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Background: Receptor-interacting protein kinase 3 (RIPK3) has been implicated in the pathogenesis of diverse human cancers. However, the role of RIPK3 in acute myeloid leukemia (AML) is not fully understood, which needs further research and clarification. Methods: We first identified the expression and clinical prognostic value of RIPK3 in AML through a public database and further validated in our research cohort. In addition, the biological function of RIPK3 in leukemic development was further verified through in vitro experiments. Results: Based on the GEPIA database, we screened that RIPK3 overexpression among RIPK family was associated with poor prognosis in AML. Afterwards, another independent cohort from our research center further confirmed the expression pattern of RIPK3 in AML patients. Clinically, increased RIPK3 expression was closely related to specific subtypes of AML, such as FAB-M4/M5, normal karyotype and NPM1 mutation. The significant association of RIPK3 overexpression with FAB-M4/M5 was further validated in AML cell lines. Notably, AML patients with RIPK3 overexpression received transplantation presented a markedly longer survival than those just receiving chemotherapy, whereas those with RIPK3 underexpression showed similar survival between transplantation and chemotherapy group. Bioinformatics analysis showed the significant association of RIPK3 expression with diverse oncogenes/tumor suppressor genes and tumor-related biological processes in AML. Subsequently, we further performed functional experiments in vitro confirmed the potential oncogenic role of RIPK3 in AML. Conclusions: Overexpression of RIPK3 was associated with specific subtypes of AML, such as FAB-M4/M5, normal karyotype and NPM1 mutation, and may facilitate the leukemic development. Moreover, RIPK3 overexpression was associated poor prognosis, and may guide treatment choice in AML. [ABSTRACT FROM AUTHOR]

Background: The homeobox (HOX) genes especially for HOXA cluster play crucial roles in leukemogenesis. HOXA overexpression caused by genetic alterations, such as KMT2A rearrangements, NUP98- fusions and FLT3-ITD mutations, is frequently identified in AML. However, very few studies determined the DNA methylation-mediated epigenetic regulation of the HOXA cluster genes in AML. Methods: We systematically first screened the prognostic value of HOXA cluster genes methylation in AML from The Cancer Genome Atlas (TCGA) datasets. Afterwards, the candidate prognosis-related gene HOXA9 were selected for clinical relevance analysis and were further validated in another independent cohort from our research center. Results: The methylation of HOXA9, among HOXA cluster genes, negatively correlated with adverse prognosis and expression were screened and identified in AML among TCGA datasets. Clinically, HOXA9 hypomethylation was positively correlated with specific subtypes of AML, such as French-American-British (FAB)-M5/M7, normal karyotype and FLT3, NPM1 and DNMT3A mutation, whereas negatively associated with FAB-M3, t(15;17), t(8;21) and t(16;16). Importantly, AML patients with HOXA9 hypomethylation may profit from transplantation, whereas AML patients with HOXA9 hypermethylation could not, suggesting that HOXA9 methylation may be used to guide therapeutic selection between transplantation and chemotherapy. Bioinformatics analysis demonstrated the association of HOXA9 expression with diverse leukemia-related genes (HOXAs, SOSTDC1, MEG3, miR-10a, miR-381 and miR-193b) and signaling pathways (PI3K-Akt signaling) in AML. Subsequently, we further validate the hypomethylation pattern of HOXA9 in AML patients and the epigenetic regulation of HOXA9 methylation in AML cell-lines. Conclusions: HOXA9 methylation linked to HOXA9 expression correlates with diverse genetic abnormalities of AML, such as normal karyotype, t(15;17), t(8;21), t(16;16) and FLT3, NPM1 and DNMT3A mutations. Moreover, HOXA9 hypomethylation may be associated with adverse prognosis, and may guide treatment choice in AML. [ABSTRACT FROM AUTHOR]

Hemoptysis is a frequently encountered manifestation in cases of acute pulmonary thromboembolism (PTE), significantly impacting clinical decision‐making. Despite its clinical relevance, studies focusing on patients with acute PTE and hemoptysis are notably scarce. In this retrospective study, we examined data from hospitalized patients with acute PTE at Peking Union Medical College Hospital (PUMCH) between January 2012 and October 2020. Among the 896 patients analyzed, 105 (11.7%) presented with hemoptysis. Patients with hemoptysis were younger, had higher RRs, and frequently reported chest pain, predominantly showing a negative sPESI score. A significant association with autoimmune diseases was observed (39.0% vs. 16.1%; p < 0.001), along with higher occurrences of pulmonary infections (29.5%), lung cancer (21.0%), and chronic heart failure (16.2%). Hemoptysis in PTE is multifactorial; 51.4% of cases were PTE‐related, with 85.2% experiencing mild hemoptysis. Among patients with disease‐related hemoptysis (13.3%), 90.9% with massive hemoptysis had underlying diseases, predominantly lung cancer. In 35.2% of cases, the cause of hemoptysis remained undetermined, with vasculitis accounting for 29.7%. Anticoagulation strategies varied with the severity of hemoptysis; 82.9% with mild and only 27.3% with massive hemoptysis received therapeutic‐dose anticoagulation. Multivariate analysis identified massive hemoptysis as the most significant determinant of anticoagulation decisions. Patients with massive hemoptysis had the poorest outcomes, with an in‐hospital mortality rate of 36.4% and 72.7% receiving reduced or no anticoagulation. [ABSTRACT FROM AUTHOR]

Introduction Immunotherapy--represented by immune checkpoint blockade using antibodies against cytotoxic T lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), and programmed cell death-ligand 1 (PD-L1)--has achieved remarkable clinical [...], Accurately identifying patients who respond to immunotherapy remains clinically challenging. A noninvasive method that can longitudinally capture information about immune cell function and assist in the early assessment of tumor responses is highly desirable for precision immunotherapy. Here, we show that PET imaging using a granzyme B-targeted radiotracer named [sup.68]Ga-grazytracer, could noninvasively and effectively predict tumor responses to immune checkpoint inhibitors and adoptive T cell transfer therapy in multiple tumor models. [sup.68]Ga-grazytracer was designed and selected from several radiotracers based on non-aldehyde peptidomimetics, and exhibited excellent in vivo metabolic stability and favorable targeting efficiency to granzyme B secreted by effector [CD8.sup.+] T cells during immune responses. [sup.68]Ga- grazytracer permitted more sensitive discrimination of responders and nonresponders than did [sup.18]F-fluorodeoxyglucose, distinguishing between tumor pseudoprogression and true progression upon immune checkpoint blockade therapy in mouse models with varying immunogenicity. In a preliminary clinical trial with 5 patients, no adverse events were observed after [sup.68]Ga- grazytracer injection, and clinical responses in cancer patients undergoing immunotherapy were favorably correlated with [sup.68]Ga-grazytracer PET results. These results highlight the potential of [sup.68]Ga-grazytracer PET to enhance the clinical effectiveness of granzyme B secretion-related immunotherapies by supporting early response assessment and precise patient stratification in a noninvasive and longitudinal manner.

Introduction: Endoplasmic reticulum stress (ERS) was a response to the accumulation of unfolded proteins and plays a crucial role in the development of tumors, including processes such as tumor cell invasion, metastasis, and immune evasion. However, the specific regulatory mechanisms of ERS in breast cancer (BC) remain unclear. Methods: In this study, we analyzed RNA sequencing data from The Cancer Genome Atlas (TCGA) for breast cancer and identified 8 core genes associated with ERS: ELOVL2, IFNG, MAP2K6, MZB1, PCSK6, PCSK9, IGF2BP1, and POP1. We evaluated their individual expression, independent diagnostic, and prognostic values in breast cancer patients. A multifactorial Cox analysis established a risk prognostic model, validated with an external dataset. Additionally, we conducted a comprehensive assessment of immune infiltration and drug sensitivity for these genes. Results: The results indicate that these eight core genes play a crucial role in regulating the immune microenvironment of breast cancer (BRCA) patients. Meanwhile, an independent diagnostic model based on the expression of these eight genes shows limited independent diagnostic value, and its independent prognostic value is unsatisfactory, with the time ROC AUC values generally below 0.5. According to the results of logistic regression neural networks and risk prognosis models, when these eight genes interact synergistically, they can serve as excellent biomarkers for the diagnosis and prognosis of breast cancer patients. Furthermore, the research findings have been confirmed through qPCR experiments and validation. Conclusion: In conclusion, we explored the mechanisms of ERS in BRCA patients and identified 8 outstanding biomolecular diagnostic markers and prognostic indicators. The research results were double-validated using the GEO database and qPCR. [ABSTRACT FROM AUTHOR]

Kidney involvement in patients with systemic lupus erythematosus — lupus nephritis (LN) — is one of the most important and common clinical manifestations of this disease and occurs in 40–60% of patients. Current treatment regimens achieve a complete kidney response in only a minority of affected individuals, and 10–15% of patients with LN develop kidney failure, with its attendant morbidity and considerable prognostic implications. Moreover, the medications most often used to treat LN — corticosteroids in combination with immunosuppressive or cytotoxic drugs — are associated with substantial side effects. Advances in proteomics, flow cytometry and RNA sequencing have led to important new insights into immune cells, molecules and mechanistic pathways that are instrumental in the pathogenesis of LN. These insights, together with a renewed focus on the study of human LN kidney tissue, suggest new therapeutic targets that are already being tested in lupus animal models and early-phase clinical trials and, as such, are hoped to eventually lead to meaningful improvements in the care of patients with systemic lupus erythematosus-associated kidney disease. This Review examines the contribution of innate and adaptive immune cells to the pathogenesis of lupus nephritis, including new insights into the molecular mechanisms that drive this disease, such as recognition of endogenous chromatin by endosomal and cytosolic nucleic acid sensors. Key points: Understanding of the cellular and molecular mechanisms underlying lupus nephritis (LN) is progressing rapidly, facilitated by new tools for advanced 'omic' analyses. Increasingly fine immune cell profiling based on patterns of expression of cell surface markers and genes is defining T cell and macrophage subsets that are important in disease mechanisms. Chromatin release and/or its ineffective clearance stimulate adaptive and innate immunity in LN. Resident kidney cells, including podocytes, mesangial cells and tubular epithelial cells, participate actively in the pathology of LN. Closer attention to technical aspects in trial design is driving successes in clinical trials in systemic lupus erythematosus and stimulating much additional interest in the rational design and application of novel LN therapies. [ABSTRACT FROM AUTHOR]

Background: Uterine corpus endometrial carcinoma (UCEC) is a common type of gynecological cancers, second only to cervical cancer in incidence. Thus, it is necessary to develop effective therapies and identify biomarkers for its prognosis. Solute carrier family 7 member 11 (SLC7A11) is well known for its role in maintaining the intracellular glutathione level and preventing oxidative-stress-induced cell death. However, the association between SLC7A11 expression and prognosis as well as the correlation between tumor-infiltrating immune cells (TIICs) and immunotherapy of UCEC has rarely been reported. This study aims to evaluate the prognostic significance and immune cell infiltration level of SLC7A11 in UCEC. Methods: Bioinformatics analysis tools and databases, including R software, National Center for Biotechnology Information (NCBI), The Cancer Genome Atlas (TCGA), GEPIA2, Sangerbox, Kaplan–Meier (K-M) Plotter, TISIDB, and TIMER2, were utilized to measure the expression level and clarify the clinical significance of SLC7A11 in UCEC. Results: SLC7A11 expression was dramatically up-regulated in UCEC patients and associated with prognosis. DNA methylation levels in the SLC7A11-promoter region were significantly higher in normal participants than in patients with UCEC. We also showed that SLC7A11 overexpression was associated with TIICs, immune checkpoint blockers (ICBs), and immunotherapy response in UCEC. The half-maximal inhibitory concentration (IC50) results obtained with the cohort from TCGA showed that Z-VAD-FMK (Caspase inhibitor), S-Triphenylmethyl-L-cysteine (S-Trityl-L-cysteine), and TAE684 (ALK inhibitor) had higher IC50 values in low-expression patient (p < 0.05). Conclusion: SLC7A11 overexpression is associated with favorable prognosis of patients with UCEC and is associated with TIICs and the responses to immunotherapy. [ABSTRACT FROM AUTHOR]

Background: Platelets occupy a prominent place in tumor proliferation and metastasis, and platelet count is relevant to the prognosis of tumor patients. But preoperative platelet counts cannot be standardized and individualized due to the variability among individuals, instruments, and regions, and the connection between postoperative platelet count and prognosis remains unknown. A standardized indicator of platelet count was designed to forecast the prognosis of colorectal cancer (CRC). Methods: Five hundred and eighty six patients who suffered radical resection of CRC between 2013 and 2019 were collected. A development‐validation cohort of standardized and individualized platelet counts for prognostic assessment of CRC was designed. We first determined the ability of PPR and other peripheral blood count‐related indicators to predict the mortality of patients with CRC and validated them in a separate cohort. Kaplan–Meier analysis was executed to evaluate the survival and univariate and multivariate analyses were executed to explore the relevance. Time‐dependent ROC was measured to estimate the predictive usefulness. Decision curve analysis was used to verify the clinical net benefit. Results: Important baseline variables showed a similar distribution in two independent queues. In the development cohort, postoperative platelet count and postoperative/preoperative platelets ratio (PPR) were independent predictors of prognosis in CRC patients. PPR showed the largest area under the curve (AUC) in evaluating 1‐year and 5‐year OS (AUC: 0.702 and 0.620) compared to others. In the validation cohort, platelet/lymphocyte ratio and PPR were validated to be independently concerned about OS of CRC patients and PPR showed the largest AUC in evaluating 1‐year and 3‐year OS (AUC: 0.663 and 0.673). PPR and joint index of platelet count and PPR showed better predictive value and clinical net benefit. Conclusions: PPR has been identified and validated to be independently concerned about OS of patients with CRC and was a reliable and economic indicator to evaluate the prognosis. [ABSTRACT FROM AUTHOR]

To evaluate the clinical characteristics and prognostic predictors of patients with diffuse alveolar hemorrhage (DAH) and/or interstitial lung disease (ILD) secondary to microscopic polyangiitis (MPA) in a Chinese general hospital. We retrospectively reviewed the medical records of MPA patients admitted to internal medicine departments between the year 2002 and 2012. The patients were divided into the ILD, DAH, DAH combined with ILD (DAHILD), and no pulmonary involvement (NPI) groups according to pulmonary involvement patterns. The clinical characteristics at diagnosis were analyzed. The risk factors associated with short-term death and long-term death were identified with Logistic regression and Cox analysis. Of 193 newly diagnosed MPA patients, 181 patients were enrolled in the research, of which 19 had DAH alone, 96 had ILD alone, 18 had DAH and DAH concurrently, and 48 had NPI. The median of serum creatine level in the DAH group was 449 µmol/L, significantly higher than that in the ILD group (123 µmol/L, Nemenyi = -35.215, P = 0.045) and DAHILD group (359 µmol/L, Nemenji = -43.609, P = 0.007). The median follow-up time was 67 (range: 1-199) months. Patients in the ILD group were older than those in the DAH group (median: 69 years vs. 57 years, Nemenji = 43.853, P = 0.005). The patients with both DAH and ILD had combined features of the two subtypes, and the highest mortality (72.2% at the end of follow-up). The elevated white blood cell count was a risk factor for short-term death (OR = 1.103, 95% CI : 1.008-1.207, P = 0.032 for one month; OR = 1.103, 95% CI : 1.026-1.186, P = 0.008 for one year). Old age (HR = 1.044, 95%C7: 1.023-1.066, P < 0.001), cardiovascular system involvement (HR = 2.093, 95% CI : 1.195-3.665, P = 0.010), poor renal function (HR = 1.001, 95% CI : 1.000-1.002, P = 0.032) were risk factors for long-term death. Pulmonary infections (38/54) were the leading causes of death, especially for the patients with ILD. Besides, 49 patients suffered from pulmonary infections in the first year after diagnosis. MPA patients who presented with different pulmonary involvement patterns have completely different clinical features. These subtypes probably have different pathogenesis and should be studied separately. [ABSTRACT FROM AUTHOR]

Objective: The definition of the tumour diameter of micro‐medullary thyroid carcinoma (micro‐MTC) is insufficient. It is controversial to perform a completion thyroidectomy immediately for incidental T1 stage MTC. Design: We used the Surveillance, Epidemiology and End Results (SEER) registry to retrospectively analyze all patients with T1 stage MTC diagnosed between 2004 and 2015. The tumour diameter 1.0 and 0.5 cm were used as the cut‐off points to group and analyze the differences of clinicopathological features. We analyzed the prognosis of patients with less than total thyroidectomy. Methods: The disease‐specific survival was the main outcome. Survival was estimated with Kaplan–Meier curves and Cox regression models estimated hazard ratios for tumour characteristics. Results: A total of 908 patients diagnosed with T1 stage MTC in the SEER database were included. Our study found that tumour diameter 1.0 cm is a key point affecting the prognosis of T1 stage MTC patients, although patients with tumour diameter ≤ 0.5 cm had a lower rate of lymph node metastasis and no distant metastasis. Cox proportional hazard multivariate analysis showed that distant metastasis was the only risk factor for survival in patients with T1 stage MTC. Kaplan–Meier survival analysis showed that, regardless of tumour diameter, there was no significant difference between less than total thyroidectomy and total thyroidectomy in T1 stage patients. Conclusions: For incidental MTC with tumour diameter ≤ 1.0 cm and without distant metastasis, if there is no significant increase in serum calcitonin level after surgery and ret proto‐oncogene (RET) gene mutation is negative, it may be not necessary to perform completion thyroidectomy immediately. [ABSTRACT FROM AUTHOR]

Long noncoding RNAs (lncRNAs) actively participate in breast cancer (BRCA) tumorigenesis via epigenetic mechanisms. Our study identified immune-related lncRNA (irlncRNA) pairs and compiled them into a set of noncoding gene signatures able to stratify subtypes of BRCA associated with variable degrees of survival and immune cell infiltration. A 40 immune-related lncRNA pair (IRLP) signature including 43 irlncRNAs was built, with high sensitivity and specificity for the prediction of survival in different molecular subtypes of BRCA. Results demonstrated that the low-risk group showed a significantly longer survival rate, and this novel IRLP signature was highly associated with survival status, T stage, metastatic disease, and overall stage in BRCA. Immune infiltrating analyses found that the low-risk group has a lower expression level of macrophage M2 and a higher expression level of immunosuppressed biomarkers than the high-risk group. DEirlncRNAs were further proven to be significantly related to the MAPK signaling, Jak-STAT signaling, and ErbB signaling pathways in BRCA. In conclusion, the 40 IRLP signature showed a promising clinical prediction value in the prognosis of different molecular subtypes and immunotherapy response in BRCA, and the underlying mechanism for these IRLPs warrants further investigations. [ABSTRACT FROM AUTHOR]

Objective. To screen the cell differentiation trajectory-related genes and build a cell differentiation trajectory-related signature for predicting the prognosis of lung adenocarcinoma (LUAD). Methods. LUAD single cell mRNA expression profile, TCGA-LUAD transcriptome data were obtained from GEO and TCGA databases. Single-cell RNA-seq data were used for cell clustering and pseudotime analysis after dimensionality reduction analysis, and the cell differentiation trajectory-related genes were acquired after differential expression analysis conducted between the main branches. Then, the consensus clustering analysis was carried out on TCGA-LUAD samples, and the GSEA analysis was performed, then the differences on the expression levels of immune checkpoint genes and immunotherapy response were compared among clusters. The prognostic model was constructed, and the GSE42127 dataset was used to validate. A nomogram evaluation model was used to predict prognosis. Results. Two subsets with distinct differentiation states were found after cell differentiation trajectory analysis. TCGA-LUAD samples were divided into two cell differentiation trajectory-related gene-based clusters, GSEA found that cluster 1 was significantly related to 20 pathways, cluster 2 was significantly enriched in three pathways, and it was also shown that clusters could better predict immune checkpoint gene expression and immunotherapy response. A six cell differentiation-related genes-based prognostic signature was constructed, and the patients in the high-risk group had poorer prognosis than those in the low-risk group. Moreover, a nomogram was constructed based on the prognostic signature and clinicopathological features, and this nomogram had strong predictive performance and high accuracy. Conclusion. The cell differentiation-related signature and the prognostic nomogram could accurately predict survival. [ABSTRACT FROM AUTHOR]

Purpose: We report the 5-year follow-up findings of a randomized, open-label, phase II trial of lobaplatin-based neoadjuvant chemotherapy plus adjuvant therapy for triple-negative breast cancer (TNBC). Patients and methods: This study included patients aged ⩾18 years with untreated, operable stage I–III TNBC and an Eastern Cooperative Oncology Group performance status of 0 or 1. One group of patients (TE group, n = 99) received four cycles of docetaxel (T, 75 mg/m²) plus epirubicin (E, 80 mg/m²) every 3 weeks, and another group (TEL group, n = 101) received the same treatment with the addition of lobaplatin (L, 30 mg/m2). Two cycles of the corresponding treatments were administered after surgery in both groups. The primary endpoints were total pathological complete response (tpCR) rate and overall response rate (ORR), and the secondary endpoints were disease-free survival, overall survival, and long-term safety. This trial is registered with the Chinese Clinical Trial Registry (ChiCTR-TRC-14005019). Results: The median follow-up was 48.2 months (interquartile range: 31.1–60.0). The tpCR rate was 41.4% and 17.8% in the TEL group and TE group, respectively (p < 0.001). The HR for comparison of DFS between the TEL group and TE group was 0.44 (95% CI: 0.21–0.90, P p = 0.028). The addition of lobaplatin resulted in an HR of 0.44 (95% CI: 0.18–1.02, P = 0.061) for the difference in OS between the two groups. The ORR, which included complete response and partial response, was 92.9% in the TEL group and 74.3% in the TE group (p = 0.001). The TEL group patients were more likely to develop grade III–IV anemia and thrombocytopenia. No lobaplatin-related deaths or increased risk of long-term toxicity was observed. Conclusion: Neoadjuvant lobaplatin therapy can improve the tpCR and ORR rates of TNBC with tolerable side effects and have a tendency to improve the long-term survival. [ABSTRACT FROM AUTHOR]

Objective To investigate the associations of mitochondrial DNA (mtDNA) genetic variants with SLE susceptibility, glucocorticoid (GC) efficacy and prognosis. Methods Our study was done in two stages. First, we performed whole mitochondrial genome sequencing in 100 patients and 100 controls to initially screen potential mtDNA variants associated with disease and GC efficacy. Then, we validated the results in an independent set of samples. In total, 605 SLE patients and 604 normal controls were included in our two-stage study. A two-stage efficacy study was conducted in 512 patients treated with GCs for 12 weeks. We also explored the association between mtDNA variants and SLE prognosis. Results In the combined sample, four mtDNA variants (A4833G, T5108C, G14569A, CA514-515-) were associated with SLE susceptibility (all P BH < 0.05). We confirmed that T16362C was related to efficacy of GCs (P BH = 0.014). Significant associations were detected between T16362C and T16519C and the efficacy of GCs in females with SLE (P BH < 0.05). In the prognosis study, variants A4833G (P BH = 0.003) and G14569A (P BH = 9.744 × 10−4) substantially increased SLE relapse risk. Female patients harbouring variants T5108C and T16362C were more prone to relapse (P BH < 0.05). Haplotype analysis showed that haplogroup G was linked with SLE susceptibility (P BH = 0.001) and prognosis (P BH = 0.013). Moreover, mtDNA variant–environment interactions were observed. Conclusion We identified novel mtDNA genetic variants that were associated with SLE susceptibility, GC efficacy, and prognosis. Interactions between mtDNA variants and environmental factors were related to SLE risk and GC efficacy. Our findings provide important information for future understanding of the occurrence and development of SLE. [ABSTRACT FROM AUTHOR]

Background: Hepatoid adenocarcinoma (HAC) of the lung (HAL) is a rare and aggressive extrahepatic adenocarcinoma with an unknown etiology and unfavorable prognosis, which is similar to the pathophysiological characteristics of hepatocellular carcinoma (HCC). Methods: We first presented a 67-year-old patient diagnosed with HAC in the right middle lobe of the lung. Then, a systematic literature search was performed for HAL cases recorded between 1990 and 2020 based on three databases. The clinicopathological features, therapeutic method, and prognosis of this rare disease were reviewed, and corresponding prognostic factors were explored using Kaplan–Meier (K-M) curve and Cox proportional hazards regression model. Additionally, the potential biological mechanisms of HAL were further explored and compared with HCC and lung adenocarcinoma (LUAD) based on online databases. Results: In the present study, we reported an HAL patient who underwent surgical resection combined with chemotherapy and succumbed to disease 13 months after surgery. Additionally, a total of 43 experimental studies with 49 HAL patients, including the present case, met the inclusion criteria and were included in the present review. We found that HAL is characterized by a male-dominated incidence and is more common in the right lung. Patients in the surgical subgroup have a better prognosis than those in the non-surgical subgroup (p = 0.034). Moreover, the Cox proportional hazards regression model demonstrated that surgical resection can significantly improve the prognosis of HAL patients (p = 0.016). HAL is a rare disease associated with gene mutations that has a distinctive cause and unique pathogenesis. Additionally, Afatinib and Gefitinib may be new effective agents to better combat HAL. Conclusion: In conclusion, males may exhibit an increased risk of developing HAL and poorer prognosis than females. Surgical resection combined with chemotherapy may prolong the survival of patients with HAL. HAL has its unique clinicopathological characteristics and biological mechanisms. [ABSTRACT FROM AUTHOR]

The neutrophil-to-lymphocyte ratio (NLR) plays an important role in the progression of intracerebral hemorrhage (ICH). An increasing number of studies have reported that a high NLR is correlated with poor clinical outcomes among patients with ICH. Here, we conducted a systematic review and meta-analysis to evaluate the prognostic value of NLR in the setting of ICH. We performed a comprehensive search of electronic literature databases to identify all relevant studies evaluating the prognostic role of NLR in patients with ICH. Two researchers independently screened the studies and extracted relevant data. We extracted, pooled, and weighted odds ratio (OR) and 95% confidence interval (CI) values using a generic inverse-variance method, and then evaluated the heterogeneity among studies using Q test and I 2 statistic. Finally, we selected a total of 26 studies including 7,317 patients for the current study. Overall, our results indicated that a high NLR was significantly associated with a poor outcome (OR, 1.32; 95% CI, 1.19–1.46; P < 0.00001), mortality (OR, 1.05; 95% CI, 1.01–1.09; P = 0.02), and neurological deterioration (OR, 1.65; 95% CI, 1.08–2.52; P = 0.02). We did not observe a significant association between NLR and hematoma expansion (OR, 1.04; 95% CI, 0.99–1.08; P = 0.09). Our study indicated that a high NLR is significantly associated with poor clinical outcomes in patients with ICH. As NLR is a simple and easily available biomarker, future studies should focus on exploring its application in the prognostic evaluation of patients with ICH. [ABSTRACT FROM AUTHOR]

Background: There is mounting evidence that demonstrated the association of aberrant NEDD4L expression with diverse human cancers. However, the expression pattern and clinical implication of NEDD4L in acute myeloid leukemia (AML) remains poorly defined. Methods: We systemically determined NEDD4L expression with its clinical significance in AML by both public data and our research cohort. Moreover, biological functions of NEDD4L in leukemogenesis were further tested by in vitro experiments. Results: By the public data, we identified that low NEDD4L expression was correlated with AML among diverse human cancers. Expression of NEDD4L was remarkably decreased in AML compared with controls, and was confirmed by our research cohort. Clinically, low expression of NEDD4L was correlated with greatly lower age, higher white blood cells, and higher bone marrow/peripheral blood blasts. Moreover, NEDD4L underexpression was positively correlated with normal karyotype, FLT3 and NPM1 mutations, but negatively associated with complex karyotype and TP53 mutations. Importantly, the association between NEDD4L expression and survival was also discovered in cytogenetically normal AML patients. Finally, a number of 1024 RNAs and 91 microRNAs were identified to be linked to NEDD4L expression in AML. Among the negatively correlated microRNAs, miR-10a was also discovered as a microRNA that may directly target NEDD4L. Further functional studies revealed that NEDD4L exhibited anti-proliferative and pro-apoptotic effects in leukemic cell line K562. Conclusions: Our findings indicated that NEDD4L underexpression, as a frequent event in AML, was associated with genetic abnormalities and prognosis in AML. Moreover, NEDD4L expression may be involved in leukemogenesis with potential therapeutic target value. [ABSTRACT FROM AUTHOR]

• FCM showed no abnormal expression of CD25, CD2 and CD30 in MCs. • MCs and myeloid LCs share a common clonal origin, possibly derived from common leukemia stem cells. • AML patients with an increased proportion of MCs had shorter survival and worse prognosis. [ABSTRACT FROM AUTHOR]

It was previously reported that PRR34‐AS1 was overexpressed in some solid tumors. PRR34‐AS1 promoter was shown to have a differential methylation region (DMR), and was hypomethylated in acute myeloid leukemia (AML). Therefore, the present study used real‐time quantitative PCR (RQ‐PCR) to explore the expression characteristics of PRR34‐AS1 in AML. In addition, the correlation between the expression of PRR34‐AS1 and clinical prognosis of AML was determined. The findings of this study indicated that high PRR34‐AS1 expression was bound up with shorter overall survival (OS) in AML patients (p = 0.002). Moreover, patients with high expression of PRR34‐AS1 had significantly lower complete remission (CR) rate compared with those with low expression of PRR34‐AS1 after induction chemotherapy. Furthermore, multivariate analysis confirmed that PRR34‐AS1 expression was an independent factor affecting CR in whole‐AML, non‐APL‐AML, and CN‐AML patients (p = 0.032, 0.039, and 0.036, respectively). Methylation‐specific PCR (MSP) and bisulfite sequencing PCR (BSP) were used to explore the methylation status of PRR34‐AS1. PRR34‐AS1 promoter showed a pattern of hypomethylation in AML patients compared with normal controls (p = 0.122). Notably, of whole‐AML and non‐APL‐AML patients, PRR34‐AS1 hypomethylated patients presented a significantly shorter OS than those with a hypermethylated PRR34‐AS1 (p = 0.010 and 0.037, respectively). Multivariate analysis confirmed that the hypomethylation of PRR34‐AS1 served as an independent prognostic indicator in both whole‐cohort AML and non‐APL‐AML categories (p = 0.057 and 0.018, respectively). In summary, the findings of this study showed that abnormalities in PRR34‐AS1 are associated with poor prognosis in AML. Therefore, monitoring this index may be important in the prognosis of AML and can provide information on effective chemotherapy against the disease. [ABSTRACT FROM AUTHOR]

Background: Primary pancreatic mucoepidermoid carcinoma (MEC) is an extremely rare malignant tumor with unclear etiology and pathogenesis. There are only eleven reported cases in English papers published from 1959 to 2020. MEC generally occurs in the salivary gland, but cases in the pancreas have also been reported. Although being considered as a low-grade indolent carcinoma, pancreatic MEC always invades the surrounding lymph node and metastasizes. The prognosis of pancreatic MEC is unsatisfactory. To date, the genetic alterations, mechanistic relationships among mutated genes and signaling pathways of pancreatic MEC are unclear. Patient and Methods: This paper presents a case of rare primary pancreatic MEC in a 56-year-old male patient with liver metastasis. Radical surgery of distal pancreatectomy and radiofrequency ablation (RFA) of two liver metastatic lesions is conducted. Targeted-gene sequencing and bioinformatics analysis tools, including STRING, DAVID, cBioPortal, DGidb and Human Protein Atlas database (HPA), are used to clarify the biological functions and features of mutated genes in pancreatic MEC. Results: Eight gene mutations (TP53, KRAS, ATR, FLI1, FLT4, MAGI2, RBM10, and TNFAIP3) were observed, and a tumor mutation burden (TMB) of 5.6 muts/Mb was calculated in the pancreatic MEC using targeted-gene sequencing. The patient subsequently underwent adjuvant chemotherapy and died three months after surgery. Gene–gene interaction network was constructed, which showed the significant interactions among eight mutated genes. In terms of the functions and pathways of eight gene mutations based on GO and KEGG, 20 tumor-related results are presented in this paper, Furthermore, the biological functions and features of pancreatic MEC are further compared with pancreatic ductal adenocarcinoma. Conclusion: Pancreatic MEC requires early and effective treatment, and lymph node metastases and multiple organ metastases were unfavorable prognostic factors. Pancreatic MEC can be compared with other pancreatic cancers that have characteristic clinical phenotype, molecular alterations, functional information and enrichment pathway. [ABSTRACT FROM AUTHOR]

Invasion and metastasis represent the primary causes of therapeutic failure in patients diagnosed with esophageal squamous cell carcinoma (ESCC). The lack of effective treatment strategies for metastatic ESCC is the major cause of the low survival rate. Therefore, it is crucial to understand the molecular mechanisms underlying ESCC metastasis and identify potential biomarkers for targeted therapy. Herein, we reported that PEDF is significantly correlated with tumor cell invasion and metastasis in ESCC. The high expression of PEDF is an independent unfavorable prognostic factor for ESCC patients' overall survival (OS). We successfully developed and verified a nomogram to predict the preoperative OS of ESCC patients, and the actual and nomogram-predicted 1-, 3-, and 5-year survival rates had good consistency. The receiver operating characteristic (ROC) curve showed that the area under the curve (AUC) values for 1-, 3- and 5- survival were 0.764, 0.871, and 0.91, respectively. Overexpression of PEDF significantly promoted the migration and invasion of ESCC cells in vitro , while silencing PEDF yielded the opposite effects. Elevated levels of PEDF altered the expression of proteins involved in epithelial–mesenchymal transition (EMT), as indicated by the upregulation of N-cadherin and the downregulation of α -catenin and E-cadherin in ESCC cells. Mechanistically, PEDF promoted tumor cell motility and EMT by activating the MAPK/ERK signaling pathway. In conclusion, our results reveal that PEDF is involved in ESCC metastasis and could act as a prognostic factor for ESCC. Our research provides a fresh perspective into the mechanism of ESCC metastasis. [ABSTRACT FROM AUTHOR]

Due to the lack of typical symptoms and signs and sensitive indicators for early diagnosis of obstructive colorectal cancer (OCRC), it is critically needed to find new novel biomarkers to ameliorate the management of OCRC patients. In this study, 472 blood samples were collected and measured by enzyme-linked immunosorbent assay (ELISA) to investigate the value of serum chemokine ligand 7 (CXCL7) in diagnosis and prognosis for OCRC patients. The median concentrations of CXCL7 in non-OCRC and OCRC were both higher than that in controls (both P < 0.05). Importantly, the median serum concentration of CXCL7 in OCRC was also higher than that in non-OCRC (P < 0.001). In all OCRC patients, the area under the curve (AUC) of CXCL7 was 0.918 with a sensitivity of 86.54% and a specificity of 81.87%. Similarly, the AUC of CXCL7 was 0.684 when the diagnostic test was performed between OCRC and CRC patients. CXCL7 had a higher AUC than other markers. The concentration of CXCL7 in 40 postoperative OCRC patients was higher than normal people and lower than preoperative patients. The median survival time was 62.00 months and the 5-year overall survival (OS) rate of the patients was 51.80% in all 155 OCRC patients. Multivariate Cox proportional hazard regression model analysis showed that high CXCL7 in serum was independent factors associated with poor OS of OCRC patients (HR = 2.216, P = 0.032). These results demonstrate that serum CXCL7 may be a potential biomarker both in diagnosis and prognosis for OCRC patients. [ABSTRACT FROM AUTHOR]

Interferon-stimulated gene 15 (ISG15) is known to be involved in tumor progression. We previously reported that ISG15 expressed on nasopharyngeal carcinoma (NPC) cells and related to poor prognosis of patients with NPC. We further observed that ISG15 can be secreted by NPC cell and expressed on the macrophages in situ. However, the role of ISG15 in tumor-associated macrophages (TAMs) remains poorly understood. In the present study, we found that ISG15 treatment induces macrophages with M2-like phenotype, and the enhancement of NPC cell migration and tumorigenicity. Mechanically, ISG15-induced M2-like phenotype is dependent on the interaction with its receptor, LFA-1, and engagement of SRC family kinase (SFK) signal, and the subsequent secretion of CCL18. Blocking LFA-1, or SRC signal with small molecular inhibitors, or neutralizing with anti-CCL18 antibody can impede the activation of LFA-1-SFK-CCL18 axis in ISG15-treated macrophages. Clinically, ISG15+ CD163+ TAMs related to impaired survival of patients and advanced tumor stage of NPC. Furthermore, we found ISG15+ CD163+ macrophages inhibited antitumor CD8+ cells responses in NPC. Together, our findings suggested tumor cell-secreted ISG15, which acted as a tumor microenvironmental factor, induces M2-like phenotype, promoting tumor progression and suppression of cytotoxic T lymphocyte response. [ABSTRACT FROM AUTHOR]

Background and Aims: Somatic mutation R249S in TP53 is highly common in hepatocellular carcinoma (HCC). We aim to investigate the effects of R249S in ctDNA on the prognosis of HCC. Methods: We analysed three cohorts including 895 HCC patients. TP53 mutation spectrum was examined by direct sequencing of genomic DNA from tissue specimens in HCC patients with hepatectomy (Cohort 1, N = 260). R249S and other recurrent missense mutations were assessed for their biological functions and associations with overall survival (OS) and progression‐free survival (PFS) of HCC patients in Cohort 1. R249S within circulating tumour DNA (ctDNA) was detected through droplet digital polymerase chain reaction (ddPCR) and its association with OS and PRS was analysed in HCC patients with (Cohort 2, N = 275) or without (Cohort 3, N = 360) hepatectomy. Results: In Cohort 1, R249S occupied 60.28% of all TP53 mutations. Overexpression of R249S induced more serious malignant phenotypes than those of the other three identified TP53 recurrent missense mutations. Additionally, R249S, but not other missense mutations, was significantly associated with worse OS (P =.006) and PFS (P =.01) of HCC patients. Consistent with the results in Cohort 1, HCC patients in Cohorts 2 and 3 with R249S had worse OS (P = 8.291 × 10−7 and 2.608 × 10−7 in Cohorts 2 and 3, respectively) and PFS (P = 5.115 × 10−7 and 5.900 × 10−13 in Cohorts 2 and 3, respectively) compared to those without this mutation. Conclusions: TP53 R249S mutation in ctDNA may serve as a promising prognosis biomarker for HCC patients with or without hepatectomy. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to investigate the clinical and prognostic relevance of B7-H3 expression and indicators of glucose metabolism in patients with colorectal cancer (CRC). Methods: Using immunohistochemistry, the expression of B7-H3 was detected in a total of 213 formalin-fixed paraffin-embedded CRC tissue specimens. Furthermore, levels of fasting blood glucose (FBG), lactic dehydrogenase (LDH), and fructosamine (FMN) as indicators of glucose metabolism were analyzed in CRC patients and stratified into high or low expression sub-groups based on Youden Index. The relationship between B7-H3, FBG, LDH, FMN expression, and clinicopathological characteristics were also evaluated to establish their prognostic significance in patients with CRC. Results: B7-H3 was highly expressed in CRC tissue. The positive rates of B7-H3 expression was 63.8% (136/213). We found a linear correlation between B7-H3 and FBG in depth of tumor invasion (T3/4) (p = 0.037, r = 0.259), lymph node metastasis (N0) (p = 0.004, r = 0.259), and TNM stage (I/II) (p = 0.009, r = 0.242). High expression of FBG, LDH, FMN [hazard ratio (HR) = 1.916, 95% CI: 1.223–3.00, p = 0.005; HR = 1.801, 95% CI: 1.153–2.813, p = 0.010; HR = 2.154, 95% CI: 1.336–3.472, p = 0.002], respectively, was identified as a significant independent predictor of poor overall survival (OS). Although B7-H3 expression did not affect OS, CRC patients expressing both high B7-H3 and high FMN contributed to a significant decrease in OS (HR = 1.881, 95%CI: 1.059–3.339, p = 0.031). Moreover, with low expression of B7-H3, high expression of FBG, LDH and FMN were also recognized as predictors of inferior OS (HR = 3.393, 95% CI: 1.493-7.709, p = 0.004; HR = 7.107, 95% CI: 2.785–18.138, p = 0.000; HR = 2.800, 95% CI: 1.184–6.625, p = 0.019). Conclusion: B7-H3 combined with FBG, LDH, or FMN, could reflect the clinical outcomes of patients with CRC. [ABSTRACT FROM AUTHOR]

Wnt2 mRNA is widely expressed in various tumor tissues. Wnt2 overexpression promotes tumor growth, migration, invasion, and metastasis. However, its underlying molecular action mechanisms and clinical implications in colon adenocarcinoma (COAD) remain unclear. mRNA expression data, obtained from tissue samples, and pathophysiological data of 368 COAD patients were obtained from the Cancer Genome Atlas (TCGA) database. Further, Pearson's correlation analysis was performed to explore the correlation between the expression levels of Wnt2 and other genes in the human genome. Subsequently, a protein-protein interaction (PPI) network was constructed for hub gene identification. Overall survival and significance were determined by Kaplan-Meier analysis, and the log-rank test was used to further identify genes with prognostic significance in COAD from GEO datasets (GSE17538 and GSE39582). Subsequently, 158 tissue samples from Affiliated Hospital of Jiangnan University were used for expression verification. Gene set enrichment analysis (GSEA) was performed on high and low Wnt2 expression datasets to identify potential signaling pathways activated in COAD. In all, 10 hub genes associated with Wnt2 were screened by Pearson's correlation analysis and PPI network, with Wnt2 and COL8A1 having significantly poor prognosis by Kaplan-Meier analysis and log-rank test. Furthermore, high expressions of COL8A1 and Wnt2 were associated with poor survival both in TCGA and GEO cohorts. We further found a correlation between the expressions of Wnt2 and COL8A1 in COAD as per immunohistochemical analysis. To further elucidate the underlying molecular mechanisms of Wnt2 in COAD, we searched for pathways enriched in Wnt2 overexpressing datasets by GSEA. Our findings revealed that high Wnt2 levels were significantly associated with extracellular matrix receptor and focal adhesion pathways. Wnt2 expression correlated with COL8A1 expression in COAD; patients with high Wnt2 and COL8A1 expressions had worse survival outcomes. Pathways identified in this study prompt the molecular role of Wnt2 in COAD and provide directions to further elucidate the involved molecular mechanisms in COAD. [ABSTRACT FROM AUTHOR]