[Short-term Effect of Venetoclax Combined with Azacitidine and "7+3" Regimen in the Treatment of Newly Diagnosed Elder Patients with Acute Myeloid Leukemia].

OBJECTIVE: To compare the short-term effect and adverse reaction of venetoclax (VEN) combined with azacitidine (AZA) versus "7+3" regimen in newly diagnosed elder patients with acute myeloid leukemia (AML). METHODS: From January 2021 to January 2022, the clinical data of seventy-nine newly diagnosed elder patients with AML at the Second Hospital of Shanxi Medical University and the Shanxi Bethune Hospital were retrospectively analyzed, including VEN+AZA group (41 cases) and "7+3" group (38 cases). The propensity score matching(PSM) method was used to balance confounding factors， then response， overall survival(OS), progressionfree survival(PFS) and adverse reactions between the two groups were compared. RESULTS: The ORR of VEN+AZA group and "7+3" group was 68% and 84%, respectively, and the CRc was 64% and 72%, respectively, the differents were not statistically significant (P >0.05). In the VEN+AZA group, there were 5 non-remission (NR) patients, 4 with chromosome 7 abnormality (7q-/-7), and 1 with ETV6 gene mutation. Median followed-up time between the two groups was 8 months and 12 months, respectively, and the 6-months OS was 84% vs 92% (P =0.389), while 6-months PFS was 84% vs 92% (P =0.258). The main hematological adverse reactions in two groups were stage Ⅲ-Ⅳ myelosuppression, and the incidence rate was not statistically different(P >0.05). The median time of neutrophil recovery in two groups was 27(11-70) d, 25(14-61) d （P =0.161）, and platelet recovery was 27(11-75) d, 25(16-50) d （P =0.270）, respectively. The infection rate of VEN+AZA group was lower than that of "7+3" group (56% vs 88%, P =0.012）. The rate of lung infections of two groups was 36% and 64%, respectively, the difference was statistically significant (P =0.048). CONCLUSION: The short-term effect of VEN+AZA group and "7+3" regimens in eldrly AML patients are similar， but the VEN+AZA regimen had a lower incidence of infection. The presence of chromosome 7 abnormality（7q-/-7） may be a poor prognostic factor for elderly AML patients treated with VEN+AZA.

Portraying the dark side of endogenous IFN-λ for promoting cancer progression and immunoevasion in pan-cancer.

BACKGROUND: IFN-λ has been shown to have a dual function in cancer, with its tumor-suppressive roles being well-established. However, the potential existence of a negative ''tumor-promoting'' effect of endogenous IFN-λ is still not fully understood. METHODS: We conducted a comprehensive review and analysis of the perturbation of IFN-λ genes across various cancer types. Correlation coefficients were utilized to examine the relationship between endogenous IFN-λ expression and clinical factors, immune cell infiltration, tumor microenvironment, and response to immunotherapy. Genes working together with IFN-λ were obtained by constructing the correlation-based network related to IFN-λ and the gene interaction network in the KEGG pathway and IFN-λ-related genes obtained from the networks were integrated as candidate markers for the prognosis model. We then applied univariate and multivariate COX regression models to select cancer-specific independent prognostic markers associated with IFN-λ and to investigate risk factors for these genes by survival analysis. Additionally, computational methods were used to analyze the transcriptome, copy number variations, genetic mutations, and methylation of IFN-λ-related patient groups. RESULT: Endogenous expression of IFN-λ has been linked to poor prognosis in cancer patients, with the genes IFN-λ2 and IFN-λ3 serving as independent prognostic markers. IFN-λ acts in conjunction with related genes such as STAT1, STAT2, and STAT3 to affect the JAK-STAT signaling pathway, which promotes tumor progression. Abnormalities in IFN-λ genes are associated with changes in immune checkpoints and immune cell infiltration, which in turn affects cancer- and immune-related pathways. While there is increased immune cell infiltration in patients with IFN-λ expression, this does not improve survival prognosis, as T-cell dysfunction and an inflammatory environment are also present. The amplification of IFNL2 and IFNL3 copy number variants drives specific endogenous expression of IFN-λ in patients, and those with this specific expression have been found to have more mutations in the TP53 gene and lower levels of DNA methylation. CONCLUSION: Our study integrated multi-omics data to provide a comprehensive insight into the dark side of endogenous IFN-λ, providing a fundamental resource for further discovery and therapeutic exploration in cancer.

[Advances of Targeted Therapy for Acute Myeloid Leukemia--Review].

Acute myeloid leukemia (AML) has highly heterogeneous clinical manifestations and poor prognosis, and traditional chemotherapy is the main treatment. In recent years, with the in-depth development of next-generation sequencing technology, the treatment of AML is gradually exploring the precise targeted therapy in the direction of molecular biology and immunophenotype. The advent of various small-molecule inhibitors and immune-targeted drugs has brought hope to patients who cannot tolerate intensive chemotherapy or with relapsed/refractory AML. Compared with traditional chemotherapy, targeted therapy has the advantages of significant curative effect and fewer adverse effects. This article reviews the latest research progress of targeted drug therapy for AML.

[Impact of CSF3R Mutation on Treatment Response and Survival of Patients with Acute Myeloid Leukemia].

OBJECTIVE: To investigate the expression of CSF3R mutation in acute myeloid leukemia (AML) and analyze its clinical characteristics and prognosis. METHODS: A retrospective study was conducted in 212 patients with AML who were newly diagnosed in the Second Hospital of Shanxi Medical University from January 1th 2018 to June 30th 2021, including 22 patients with CSF3R mutations as mutation group and 190 patients with CSF3R wild type ï¼»66 cases of them were screened by propensity score matching (PSM), as control groupï¼½. The early efficacy and survival between the two groups were compared. RESULTS: The median age of patients in the mutation group was 50(17-73) years old, and the ratio of male to female was 1.2:1 The main types were AML with maturation (11 cases) and acute myelomonocytic leukemia (9 cases). Prognostic stratification was carried out according to the risk stratification system of the European leukemia network in 2017, with 16 cases (72.73%) in the middle and high-risk group. At the initial diagnosis, the median count of white blood cell (WBC) was 44.75(1.30-368.71)×109/L, among which 15 cases (68.18%) were >10×109/L, and the median count of platelet (PLT) was 24(4-55)×109/L. CSF3R T618I (68.18%) was a common mutation site, which had concomitant gene mutations, in which CEBPA mutation was the most common (10 cases, 45.45%), but only existed in CSF3R T618I mutation. The CR/CRi rate was 68.18% and 71.21% in the mutant group and the control group (P >0.05), the median over all survival time was 15 months and 9 months (P >0.05), and the median disease-free survival time was 8 months and 4 months (P >0.05), respectively. CONCLUSION: Most AML patients with CSF3R mutation are middle-aged patients, the main types are AML with maturation and acute myelomonocytic leukemia, and most of them have middle and high-risk prognosis. CSF3R mutation may not be an independent prognostic marker for newly diagnosed AML patients.

Multi-omics analysis reveals a molecular landscape of the early recurrence and early metastasis in pan-cancer.

Cancer remains a formidable challenge in medicine due to its propensity for recurrence and metastasis, which can result in unfavorable treatment outcomes. This challenge is particularly acute for early-stage patients, who may experience recurrence and metastasis without timely detection. Here, we first analyzed the differences in clinical characteristics among the primary tumor, recurrent tumor, and metastatic tumor in different stages of cancer, which may be caused by the molecular level. Moreover, the importance of predicting early cancer recurrence and metastasis is emphasized by survival analyses. Next, we used a multi-omics approach to identify key molecular changes associated with early cancer recurrence and metastasis and discovered that early metastasis in cancer demonstrated a high degree of genomic and cellular heterogeneity. We performed statistical comparisons for each level of omics data including gene expression, mutation, copy number variation, immune cell infiltration, and cell status. Then, various analytical techniques, such as proportional hazard model and Fisher's exact test, were used to identify specific genes or immune characteristics associated with early cancer recurrence and metastasis. For example, we observed that the overexpression of BPIFB1 and high initial B-cell infiltration levels are linked to early cancer recurrence, while the overexpression or amplification of ANKRD22 and LIPM, mutation of IGHA1 and MUC16, high fibroblast infiltration level, M1 polarization of macrophages, cellular status of DNA repair are all linked to early cancer metastasis. These findings have led us to construct classifiers, and the average area under the curve (AUC) of these classifiers was greater than 0.75 in The Cancer Genome Atlas (TCGA) cancer patients, confirming that the features we identified could be biomarkers for predicting recurrence and metastasis of early cancer. Finally, we identified specific early sensitive targets for targeted therapy and immune checkpoint inhibitor therapy. Once the biomarkers we identified changed, treatment-sensitive targets can be treated accordingly. Our study has comprehensively characterized the multi-omics characteristics and identified a panel of biomarkers of early cancer recurrence and metastasis. Overall, it provides a valuable resource for cancer recurrence and metastasis research and improves our understanding of the underlying mechanisms driving early cancer recurrence and metastasis.

Integration of multi-omics data reveals a novel hybrid breast cancer subtype and its biomarkers.

Tumor heterogeneity in breast cancer hinders proper diagnosis and treatment, and the identification of molecular subtypes may help enhance the understanding of its heterogeneity. Therefore, we proposed a novel integrated multi-omics approach for breast cancer typing, which led to the identification of a hybrid subtype (Mix_Sub subtype) with a poor survival prognosis. This subtype is characterized by lower levels of the inflammatory response, lower tumor malignancy, lower immune cell infiltration, and higher T-cell dysfunction. Moreover, we found that cell-cell communication mediated by NCAM1-FGFR1 ligand-receptor interaction and cellular functional states, such as cell cycle, DNA damage, and DNA repair, were significantly altered and upregulated in patients with this subtype, and that such patients displayed greater sensitivity to targeted therapies. Subsequently, using differential genes among subtypes as biomarkers, we constructed prognostic risk models and subtype classifiers for the Mix_Sub subtype and validated their generalization ability in external datasets obtained from the GEO database, indicating their potential therapeutic and prognostic significance. These biomarkers also showed significant spatially variable expression in malignant tumor cells. Collectively, the identification of the Mix_Sub breast cancer subtype and its biomarkers, based on the driving relationship between omics, has deepened our understanding of breast cancer heterogeneity and facilitated the development of breast cancer precision therapy.

Oncogenic signaling pathway dysregulation landscape reveals the role of pathways at multiple omics levels in pan-cancer.

Dysregulation of signaling pathways plays an essential role in cancer. However, there is not a comprehensive understanding on how oncogenic signaling pathways affect the occurrence and development with a common molecular mechanism of pan-cancer. Here, we investigated the oncogenic signaling pathway dysregulation by using multi-omics data on patients from TCGA from a pan-cancer perspective to identify commonalities across different cancer types. First, the pathway dysregulation profile was constructed by integrating typical oncogenic signaling pathways and the gene expression of TCGA samples, and four molecular subtypes with significant phenotypic and clinical differences induced by different oncogenic signaling pathways were identified: TGF-ß+ subtype; cell cycle, MYC, and NF2- subtype; cell cycle and TP53+ subtype; and TGF-ß and TP53- subtype. Patients in the TGF-ß+ subtype have the best prognosis; meanwhile, the TGF-ß+ subtype is associated with hypomethylation. Moreover, there is a higher level of immune cell infiltration but a slightly worse survival prognosis in the cell cycle, MYC, and NF2- subtype patients due to the effect of T-cell dysfunction. Then, the prognosis and subtype classifiers constructed by differential genes on a multi-omics level show great performance, indicating that these genes can be considered as biomarkers with potential therapeutic and prognostic significance for cancers. In summary, our study identified four oncogenic signaling pathway-driven patterns presented as molecular subtypes and their related potential prognostic biomarkers by integrating multiple omics data. Our discovery provides a perspective for understanding the role of oncogenic signaling pathways in pan-cancer.

Comparison of Silicosis and Tuberculosis Involving Mediastinal Lymph Nodes Based on Contrast-Enhanced Multidetector-Row Computed Tomography.

PURPOSE: To investigate the different imaging features of contrast-enhanced multidetector-row-computed tomography (MDCT) for distinguishing between silicosis and tuberculosis involving the mediastinal lymph nodes. METHODS: 86 silicosis patients and 61 tuberculosis patients with mediastinal lymphadenopathy based on contrast-enhanced MDCT were included. The enhanced patterns, anatomical distribution and calcification features of the enlarged lymph nodes were retrospectively compared between the groups using the Pearson chi-square test or Fisher's exact test. RESULTS: Homogeneous enhancement of the mediastinal lymph nodes was more commonly observed in silicosis (94.2%, 81/86) than in tuberculosis (19.7%, 12/61). Peripheral enhancement was more frequent in tuberculosis (n = 44, 72.1%) than in silicosis involving the mediastinal lymph nodes (n = 1, 1.2%), and multilocular appearance was more frequent in TB than in silicosis. Tuberculosis was more likely to affect regions 1R, 2R, 2L, 3A, 5 and 6 than silicosis (all p < 0.05), especially region 2R. Calcification of the lymph nodes was more common in the silicosis group than in tuberculosis group. The sensitivity, specificity, and accuracy of silicosis with lymphadenopathy with homogeneous enhanced pattern were 94.2%, 80.3% and 88.4%, respectively. The sensitivity, specificity, and accuracy of tuberculosis lymphadenopathy with peripheral enhanced pattern were 72.1%, 98.8%, and 87.7%, respectively. CONCLUSION: The predominant enhanced patterns, anatomical distribution, and calcification features of mediastinal lymph nodes were different between tuberculosis and silicosis. These radiographic features might help differentiate tuberculosis from silicosis, which provides imaging information for the differential diagnosis of the two diseases in a clinical setting.

Effect of Mitral Regurgitation on Left Ventricular Deformation in Myocardial Infarction Patients: Evaluation by Cardiac Magnetic Resonance Imaging.

BACKGROUND: Mitral regurgitation (MR) is a comorbidity of myocardial infarction (MI), which may promote the incidence of adverse cardiovascular clinical events. However, it is not yet completely understood how MR in MI patients is associated with impaired myocardial deformation. PURPOSE: To determine the damaging myocardium effects of MR in MI patients in terms of the global peak strain (PS) and left ventricular (LV) function, and evaluate the independent risk factors impacting LV deformation after MI. STUDY TYPE: Retrospective. POPULATION: One hundred eighty-six MI patients (17.7% female) and 84 normal control subjects (27.4% female). FIELD STRENGTH/SEQUENCE: 3.0T; late gadolinium enhancement sequence, balanced steady-state free precession. ASSESSMENT: LV function and LV global PS (global radial peak strain [GRPS]; global circumferential peak strain [GCPS]; and global longitudinal peak strain [GLPS]) were compared among normal controls, MI without MR (MR-) and MI with MR (MR+, mild, moderate, severe) patients. STATISTICAL TESTS: One-way analysis of variance (ANOVA) test, Mann-Whitney U test, Kruskal-Wallis test, and multiple linear regressions were used. A P value <0.05 indicated statistically significant difference (two-tailed). RESULTS: The MI (MR+) patients showed significantly lower LV global PS than both MI (MR-) and control groups in three directions (GRPS 16.66 ± 7.43%; GCPS -11.27 ± 4.27%; GLPS -7.75 ± 3.44%), and significantly higher LV end-systolic (128.85 [87.91, 188.01] mL) and end-diastolic volumes (210.29 [164.07, 264.00] mL) and significantly lower LV ejection fraction (38.23 ± 13.02%). Multiple regression analysis demonstrated that MR was independently associated with LV GCPS (ß = -0.268) and GLPS (ß = -0.320). LV infarct size was an independent indicator of LV GRPS (ß = -0.215) and GCPS (ß = -0.222). LV end-diastolic volume was an independent indicator of LV GRPS (ß = -0.518), GCPS (ß = -0.503), and GLPS (ß = -0.331). DATA CONCLUSION: MR may further exacerbate the reduction of LV global peak strains and function. The MR, infarct size, and LV end-diastolic volume can be used as independent association indicators for LV global PS in MI (MR+) patients. LEVEL OF EVIDENCE: 4 Technical Efficacy Stage: 2 TOC Category: Chest.

Compound heterozygous p.L483P and p.S310G mutations in GBA1 cause type 1 adult Gaucher disease: A case report.

BACKGROUND: Gaucher disease (GD) is caused by a GBA1 gene mutation that leads to decreased acid ß-glucosidase activity [glucocerebrosidase (GCase)]. This study aimed to identify and characterise compound heterozygous mutations in GBA1 in a patient with type 1 GD. CASE SUMMARY: Here, we report a rare adult-onset type 1 GD in a 46-year-old female patient with clinical manifestations of giant spleen, thrombocytopenia, and bone pain, diagnosed by enzymatic and genetic testing. Enzymology and whole exome sequencing revealed heterozygous missense mutations in exon 10 c.1448T>C (p.L483P) and exon 7 c.928A>G (p.S310G) of GBA1. The latter was first reported in patients with GD. Structural modelling showed that p.S310G and p.L483P were distant from the GCase active site. The p.S310G mutation in domain 1 may decrease stability between the α2 and α3 helices of GBA1. The p.L483P mutation in domain 2 reduced the van der Waals force of the side chain and disrupted the C-terminal ß-sheet. The patient was treated with imiglucerase replacement therapy, and her condition was stable. CONCLUSION: The p.L483P/p.S310G novel compound heterozygous mutation underlies type 1 GD and likely affects GCase protein function. This is the first description of p.S310G being associated with mild type 1 GD in the context of a coinherited p.L483P mutation.

Impact of myocardial scars on left ventricular deformation in type 2 diabetes mellitus after myocardial infarction by contrast-enhanced cardiac magnetic resonance.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a major risk factor for coronary artery disease and myocardial infarction (MI). The interaction of diabetic cardiomyopathy and MI scars on myocardial deformation in T2DM patients is unclear. Therefore, we aimed to evaluate myocardial deformation using cardiac magnetic resonance (CMR) in T2DM patients with previous MI and investigated the influence of myocardial scar on left ventricular (LV) deformation. METHODS: Overall, 202 T2DM patients, including 46 with MI (T2DM(MI+)) and 156 without MI (T2DM(MI-)), and 59 normal controls who underwent CMR scans were included. Myocardial scars were assessed by late gadolinium enhancement. LV function and deformation, including LV global function index, LV global peak strain (PS), peak systolic strain rate (PSSR), and peak diastolic strain rate (PDSR), were compared among these groups. Correlation and multivariate linear regression analyses were used to investigate the relationship between myocardial scars and LV deformation. RESULTS: Decreases were observed in LV function and LV global PS, PSSR, and PDSR in the T2DM(MI+) group compared with those of the other groups. Reduced LV deformation (p < 0.017) was observed in the T2DM(MI+) group with anterior wall infarction. The increased total LV infarct extent and infarct mass of LV were related to decreased LV global PS (radial, circumferential, and longitudinal directions; p < 0.01) and LV global PSSR (radial and circumferential directions, p < 0.02). Multivariate analysis demonstrated that NYHA functional class and total LV infarct extent were independently associated with LV global radial PS (ß = - 0.400 and ß = - 0.446, respectively, all p < 0.01; model R2 = 0.37) and circumferential PS (ß = 0.339 and ß = 0.530, respectively, all p < 0.01; model R2 = 0.41), LV anterior wall infarction was independently associated with LV global longitudinal PS (ß = 0.398, p = 0.006). CONCLUSIONS: The myocardial scarring size in T2DM patients after MI is negatively correlated with LV global PS and PSSR, particularly in the circumferential direction. Additionally, different MI regions have different effects on the reduction of LV deformation, and relevant clinical evaluations should be strengthened.

Suspension array-based deafness genetic screening in 53,033 Chinese newborns identifies high prevalence of 109 G>A in GJB2.

OBJECTIVES: More than 50% of congenital hearing loss is attributed to genetic factors. Data of gene mutation associated with hearing loss from large population studies in Chinese population are scarce. In this study, we conducted a comprehensive newborn genetic screening in China to establish the carrier frequency and mutation spectrum of deafness-associated genes. METHODS: A total of 53,033 newborns were screened for hearing defects associated mutations. Twenty hot spot mutations in GJB2, GJB3, SLC26A4 and mitochondria12S rRNA were examined using suspension array analysis. RESULTS: 14,185 newborns (26.75%) were identified with at least one mutated allele. 872 (1.64%) neonates carried homozygous mutations including 112 (0.21%) mitochondrial DNA homoplasmy, 228 (0.43%) were compound heterozygotes, and 11,985 (22.59%) were heterozygotes including 11 (0.02%) mitochondrial DNA heteroplasmy. Top five mutations included 109 G > A, 235 delC, 299-300 delAT in GJB2, IVS7-2 A > G in SLC26A4 and 1555 A > G in mitochondria12S rRNA. Notably, a total of 10,995 neonates (20.73%) carried 109 G > A in GJB2. Moreover, the allele frequencies of 109 G > A were detected 11.61% in Guangdong, 10.44% in Sichuan and 2.88% in Shandong, respectively, a significant difference in prevalence among these geographic regions (p<0.01). In addition, the high frequency of 109 G > A in GJB2 was confirmed by a TaqMan probe-based qPCR assay. Very recently, the ClinGen Hearing Loss Expert Panel reached a consensus and confirmed its pathogenic role in hearing impairment. CONCLUSION: We delineated the mutation profile of common deafness-causing genes in the Chinese population and highlighted the high prevalence of 109 G > A pathogenic mutation. Our study may facilitate early diagnosis/intervention and genetic counseling for hearing impairment in clinical practice.

[Clinical Value of Multi-slice Spiral Enhanced CT in Diagnosing Mild Digestive Tract Hemorrhage].

Objective To investigate the clinical value of multi-slice spiral CT(MSCT) in the diagnosis of mild digestive tract hemorrhage. Methods Thirty-five patients with mild gastrointestinal hemorrhage were examined by enhanced MSCT.CT signs were observed and compared with pathologic examination findings.Results Diseases in these 35 patients included gastric and duodenal ulcer and inflammation(n=4,11.4%),esophagogastric variceal rupture(n=7,20.0%),gastric carcinoma(n=3,8.6%),gastric stromal tumor(n=3,8.6%),gastric polyp(n=1,2.9%),colonic malignancy(n=5,14.2%),small intestinal stromal tumor(n=6,17.1%),rectal cancer(n=2,5.7%),intestinal Crohn disease(n=3,8.6%),and jejunum diverticulum combined with hemorrhage(n=1,2.9%).All of them were diagnosed by endoscopy of the digestive tract and confirmed by operation and pathology.The accuracy rate of CT was 100%.The coincidence rate of CT diagnosis was 97.1%.Conclusion MSCT is a promising technique in the localization,qualitative diagnosis,and clinical treatment of mild gastrointestinal hemorrhage.

[Components of Urinary Nanocrystals and Their Influence on Formation of Calcium Oxalate Stones].

High-resolution transmission electron microscopy, X-ray diffraction, selected area electron diffraction (SAED), and energy dispersive spectroscopy (EDS) were accurately performed to analyze the components of nanocrystals in the urine of patients with calcium oxalate (CaOx) stones. XRD, SAED and FFT detected the presence of calcium oxalate monohydrate (COM), uric acid (UA), and calcium phosphate (CaP). EDS detected the elements of C, O, Ca, with a small amount of N and P. These results showed that the main components of urinary nanocrystals were COM, with a small amount UA and phosphate. HRTEM observation showed that the particle size of urinary nanocrystals was dozens of nanometers. The result was consistent with the calculation by Debye-Scherrer equation. When the urine was filtered through a microporous membrane of 0.45, 1.2, and 3 µm, respectively, the number of diffraction peaks of the obtained urine crystallites increased with the increased pore size, indicating the increase of urinary crystallite species. Crystal nucleation, growth, aggregation, and adhesion of crystals to the renal epithelial cells are important processes for CaOx stone formation. The presence of a large amount of COM crystals in patients' urine is a critical factor for CaOx stones formation. Nano UA and CaP crystallite can induce the CaOx stone formation as central nidus.