bluuebunny/crossref_metadata_2025 huggingface dataset:
In vivo Illustration of Altered Dopaminergic and GABAergic Systems in Early Parkinson's Disease
Authors: Takashima Hirotsugu , Terada Tatsuhiro , Bunai Tomoyasu , Matsudaira Takashi , Obi Tomokazu , Ouchi Yasuomi
Published: May 2022

Background

Changes in γ-aminobutyric acid (GABA) function are noted in patients with Parkinson's disease (PD) who have some non-motor impairments. However, dopamine-related GABA function and GABA-related cognitive changes are still unclear.

Methods

Thirteen drug-naive early-stage PD patients underwent a series of PET scans with [11C]flumazenil(FMZ) and [11C]CFT. The [11C]FMZ binding potential (BPND) derived from a Logan plot analysis was compared between PD patients and age-matched controls. The [11C]CFT radioactivity relative to the cerebellar counterpart was estimated as a semiquantitative value [11C]CFT SUVR. Correlations between [11C]FMZ BPND and [11C]CFT SUVR in the same region of interest were also examined.

Results

In patients in the PD group, [11C]CFT SUVR was significantly lower in the putamen. The levels of [11C]FMZ BPND in the cerebral cortex (frontal lobe dominancy) and the affected-side putamen were also reduced. In addition, [11C]CFT SUVR was negatively correlated with the [11C]FMZ BPND level in the affected-side putamen. In patients in the PD group, the total frontal assessment battery (FAB) score was positively correlated with the [11C]FMZ BPND in the frontal region.

Conclusion

GABAergic dysfunction coexists with dopaminergic loss not only in the putamen but also over the extrastriatal region in patients with early PD and is related to frontal dysfunction. The negative correlation of [11C]CFT SUVR with [11C]FMZ BPND in the affected putamen suggests that a greater dopaminergic demise would decelerate GABA release (or an increase in tracer binding), resulting in persistent failure of the GABAergic system in PD patients.
Traditional Chinese Medicine Interventions in the Rehabilitation of Cognitive and Motor Function in Patients With Stroke: An Overview and Evidence Map
Authors: Choi Tae-Young , Jun Ji Hee , Lee Hye Won , Yun Jong-Min , Joo Min Cheol , Lee Myeong Soo
Published: May 2022

Evidence mapping of systematic reviews (SRs) systematically and comprehensively identifies, organizes, and summarizes the distribution of scientific evidence in a field. The aim of this evidence map is to provide a synopsis of the best clinical practices and interventions in stroke rehabilitative care and to identify areas with a paucity of evidence to guide future research. PubMed, EMBASE, CDSR, six Korean databases, and two Chinese databases were searched for SRs evaluating the effectiveness of any stroke rehabilitation intervention through October 2021. The quality of the SRs was assessed using AMSTAR 2. A bubble plot was used to graphically display clinical topics, the number of articles, the number of patients included, confidence, and effectiveness. In total, ninety-five SRs were identified; however, after methodological analysis, only 48 had sufficient quality to be included. In total, forty-eight SRs were included in the evidence mapping. The overall search identified SRs from 2015 to 2021. A total of four SRs focused on post-stroke cognitive impairment, whereas the other forty-four SRs focused on post-stroke motor function. In total, nineteen different traditional Chinese medicine (TCM) intervention modalities were included. Acupuncture was the most commonly used treatment. Overall, the quality of the included SRs was low or very low. Most SRs concluded that TCM interventions may have potential benefits in stroke rehabilitation. The results were more promising when acupuncture was used for shoulder–hand syndrome. However, the identified reviews cautioned that firm conclusions cannot be drawn. The evidence map provides a visual overview of the research volume and content involving TCM interventions in stroke rehabilitation. Evidence mapping can facilitate the process of knowledge translation from scientific findings to researchers and policymakers and possibly reduce waste in research.
A Single-Center Analysis of Sex Differences in Patients With Chronic Subdural Hematoma in China
Authors: Ou Yunwei , Fan Wenhua , Yu Xiaofan , Wu Liang , Liu Weiming
Published: May 2022

Background

Given the men's predominance in the prevalence of chronic subdural hematoma (CSDH), we investigated the relationship between sex differences and clinical features of CSDH.

Methods

We retrieved a large collection of clinical factors from CSDH patients between August 2011 and May 2019, and analyzed the differences and similarities in the clinical data and outcomes between men and women.

Results

In total 1,307 CSDH patients were enrolled in this study. When we did not account for age, a greater proportion of women relative to men manifested diabetes (p = 0.001) and cardiac disease (p = 0.035) prior to the onset of CSDH. Regarding recovery outcome and recurrence rate, we observed no significant differences between men and women. The sole difference between women and men after surgery was that women experienced more complications than men (p = 0.044), and both length of hospital stay (p < 0.001, B = 0.159, Exp [B] = 1.172, 95% CI = 1.078–1.274) and the presence of cardiac disease (p = 0.002, B = 2.063, Exp [B] = 7.867, 95% CI = 2.167–28.550) were identified as independent risk factors. After accounting for age, women with CSDH exhibited more frequent disorders of consciousness at admission than men in group of ≤ 40-year-old patients (p = 0.018), while proportion of women with diabetes was higher than that of men in 41–79 year-old group (p < 0.001). However, women after surgery experienced more complications (p = 0.047), longer length of hospital stays (p = 0.005), and higher mortality at discharge (p = 0.035) than men in middle-aged group. Finally, length of hospital stay (p < 0.001, B = 0.186, Exp [B] = 1.205, 95% CI = 1.091–1.331) and cardiac disease (p = 0.017, B = 2.040, Exp [B] = 7.693, 95% CI = 1.430–41.372) impacted occurrence of complications in women 41–79-year-old, while duration of drainage catheter use (p < 0.001, B = 1.132, beta = 0.280) and complications (p < 0.001, B = 5.615, beta = 0.366) were identified as independent risk factors for length of hospital stay in the same group of women.

Conclusions

Although sex differences did not constitute a crucial factor in all the CSDH patients, we still need to pay closer attention to disparities between men and women with respect to complications, length of hospital stay, and mortality at discharge in the various age groups (particularly with respect to 41–79 year-old women patients), to provide satisfactory management and treatment of CSDH patients.
Plasma miR-153 and miR-223 Levels as Potential Biomarkers in Parkinson’s Disease
Authors: Wu Li , Xu Qian , Zhou Mengxi , Chen Yajing , Jiang Chunyan , Jiang Yuhan , Lin Yin , He Qing , Zhao Lei , Dong Yourong , Liu Jianren , Chen Wei
Published: May 2022

Background

Small molecule RNAs (miRNAs) could induce downregulation of α-synuclein (SNCA) expression by binding the 3’ untranslated region of SNCA, thus playing an important role in the pathogenesis of Parkinson’s disease (PD). Recent studies suggest that SNCA-related miRNAs in saliva are promising PD biomarkers. Research on those miRNAs in plasma is rare in patients with PD.

Objective

To detect the plasma expression levels of three SNCA related miRNAs (miR-7, miR-153, and miR-223) in PD, and to explore their diagnostic value and associations with clinical phenotype.

Methods

MiR-7, miR-153, and miR-223 levels were detected in the plasma of 75 PD patients and 73 normal controls (NCs) via real-time quantitative polymerase chain reaction. The receiver operating characteristic (ROC) curves were delineated to evaluate their diagnostic value in PD. In addition, their associations with demographic, key motor, and non-motor symptoms were explored by serial scales.

Results

The expression levels of plasma miR-153 and miR-223 were significantly decreased in patients with PD relative to NCs. The area under the ROC curve separating PD from NCs was 63.1% for miR-153 and 86.2% for miR-223, respectively. The plasma miR-153 level in de novo PD was lower than that in treated patients (p = 0.006), its level increased gradually with disease duration (r = 0.358, p = 0.002) and Unified Parkinson’s Disease Rating Scale Part III score (r = 0.264, p = 0.022). Plasma miR-223 level was decreased in patients with clinical possible rapid eye movement sleep behavior disorder (cpRBD) compared with those without cpRBD (p < 0.001), and its level was negatively associated with RBDSQ score (r = -0.334, p = 0.003). Multiple linear regression analysis revealed that disease duration (p = 0.049) was the independently associated factor of miR-153 level; whereas, RBDSQ (p = 0.009) was related to miR-223 level in PD.

Conclusion

Plasma miR-153 and miR-223 levels could be potential biomarkers of PD.
Proficiency of Extracellular Vesicles From hiPSC-Derived Neural Stem Cells in Modulating Proinflammatory Human Microglia: Role of Pentraxin-3 and miRNA-21-5p
Authors: Upadhya Raghavendra , Madhu Leelavathi N. , Rao Shama , Shetty Ashok K.
Published: May 2022

Extracellular vesicles (EVs) shed by human-induced pluripotent stem cell (hiPSC)-derived neural stem cells (hNSC-EVs) have shown potent antiinflammatory properties in a mouse macrophage assay and a mouse model of acute neuroinflammation. They can also quickly permeate the entire brain after intranasal administration, making them attractive as an autologous or allogeneic off-the-shelf product for treating neurodegenerative diseases. However, their ability to modulate activated human microglia and specific proteins and miRNAs mediating antiinflammatory effects of hNSC-EVs are unknown. We investigated the proficiency of hNSC-EVs to modulate activated human microglia and probed the role of the protein pentraxin 3 (PTX3) and the miRNA miR-21-5p within hNSC-EVs in mediating the antiinflammatory effects. Mature microglia generated from hiPSCs (iMicroglia) expressed multiple microglia-specific markers. They responded to lipopolysaccharide (LPS) or interferon-gamma challenge by upregulating tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β) mRNA expression and protein release. iMicroglia also exhibited proficiency to phagocytose amyloid-beta (Aβ). The addition of hNSC-EVs decreased TNF-α and IL-1β mRNA expression and the release of TNF-α and IL-1β by LPS-stimulated iMicroglia (proinflammatory human Microglia). However, the antiinflammatory activity of hNSC-EVs on LPS-stimulated microglia was considerably diminished when the PTX3 or miR-21-5p concentration was reduced in EVs. The results demonstrate that hNSC-EVs are proficient for modulating the proinflammatory human microglia into non-inflammatory phenotypes, implying their utility to treat neuroinflammation in neurodegenerative diseases. Furthermore, the role of PTX3 and miR-21-5p in the antiinflammatory activity of hNSC-EVs provides a new avenue for improving the antiinflammatory effects of hNSC-EVs through PTX3 and/or miR-21-5p overexpression.
Layered Double Hydroxide@Metal–Organic Framework Hybrids for Extraction of Indole-3-Carbinol From Cruciferous Vegetables
Authors: Tan Qiyue , Liu Guangyang , Zhao Chenxi , Gao Mingkun , Zhang Xuan , Chen Ge , Li Lingyun , Huang Xiaodong , Zhang Yaowei , Lv Jun , Xu Donghui
Published: May 2022

Cruciferous vegetables are rich in glucosinolates, which can be metabolized to produce the antitumor compound indole-3-carbinol (I3C). The conventional solvent extraction method for I3C is inefficient. To improve the extraction efficiency of I3C from cruciferous vegetables, we prepared a metal-organic framework (MOF) material (Fe3O4@Zn-Al-LDH@B-D-MIL-100). First, Fe3O4 nanoparticles were introduced to layered double hydroxides by in situ polymerization. Then, the MOF material was grown on the surface of the layered double hydroxide by co-precipitation and the layer-by-layer self-assembly method. This gave Fe3O4@Zn-Al-LDH@B-D-MIL-100, which was characterized using a variety of techniques. The results showed that Fe3O4@Zn-Al-LDH@B-D-MIL-100 had a double-layer porous structure, excellent superparamagnetism (11.54955 emu/g), a large specific surface area (174.04 m2/g), and a pore volume (0.26 cm3/g). The extraction conditions for I3C were optimized. Non-linear fitting of the static adsorption model showed that the adsorption was mainly monolayer. Fe3O4@Zn-Al-LDH@B-D-MIL-100 had fast adsorption kinetics and could extract 95% of I3C in 45 min. It is superior to the traditional solvent extraction method because of its high enrichment efficiency in a short time and environmental friendliness. The successful preparation of the new nanomaterial will provide a new reference for the enrichment and extraction of the I3C industry.
Regulatory Effect of Sea-Buckthorn Procyanidins on Oxidative Injury HUVECs
Authors: Lin Ximeng , Yuen Michael , Yuen Tina , Yuen Hywel , Wang Min , Peng Qiang
Published: May 2022

As society develops and aging populations increase, the incidence of arteriosclerosis, a seriously harmful cardiovascular disease (CVD) which mostly results from endothelial cellular oxidative damage, has continuously risen. Procyanidins from sea-buckthorn is a powerful antioxidant, although its protective effect on the cardiovascular system is not yet clearly understand. In this study, oxidative damaged HUVECs induced by palmitate acid (PA) were used as a model and the regulatory effect of procyanidins from sea-buckthorn (SBP) on HUVECs were investigated. The results showed SBP can be used for 12 h by HUVECs and had no detective cytotoxicity to them under 400 μg/L. Also, different concentrations of SBP can increase mitochondrial membrane potential and NO level and decrease LDH leakage in a dose-effect relationship, indicating SBP can improve oxidative damage. In addition, western blots and qPCR results showed SBP regulation on oxidative injured HUVECs is probably through p38MAPK/NF-κB signal pathway. This study revealed the molecular mechanism of procyanidins in decreasing endothelial oxidative damage, providing a theoretical foundation for further research on natural bioactive compounds to exert antioxidant activity in the body and prevent and improve cardiovascular diseases.
The Therapeutic Effect of SCFA-Mediated Regulation of the Intestinal Environment on Obesity
Authors: You Huimin , Tan Yue , Yu Dawei , Qiu Shuting , Bai Yan , He Jincan , Cao Hua , Che Qishi , Guo Jiao , Su Zhengquan
Published: May 2022

Intestinal environment disorder is a potential pathological mechanism of obesity. There is increasing evidence that disorders in the homeostasis of the intestinal environment can affect various metabolic organs, such as fat and liver, and lead to metabolic diseases. However, there are few therapeutic approaches for obesity targeting the intestinal environment. In this review, on the one hand, we discuss how intestinal microbial metabolites SCFA regulate intestinal function to improve obesity and the possible mechanisms and pathways related to obesity-related pathological processes (depending on SCFA-related receptors such as GPCRs, MCT and SMCT, and through epigenetic processes). On the other hand, we discuss dietary management strategies to enrich SCFA-producing bacteria and target specific SCFA-producing bacteria and whether fecal bacteria transplantation therapy to restore the composition of the gut microbiota to regulate SCFA can help prevent or improve obesity. Finally, we believe that it will be of great significance to establish a working model of gut– SCFA– metabolic disease development in the future for the improvement this human health concern.
Engineering Emulsion Gels as Functional Colloids Emphasizing Food Applications: A Review
Authors: Abdullah  , Liu Lang , Javed Hafiz Umer , Xiao Jie
Published: May 2022

Gels are functional materials with well-defined structures (three-dimensional networks) assembled from the dispersed colloids, and capable of containing a large amount of water, oil, or air (by replacing the liquid within the gel pores), known as a hydrogel, oleogel, and aerogel, respectively. An emulsion gel is a gelled matrix filled with emulsion dispersion in which at least one phase, either continuous phase or dispersed phase forms spatial networks leading to the formation of a semisolid texture. Recently, the interest in the application of gels as functional colloids has attracted great attention in the food industry due to their tunable morphology and microstructure, promising physicochemical, mechanical, and functional properties, and superior stability, as well as controlled release, features for the encapsulated bioactive compounds. This article covers recent research progress on functional colloids (emulsion gels), including their fabrication, classification (protein-, polysaccharide-, and mixed emulsion gels), and properties specifically those related to the gel-body interactions (texture perception, digestion, and absorption), and industrial applications. The emerging applications, including encapsulation and controlled release, texture design and modification, fat replacement, and probiotics delivery are summarized. A summary of future perspectives to promote emulsion gels' use as functional colloids and delivery systems for scouting potential new applications in the food industry is also proposed. Emulsion gels are promising colloids being used to tailor breakdown behavior and sensory perception of food, as well as for the processing, transportation, and targeted release of food additives, functional ingredients, and bioactive substances with flexibility in designing structural and functional parameters.
Impact of Adjuvant Chemotherapy on FIGO Stage I Ovarian Clear Cell Carcinoma: A Systematic Review and Meta-Analysis
Authors: Yin Min , Yang Jiaxin , Zhou Huimei , Liu Qian , Li Sijian , Zhang Xinyue
Published: May 2022

Background

Ovarian clear cell carcinoma (OCCC) is an uncommon subtype of epithelial ovarian carcinoma (EOC) that is often diagnosed at an earlier stage in younger women. It remains uncertain whether adjuvant chemotherapy improves the prognosis of patients with stage I OCCC.

Objective

This systematic review and meta-analysis aimed to assess the impact of adjuvant chemotherapy on survival in patients with stage I OCCC.

Search Strategy

Eligible studies were screened from PubMed, Web of Science, Embase, and the Cochrane Library up to October 10, 2021.

Selection Criteria

Studies that compared the oncological outcomes of adjuvant chemotherapy with observation were included.

Data Collection and Analysis

Six studies comprising a total of 4553 patients were enrolled in our study, of whom 3320 (72.9%) patients had undergone adjuvant chemotherapy and 1233 (27.1%) had not.

Main Results

The 5-year disease-free survival (DFS) and 5-year overall survival (OS) of stage I OCCC were 82.7% and 86.3%, respectively. In the overall population, adjuvant chemotherapy did not improve the 5-year DFS (83.2% vs 83.7%, OR 0.77, 95% CI 0.21-2.82, P=0.69) or 5-year OS (87.3% vs 83.6%, OR 1.30, 95% CI 0.86–1.98, P=0.22). Further subgroup analysis on stage IA/IB suggested that adjuvant chemotherapy did not impact 5-year DFS (OR 0.20, 95% CI 0.01-5.29, P=0.34) or 5-year OS (OR 1.52, 95% CI 0.78-2.98, P=0.22). For stage IC including 1798 patients, adjuvant chemotherapy revealed a significant survival benefit for 5-year OS (84.5% vs 83.3%, OR 1.44, 95% CI 1.08-1.94, P=0.01). Furthermore, the administration of adjuvant chemotherapy was found to be associated with a better 5-year OS (OR 4.98, 95% CI 1.12-22.22, P=0.04) in stage IC2/3. But no inferences regarding the effect of AC on stage IC2/3 can be made due to the limited size of the non-AC arm.

Conclusion

This study indicated that adjuvant chemotherapy did not improve the prognosis of stage IA and IB OCCC patients. However, for patients with stage IC, due to the retrospective, heterogenous and older data with limited sample size, the pooled results of our study should be interpreted with caution. More prospective studies on the role of adjuvant chemotherapy in stage I OCCC are warranted.

Systematic Review Registration

PROSPERO, CRD42021287749.
Ultrasound-Based Radiomics Can Classify the Etiology of Cervical Lymphadenopathy: A Multi-Center Retrospective Study
Authors: Liu Yajing , Chen Jifan , Zhang Chao , Li Qunying , Zhou Hang , Zeng Yiqing , Zhang Ying , Li Jia , Xv Wen , Li Wencun , Zhu Jianing , Zhao Yanan , Chen Qin , Huang Yi , Li Hongming , Huang Ying , Yang Gaoyi , Huang Pintong
Published: May 2022

Medical diagnostic imaging is essential for the differential diagnosis of cervical lymphadenopathy. Here we develop an ultrasound radiomics method for accurately differentiating cervical lymph node tuberculosis (LNTB), cervical lymphoma, reactive lymph node hyperplasia, and metastatic lymph nodes especially in the multi-operator, cross-machine, multicenter context. The inter-observer and intra-observer consistency of radiomics parameters from the region of interest were 0.8245 and 0.9228, respectively. The radiomics model showed good and repeatable diagnostic performance for multiple classification diagnosis of cervical lymphadenopathy, especially in LNTB (area under the curve, AUC: 0.673, 0.662, and 0.626) and cervical lymphoma (AUC: 0.623, 0.644, and 0.602) in the whole set, training set, and test set, respectively. However, the diagnostic performance of lymphadenopathy among skilled radiologists was varied (Kappa coefficient: 0.108, *p < 0.001). The diagnostic performance of radiomics is comparable and more reproducible compared with those of skilled radiologists. Our study offers a more comprehensive method for differentiating LNTB, cervical lymphoma, reactive lymph node hyperplasia, and metastatic LN.
PD-L1 Mediates IFNγ-Regulation of Glucose but Not of Tryptophan Metabolism in Clear Cell Renal Cell Carcinoma
Authors: Garige Mamatha , Ghosh Susmita , Norris Alexis , Li Guangyuan , Poncet Sarah , Chou Chao-Kai , Wu Wells W. , Shen Rong-Fong , Sourbier Carole
Published: May 2022

The immune checkpoint programmed death-ligand 1 (PD-L1) is expressed on the cell surface of tumor cells and is key for maintaining an immunosuppressive microenvironment through its interaction with the programmed death 1 (PD-1). Clear cell renal cell carcinoma (ccRCC) is a highly immunogenic cancer characterized by an aberrant aerobic glycolytic metabolism and is known to overexpress PD-L1. Multiple immunotherapies have been approved for the treatment of ccRCC, including cytokines and immune checkpoint inhibitors. Recently the intrinsic role of PD-L1 and interferon gamma (IFNγ) signaling have been studied in several types of tumor cells, yet it remains unclear how they affect the metabolism and signaling pathways of ccRCC. Using metabolomics, metabolic assays and RNAseq, we showed that IFNγ enhanced aerobic glycolysis and tryptophan metabolism in ccRCC cells in vitro and induced the transcriptional expression of signaling pathways related to inflammation, cell proliferation and cellular energetics. These metabolic and transcriptional effects were partially reversed following transient PD-L1 silencing. Aerobic glycolysis, as well as signaling pathways related to inflammation, were not induced by IFNγ when PD-L1 was silenced, however, tryptophan metabolism and activation of Jak2 and STAT1 were maintained. Our data demonstrate that PD-L1 expression is required to mediate some of IFNγ’s effect in ccRCC cells and highlight the importance of PD-L1 signaling in regulating the metabolism of ccRCC cells in response to inflammatory signals.
Early-Stage Ruptured Hepatocellular Carcinoma With Different Tumor Diameters: Small Tumors Have a Better Prognosis
Authors: Xia Feng , Huang Zhiyuan , Zhang Qiao , Ndhlovu Elijah , Zhang Mingyu , Chen Xiaoping , Zhang Bixiang , Zhu Peng
Published: May 2022

Background and Aim

Ruptured hepatocellular carcinoma (rHCC) is classified as T4 according to the TNM staging system with a very poor (does not achieve expected) prognosis, which has always been controversial. This study aimed at assessing the specific impact of different tumor diameters on the posttreatment prognosis of BCLC stage 0/A rHCC patients.

Methods

Data from 258 patients with BCLC stage 0/A HCC treated in our center from January 2008 to December 2017 were collected, including 143 rHCC patients and 115 patients with non-ruptured HCC (nrHCC). With the help of X-tile software, we determined the cutoff value of the tumor diameter in patients with rHCC. Using 8 cm as the cutoff, we divided rHCC patients into Small-rHCC (n = 96) and Large-rHCC (n = 47) groups, compared the prognoses of the S-rHCC and L-rHCC groups, as well as the prognoses of the two groups with the nrHCC group using the Kaplan–Meier method, and screened the prognostic factors of rHCC patients using the multivariate Cox risk model.

Results

The OS of the S-rHCC group was significantly higher than that of the L-rHCC group [HR = 2.41 (1.60–3.63)], and the OS of the nrHCC group was comparable to that of the S-rHCC group (P = 0.204). In patients treated with surgery only, OS and RFS were also comparable in the S-rHCC nrHCC group. Meanwhile, multivariate Cox regression analysis revealed that alpha-fetoprotein (AFP), alkaline phosphatase (ALP), and the main method of treatment were also prognostic factors for OS in patients with rHCC.

Conclusions

Ruptured HCC with a relatively small diameter (≤8 cm) can also achieve the same prognosis as nrHCC patients after aggressive treatment. It is also not recommended to include all patients with rHCC in stage T4.
Update in TIGIT Immune-Checkpoint Role in Cancer
Authors: Annese Tiziana , Tamma Roberto , Ribatti Domenico
Published: May 2022

The in-depth characterization of cross-talk between tumor cells and T cells in solid and hematological malignancies will have to be considered to develop new therapeutical strategies concerning the reactivation and maintenance of patient-specific antitumor responses within the patient tumor microenvironment. Activation of immune cells depends on a delicate balance between activating and inhibitory signals mediated by different receptors. T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) is an inhibitory receptor expressed by regulatory T cells (Tregs), activated T cells, and natural killer (NK) cells. TIGIT pathway regulates T cell-mediated tumor recognition in vivo and in vitro and represents an exciting target for checkpoint blockade immunotherapy. TIGIT blockade as monotherapy or in combination with other inhibitor receptors or drugs is emerging in clinical trials in patients with cancer. The purpose of this review is to update the role of TIGIT in cancer progression, looking at TIGIT pathways that are often upregulated in immune cells and at possible therapeutic strategies to avoid tumor aggressiveness, drug resistance, and treatment side effects. However, in the first part, we overviewed the role of immune checkpoints in immunoediting, the TIGIT structure and ligands, and summarized the key immune cells that express TIGIT.
The Acquired Vulnerability Caused by CDK4/6 Inhibition Promotes Drug Synergism Between Oxaliplatin and Palbociclib in Cholangiocarcinoma
Authors: Suppramote Orawan , Prasopporn Sunisa , Aroonpruksakul Satinee , Ponvilawan Ben , Makjaroen Jiradej , Suntiparpluacha Monthira , Korphaisarn Krittiya , Charngkaew Komgrid , Chanwat Rawisak , Pisitkun Trairak , Okada Seiji , Sampattavanich Somponnat , Jirawatnotai Siwanon
Published: May 2022

Cholangiocarcinoma (CCA) is one of the most difficult to treat cancers, and its nature of being largely refractory to most, if not all, current treatments results in generally poor prognosis and high mortality. Efficacious alternative therapies that can be used ubiquitously are urgently needed. Using acquired vulnerability screening, we observed that CCA cells that reprofile and proliferate under CDK4/6 inhibition became vulnerable to ribosomal biogenesis stress and hypersensitive to the anti-ribosome chemotherapy oxaliplatin. CCA cells overexpress the oncogenic ribosomal protein RPL29 under CDK4/6 inhibition in a manner that correlated with CDK4/6 inhibitor resistance. Depletion of RPL29 by small interfering RNAs (siRNAs) restored the sensitivity of CCA cells to CDK4/6 inhibition. Oxaliplatin treatment suppressed the RPL29 expression in the CDK4/6 inhibitor treated CCA cells and triggered RPL5/11-MDM2-dependent p53 activation and cancer apoptosis. In addition, we found that combination treatment with oxaliplatin and the CDK4/6 inhibitor palbociclib synergistically inhibited both parental and CDK4/6 inhibitor-resistant CCA, and prevented the emergence of CDK4/6 and oxaliplatin-resistant CCA. This drug combination also exerted suppressive and apoptosis effects on CCA in the in vitro 3-dimensional culture, patient-derived organoid, and in vivo xenograft CCA models. These results suggest the combination of the CDK4/6 inhibitor palbociclib and the anti-ribosome drug oxaliplatin as a potentially promising treatment for cholangiocarcinoma.
Postmastectomy Radiotherapy After Neoadjuvant Chemotherapy in cT1-2N+ Breast Cancer Patients: A Single Center Experience and Review of Current Literature
Authors: Luo Meng , Chen Huihui , Deng Hao , Jin Yao , Wang Gui , Zhang Kun , Ma Hong , Chen Yiding , Zhang Suzhan , Zhou Jiaojiao
Published: May 2022

Purpose

Postmastectomy radiotherapy (PMRT) after neoadjuvant chemotherapy (NAC) in breast cancer patients with initial clinical stage cT1-2N+, especially for those who achieved ypT1-2N0, is still controversial. This study was to evaluate the survival prognosis of cT1-2N+ patients after NAC with or without PMRT, and to discuss the selection of patients who may omit PMRT.

Patients and Methods

From January 2005 to December 2017, 3055 female breast cancer patients underwent mastectomy in our medical center, among whom 215 patients of cT1-2N+ stage, receiving NAC with or without PMRT were finally analyzed. The median follow-up duration was 72.6 months. The primary endpoint was disease-free survival (DFS), and secondary endpoint was overall survival (OS). Comparison was conducted between PMRT and non-PMRT subgroups.

Results

Of the 215 eligible patients, 35.8% (77/215) cT1-2N+ patients achieved ypT0-2N0 after NAC while 64.2% (138/215) of the patients remained nodal positive (ypT0-2N+). The 5-year DFS of ypT0-2N0 non-PMRT was 79.5% (95% confidence interval [CI] 63.4-95.6%). No statistically significant difference was observed between the ypT0-2N0 PMRT and non-PMRT subgroups for the 5-year DFS (78.5% vs 79.5%, p = 0.673) and OS (88.8% vs 90.8%, p = 0.721). The 5-years DFS didn’t obviously differ between the ypT0-2N0 non-PMRT subgroup and cT1-2N0 subgroup (79.5% vs 93.3%, p = 0.070). By using Cox regression model in multivariate analyses of prognosis in ypT0-2N+ PMRT subgroup, HER2 overexpression and triple-negative breast cancer were significantly poor predictors of DFS and OS, while ypN stage was significant independent predictors of OS.

Conclusion

An effective response to NAC (ypT0-2N0) indicates a sufficiently favorable prognosis, and PMRT might be omitted for cT1-2N+ breast cancer patients with ypT0-2N0 after NAC.
A Novel Classification and Scoring Method Based on Immune-Related Transcription Factor Regulation Patterns in Gastric Cancer
Authors: Wang Gang-Jian , Huangfu Long-Tao , Gao Xiang-Yu , Gan Xue-Jun , Xing Xiao-Fang , Ji Jia-Fu
Published: May 2022

Background

Transcription factors (TFs) play a crucial role in tumorigenesis and anti-tumor immunity. However, the potential role of large-scale transcription factor regulation patterns in the progression in gastric cancer (GC) is unknown.

Methods

We comprehensively assessed the relevance of immune-related TF (IRTF) regulation patterns in anti-tumor immunity and immunotherapy in 1,136 gastric cancer (GC) patients, and evaluated the IRTF score based on IRTF regulation patterns using random forests.

Results

Two distinct IRTF regulation patterns were identified, which demonstrating the distinct characteristics in clinical phenotypes, tumor immune microenvironment (TIME), immunogenicity and prognosis in GC. Subsequently, the IRTF score was established to quantify the IRTF regulation pattern for each GC patient. Analysis of large conventional therapy cohorts showed low IRTF score was associated with a better prognosis. In addition, analysis of multiple immunotherapy cohorts showed low IRTF score was also linked to enhanced response to immunotherapy.

Conclusion

TF regulation patterns were found to play an important role in the complex immune regulatory relationships in GC. Evaluation of the IRTF regulation patterns in patients will enhance our understanding of immune specificities, and thus, provide effective strategies for personalized therapy.
Integrated Features for Optimizing Machine Learning Classifiers of Pediatric and Young Adults With a Post-Traumatic Headache From Healthy Controls
Authors: Holmes Scott , Mar'i Joud , Simons Laura E. , Zurakowski David , LeBel Alyssa Ann , O'Brien Michael , Borsook David
Published: May 2022

Post-traumatic headache (PTH) is a challenging clinical condition to identify and treat as it integrates multiple subjectively defined symptoms with underlying physiological processes. The precise mechanisms underlying PTH are unclear, and it remains to be understood how to integrate the patient experience with underlying biology when attempting to classify persons with PTH, particularly in the pediatric setting where patient self-report may be highly variable. The objective of this investigation was to evaluate the use of different machine learning (ML) classifiers to differentiate pediatric and young adult subjects with PTH from healthy controls using behavioral data from self-report questionnaires that reflect concussion symptoms, mental health, pain experience of the participants, and structural brain imaging from cortical and sub-cortical locations. Behavioral data, alongside brain imaging, survived data reduction methods and both contributed toward final models. Behavioral data that contributed towards the final model included both the child and parent perspective of the pain-experience. Brain imaging features produced two unique clusters that reflect regions that were previously found in mild traumatic brain injury (mTBI) and PTH. Affinity-based propagation analysis demonstrated that behavioral data remained independent relative to neuroimaging data that suggest there is a role for both behavioral and brain imaging data when attempting to classify children with PTH.
Evaluation of Neck Disability Using Computed-Tomography in Head and Neck Cancer Survivors
Authors: Harris Alexandria , Branstetter Barton , Li Jinhong , Piva Sara R. , Johnson Jonas T. , Nilsen Marci Lee
Published: May 2022

Objective

We have previously reported that 55% of head and neck cancer survivors have neck disability. However, it is unclear what factors contribute to their neck disability. Our study aim is to determine if survivors with neck disability have evidence of cervical spine degenerative disease assessed by computed tomography (CT).

Materials/Methods

Cross-sectional analysis of patient-reported neck disability, prospectively collected on survivors of squamous cell carcinomas without recurrence or metastasis over one-year post-treatment. Neck disability and its impact on daily life was measured using the Neck Disability Index (NDI) and compared with cervical CT scans within 6 months. Scans were evaluated for degeneration of the disc and facet of the cervical vertebrae rated on a 5-point scale where 5 indicates more severe disease. Multivariable linear regression was used to analyze the association between NDI and radiographic findings.

Results

116 survivors of oropharyngeal carcinomas were identified, predominantly male (81.9%) with an average age of 62.8 ± 8.2 (range 43.8–81.4). Most survivors had advanced stage III-IVa cancer (94.0%) with treatment modalities including surgery (n=26, 52.0%), chemotherapy (n = 45, 90.0%), and radiation therapy (n = 49, 98.0%). Absence of neck disability was observed in 44.0% of survivors, 39.7% had mild disability, and 16.4% moderate disability. The time from treatment to clinic visit was an average of 3.1 ± 2.7 years (range 1.1–13.4). Multivariable analysis of NDI controlling for age, time since treatment, and treatment modality identified an inverse association between NDI and spinal degenerative disease examining cervical discs (−1.46 95% confidence interval (CI) [−2.86, −0.06], p = 0.041) and age (−0.24 95% CI[−0.40, −0.08], p = 0.004).

Conclusions

Our study shows that neck impairment and pain in head and neck cancer survivors is not sufficiently explained by cervical degeneration related to age or trauma, supporting the theory that post-treatment neck disability occurs as a side effect of treatment. These results support the further assessment of structure and function of cervical musculature and degeneration following HNC treatment.
Small Bowel Obstruction After Neonatal Repair of Congenital Diaphragmatic Hernia—Incidence and Risk-Factors Identified in a Large Longitudinal Cohort-Study
Authors: Zahn Katrin B. , Franz Anna-Maria , Schaible Thomas , Rafat Neysan , Büttner Sylvia , Boettcher Michael , Wessel Lucas M.
Published: May 2022

Objective

In patients with a congenital diaphragmatic hernia (CDH), postoperative small bowel obstruction (SBO) is a life-threatening event. Literature reports an incidence of SBO of 20% and an association with patch repair and ECMO treatment. Adhesions develop due to peritoneal damage and underly various biochemical and cellular processes. This longitudinal cohort study is aimed at identifying the incidence of SBO and the risk factors of surgical, pre-, and postoperative treatment.

Methods

We evaluated all consecutive CDH survivors born between January 2009 and December 2017 participating in our prospective long-term follow-up program with a standardized protocol.

Results

A total of 337 patients were included, with a median follow-up of 4 years. SBO with various underlying causes was observed in 38 patients (11.3%) and significantly more often after open surgery (OS). The majority of SBOs required surgical intervention (92%). Adhesive SBO (ASBO) was detected as the leading cause in 17 of 28 patients, in whom surgical reports were available. Duration of chest tube insertion [odds ratio (OR) 1.22; 95% CI 1.01–1.46, p = 0.04] was identified as an independent predictor for ASBO in multivariate analysis. Beyond the cut-off value of 16 days, the incidence of serous effusion and chylothorax was higher in patients with ASBO (ASBO/non-SBO: 2/10 vs. 3/139 serous effusion, p = 0.04; 2/10 vs. 13/139 chylothorax, p = 0.27). Type of diaphragmatic reconstruction, abdominal wall closure, or ECMO treatment showed no significant association with ASBO. A protective effect of one or more re-operations has been detected (RR 0.16; 95% CI 0.02–1.17; p = 0.049).

Conclusion

Thoracoscopic CDH repair significantly lowers the risk of SBO; however, not every patient is suitable for this approach. GoreTex®-patches do not seem to affect the development of ASBO, while median laparotomy might be more favorable than a subcostal incision. Neonates produce more proinflammatory cytokines and have a reduced anti-inflammatory capacity, which may contribute to the higher incidence of ASBO in patients with a longer duration of chest tube insertion, serous effusion, chylothorax, and to the protective effect of re-operations. In the future, novel therapeutic strategies based on a better understanding of the biochemical and cellular processes involved in the pathophysiology of adhesion formation might contribute to a reduction of peritoneal adhesions and their associated morbidity and mortality.
Characteristics of Kawasaki Disease Before and After the COVID-19 Pandemic in a Large Pediatric Heart Disease Center
Authors: Yu Huan , Ni Chao , Xia Yuhan , Li Jie , Hang Biyao , Han Cheng , Xu Zhipeng , Luo Ming , Rong Xing , Zhu Jinshun , Chu Maoping
Published: May 2022

Background

Kawasaki disease (KD) is an acute febrile systemic vasculitis of unknown etiology. After the pandemic of coronavirus disease 2019 (COVID-19), some children infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) showed clinical symptoms similar to KD, indicating a close relationship between KD and SARS-CoV-2. Therefore, we designed this retrospective study to analyze the characteristics of KD patients before and after the COVID-19 pandemic.

Methods

We retrospectively collected demographic and laboratory data of KD patients in Yuying Children's Hospital of Wenzhou Medical University from 1 January 2015 to 31 December 2020. Yuying Children's Hospital of Wenzhou Medical University is located in eastern China and is the largest pediatric heart disease center in the region, which includes a population of nearly 10 million. We studied the characteristics of KD patients and analyzed the changes in these characteristics before and after the emergence of SARS-CoV-2 in this area.

Results

The analysis revealed the following novel features: (1) Under the influence of the COVID-19 pandemic, the onset age of Kawasaki disease became younger. (2) After the occurrence of COVID-19, the hospitalization days of KD patients were shorter than before the pandemic. (3) After the occurrence of COVID-19, the albumin of KD patients was higher than before the pandemic. (4) The COVID-19 pandemic did not have a significant effect on the incidence of coronary artery lesions (CALs) in Kawasaki disease.

Conclusion

After the COVID-19 outbreak, the characteristics of KD patients showed a younger trend of age, shorter hospitalization days and higher levels of albumin, but the incidence of CALs did not change significantly.
Effectiveness of Community Pharmacy Diabetes and Hypertension Care Program: An Unexplored Opportunity for Community Pharmacists in Pakistan
Authors: Malik Madeeha , Hussain Azhar , Aslam Usman , Hashmi Ayisha , Vaismoradi Mojtaba , Hayat Khezar , Jamshed Shazia
Published: May 2022

Background: The effective management of patients diagnosed with both Diabetes as well as Hypertension is linked with administration of efficacious pharmacological therapy as well as improvement in adherence through counseling and other strategies. Being a part of primary healthcare team, community pharmacists can effectively provide patient care for chronic disease management. The objective of the study was to evaluate the impact of pharmacist counseling on blood pressure and blood glucose control among patients having both hypertension and diabetes attending community pharmacies in Pakistan.

Method: A randomized, controlled, single-blind, pre-post-intervention study design was used. The respondents included patients diagnosed with diabetes mellitus (Type I or II) and hypertension visiting community pharmacies to purchase their regular medicine. A simple random sampling technique using the lottery method was used to select community pharmacies in groups A (intervention, n = 4) and group B (control, n = 4). The total number of patients was 40 in each group, while estimating a dropout rate of 25%. The patients in the intervention group received special counseling. Blood pressure and blood glucose were checked after every 15 days for 6 months. Prevalidated tools such as the hypertension knowledge level scale, the diabetes knowledge questionnaire 24, and a brief medication questionnaire was used. Data were coded and analyzed using SPSS 21. Wilcoxon test (p < 0.05) was used to compare pre-post intervention knowledge regarding the disease, while the Mann-Whitney test (p < 0.05) was used to find differences in medication adherence among control and intervention groups.

Results: A significant improvement in mean knowledge scores of patients with diabetes (16.02 ±2.93 vs. 19.97 ±2.66) and hypertension (15.60 ±3.33 vs. 18.35 ±2.31) in the intervention group receiving counseling for 6 months than control group (p < 0.05) was noted. Furthermore, the fasting blood glucose levels (8.25 ±1.45) and systolic BP (130.10 ±6.89) were significantly controlled after 6 months in the intervention group.

Conclusion: The current study results concluded that community pharmacists’ counselling has a positive impact on blood glucose and blood pressure management among patients suffering with both diabetes and hypertension.
Comprehensive Analysis of Eleutherococcus senticosus (Rupr. & Maxim.) Maxim. Leaves Based on UPLC-MS/MS: Separation and Rapid Qualitative and Quantitative Analysis
Authors: Hu Jianping , Wu Dan , Sun Yanping , Zhao Hongquan , Wang Yangyang , Zhang Wensen , Su Fazhi , Yang Bingyou , Wang Qiuhong , Kuang Haixue
Published: May 2022

Eleutherococcus senticosus (Rupr. & Maxim.) Maxim. leaves (ESL) have long been people’s favorite as a natural edible green vegetable, in which phenols and saponins are the main characteristic and bioactive components. This study was first carried out to comprehensively analyze the phenols and saponins in ESL, including phytochemical, qualitative, quantitative, and bioactivity analysis. The results showed that 30 compounds, including 20 phenolic compounds and 7 saponins, were identified. Twelve of them were isolated from Eleutherococcus Maxim. for the first time. In the qualitative analysis, 30 phenolic compounds and 28 saponins were accurately detected. Their characteristic cleavage processes were described by UPLC-QTOF-MS/MS. Ten representative ingredients were quantitated in 29 different regions via a 4000 QTRAP triple quadrupole tandem mass spectrometer (UPLC-QTRAP-MS/MS), and it was found that S19 (69.89 ± 1.098 mg/g) and S1 (74.28 ± 0.733 mg/g) had the highest contents of total phenols and saponins, respectively. The newly developed analysis method for the quantitative determination was validated for linearity, precision, and limits of detection and quantification, which could be applied to the quality assessment of ESL. In vitro experiment, the α-glucosidase inhibitory effect of the phenolic fraction was higher than others, indicating that the phenolic content may be related to the hypoglycemic activity. It was also suggested that ESL could be developed as a natural potential effective drug or functional food.
Single Cell Biology: Exploring Somatic Cell Behaviors, Competition and Selection in Chronic Disease
Authors: Zhu Wandi , Deo Rahul C. , MacRae Calum A.
Published: May 2022

The full range of cell functions is under-determined in most human diseases. The evidence that somatic cell competition and clonal imbalance play a role in non-neoplastic chronic disease reveal a need for a dedicated effort to explore single cell function if we are to understand the mechanisms by which cell population behaviors influence disease. It will be vital to document not only the prevalent pathologic behaviors but also those beneficial functions eliminated or suppressed by competition. An improved mechanistic understanding of the role of somatic cell biology will help to stratify chronic disease, define more precisely at an individual level the role of environmental factors and establish principles for prevention and potential intervention throughout the life course and across the trajectory from wellness to disease.