Multiparametric simultaneous hybrid 18F-fluorodeoxyglucose positron emission tomography/magnetic resonance imaging (18F-FDG PET/MRI) incorporating intratumoral and peritumoral regions for grading of glioma.

Background: Preoperative grading gliomas is essential for therapeutic clinical decision-making. Current non-invasive imaging modality for glioma grading were primarily focused on magnetic resonance imaging (MRI) or positron emission tomography (PET) of the tumor region. However, these methods overlook the peritumoral region (PTR) of tumor and cannot take full advantage of the biological information derived from hybrid-imaging. Therefore, we aimed to combine multiparameter from hybrid 18F-fluorodeoxyglucose (18F-FDG) PET/MRI of the solid component and PTR were combined for differentiating high-grade glioma (HGG) from low-grade glioma (LGG). Methods: A total of 76 patients with pathologically confirmed glioma (41 HGG and 35 LGG) who underwent simultaneous 18F-FDG PET, arterial spin labelling (ASL), and diffusion-weighted imaging (DWI) with hybrid PET/MRI were retrospectively enrolled. The relative maximum standardized uptake value (rSUVmax), relative cerebral blood flow (rCBF), and relative minimum apparent diffusion coefficient (rADCmin) for the solid component and PTR at different distances outside tumoral border were compared. Receiver operating characteristic (ROC) curves were applied to assess the grading performance. A nomogram for HGG prediction was constructed. Results: HGGs displayed higher rSUVmax and rCBF but lower rADCmin in the solid component and 5 mm-adjacent PTR, lower rADCmin in 10 mm-adjacent PTR, and higher rCBF in 15- and 20-mm-adjacent PTR. rSUVmax in solid component performed best [area under the curve (AUC) =0.865] as a single parameter for grading. Combination of rSUVmax in the solid component and adjacent 20 mm performed better (AUC =0.881). Integration of all 3 indicators in the solid component and adjacent 20 mm performed the best (AUC =0.928). The nomogram including rSUVmax, rCBF, and rADCmin in the solid component and 5-mm-adjacent PTR predicted HGG with a concordance index (C-index) of 0.906. Conclusions: Multiparametric 18F-FDG PET/MRI from the solid component and PTR performed excellently in differentiating HGGs from LGGs. It can be used as a non-invasive and effective tool for preoperative grade stratification of patients with glioma, and can be considered in clinical practice.

Metagenomic Next-generation Sequencing in the Diagnosis of Pulmonary Infections After Allogeneic Hematopoietic Stem Cell Transplantation.

BACKGROUND: Early and accurate identification of pathogens is still challenging in pulmonary infections after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The clinical usefulness of metagenomic next-generation sequencing (mNGS) remains under discussion in diagnosis of pulmonary infections after allo-HSCT. METHODS: This multi-center retrospective study was conducted to compare mNGS and conventional microbiological tests (CMTs) in investigating the pathogens of pulmonary infections in allo-HSCT recipients. A hundred and forty allo-HSCT recipients with suspected pulmonary infections who underwent bronchoscopy were included. mNGS and CMTs were performed in BALF. RESULTS: Among 140 allo-HSCT recipients with suspected pulmonary infections, the positive rate of mNGS was 71.4% whereas the positive rate of CMTs was 55.0%. mNGS identified 182 pathogens included bacteria (n = 88), fungi (n = 35) and viruses (n = 59) while 106 pathogens were detected by CMTs included bacteria (n = 31), fungi (n = 24) and viruses (n = 51). Ninety-eight patients were finally diagnosed as pulmonary infections, including 22 bacterial infections, 7 fungal,18 viral, 48 mixed infections, and 3 with unknown pathogen. Mixed infections were identified in 50.5% of the patients with pulmonary infection. The sensitivity of mNGS and CMTs for diagnosing pulmonary infections were 88.8% and 69.4%, respectively (P=0.001) while the specificity were 81.0% and 85.7%, respectively (P = 0.688). CONCLUSIONS: mNGS might be a promising technology for diagnosis of pulmonary infections in the recipients of allo-HSCT.

Multifunctional single-component photosensitizers as metal-free ferroptosis inducers for enhanced photodynamic immunotherapy.

Immunotherapy can enhance primary tumor efficacy, restrict distant growth, and combat lung metastasis. Unfortunately, it remains challenging to effectively activate the immune response. Here, tertiary butyl, methoxy, and triphenylamine (TPA) were utilized as electron donors to develop multifunctional photosensitizers (PSs). CNTPA-TPA, featuring TPA as the donor (D) and cyano as the acceptor (A), excelled in reactive oxygen species (ROS) generation due to its smaller singlet-triplet energy gap (ΔES-T) and larger spin-orbit coupling constant (SOC). Additionally, cyano groups reacted with glutamate (Glu) and glutathione (GSH), reducing intracellular GSH levels. This not only enhanced PDT efficacy but also triggered redox dyshomeostasis-mediated ferroptosis. The positive effects of photodynamic therapy (PDT) and ferroptosis promoted immunogenic cell death (ICD) and immune activation. By further combining anti-programmed cell death protein ligand-1 (anti-PD-L1) antibody, the powerful treatments of ferroptosis-assisted photodynamic immunotherapy significantly eradicated the primary tumors, inhibited the growth of distant tumors, and suppressed lung metastasis. In this study, a three-pronged approach was realized by single-component CNTPA-TPA, which simultaneously served as metal-free ferroptosis inducers, type-I photosensitizers, and immunologic adjuvants for near-infrared fluorescence imaging (NIR FLI)-guided multimodal phototheranostics of tumor. STATEMENT OF SIGNIFICANCE: (1) CNTPA-TPA shared the smallest singlet-triplet energy gap and the largest spin-orbit coupling constant, which boosted intersystem crossing for efficient type-I photodynamic therapy (PDT); (2) Special reactions between cyano groups with glutamate and glutathione in mild conditions restricted the biosynthesis of intracellular GSH. GSH-depletion efficiently induced glutathione peroxidase 4 inactivation and lipid peroxide, resulting in ferroptosis of tumor cells; (3) The combination treatments of ferroptosis-assisted photodynamic immunotherapy induced by single-component CNTPA-TPA with the participation of anti-PD-L1 antibody resulted in increased T-cell infiltration and profound suppression of both primary and distant tumor growth, as well as lung metastasis.

Aggressive angiomyxoma of female pelvis and perineum: Retrospective study of 17 cases.

OBJECTIVE: Aggressive angiomyxoma is an uncommon mesenchymal neoplasm characterized by a high recurrence rate, usually observed in the lower genital tract of women during their reproductive age. STUDY DESIGN: Seventeen cases of aggressive angiomyxoma confirmed by pathology from January 2007 to December 2021 in Beijing Chao-yang Hospital were included. We collected clinical data and summarized the clinical and immunohistochemical features. RESULTS: All seventeen included patients were females, aged between 23 and 57 years (mean, 37.7 years; median, 42 years). Fourteen patients were newly diagnosed and three were recurrent. The tumors were located in vulva (58.8 %), vagina (23.5 %), buttock (11.8 %), and cervix (5.9 %). The tumors size were 2 to 15 cm in greatest dimension (mean 8 ± 4.4 cm, median 6 cm). Follow-up data was available for nine patients, which ranged from 25 to 124 months (mean, 82 months; median, 80 months). At the end of follow-up, no other recurrence or metastasis was reported. Immunohistochemical analysis showed immunoreactive for estrogen (10/11) and progesterone (8/11) receptor, desmin (6/8), smooth muscle actin (4/10), and vimentin (4/4), S-100 (1/8) and CD34 (1/7). The Ki67 level was less than 5 % in five cases. CONCLUSIONS: AAM is a hormone-sensitive, distinct rare mesenchymal neoplasm with high incidence of local recurrence. Surgery is the preferred treatment, with complete resection being an essential prerequisite for minimizing the risk of recurrence.

Pyroptotic macrophages induce disruption of glutamate metabolism in periodontal ligament stem cells contributing to their compromised osteogenic potential.

Macrophage pyroptosis is of key importance to host defence against pathogen infections and may participate in the progression and recovery of periodontitis. However, the role of pyroptotic macrophages in regulating periodontal ligament stem cells (PDLSCs), the main cell source for periodontium renewal, remains unclear. First, we found that macrophage pyroptosis were enriched in gingiva tissues from periodontitis patients compared with those of healthy people through immunofluorescence. Then the effects of pyroptotic macrophages on the PDLSC osteogenic differentiation were investigated in a conditioned medium (CM)-based coculture system in vitro. CM derived from pyroptotic macrophages inhibited the osteogenic differentiation-related gene and protein levels, ALP activity and mineralized nodule formation of PDLSCs. The osteogenic inhibition of CM was alleviated when pyroptosis was inhibited by VX765. Further, untargeted metabolomics showed that glutamate limitation may be the underlying mechanism. However, exogenous glutamate supplementation aggravated the CM-inhibited osteogenic differentiation of PDLSCs. Moreover, CM increased extracellular glutamate and decreased intracellular glutamate levels of PDLSCs, and enhanced the gene and protein expression levels of system xc - (a cystine/glutamate antiporter). After adding cystine to CM-based incubation, the compromised osteogenic potency of PDLSCs was rescued. Our data suggest that macrophage pyroptosis is related to the inflammatory lesions of periodontitis. Either pharmacological inhibition of macrophage pyroptosis or nutritional supplements to PDLSCs, can rescue the compromised osteogenic potency caused by pyroptotic macrophages.

Esophageal cancer screening, early detection and treatment: Current insights and future directions.

Esophageal cancer ranks among the most prevalent malignant tumors globally, primarily due to its highly aggressive nature and poor survival rates. According to the 2020 global cancer statistics, there were approximately 604000 new cases of esophageal cancer, resulting in 544000 deaths. The 5-year survival rate hovers around a mere 15%-25%. Notably, distinct variations exist in the risk factors associated with the two primary histological types, influencing their worldwide incidence and distribution. Squamous cell carcinoma displays a high incidence in specific regions, such as certain areas in China, where it meets the cost-effectiveness criteria for widespread endoscopy-based early diagnosis within the local population. Conversely, adenocarcinoma (EAC) represents the most common histological subtype of esophageal cancer in Europe and the United States. The role of early diagnosis in cases of EAC originating from Barrett's esophagus (BE) remains a subject of controversy. The effectiveness of early detection for EAC, particularly those arising from BE, continues to be a debated topic. The variations in how early-stage esophageal carcinoma is treated in different regions are largely due to the differing rates of early-stage cancer diagnoses. In areas with higher incidences, such as China and Japan, early diagnosis is more common, which has led to the advancement of endoscopic methods as definitive treatments. These techniques have demonstrated remarkable efficacy with minimal complications while preserving esophageal functionality. Early screening, prompt diagnosis, and timely treatment are key strategies that can significantly lower both the occurrence and death rates associated with esophageal cancer.

RNF144B-mediated p21 degradation regulated by HDAC3 contribute to enhancing ovarian cancer growth and metastasis.

We have shown before that HDAC3 was involved in the pathogenesis of ovarian cancer; however, the specific mechanism of HDAC3 on the pathogenesis of ovarian cancer has not been thoroughly studied. To explore the related proteins in the mechanism of HDAC3 on ovarian cancer. The transcriptome profiles were identified in ovarian carcinoma cells with HDAC3 knockdown or overexpression. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot analysis were used to verify transfection efficiency. Immunofluorescence staining were performed to detect the expression levels of HDAC3 and RNF144B in tissues. Cell proliferation, apoptosis, migration and invasion were confirmed by cell counting Kit-8 (CCK-8), terminal deoxynucleotidyl transferase (TUNEL) and transwell assay, respectively. The protein expression of p53, p21, Bax and Bcl-2 was confirmed by western blot, and CoIP assay was used to validate RNF144B/P21/P53 interaction. Meanwhile, the protein synthesis inhibitor cycloheximide (CHX) was performed to treat cells to probe p21 stability. Finally, we established an in vivo tumor model to explore the effects of HDAC3 and RNF144B on tumor growth. Microarray results showed that among the overlapping genes in the two profiles (HDAC3 knockdown and overexpression), RNF144B was decreased or increased in ovarian carcinoma cells with HDAC3 knockdown or overexpression, HDAC3 overexpression promoted RNF144B expression, and HDAC3 knockdown hindered RNF144B levels. The levels of HDAC3 and RNF144B in malignant ovarian cancer were significantly higher than those in normal ovarian tissue and benign ovarian cancer tissue. RNF144B promoted cell proliferation, migration and invasion, and inhibited cell apoptosis. In addition, overexpression of HDAC3 or RNF144B inhibited p53/p21/Bax expression and promoted Bcl-2 expression. Knockout of HDAC3 or RNF144B has the opposite effect, and RNF144B interacted with p21 and regulated the p21/p53 complex degradation, and finally in vivo experiments proved that HDAC3 and RNF144B promoted tumor growth. RNF144B-mediated p21 degradation regulated by HDAC3 contributed to enhancing ovarian cancer growth and metastasis.

Mn(II) Optimized Sono/Chemodynamic Effect of Porphyrin-Metal-Organic Framework Nanosheets for MRI-Guided Colon Cancer Therapy and Metastasis Suppression.

Sonodynamic therapy (SDT) offers a remarkable non-invasive ultrasound (US) treatment by activating sonosensitizer and generating reactive oxygen species (ROS) to inhibit tumor growth. The development of multifunctional, biocompatible, and highly effective sonosensitizers remains a current priority for SDT. Herein, the first report that Mn(II) ions chelated Gd-TCPP (GMT) nanosheets (NSs) are synthesized via a simple reflux method and encapsulated with pluronic F-127 to form novel sonosensitizers (GMTF). The GMTF NSs produce a high yield of ROS under US irradiation due to the decreased highest occupied molecular orbital-lowest unoccupied molecular orbital gap energy (2.7-1.28 eV). Moreover, Mn(II) ions endow GMTF with a fascinating Fenton-like activity to produce hydroxyl radicals in support of chemodynamic therapy (CDT). It is also effectively used in magnetic resonance imaging (MRI) with high relaxation rate (r 1: 4.401 mM-1 s-1) to track the accumulation of NSs in tumors. In vivo results indicate that the SDT and CDT in combination with programmed cell death protein 1 antibody (anti-PD-1) show effective metastasis prevention effects, and 70% of the mice in the GMTF + US + anti-PD-1 group survived for 60 days. In conclusion, this study develops a sonosensitizer with promising potential for utilizing both MRI-guided SDT and CDT strategies.

Patient Versus Physician Perspective in the Management of Chronic Myeloid Leukemia During Treatment with Tyrosine Kinase Inhibitors.

INTRODUCTION: Chronic myeloid leukemia (CML) is a chronic disease with treatment-free remission (TFR) increasingly regarded as a feasible goal of treatment. However, various factors may influence adherence to international guidelines for CML management. This study aimed to compare the reporting of care between patients with CML and their treating doctors. METHODS: Parallel patient and physician online surveys were conducted between September 22, 2021, and March 15, 2022, which focused on the perceptions of 1882 adult patients with CML and 305 physicians regarding tyrosine kinase inhibitor (TKI) treatment options, monitoring and toxicities, TFR, and challenges faced. RESULTS: Among the enrolled patients, 69.9% received first-line imatinib treatment, 18.6% received nilotinib, and 4.7% received dasatinib. Among the patients treated with imatinib, 36.7% switched to other TKIs due to imatinib resistance/intolerance (71.1%), exploration of more potent TKIs to achieve TFR (8.9%), and treating physicians' recommendation (14.0%), with a median duration of initial treatment of 14 months [interquartile range (IQR) 6-36]. Most (91.8%) physicians agreed that the breakpoint cluster region-Abelson 1 (BCR::ABL1) transcript level should be assessed every 3 months, but only 42.7% of individuals committed to 3-monthly testing and only 17.8% strictly followed their treating physicians' recommendation. Half of the patients aimed for TFR; however, just 45.2% of physicians considered TFR as one of the top three goals for their patients. The major concern in obtaining TFR was patients' adherence. Fatigue was often distressing for patients with TKIs, while physicians were more concerned about platelet and neutrophil counts. A total of 12% and 20.8% of patients reported moderate/severe anxiety and depression, respectively, while only 53.7% of physicians had concerns about their patients' mental health. During the coronavirus disease 2019 (COVID-19) pandemic, 69.2% of patients reported a reduction in their income. Among these patients, 61.8% maintained their current treatment, while 7.3% switched to cheaper alternatives or discontinued treatment, with over 80% of these patients belonging to the low-income group. CONCLUSIONS: Overcoming challenges in patient-physician communication and treatment access is key to improving disease management and quality of life, especially for patients with low income. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT05092048.

Identification of cytokine-induced cell communications by pan-cancer meta-analysis.

Cancer immune responses are complex cellular processes in which cytokine-receptor interactions play central roles in cancer development and response to therapy; dysregulated cytokine-receptor communication may lead to pathological processes, including cancer, autoimmune diseases, and cytokine storm; however, our knowledge regarding cytokine-mediated cell-cell communication (CCI) in different cancers remains limited. The present study presents a single-cell and pan-cancer-level transcriptomics integration of 41,900 cells across 25 cancer types. We developed a single-cell method to actively express 62 cytokine-receptor pairs to reveal stable cytokine-mediated cell communications involving 84 cytokines and receptors. The correlation between the sample-based CCI profile and the interactome analysis indicates multiple cytokine-receptor modules including TGFB1, IL16ST, IL15, and the PDGF family. Some isolated cytokine interactions, such as FN1-IL17RC, displayed diverse functions within over ten single-cell transcriptomics datasets. Further functional enrichment analysis revealed that the constructed cytokine-receptor interaction map is associated with the positive regulation of multiple immune response pathways. Using public TCGA pan-cancer mutational data, co-mutational analysis of the cytokines and receptors provided significant co-occurrence features, implying the existence of cooperative mechanisms. Analysis of 10,967 samples from 32 TCGA cancer types revealed that the 84 cytokine and receptor genes are significantly associated with clinical survival time. Interestingly, the tumor samples with mutations in any of the 84 cytokines and receptors have a substantially higher mutational burden, offering insights into antitumor immune regulation and response. Clinical cancer stage information revealed that tumor samples with mutations in any of the 84 cytokines and receptors stratify into earlier tumor stages, with unique cellular compositions and clinical outcomes. This study provides a comprehensive cytokine-receptor atlas of the cellular architecture in multiple cancers at the single-cell level.

Dual-targeting nanotheranostics for MRI-guided enhanced chemodynamic therapy of hepatoma via regulating the tumor microenvironment.

Chemodynamic therapy (CDT), as a reactive oxygen species (ROS)-based therapeutic modality, has attracted much attention in recent years. However, the insufficient therapeutic effect of CDT is due to the antioxidant system in the tumor microenvironment, such as high levels of glutathione (GSH). In this study, we developed a biological/physical dual-targeting nanotheranostic agent (relaxation rate, r1: 6.3 mM-1 s-1 and r2: 13.11 mM-1 s-1) for enhanced CDT of SMCC-7721 tumors. This nanotheranostic agent is composed of a homologous tumor cell membrane (TCM), magnetic ferric oxide, and manganese oxide and is denoted as FM@TCM nanoparticles (NPs). A favorable effect of in vitro CDT on SMCC-7721 cells (IC50: 20 µg mL-1) is demonstrated, attributed to the Fenton reaction and oxidative stress resulting from the reduction of the GSH level. In vivo T1/T2 magnetic resonance imaging (MRI) confirms that the tumor accumulation of FM@TCM NPs is promoted by concurrent bioactive targeting of the homologous TCM and physico-magnetic targeting of tumor tissues with an external magnetic field. Impressive chemodynamic therapeutic effects on SMCC-7721 tumors are demonstrated through the catalysis of endogenous hydrogen peroxide and depletion of GSH to generate high levels of ROS. Dual-targeting FM@TCM NPs inhibit SMCC-7721 tumor growth (∼90.9%) in vivo without any biotoxicity. This nanotheranostic agent has great potential for use in MRI-guided CDT.

TPM3: a novel prognostic biomarker of cervical cancer that correlates with immune infiltration and promotes malignant behavior in vivo and in vitro.

Cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) has become increasingly prevalent in younger women. Tropomyosin 3 (TPM3), a thin filament actin-binding protein, has been implicated in various malignancies. In this study, TPM3 expression was evaluated using RNA-seq data from The Cancer Genome Atlas (TCGA), and its relationship with CESC prognosis was examined with receiver operating characteristic (ROC) curves. The effects of TPM3 on cellular proliferation and migration were examined in CESC cell lines using Cell Counting Kit-8 (CCK-8), colony formation, and Transwell assays, while in vivo effects were assessed in mouse xenograft models. Furthermore, differentially expressed genes (DEGs) associated with TPM3 were investigated to determine their tumorigenic functions. Associations between TPM3, chemosensitivity, and immune infiltration were analyzed, as were links between mutations, methylation, and prognosis using the cBioPortal and MethSurv databases. Upregulation of TMP3 mRNA and protein levels was observed in CESC samples, with elevated mRNA levels associated with reduced overall survival. TPM3 showed an area under the curve (AUC) of 0.946 for CESC diagnosis and was found to regulate tumor proliferation and metastasis in vitro and in vivo. Overall, 3099 DEGs were identified and found to be enriched in key CESC progression-related signaling pathways. TPM3 expression was also correlated with intratumoral immune cell infiltration and immune checkpoint activity. Patients with higher TPM3 expression showed distinctive chemosensitivity profiles, and TPM3 gene methylation was linked to poorer CESC patient prognostic outcomes. In conclusion, TPM3 is a key regulator of CESC progression, prognosis, and the tumor immune microenvironment, suggesting its potential as a diagnostic or prognostic biomarker and target for CESC immunotherapy.

The induction of ferroptosis by KLF11/NCOA4 axis: the inhibitory role in clear cell renal cell carcinoma.

Ferroptosis is a form of cell death and has great potential application in the treatment of many cancers, including clear cell renal cell carcinoma (ccRCC). Herein, we identified the essential roles of Krüppel-like factor 11 (KLF11) in suppressing the progression of ccRCC. By analyzing mRNA expression data from the Gene Expression Omnibus (GEO) database, we found that KLF11 was a significantly downregulated gene in ccRCC tissues. The results of subsequent functional assays verified that KLF11 played an antiproliferative role in ccRCC cells and xenograft tumors. Furthermore, gene set enrichment analysis indicated that ferroptosis was involved in ccRCC development, and correlation analysis revealed that KLF11 was positively related to ferroptosis drivers. We also found that KLF11 promoted ferroptosis in ccRCC by downregulating the protein expression of ferritin, system xc (-) cystine/glutamate antiporter (xCT), and glutathione peroxidase 4 (GPX4), acting as the inhibitory factors of ferroptosis and increasing the intracellular levels of lipid reactive oxygen species (ROS). As a transcriptional regulator, KLF11 significantly increased the promoter activity of nuclear receptor coactivator 4 (NCOA4), a gene significantly downregulated in ccRCC and whose low expression is associated with poor survival. The characteristics of ccRCC cells caused by KLF11 overexpression were reversed after NCOA4 silencing. In summary, the present study suggests that KLF11 suppresses the progression of ccRCC by increasing NCOA4 transcription. Therefore, the KLF11/NCOA4 axis may serve as a novel therapeutic target for human ccRCC.

WFDC3 inhibits tumor metastasis by promoting the ERß-mediated transcriptional repression of TGFBR1 in colorectal cancer.

Estrogen plays a protective role in colorectal cancer (CRC) and primarily functions through estrogen receptor ß (ERß). However, clinical strategies for CRC therapy associated with ERß are still under investigation. Our discoveries identified WFDC3 as a tumor suppressor that facilitates estrogen-induced inhibition of metastasis through the ERß/TGFBR1 signaling axis. WFDC3 interacts with ERß and increases its protein stability by inhibiting its proteasome-dependent degradation. WFDC3 represses TGFBR1 expression through ERß-mediated transcription. Blocking TGFß signaling with galunisertib, a drug used in clinical trials that targets TGFBR1, impaired the migration of CRC cells induced by WFDC3 depletion. Moreover, there was clinical significance to WFDC3 in CRC, as CRC patients with high WFDC3 expression in tumor cells had favorable prognoses. Therefore, this work suggests that WFDC3 could be an indicator for therapies targeting the estrogen/ERß pathway in CRC patients.

Evaluation of physician guideline adherence and areas for improvement in managing patients with chronic myeloid leukemia: a cross-sectional survey.

The experience of a physician at a clinical center is among the critical factors in managing chronic myeloid leukemia (CML) during its treatment with tyrosine kinase inhibitors (TKIs). The authors conducted a cross-sectional questionnaire to investigate barriers to physician use of published evidence-based guidelines in CML management in a real-world setting. Among the participating physicians (N = 407), 99.8% of physicians reported that CML guidelines were useful; however, only 62.9% of physicians reported that they follow guidelines in real-time. Although 90.7% of physicians prefer second-generation TKIs as the first-line treatment, imatinib (88.2%) remains the most widely administered TKI in the first-line setting. Only 50.6% of physicians switched the treatment when patients failed to achieve early molecular response (at 3 months), whereas 70.3% of physicians switched the treatment when patients' response to TKI was inadequate at 6 months and/or 12 months. Moreover, only 43.5% of physicians considered treatment-free remission (TFR) as one of the top 3 goals for their patients. The major concern to obtain TFR was patients' adherence. This study demonstrated that CML management was generally in line with the current guidelines, but some of the details at the point of care are needed to be improved in CML.

Busulfan Plus Fludarabine Compared With Busulfan Plus Cyclophosphamide for AML Undergoing HLA-Haploidentical Hematopoietic Cell Transplantation: A Multicenter Randomized Phase III Trial.

PURPOSE: The busulfan plus fludarabine (BuFlu) conditioning regimen has lower transplant-related mortality (TRM) than busulfan plus cyclophosphamide (BuCy) in HLA-matched transplantation. We aimed to compare outcomes of the BuFlu regimen with those of the BuCy regimen in HLA-haploidentical hematopoietic cell transplantation (haplo-HCT). METHODS: We performed an open-label, randomized phase III trial at 12 hospitals in China. Eligible patients with AML (18-65 years) were randomly assigned 1:1 to receive BuFlu (busulfan 0.8 mg/kg four times per day on days -6 to -3; fludarabine 30 mg/m2 once daily on days -7 to -3) or BuCy (same dose of busulfan; cyclophosphamide 60 mg/kg once daily on days -3 and -2). The primary end point was 1-year TRM in the intention-to-treat population and safety in the per-protocol population. This trial is registered with ClinicalTrials.gov (identifier: NCT02487069) and is complete. RESULTS: From November 20, 2015, to September 30, 2019, 386 patients were randomly assigned to receive the BuFlu (n = 194) or BuCy (n = 192) regimen. The median follow-up was 55.0 (IQR, 46.5-69.0) months after random assignment. The 1-year TRM was 7.2% (95% CI, 4.1 to 11.4) and 14.1% (95% CI, 9.6 to 19.4; hazard ratio [HR], 0.51; 95% CI, 0.27 to 0.97; P = .041), the 5-year relapse was 17.9% (95% CI, 9.6 to 28.3) and 14.2% (95% CI, 9.1 to 20.5; HR, 1.12; 95% CI, 0.65 to 1.95; P = .670), and the 5-year overall survival was 72.5% (95% CI, 62.2 to 80.4) and 68.2% (95% CI, 58.9 to 75.9; HR, 0.84; 95% CI, 0.56 to 1.26; P = .465) in two groups, respectively. Grade 3 regimen-related toxicity (RRT) was reported for 0 of 191 patients following the BuFlu regimen and 9 (4.7%) of 190 patients following the BuCy regimen (P = .002). At least one type of grade 3-5 adverse event was reported for 130 (68.1%) of the 191 patients and 147 (77.4%) of the 190 patients in two groups, respectively (P = .041). CONCLUSION: The BuFlu regimen has a lower TRM and RRT and similar relapse for patients with AML undergoing haplo-HCT compared with the BuCy regimen.

Renal clear cell carcinoma-derived CXCL5 drives tumor-associated fibroblast formation and facilitates cancer progression.

BACKGROUND: Kidney renal clear cell carcinoma (KIRC, ccRCC) is one of the most common and aggressive subtypes of urinary system cancer. Cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME) exacerbate the malignant phenotype of KIRC. It is necessary to explore further how KIRC induces normal fibroblasts (NFs) into CAFs. METHODS: The transcriptome data of KIRC was obtained from The Cancer Genome Atlas (TCGA), and the hub-genes and their corresponding functions in the co-expression module were obtained through differential analysis, enrichment analysis, and weighted correlation network analysis (WGCNA) analysis. RT-PCR, western-blot, and Elisa assays were used to detect the expression of CXCL5 (C-X-C Motif Chemokine Ligand 5) in KIRC cells and medium. Western-blot and immunofluorescence were used to demonstrate the transformation of NFs to CAF-like cells and relevant pathways. Human umbilical vein endothelial cells (huvec) were seeded within collagen gel to represent the neo-vascular network. Transwell, scrape, colony formation, and CCK-8 assays were performed to reveal the feedback effect of KIRC cells. RESULTS: Bioinformatics analysis showed that CXCL5 was a core gene in differential expression genes (DEGs) and was associated with extracellular matrix (ECM), which was associated with CAFs. KIRC-derived CXCL5 promoted the conversion of NFs to CAF-like cells. It included morphological and corresponding molecular marker changes. Activation of the JAK/STAT3 pathway was involved in this process. Corresponding, CAFs cells could secrete vascular endothelial growth factor (VEGF), which induced angiogenesis. CXCL5 promoted KIRC invasion and proliferation. CONCLUSIONS: Our research suggested that KIRC-derived CXCL5 could induce NFs to become CAFs-like cells that promote angiogenesis in the TME. The positive feedback of CXCL5 promoted its own invasive growth. The intercellular communication with CXCL5 as the core might be the critical node in the occurrence and development of KIRC.

A Database of Lung Cancer-Related Genes for the Identification of Subtype-Specific Prognostic Biomarkers.

The molecular subtype is critical for accurate treatment and follow-up in patients with lung cancer; however, information regarding subtype-associated genes is dispersed among thousands of published studies. Systematic curation and cross-validation of the scientific literature would provide a solid foundation for comparative genetic studies of the major molecular subtypes of lung cancer. Here, we constructed a literature-based lung cancer gene database (LCGene). In the current release, we collected and curated 2507 unique human genes, including 2267 protein-coding and 240 non-coding genes from comprehensive manual examination of 10,960 PubMed article abstracts. Extensive annotations were added to aid identification of differentially expressed genes, potential gene editing sites, and non-coding gene regulation. For instance, we prepared 607 curated genes with CRISPR knockout information in 43 lung cancer cell lines. Further comparison of these implicated genes among different subtypes identified several subtype-specific genes with high mutational frequencies. Common tumor suppressors and oncogenes shared by lung adenocarcinoma and lung squamous cell carcinoma, for example, exhibited different mutational frequencies and prognostic features, suggesting the presence of subtype-specific biomarkers. Our retrospective analysis revealed 43 small cell lung cancer-specific genes. Moreover, 52 tumor suppressors and oncogenes shared by lung adenocarcinoma and squamous cell carcinoma confirmed the different molecular mechanisms of these two cancer subtypes. The subtype-based genetic differences, when combined, may provide insight into subtype-specific biomarkers for genetic testing.

Risk factors and the nomogram model for intraoperatively acquired pressure injuries in children with brain tumours: A retrospective study.

This study aimed to investigate the clinical features and incidence of Intraoperatively Acquired Pressure Injuries (IAPIs) of brain tumours in children, to screen the risk factors and to establish a nomogram model for making prevention strategies against the development of IAPIs. Clinical data of 628 children undergoing brain tumour surgery from August 2019 to August 2021 were extracted from the adverse events and the electronic medical systems. They were randomly divided into a training cohort(n = 471) and a validation cohort(n = 157). The univariate and multivariate analysis was performed to identify the risk factors in training cohort; R software was used to construct a nomogram model; the area under the receiver operator characteristic curve (AUC) and calibration plots were used to judge the predictive performance of the nomogram model; decision curve analysis (DCA) was used to assess the clinical usefulness of the nomogram model. Age, haemorrhage, use of vasopressor, temperature, operation time and operation position were considered as significant risk factors, and enrolled to construct a nomogram model. The results of AUC showed satisfactory discrimination of the nomogram; the calibration plots indicated favourable consistency between the prediction of the nomogram and actual observations in both the training and validation cohorts; DCA showed better net benefit and threshold probability of the nomogram model. The nomogram model illustrates significant predictive ability, which can provide scientific and individual guidance for preventing development of IAPIs.

Genome-wide transcriptomics and copy number profiling identify patient-specific CNV-lncRNA-mRNA regulatory triplets in colorectal cancer.

Screening cancer genomes has provided an in-depth characterization of genetic variants such as copy number variations (CNVs) and gene expression changes of non-coding transcripts. Single-dimensional experiments are often designed to differentiate a patient cohort into various sets with the aim of identifying molecular changes among groups; however, this may be inadequate to decipher the causal relationship between molecular signatures in individual patients. To overcome this challenge with respect to personalized medicine, we implemented a patient-specific multi-dimensional integrative approach to uncover coherent signals from multiple independent platforms. In particular, we focused on the consistent gene dosage effects of CNVs for both mRNA and long non-coding RNA (lncRNA) expression in nine colorectal cancer patients. We identified 511 CNV-lncRNA-mRNA regulatory triplets associated with CNVs and aberrant expression of both mRNAs and lncRNAs. By filtering out inconsistent changes among CNVs, mRNAs, and lncRNAs, we further characterized 165 coherent motifs associated with 56 genes. In total, 108 motifs were linked with 31 copy number gains, 44 upregulated lncRNAs, and 45 upregulated mRNAs. Another 57 coherent downregulated motifs were also collected. We discuss how for many of these CNV-lncRNA-mRNA regulatory triplets, their clinical impact remains to be explored, including survival time, microsatellite instability, tumor stage, and primary tumor sites. By validating two example CNV-lncRNA-mRNA triplets with up- and down-regulation, we confirmed that individual variations in multiple dimensions are a robust tool to identify reliable molecular signals for personalized medicine. In summary, we utilized a patient-specific computational pipeline to explore the consistent CNV-driven motifs consisting of lncRNAs and mRNAs. We also identified LSM14B as a potential promoter in colorectal cancer progression, suggesting that it may serve as a target for colorectal cancer treatment.