bluuebunny/crossref_metadata_2025_split huggingface dataset:
Distant metastasis without regional progression in non-muscle invasive bladder cancer: case report and pooled analysis of literature
Authors: Xu Tianyuan , Gu Wenyu , Wang Xianjin , Xia Leilei , He Yanyan , Dong Fan , Yang Bin , Yao Xudong 
Published: July 2022

Abstract
Background
Non-muscle invasive bladder cancer (NMIBC) represents the majority of bladder neoplasms. It is unusual for NMIBC metastasizing distantly without regional progression, namely metastatic NMIBC (mNMIBC), which is still poorly understood and easily omitted based on current management policies. So far, description of mNMIBC is limited to a few case reports.

Methods
We reported a 70-year-old man with NMIBC who suffered from cervical metastasis without pelvic recurrence at 41 months after initial diagnosis. Then we performed a collective analysis of this case together with published mNMIBC cases searched from PubMed, Embase, and Web of Science, aiming to illustrate baseline clinicopathologic parameters, metastatic patterns, and treatment outcomes of these patients and analyze associated influencing factors.

Results
After scrupulous review, 45 cases previous reported and the one from our center were incorporated into the aggregated cohort of mNMIBC, including 34 males and 12 females. Primary tumors from 46.7% of patients were high-grade (HG) or grade 3 (G3) and 65.1% had T1 lesions. Aberrant biomarker expression was found in tumors of some cases. Most (40/46) metastases of mNMIBC occurred at a single site, mainly in lung, bone and lymph nodes. Apart from three cases of de novo mNMIBC, the mean metastasis-free survival (MFS) interval of metachronous mNMIBC was 42.5 months, which was obviously longer than conventional metastatic bladder cancer. Shortened MFS interval was associated with old age, T1 or HG/G3 primary tumors, and non-lung metastases. Systemic chemotherapy and metastasectomy or radiotherapy for oligometastatic lesion were main therapeutic approaches of mNMIBC, and immunotherapy was adopted for the case from our center. Lung and bone metastases correlated with relatively favorable and unfavorable survival outcomes, respectively. Compared with monotherapy, chemotherapy, or immunotherapy combined with local cytoreduction got more favorable outcomes.

Conclusion
Although rare, mNMIBC occurs more in tumors with high-risk features. Usually, mNMIBC metastasizes later than conventional metastatic bladder cancer and manifests as solitary lesion. Outcomes of mNMIBC would be influenced by metastatic site and post-metastatic treatment. Systemic treatment combined with local cytoreduction may render survival benefit in selected patients.
SEMA4D/PlexinB1 promotes AML progression via activation of PI3K/Akt signaling
Authors: Liu Lu , Yang Lin , Liu Xiaojun , Liu Menghan , Liu Jing , Feng Xuefeng , Nie Ziyuan , Luo Jianmin 
Published: July 2022

Abstract
Background
Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults. SEMA4D is a 150 kDa transmembrane protein that belongs to the IV class of the subfamily of semaphorin family. Previous studies have reported that SEMA4D is a multifunctional target in many solid tumors, involving multiple physiological systems, and there are emerging therapies to target these pathways. The role of SEMA4D in AML has not yet been explored.

Methods
The SEMA4D expression prolile, clinical data and potential prognostic analysis were acquired via the cBioPortal and GEPIA databases. SEMA4D expression was measured using real-time quantitative PCR and western blot. Cell counting kit-8 (CCK8) and flow cytometry were used to evaluate the malignant biological characteristics.

Results
We observed that SEMA4D was increased in AML patients and correlated with risk stratification and prognosis. Moreover, SEMA4D promotes the proliferation and inhibits apoptosis of AML cells by binding to its receptor, PlexinB1, and reduces the sensitivity of AML cells to daunorubicin. In addition, SEMA4D/PlexinB1 promotes the proliferation and survival of AML cells by activating the PI3K/Akt signaling pathway. VX15/2503, an anti-SEMA4D antibody, can inhibit the proliferation of AML cells in xenograft mouse models, thereby inhibiting the development of AML.

Conclusion
SEMA4D will serve as a unique predictive biomarker and a possible therapeutic target in AML.
eIF6 is potential diagnostic and prognostic biomarker that associated with 18F-FDG PET/CT features and immune signatures in esophageal carcinoma
Authors: Gao Yan , Yuan Lingling , Zeng Jing , Li Fuyan , Li Xiaohui , Tan Fan , Liu Xusheng , Wan Huabing , Kui Xueyan , Liu Xiaoyu , Ke Changbin , Pei Zhijun 
Published: July 2022

Abstract
Background
Although eukaryotic initiation factor 6 (eIF6) is a novel therapeutic target, data on its importance in the development of esophageal carcinoma (ESCA) remains limited. This study evaluated the correlation between eIF6 expression and metabolic analysis using fluorine-18 fluorodeoxyglucose (18F-FDG) -Positron emission tomography (PET) and immune gene signatures in ESCA.

Methods
This study employed The Cancer Genome Atlas (TCGA) to analyze the expression and prognostic value of eIF6, as well as its relationship with the immune gene signatures in ESCA patients. The qRT-PCR and Western blot analyses were used to profile the expression of eIF6 in ESCA tissues and different ESCA cell lines. The expression of tumor eIF6 and glucose transporter 1 (GLUT1) was examined using immunohistochemical tools in fifty-two ESCA patients undergoing routine 18F-FDG PET/CT before surgery. In addition, the cellular responses to eIF6 knockdown in human ESCA cells were assessed via the MTS, EdU, flow cytometry and wound healing assays.

Results
Our data demonstrated that compared with the normal esophageal tissues, eIF6 expression was upregulated in ESCA tumor tissues and showed a high diagnostic value with an area under curve of 0.825 for predicting ESCA. High eIF6 expression was significantly correlated with shorter overall survival of patients with esophagus adenocarcinoma (p = 0.038), but not in squamous cell carcinoma of the esophagus (p = 0.078). In addition, tumor eIF6 was significantly associated with 18F-FDG PET/CT parameters: maximal and mean standardized uptake values (SUVmax and SUVmean) and total lesion glycolysis (TLG) (rho = 0.458, 0.460, and 0.300, respectively, p < 0.01) as well as GLUT1 expression (rho = 0.453, p < 0.001). A SUVmax cutoff of 18.2 led to prediction of tumor eIF6 expression with an accuracy of 0.755. Functional analysis studies demonstrated that knockdown of eIF6 inhibited ESCA cell growth and migration, and fueled cell apoptosis. Moreover, the Bulk RNA gene analysis revealed a significant inverse association between eIF6 and the tumor-infiltrating immune cells (macrophages, T cells, or Th1 cells) and immunomodulators in the ESCA microenvironment.

Conclusion
Our study suggested that eIF6 might serve as a potential prognostic biomarker associated with metabolic variability and immune gene signatures in ESCA tumor microenvironment.
Bladder cancer-derived exosomal KRT6B promotes invasion and metastasis by inducing EMT and regulating the immune microenvironment
Authors: Song Qiang , Yu Hao , Cheng Yidong , Han Jie , Li Kai , Zhuang Juntao , Lv Qiang , Yang Xiao , Yang Haiwei 
Published: July 2022

Abstract
Background
Tumour-derived exosomes have recently been shown to participate in the formation and progression of different cancer processes, including tumour microenvironment remodelling, angiogenesis, invasion, metastasis, and drug resistance. However, the function and mechanism of exosome-encapsulated nucleic acids and proteins in bladder cancer remain unclear. This study aimed to investigate the effects of tumour-derived exosomes on the tumorigenesis and development of bladder cancer.

Methods
In this study, gene expression profiles and clinical information were collected from The Cancer Genome Atlas (TCGA) database and two independent Gene Expression Omnibus (GEO) datasets. The nucleic acids and proteins encapsulated in bladder cancer-derived exosomes were obtained from the ExoCarta database. Based on these databases, the expression patterns of exosomal mRNAs and proteins and the matched clinicopathological characteristics were analysed. Furthermore, we carried out a series of experiments to verify the relevant findings.

Results
A total of 7280 differentially expressed mRNAs were found in TCGA data, of which 52 mRNAs were shown to be encapsulated in bladder cancer-derived exosomes. Survival analysis based on the UALCAN database showed that among the top 10 upregulated and the top 10 downregulated exosomal genes, only the expression of KRT6B had a statistically significant effect on the survival of bladder cancer patients. Additionally, clinical correlation analysis showed that the elevated level of KRT6B was highly associated with bladder cancer stage, grade, and metastasis status. GSEA revealed that KRT6B was involved not only in epithelial–mesenchymal transition-related pathways but also in the immune response in bladder cancer. Ultimately, our experimental results were also consistent with the bioinformatic analysis.

Conclusion
KRT6B, which can be detected in bladder cancer-derived exosomes, plays an important role in the epithelial–mesenchymal transition and immune responses in bladder cancer. Further research will enable its potentially prognostic marker and therapeutic target for bladder cancer.
Spatial transcriptomics atlas reveals the crosstalk between cancer-associated fibroblasts and tumor microenvironment components in colorectal cancer
Authors: Peng Zhiwei , Ye Manping , Ding Huiming , Feng Zhenyou , Hu Kongwang 
Published: July 2022

Abstract
Background
The tumor-promoting role of tumor microenvironment (TME) in colorectal cancer has been widely investigated in cancer biology. Cancer-associated fibroblasts (CAFs), as the main stromal component in TME, play an important role in promoting tumor progression and metastasis. Hence, we explored the crosstalk between CAFs and microenvironment in the pathogenesis of colorectal cancer in order to provide basis for precision therapy.

Methods
We integrated spatial transcriptomics (ST) and bulk-RNA sequencing datasets to explore the functions of CAFs in the microenvironment of CRC. In detail, single sample gene set enrichment analysis (ssGSEA), gene set variation analysis (GSVA), pseudotime analysis and cell proportion analysis were utilized to identify the cell types and functions of each cell cluster. Immunofluorescence and immunohistochemistry were applied to confirm the results based on bioinformatics analysis.

Results
We profiled the tumor heterogeneity landscape and identified two distinct types of CAFs, which myo-cancer-associated fibroblasts (mCAFs) is associated with myofibroblast-like cells and inflammatory-cancer-associated fibroblasts (iCAFs) is related to immune inflammation. When we carried out functional analysis of two types of CAFs, we uncovered an extensive crosstalk between iCAFs and stromal components in TME to promote tumor progression and metastasis. Noticeable, some anti-tumor immune cells such as NK cells, monocytes were significantly reduced in iCAFs-enriched cluster. Then, ssGSEA analysis results showed that iCAFs were related to EMT, lipid metabolism and bile acid metabolism etc. Besides, when we explored the relationship of chemotherapy and microenvironment, we detected that iCAFs influenced immunosuppressive cells and lipid metabolism reprogramming in patient who underwent chemotherapy. Additionally, we identified the clinical role of iCAFs through a public database and confirmed it were related to poor prognosis.

Conclusions
In summary, we identified two types of CAFs using integrated data and explored their functional significance in TME. This in-depth understanding of CAFs in microenvironment may help us to elucidate its cancer-promoting functions and offer hints for therapeutic studies.
Spatial and temporal variation of routine parameters: pitfalls in the cerebrospinal fluid analysis in central nervous system infections
Authors: Djukic Marija , Lange Peter , Erbguth Frank , Nau Roland 
Published: July 2022

AbstractThe cerebrospinal fluid (CSF) space is convoluted. CSF flow oscillates with a net flow from the ventricles towards the cerebral and spinal subarachnoid space. This flow is influenced by heartbeats, breath, head or body movements as well as the activity of the ciliated epithelium of the plexus and ventricular ependyma. The shape of the CSF space and the CSF flow preclude rapid equilibration of cells, proteins and smaller compounds between the different parts of the compartment. In this review including reinterpretation of previously published data we illustrate, how anatomical and (patho)physiological conditions can influence routine CSF analysis. Equilibration of the components of the CSF depends on the size of the molecule or particle, e.g., lactate is distributed in the CSF more homogeneously than proteins or cells. The concentrations of blood-derived compounds usually increase from the ventricles to the lumbar CSF space, whereas the concentrations of brain-derived compounds usually decrease. Under special conditions, in particular when distribution is impaired, the rostro-caudal gradient of blood-derived compounds can be reversed. In the last century, several researchers attempted to define typical CSF findings for the diagnosis of several inflammatory diseases based on routine parameters. Because of the high spatial and temporal variations, findings considered typical of certain CNS diseases often are absent in parts of or even in the entire CSF compartment. In CNS infections, identification of the pathogen by culture, antigen detection or molecular methods is essential for diagnosis.
Medicaid professional fees for treatment of opioid use disorder varied widely across states and were substantially below fees paid by medicare in 2021
Authors: Clemans-Cope Lisa , Lynch Victoria , Payton Maya , Aarons Joshua 
Published: July 2022

Abstract
Background
As Medicaid is the largest payer for opioid use disorder (OUD) treatment services in the United States, information about Medicaid provider reimbursement is critical, and Medicaid payment policies influence the structure of OUD treatment services for everyone with OUD treatment needs.

Methods
We collected Medicaid professional fees for OUD treatment and related services for the District of Columbia and fifty state Medicaid programs and the Medicare program in 2021. We create three fee indexes related to OUD treatment, with an emphasis on services related to first-line medication treatments in outpatient settings. We then create Medicaid fee indexes and Medicaid-to-Medicare fee indexes.

Results
Weekly Medicaid fee bundles for methadone treatment at OTPs in 2021 varied widely, more than 4-fold across states. The Medicaid-to-Medicare fee index shows that the national average Medicaid fee bundle was 56 percent of Medicare fees for regular methadone treatment at OTPs in 2021. For services related to OUD treatment, Medicaid fees varied up to 5-fold and larger across the components of each of the four services, and Medicaid fees were low relative to Medicare for almost all state services examined. The Medicaid-to-Medicare fee index was 64 percent of Medicare fees in 2021, ranging from 52 percent for evaluation & management to 76 percent for toxicology testing.

Conclusions
There appears to be little justification for such large variation in Medicaid fees across states. In addition, the generally low fees in Medicaid persist despite recent efforts to increase access to opioid use disorder treatment for Medicaid enrollees, and have important implications for access to life-saving treatment during the current opioid overdose crisis.
The role of the Smad2/3/4 signaling pathway in osteogenic differentiation regulation by ClC-3 chloride channels in MC3T3-E1 cells
Authors: Lu Xiaolin , Li Weixu , Wang Huan , Cao Meng , Jin Zuolin 
Published: July 2022

Abstract
Background
ClC-3 chloride channels promote osteogenic differentiation. Transforming growth factor-β1 (TGF-β1) and its receptors are closely related to ClC-3 chloride channels, and canonical TGF-β1 signaling is largely mediated by Smad proteins. The current study aimed to explore the role of the Smad2/3/4 signaling pathway in the mechanism by which ClC-3 chloride channels regulate osteogenic differentiation in osteoblasts.

Methods
First, real-time PCR and western blotting were used to detect the expression of Smad and mitogen-activated protein kinase (MAPK) proteins in response to ClC-3 chloride channels. Second, immunocytochemistry, coimmunoprecipitation (Co-IP) and immunofluorescence analyses were conducted to assess formation of the Smad2/3/4 complex and its translocation to the nucleus. Finally, markers of osteogenic differentiation were determined by real-time PCR, western blotting, ALP assays and Alizarin Red S staining.

Results
ClC-3 chloride channels knockdown led to increased expression of Smad2/3 but no significant change in p38 or Erk1/2. Furthermore, ClC-3 chloride channels knockdown resulted in increases in the formation of the Smad2/3/4 complex and its translocation to the nucleus. In contrast, the inhibition of TGF-β1 receptors decreased the expression of Smad2, Smad3, p38, and Erk1/2 and the formation of the Smad2/3/4 complex. Finally, the expression of osteogenesis-related markers were decreased upon ClC-3 and Smad2/3/4 knockdown, but the degree to which these parameters were altered was decreased upon the knockdown of ClC-3 and Smad2/3/4 together compared to independent knockdown of ClC-3 or Smad2/3/4.

Conclusions
The Smad2/3 proteins respond to changes in ClC-3 chloride channels. The Smad2/3/4 signaling pathway inhibits osteogenic differentiation regulation by ClC-3 chloride channels in MC3T3-E1 cells.
Using short knee radiographs to predict the coronal alignment after TKA: Is it an accurate proxy for HKA on full-length images?
Authors: Shang Guangqian , Hu Mingwei , Guo Jianjun , Hao Xu , Xiang Shuai 
Published: July 2022

Abstract
Background
The postoperative clinical outcomes has been extensively demonstrated to correlate with the coronal alignment after total knee arthroplasty (TKA). However, in different studies, either the hip-knee-ankle angle (HKA) on a full-length radiograph or the femorotibial angle (FTA) on a short knee film was used to categorize the postoperative coronal alignment. Meanwhile, several different FTA ranges were regarded as neutral alignment in different studies. As a result, it is still unknown that how FTA on short knee films and HKA related to each other. The FTA may be able to become an accurate proxy of HKA to predict the coronal alignment. The purpose of this study was to explore the correlation between the FTA and the HKA after TKA and to find the most accurate FTA range.

Methods
About 223 patients were included in this study and standard weight-bearing short knee films as well as full-length radiographs were acquired. The pre- and postoperative FTA, as well as the postoperative anatomical lateral distal femoral angle (aLDFA) and anatomical medial proximal tibial angle (aMPTA) were measured on short knee films by two orthopedic surgeons independently. On full-length films, the pre- and postoperative FTA, the pre- and postoperative HKA, as well as the postoperative mechanical lateral distal femoral angle (mLDFA) and mechanical medial proximal tibial angle (mMPTA) were also recorded by two other surgeons independently. Pearson correlation analysis was performed to compare FTA and HKA, aMTPA and mMTPA, aLDFA and mLDFA, respectively.

Results
The postoperative FTA and HKA had a good correlation (r = 0.86). The agreements were reached 82.7%, 71.0%, and 68.2% of all patients using three previously reported FTA ranges. When analyzing the independent alignment of the tibial tray and the femoral component, 84.1% and 57.9% of all patients was reached an agreement on the classification.

Conclusions
On most occasions, the consistence between the FTA and HKA in assessing the coronal limb alignment of the lower extremity and the tibial component is satisfactory. However, the postoperative full-length film is still needed to evaluate accurately the coronal alignment of the femoral component.
The impact of CK-MB elevation in patients with acute type A aortic dissection with coronary artery involvement
Authors: Minamidate Naoshi , Takashima Noriyuki , Suzuki Tomoaki 
Published: July 2022

Abstract
Background
Acute type A aortic dissection (ATAAD) is a fatal disease and requires emergency surgery. In particular, it is known that mortality is high when a coronary artery is involved. However, the degree of myocardial damage of the coronary acute artery involvement (ACI) varies and may or may not increase creatine kinase muscle and brain isoenzyme (CK-MB). It is unknown how CK-MB elevation affects the surgical outcome. This study compared the surgical results between the two groups of ACI with or without CK-MB elevation.

Methods
Among 348 patients who underwent an emergency operation for acute type A aortic dissection, there were 28 (8.0%) patients complicated by ACI and underwent additional coronary artery bypass grafting. We divided 26 of those patients into two groups; the MI group ( with CK-MB elevation) and the NMI group (without CK-MB elevation), and compared both groups.

Results
Of the 26, sixteen were in the MI group, and ten were in the NMI group. The average CK-MB in the MI group was 225.5 IU/L, and that in the NMI group was 13.5 IU/L. The mean time from onset to surgery was 248 min in the MI group and 250 min in the NMI group. There was statistical significance in mortality ( 69% vs. 13%, p = 0.03). There was no significance in major complications (ICU days, reintubation, reoperation, pneumonia, sepsis).

Conclusions
Acute coronary artery involvement was associated with 8.0% of patients with ATAAD, and 62% had myocardial ischemia with CK-MB elevation. The MI group had significantly higher mortality than the NMI group. It is crucial for cases with suspected ACI to obtain coronary perfusion as soon as possible to prevent CK-MB from elevating.