, TLR10, FCRL3, and IFI30) finally. The four genes could be applied to the prediction of the prognosis of cervical cancer, and relatively higher expression of these four genes predicted a better prognosis. These findings contributed to our understanding of the prognostic values of CD8+ T cell infiltration and its associated genes in cervical cancer and thus might benefit future immune-related therapies.
Activity and rational combinations of a novel, engineered chimeric, TRAIL-based ligand in diffuse large B-cell lymphoma
Authors: Piechna Karolina , Żołyniak Aleksandra , Jabłońska Ewa , Noyszewska-Kania Monika , Szydłowski Maciej , Żerek Bartłomiej , Kulecka Maria , Rumieńczyk Izabela , Mikula Michał , Juszczyński Przemysław
Published: October 2022

Background

TRAIL (TNF-related apoptosis inducing ligand) exhibits selective proapoptotic activity in multiple tumor types, while sparing normal cells. This selectivity makes TRAIL an attractive therapeutic candidate. However, despite encouraging activity in preclinical models, clinical trials with TRAIL mimetics/death receptor agonists demonstrated insufficient activity, largely due to emerging resistance to these agents. Herein, we investigated the cytotoxic activity of a novel, TRAIL-based chimeric protein AD-O51.4 combining TRAIL and VEGFA-derived peptide sequences, in hematological malignancies. We characterize key molecular mechanisms leading to resistance and propose rational pharmacological combinations sensitizing cells to AD-O51.4.

Methods

Sensitivity of DLBCL, classical Hodgkin lymphoma, (cHL), Burkitt lymphoma (BL) and acute myeloid leukemia (AML) to AD-O51.4 was assessed in vitro with MTS assay and apoptosis tests (Annexin V/PI staining). Markers of apoptosis were assessed using immunoblotting, flow cytometry or fluorogenic caspase cleavage assays. Resistant cell lines were obtained by incubation with increasing doses of AD-O51.4. Transcriptomic analyses were performed by RNA sequencing. Sensitizing effects of selected pathway modulators (BCL2, dynamin and HDAC inhibitors) were assessed using MTS/apoptosis assays.

Results

AD-O51.4 exhibited low-nanomolar cytotoxic activity in DLBCL cells, but not in other lymphoid or AML cell lines. AD-O51.4 induced death-receptor (DR) mediated, caspase-dependent apoptosis in sensitive DLBCL cells, but not in primary resistant cells. The presence of DRs and caspase 8 in cancer cells was crucial for AD-O51.4-induced apoptosis. To understand the potential mechanisms of resistance in an unbiased way, we engineered AD-O51.4-resistant cells and evaluated resistance-associated transcriptomic changes. Resistant cells exhibited changes in the expression of multiple genes and pathways associated with apoptosis, endocytosis and HDAC-dependent epigenetic reprogramming, suggesting potential therapeutic strategies of sensitization to AD-O51.4. In subsequent analyses, we demonstrated that HDAC inhibitors, BCL2 inhibitors and endocytosis/dynamin inhibitors sensitized primary resistant DLBCL cells to AD-O51.4.

Conclusions

Taken together, we identified rational pharmacologic strategies sensitizing cells to AD-O51.4, including BCL2, histone deacetylase inhibitors and dynamin modulators. Since AD-O51.4 exhibits favorable pharmacokinetics and an acceptable safety profile, its further clinical development is warranted. Identification of resistance mechanisms in a clinical setting might indicate a personalized pharmacological approach to override the resistance.
Impact of perioperative blood transfusion on long-term survival in patients with different stages of perihilar cholangiocarcinoma treated with curative resection: A multicentre propensity score matching study
Authors: Liu Zhi-Peng , Cheng Zheng-Jun , Dai Hai-Su , Zhong Shi-Yun , Zhao Dong-Chu , Gong Yi , Zuo Jing-Hua , Che Xiao-Yu , Chen Wei-Yue , Wang Zi-Ran , Yu Ting , Cheng Jun-Jie , Liu Xing-Chao , Bai Jie , Jiang Yan , Zhang Yan-Qi , Lau Wan Yee , Deng Shi-Quan , Chen Zhi-Yu
Published: October 2022

Background & aim

The association of perioperative blood transfusion (PBT) with long-term survival in perihilar cholangiocarcinoma (pCCA) patients after surgical resection with curative intent is controversial and may differ among different stages of the disease. This study aimed to investigate the impact of PBT on long-term survival of patients with different stages of pCCA.

Methods

Consecutive pCCA patients from three hospitals treated with curative resection from 2012 to 2019 were enrolled and divided into the PBT and non-PBT groups. Propensity score matching (PSM) was used to balance differences in baseline characteristics between the PBT and non-PBT groups. Kaplan–Meier curves and log-rank test were used to compare overall survival (OS) and recurrence-free survival (RFS) between patients with all tumor stages, early stage (8th AJCC stage I), and non-early stage (8th AJCC stage II-IV) pCCA in the PBT and non-PBT groups. Cox regression analysis was used to determine the impact of PBT on OS and RFS of these patients.

Results

302 pCCA patients treated with curative resection were enrolled into this study. Before PSM, 68 patients (22 patients in the PBT group) were in the early stage and 234 patients (108 patients in the PBT group) were in the non-early stage. Patients with early stage pCCA in the PBT group had significantly lower OS and RFS rates than those in the non-PBT group. However, there were with no significant differences between the 2 groups with all tumor stages and non-early stage pCCA. After PSM, there were 18 matched pairs of patients with early stage and 72 matched pairs of patients with non-early stage. Similar results were obtained in the pre- and post-PSM cohorts: patients with early stage pCCA in the PBT group showed significantly lower OS and RFS rates than those in the non-PBT group, but there were no significant differences between the 2 groups for patients with all tumor stages and non-early stage pCCA. Cox regression analysis demonstrated that PBT was independently associated with worse OS and RFS for patients with early stage pCCA.

Conclusions

PBT had a negative impact on long-term survival in patients with early stage pCCA after curative resection, but not in patients with non-early stage pCCA.