The mixed subtype has a worse prognosis than other histological subtypes: a retrospective analysis of 217 patients with metaplastic breast cancer.

OBJECTIVE: Metaplastic breast cancer (MpBC) is an aggressive subtype of all breast cancer. We aimed to investigate the clinicopathological features, treatments and prognoses of MpBC patients. METHODS: We collected the data from MpBC patients diagnosed at Tianjin Medical University Cancer Hospital from 2010 to 2017. Kaplan Meier curves and Cox regression model were used to evaluating clinical outcomes and prognostic factors. After removing baseline differences by propensity score matching (PSM), we analyzed the prognosis between MpBC patients and invasive ductal carcinomas of no special type (IDC-NST) patients. RESULTS: A total of 217 MpBC patients were subsumed. Of all histological subtypes, 45.1% were mixed subtypes, followed by with mesenchymal differentiation (27.2%), pure squamous (15.2%) and pure spindle (12.4%) subtypes. 69.6% of MpBC were triple-negative, 25.3% and 6.5% were HR-positive and HER2-positive. MpBC patients had worse survival compared to IDC-NST patients, with 5-year RFS of 73.8 and 83.6% (HR = 1.177 95%CI (1.171-2.676) P = 0.0068), and 5-year BCSS of 79.0% and 89.7% (HR = 2.187 95%CI (1.357-3.523) P = 0.0013). In the multivariate COX model, AJCC stage, mixed subtype and chemotherapy were independent prognostic factors. Mixed MpBC is more aggressive than pure and with heterologous mesenchymal differentiation subtypes. And whether squamous or spindle MpBC, mixed forms have shorter outcomes than pure forms. CONCLUSIONS: MpBCs are associated with poorer prognoses than IDC-NSTs. They are heterogeneous with different clinicopathological features and clinical outcomes between histological subtypes. Pure and with heterologous mesenchymal differentiation subtypes have more survival benefits than the mixed subtype.

Ado-trastuzumab emtansine in the treatment of lung adenocarcinoma with ERBB2 mutation: a case report and literature review.

The erb-b2 receptor tyrosine kinase 2 (ERBB2), also known as HER2, has long been recognized as an oncogenic driver in some breast and gastroesophageal cancers, and ERBB2-targeted therapies are standard for ERBB2-positive breast and gastric cancer. However, there are currently no standard therapies targeting the ERBB2 pathway in non-small cell lung cancer. Recently, somatic mutations in ERBB2 have been reported in 2-3% of patients with advanced lung adenocarcinoma, these mutations are trans-forming in lung cancer models and result in kinase activation, conferring some in-vitro sensitivity to trastuzumab. The ado-trastuzumab emtansine (T-DM1) is an antibody-drug conjugate composed of trastuzumab joined via a stable linker to DM1. In this report, a 67-year-old male patient was diagnosed with advanced lung adenocarcinoma with multiple lymph node metastases, and multi-chemotherapy and immunotherapy were not effective. The results of genetic testing indicated a non-frameshift insertion mutation in exon 20 of the ERBB2 gene. The patients received T-DM1 at a dose of 3.6 mg/kg by intravenous infusion every 21 days until for 12 cycles. Partial response appeared in the tumor lesions after treatment for four cycles, and PET-computer tomography showed the tumor lesions were effectively controlled, and the efficacy evaluation was complete response after treatment for six cycles. Although the patient experienced second degree of thrombocytopenia during the treatment, the corresponding symptomatic treatment was taken, and the platelets could return to normal before the next cycle of T-DM1. Follow-up review showed the patient is in good health and the tumor has not recurred.

Cardiac angiosarcoma: A case report and review of the literature.

Primary cardiac tumors are extremely rare, among which malignancies comprise about 15-25%. As the most common type of primary cardiac malignancies, angiosarcomas tend to arise in the right heart, especially right atrium. In this case report, we presented a 32-year-old female with primary cardiac angiosarcoma in the right atrial appendage detected by transesophageal echocardiography, as it is difficult to display on conventional transthoracic echocardiography.

Loci and natural alleles underlying robust roots and adaptive domestication of upland ecotype rice in aerobic conditions.

A robust (long and thick) root system is characteristic of upland japonica rice adapted to drought conditions. Using deep sequencing and large scale phenotyping data of 795 rice accessions and an integrated strategy combining results from high resolution mapping by GWAS and linkage mapping, comprehensive analyses of genomic, transcriptomic and haplotype data, we identified large numbers of QTLs affecting rice root length and thickness (RL and RT) and shortlisted relatively few candidate genes for many of the identified small-effect QTLs. Forty four and 97 QTL candidate genes for RL and RT were identified, and five of the RL QTL candidates were validated by T-DNA insertional mutation; all have diverse functions and are involved in root development. This work demonstrated a powerful strategy for highly efficient cloning of moderate- and small-effect QTLs that is difficult using the classical map-based cloning approach. Population analyses of the 795 accessions, 202 additional upland landraces, and 446 wild rice accessions based on random SNPs and SNPs within robust loci suggested that there could be much less diversity in robust-root candidate genes among upland japonica accessions than in other ecotypes. Further analysis of nucleotide diversity and allele frequency in the robust loci among different ecotypes and wild rice accessions showed that almost all alleles could be detected in wild rice, and pyramiding of robust-root alleles could be an important genetic characteristic of upland japonica. Given that geographical distribution of upland landraces, we suggest that during domestication of upland japonica, the strongest pyramiding of robust-root alleles makes it a unique ecotype adapted to aerobic conditions.

Serum soluble VSIG4 as a surrogate marker for the diagnosis of lymphoma-associated hemophagocytic lymphohistiocytosis.

Lymphoma-associated haemophagocytic lymphohistiocytosis (L-HLH) is characterized by excessively activated macrophages and cytotoxic T lymphocytes, but few reliable markers for activated macrophages are available clinically. This study, designed to discover novel biomarkers for the diagnosis of lymphoma patients with L-HLH, was initiated between 2016 and 2018. Fifty-seven adult lymphoma patients were enrolled - 39 without HLH and 18 with HLH. The differential serum protein expression profile was first screened between lymphoma patients with and without L-HLH by a quantitative mass spectrometric approach. Soluble V-set and immunoglobulin domain-containing 4 (sVSIG4), specifically expressed by macrophages, was significantly upregulated in the L-HLH group. Subsequently, sVSIG4 concentration was confirmed by enzyme-linked immunosorbent assay to be significantly increased in lymphoma patients with L-HLH. When it was exploited for the diagnosis of lymphoma patients with L-HLH, the area under a receiver operating characteristic curve was 0·98 with an optimal cut-off point of 2195 pg/ml and the corresponding sensitivity and specificity were 94·44% and 94·87% respectively. In addition, the one-year overall survival was significantly worse in patients with a sVSIG4 concentration above 2195 pg/ml compared with those below 2195 pg/ml (5·3% vs. 72·2%, P < 0·0001). sVSIG4 may be a surrogate marker of activated macrophages for the diagnosis of lymphoma patients with L-HLH.

SRGN Promotes Colorectal Cancer Metastasis as a Critical Downstream Target of HIF-1α.

BACKGROUND/AIMS: The chondroitin sulfate proteoglycan serglycin (SRGN), a hematopoietic cell granule proteoglycan, has been implicated in promoting tumor metastasis; however, the underlying mechanisms remain to be elucidated. The present study aimed to investigate the SRGN gene expression and its regulation as downstream signaling of hypoxia-inducible transcription factor 1 alpha (HIF-1α) in colorectal cancer (CRC) cells and tissues. METHODS: The expression of SRGN was analyzed in CRC specimens for its correlation with progression and metastasis. Using chromatin-immunoprecipitation (ChIP), quantitative real-time PCR, Western blot, and transwell assay, the functional role and underlying mechanism of SRGN in CRC metastasis were elucidated. Thus, this study provides evidence of a critical role of SRGN in metastatic progression of CRC. RESULTS: Our results indicated that SRGN overexpression was significantly associated with poor prognosis in CRC specimens. SRGN overexpression promoted CRC cell migration and invasion in vitro; however, SRGN depletion exhibited contrasting effects. Mechanistic investigations revealed that HIF-1α regulated SRGN transcription via physically binding to a hypoxia response element in its promoter region. CONCLUSIONS: In conclusion, we demonstrated that dysregulated HIF-1α/SRGN signaling promotes CRC progression and metastasis. SRGN may serve as a potential candidate therapeutic target for metastatic CRC.

Decreasing Eukaryotic Initiation Factor 3C (EIF3C) Suppresses Proliferation and Stimulates Apoptosis in Breast Cancer Cell Lines Through Mammalian Target of Rapamycin (mTOR) Pathway.

BACKGROUND Translation initiation is the rate limiting step of protein synthesis and is highly regulated. Eukaryotic initiation factor 3C (EIF3C), an oncogene overexpressed in several human cancers, plays an important role in tumorigenesis and cell proliferation. MATERIAL AND METHODS Immunohistochemistry was used to determine the expression of EIF3C in breast cancer tissues from 42 patients. We investigated whether EIF3C silencing decreases breast cancer cell proliferation as assessed by colony formation assay, and whether EIF3C gene knockdown induces apoptosis as assessed by flow cytometry analysis. We utilized the stress and apoptosis signaling antibody array kit, while p-ERK1/2, p-Akt, p-Smad2, p-p38 MAPK, cleaved caspase-3, and cleaved caspase-7 were explored between EIF3C-siRNA and controls. Furthermore, the effects of EIF3C gene knockdown in mTOR pathway were analyzed by western blotting for different cell lines. RESULTS In EIF3C-positive tumors, 32 out of 42 showed significantly higher frequencies of high grade group by immunoreactivity (p=0.0016). BrdU incorporation after four days of cell plating was significantly suppressed in MDA-MB-231 cells by EIF3C knockdown compared with controls, with average changes of 7.8-fold (p<0.01). Clone number was significantly suppressed in MDA-MB-231 cells by EIF3C knockdown compared with controls (p<0.05). Cell apoptosis was significantly increased in the EIF3C-siRNA group when compared with the cells that were transfected with scrambled siRNA (3.51±0.0842 versus 13.24±0.2307, p<0.01). The mTOR signaling pathway was involved in decreasing EIF3C translational efficiency. CONCLUSIONS Unveiling the mechanisms of EIF3 action in tumorigenesis may help identify attractive targets for cancer therapy.

Early Assistance With Left Ventricular Assist Device Limits Left Ventricular Remodeling After Acute Myocardial Infarction in a Swine Model.

UNLABELLED: Although left ventricular assist devices (LVADs) have been commonly used for patients with cardiogenic shock after acute myocardial infarction (AMI), their effects on post-AMI prognosis remain to be elucidated. In this study, we aimed to explore the effects of an LVAD on left ventricular (LV) remodeling and function at the postinfarction stage in a swine model. AMI was induced by ligation of the circumflex artery or its branches for 120 min, followed by 120 min of reperfusion. In the assist group (n = 6), LVAD was initiated at 90 min after ischemia and was maintained for support until 120 min after reperfusion, whereas the control group (n = 6) received no support. LV pressure, volume, wall stress, and stroke work were all decreased by LVAD assistance at the ischemia and reperfusion stages, and blood pressure and cardiac output were maintained. All swine were studied 1 month after the procedure, and those in the assist group showed less increased end-diastolic volumes (assist vs. CONTROL: 57.9 ± 6.6 vs. 79.0 ± 6.7 mL, P = 0.032) and sphericity (assist vs. CONTROL: 1.33 ± 0.16 vs. 1.51 ± 0.12, P = 0.01), as well as improved ejection fractions (assist vs. CONTROL: 59.0 ± 7.8 vs. 42.3 ± 6.0%, P = 0.002). Furthermore, despite a presence of a similar initial ischemic area, the percent of infarcted myocardium was reduced by 49.9% in the assist group (assist vs. CONTROL: 18.1 ± 4.8 vs. 35.3 ± 6.2%, P < 0.001). These results suggested that early assistance with an LVAD in AMI limited LV remodeling, preserved postinfarction systolic function, and improved the prognosis.

Toll-like receptor 4-induced inflammatory responses contribute to the tumor-associated macrophages formation and infiltration in patients with diffuse large B-cell lymphoma.

To evaluate the expression of tumor-associated macrophages (TAMs) and Toll-like receptor 4 (TLR4) in diffuse large B-cell lymphoma (DLBCL) and their correlation with patient clinical characteristics, we detected using immunohistochemistry in 81 specimens of patients with DLBCL. The correlation between protein expression levels and clinical parameters, as well as the association between CD68 and TLR4 were analyzed. The number of CD68 TAMs was closely related to ß2-microglobulin (P = .028 and P < .05), whereas there was no significant correlation between the number of CD68 TAMs and other clinical factors. Toll-like receptor 4 was related to tumor size and peripheral blood lymphocyte to monocyte ratio. The Spearman correlation coefficient indicated a significant positive correlation between CD68 TAMs and TLR4 expression (r = 0.240; P = .038, P = .05). These results, on one hand, indicated that TLR4-induced inflammatory responses may affect TAM infiltration and accumulation, and that TAMs and TLR4 may interact to play important roles in DLBCL microenvironment regulating the tumor growth, but, on the other hand demonstrated that both of TAMs and TLR4 had not only one side on DLBCL growth.

Enhancement of radiosensitivity of lung adenocarcinoma using a decoction from the Fuzhengzengxiao formula.

OBJECTIVE: To study the effects of a decoction of Fuzhengzengxiao formula on lung adenocarcinoma regarding the inflammatory protein S100A9 known to enhance cancer cell sensitivity. METHODS: A nude mouse model of human lung adenocarcinoma was established. The mice were randomly divided into four groups using the random number table method: Group I, control; Group II, treatment with a decoction of the Fuzhengzengxiao formula alone; Group III, treatment with radiotherapy alone; and Group IV, treatment with radiotherapy plus a decoction of Fuzhengzengxiao formula. When the tumor body was 1 cm3 in diameter, the tumor bearing mice in Groups III and IV were irradiated at a single dose of 10 Gy and the tumor inhibition rate was evaluated. The expression of S100A9 was determined using Western blotting and q-PCR (Real-time Quantitative PCR Detecting System). The sensitivity of cells containing RNAi S100A9 to radiotherapy was evaluated using the Click multiple target model,and the cell cycle was analyzed using flow cytometry. RESULTS: Relative to the control group, the expression of S100A9 in the tumors in each treatment group was decreased, especially in Group IV. The sensitizing enhancement ratio (SER) Dq was > 1 after RNAi S100A9; it decreased the surviving fraction after a 2 Gy dose exposure,and also the D0 and Dq of the tumor cells; in addition, the radiosensitivity of G2/M cells was significantly increased. CONCLUSION: The decoction of the Fuzhengzengxiao formula downregulated the expression of S100A9 in lung adenocarcinoma cells.

Circ_0084653 promotes the tumor progression and immune escape in triple-negative breast cancer via the deubiquitination of MYC and upregulation of SOX5.

The role of circular RNAs (circRNAs) in cancers is gaining more and more attention, yet related reporters are limited. In triple-negative breast cancer (TNBC), circRNA circ_0084653 originated from COP9 signalosome subunit 5 (COPS5), and COPS5 has been validated to be upregulated in breast cancer before. In our research, COPS5 was also upregulated in TNBC cells, and knockdown of it repressed cell proliferation, invasion, EMT, stemness and PDL-1 protein expression but increased T-cell percentage. Further, circ_0084653 was an aberrantly upregulated circRNA in TNBC cells, and similarly, circ_0084653 silence inhibited TNBC development. Besides, circ_0084653 expression was distributed in both cytoplasm and nucleus. COPS5 overexpression partially rescued the suppressing effects of circ_0084653 depletion in TNBC. Subsequently, circ_0084653 triggered deubiquitination of MYC, the upstream transcription factor of COPS5, via recruiting ubiquitin specific peptidase 36 (USP36). Moreover, circ_0084653 served as the sponge of miR-1323 to release the expression the target gene SRY-box transcription factor 5 (SOX5). SOX5 upregulation completely remedied the inhibiting influence of circ_0084653 downregulation in TNBC. Meanwhile, transcription factor SOX5 activated transcriptionally circ_0084653. To sum up, SOX5-induced circ_0084653 promotes TNBC via the deubiquitination of USP36, which may provide some fresh ideas for TNBC-related molecular mechanisms.

Serum HER2 Level Predicts Therapeutic Efficacy and Prognosis in Advanced Breast Cancer Patients.

Background: The purpose of this study was to investigate the therapeutic efficacy and prognosis of serum HER2 (sHER2) in patients with advanced breast cancer. Methods: We analyzed the sHER2 levels of 200 patients with advanced breast cancer receiving first or second line treatment, the tissue HER2 (tHER2) level was also analyzed. Indicators of therapeutic efficacy and prognosis were objective response rate (ORR), disease control rate (DCR), and time to progression (TTP). Results: The baseline sHER2 level was high in 132 patients and low in 68 patients. The high level of sHER2 is correlated with molecular subtype (p=0.016), visceral metastasis (p<0.001), liver metastasis (p<0.001), tissue HER-2 (tHER2) (p=0.001), and, among tHER2-low tumors (59 patients), the baseline sHER2 high level was associated with a higher proportion of brain metastasis. The ORR of patients with baseline sHER2 high level is higher than those with baseline sHER2 low level (p=0.026). The TTP of patients with baseline sHER2 low level is longer than the patients with baseline sHER2 high level (p=0.024). For patients with baseline sHER2 high level, a significant decrease in sHER2 after two cycles of treatment indicates higher ORR, DCR, and an extension of TTP. After multiple cycles of treatment, for patients with tHER-2 positive and baseline sHER2 high level, the DCR in the sHER2 decrease in the negative group was higher than that in the continuous positive group (p=0.037). Patients with a rapid decline type of sHER2 dynamic change curve had higher ORR and prolonged TTP compared with patients with other types of sHER2 dynamic change curve. There is no correlation between OS and sHER2 levels. Conclusion: Our study showed that patients with advanced breast cancer had a high level of sHER2 at recurrence, regardless of whether they are tHER2 positive or negative. Dynamic detection of sHER2 can help predict therapeutic efficacy and prognosis, regardless of whether tHER-2 is positive or negative.

Evaluation of prognostic risk factors of triple-negative breast cancer with 18F-FDG PET/CT parameters, clinical pathological features and biochemical indicators.

Introduction: Breast cancer is a heterogeneous disease comprising various molecular subtypes, including Luminal A, Luminal B, human epidermal growth factor receptor-2 (HER2) positive, and triple negative types, each with distinct biological characteristics and behaviors. Triple negative breast cancer (TNBC) remains a particularly challenging subtype worldwide. Our study aims to evaluate whether Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography (18F-FDG PET/CT) parameters, clinical pathological features, and biochemical indicators serve as prognostic risk factors for TNBC. Additionally, we explore correlations between biochemical indicators and 18F-FDG PET/CT parameters. Methods: We conducted a retrospective analysis of 95 TNBC patients who underwent preoperative 18F-FDG PET/CT examinations at Tianjin Medical University Cancer Institute and Hospital from 2013 to 2018. Collected data included 18F-FDG PET/CT parameters, clinical and pathological features, and biochemical indicators. We used Kaplan-Meier survival analysis and multivariate Cox regression analysis to evaluate associations between 18F-FDG PET/CT parameters/biochemical indicators and disease free survival (DFS)/overall survival (OS). The log-rank test determined significant differences in survival curves, and the Spearman correlation coefficient analyzed correlations between quantitative variables. Visualization and analysis were performed using R packages. Results: Among 95 TNBC patients, mean standardized uptake value (SUVmean) was significantly correlated with DFS. Fasting blood glucose (FBG), α- L-fucosylase (AFU) and Creatine kinase (CK) were independent predictors of DFS, while Precursor albumin (PALB) and CK were independent predictors of OS. FBG showed correlations with SUVpeak and SUVmean, and CK was correlated with peak standardized uptake value (SUVpeak). Our results indicated that 18F-FDG PET/CT parameters and biochemical indicators may constitute a new prognostic model for TNBC patients post-surgery. Discussion: We found that SUVmean, FBG, AFU and CK are predictive factors for DFS in TNBC patients post-surgery, while PALB and CK are predictive factors for OS, which prompts us to pay more attention to these indicators in clinical practice. Also 18F-FDG PET/CT parameters and biochemical indicators have potential utility in constituting a new prognostic model for TNBC patients post-surgery.

Continuous 3D Myocardial Motion Tracking via Echocardiography.

Myocardial motion tracking stands as an essential clinical tool in the prevention and detection of cardiovascular diseases (CVDs), the foremost cause of death globally. However, current techniques suffer from incomplete and inaccurate motion estimation of the myocardium in both spatial and temporal dimensions, hindering the early identification of myocardial dysfunction. To address these challenges, this paper introduces the Neural Cardiac Motion Field (NeuralCMF). NeuralCMF leverages implicit neural representation (INR) to model the 3D structure and the comprehensive 6D forward/backward motion of the heart. This method surpasses pixel-wise limitations by offering the capability to continuously query the precise shape and motion of the myocardium at any specific point throughout the cardiac cycle, enhancing the detailed analysis of cardiac dynamics beyond traditional speckle tracking. Notably, NeuralCMF operates without the need for paired datasets, and its optimization is self-supervised through the physics knowledge priors in both space and time dimensions, ensuring compatibility with both 2D and 3D echocardiogram video inputs. Experimental validations across three representative datasets support the robustness and innovative nature of the NeuralCMF, marking significant advantages over existing state-of-the-art methods in cardiac imaging and motion tracking. Code is available at: https://njuvision.github.io/NeuralCMF.

2-year results and myocardial impact of transapical mitral valve repair in patients with primary mitral regurgitation: an echocardiographic study.

BACKGROUND: There is limited data on the 2-year outcomes of transapical transcatheter edge-to-edge repair (TA-TEER) using the ValveClamp in patients with severe primary mitral regurgitation (MR) and its impact on myocardial deformation. METHODS: From July 2018 to March 2021, 53 patients with symptomatic severe primary MR underwent TA-TEER were enrolled. The endpoint was the composite of all-cause mortality, recurrent 3 + or 4 + MR, or need for mitral surgery. RESULTS: Among the 53 patients who had successfully ValveClamp implantation, 8(15.1%) reached the composite endpoint. Significant improvement in left ventricular (LV) end-diastolic volume, pulmonary artery systolic pressure, NYHA functional class, and MR severity were observed (P < 0.05 for all). Univariate Cox's regression analysis revealed that LV end-diastolic volume index, LV end-systolic volume index, left atrial volume index, and pulmonary artery systolic pressure were associated with adverse events (P < 0.05 for all). On multivariate Cox regression analysis, left atrial volume index was independently associated with the endpoint (hazard ratio, 1.049; 95% CI, 1.009-1.091; P < 0.001) after adjustment for above echocardiographic parameters. LV global longitudinal strain and apical longitudinal strain in global and regional segments decreased at 30 days, but showed a recovery at 2 years with no significant difference compared to the baseline. CONCLUSION: TA-TEER using the ValveClamp presented favorable safety and efficacy at 2-year. Myocardial deformation impairment was observed at 30 days post-procedure, but did not persist at 2 years.

HDAC inhibitors target IRS4 to enhance anti­AR therapy in AR­positive triple­negative breast cancer.

Triple­negative breast cancer (TNBC) is the most malignant subtype of breast cancer. Androgen receptor (AR) has been identified as a potential therapeutic target for AR­positive TNBC; however, clinical trials have not yet produced an effective treatment. The present study aimed to identify a novel treatment regimen to improve the prognosis of AR­positive TNBC. First, a combination of an AR inhibitor (enzalutamide, Enz) and a selective histone deacetylase inhibitor (chidamide, Chid) was used to treat AR­positive TNBC cell lines, and a synergistic effect of these drugs was observed. The combination treatment inhibited cell proliferation and migration by arresting the cell cycle at the G2/M phase. Subsequently, next­generation sequencing was performed to detect changes in gene regulation. The results showed that the PI3K/Akt signalling pathway was significantly inhibited by the combination treatment of Enz and Chid. Gene Set Enrichment Analysis revealed that the combination group was significantly enriched in KRAS signalling. Analysis of the associated genes revealed that insulin receptor substrate 4 (IRS4) may have a critical role in blocking the activation of KRAS signalling. In a mouse xenograft model, combination treatment also inhibited the PI3K/Akt signalling pathway by upregulating the expression of IRS4 and thereby suppressing tumour growth. In conclusion, the results of the present study revealed that combination treatment with Enz and Chid can upregulate IRS4, which results in the blocking of KRAS signalling and suppression of tumour growth. It may be hypothesised that the expression levels of IRS4 could be used as a biomarker for screening patients with AR­positive TNBC using Enz and Chid combination therapy.

Three-dimensional echocardiography reveals early mitral valve alterations in hypertrophic cardiomyopathy genetic mutation carriers.

BACKGROUND: The mitral valve undergoes structural modifications in response to cardiac functional changes, often predating cardiac decompensation and overt clinical signs. Our study assessed the potential of mitral valve morphological changes as early indicators for detecting carriers of hypertrophic cardiomyopathy (HCM)-associated gene mutations. METHODS: We studied 505 participants: 189 without the pathogenic gene mutations and left ventricular hypertrophy (G-/LVH-), 149 carriers without LV hypertrophy (G+/LVH-), and 167 manifest HCM patients (G+/LVH+). We juxtaposed the mitral valve morphology and associated metrics across these groups, emphasizing those carrying MYH7 and MYBPC3 mutations. RESULTS: We discerned pronounced disparities in the mitral annulus and leaflet structures across the groups. The mitral valve apparatus in mutation carriers exhibited a tendency towards a flattened profile. Detailed analysis spotlighted MYBPC3 mutation carriers, whose mitral valves were notably flatter (with notably lower AHCWR values than non-carriers); this contrast was not evident in MYH7 mutation carriers. This mitral valve flattening, manifest in the mutation carriers, suggests it might be an adaptive response to incipient cardiac dysfunction in HCM's nascent stages. CONCLUSIONS: Three-dimensional echocardiography illuminates the initial mitral valve structural changes in HCM patients bearing pathogenic gene mutations. These morphological signatures hold promise as sensitive imaging markers, especially for asymptomatic carriers of the MYBPC3 mutation.

[Role of c-Myc in mesenchymal stromal cell-mediated drug resistance in acute leukemia cells].

OBJECTIVE: To explore the role of c-Myc in mesenchymal stromal cell-mediated drug resistance and elucidate the molecular mechanism of acute myeloid leukemia (AML) from the version of tumor microenvironment. METHODS: AML cell lines U937 and KG1a were co-cultured with mesenchymal stromal cells (MSC) from bone marrow of healthy donors between January to March 2012. The AML cell lines plated alone was cultured as controls. Apoptosis induced by mitoxantrone was measured by flow cytometry and Annexin V/PI double and 4'-6-diamidino-2-phenylindole (DAPI) staining. And c-Myc protein was detected by Western blot under both culturing conditions. After a pre-treatment of c-Myc inhibitor 10058-F4, the apoptosis of AML cell was also evaluated. RESULTS: Apoptosis of AML cells (U937 and KG1a) significantly decreased during co-culturing with MSC (9.88% ± 1.53% vs 42.83% ± 2.03%, P = 0.004;20.60% ± 2.87% vs 42.53% ± 5.29%, P = 0.030). Drug resistance was implicated. The co-culturing of AML cells with MSC significantly induced an up-regulation of c-Myc. The inhibition of c-Myc with 10058-F4 could induce apoptosis of AML cells. After an addition of 10058-F4 into the co-culture system, the apoptotic rate of KG1a cells significantly increased from 23.87% ± 1.55% to 57.23% ± 3.88% (P = 0.009). Similarly the apoptotic rates spiked from 16.07% ± 2.11% to 53.47% ± 4.08% in U937 cells (P = 0.004) to overcome the stromal cell-mediated drug resistance. CONCLUSIONS: The co-culturing of AML cells and MSC induces an up-regulation of c-Myc protein so as to cause the emergence of chemoresistance. Therefore targeting c-Myc protein may provide a novel therapeutic strategy of AML.

Coupled Co-Doped MoS2 and CoS2 as the Dual-Active Site Catalyst for Chemoselective Hydrogenation.

Catalytic hydrogenation plays an important role in the industrial production of fine chemicals. Herein, we report a Co-doped MoS2 and CoS2 composite with a coupling interface and successfully apply it for the chemoselective hydrogenation of p-chloronitrobenzene to p-chloroaniline. The target catalyst 0.5CoMoS has ∼100% conversion and ∼100% selectivity. Experiments and theoretical calculations reveal that CoS2 is more favorable for adsorbing and activating H2 and provides active hydrogen (Ha) to Co-doped MoS2 by the coupling interface. By matching the production and consumption rates of Ha, the maximization of the reaction yield was achieved. This work may promote the study of MoS2-based catalysts for chemoselective hydrogenation.

Development of a nomogram based on serum cytokine-related riskscore in breast cancer.

Background: Cytokines are involved in many inflammatory diseases and thus play an important role in tumor immune regulation. In recent years, researchers have found that breast cancer is not only related to genetic and environmental factors, but also to the chronic inflammation and immunity. However, the correlation between serum cytokines and blood tests indicators remain unclear. Methods: A total of 84 serum samples and clinicopathological data of breast cancer patients from Tianjin Cancer Institute & Hospital, Tianjin Medical University, Tianjin, P. R. China were collected. The expression levels of the 12 cytokines were detected by immunofluorescence method. Blood tests results were obtained from medical records. By stepwise Cox regression analysis, a cytokine-related gene signature was generated. Univariate and multivariate Cox regression were used to analyze the influence on the prognosis of patients. A nomogram was constructed to illustrate the cytokine-related riskscore predicting 5-year OS, which was further evaluated and validated by C-index and ROC curve. The correlation between the expression of cytokines in serum and other blood indicators was studied by using Spearman's test. Results: The riskscore was calculated as IL-4×0.99069 + TNF-α×0.03683. Patients were divided into high and low risk groups according to the median riskscore, with the high-risk group has a shorter survival time by log-rank test (training set, P=0.017; validation set, P=0.013). Combined with the clinical characteristics, the riskscore was found to be an independent factor for predicting the OS of breast cancer patients in both training cohort (HR=1.2, P<0.01) and validation cohort (HR=1.6, P=0.023). The 5-year C-index and AUC of the nomogram were 0.78 and 0.68, respectively. IL-4 was further found to be negatively correlated with ALB. Conclusion: In summary, we have developed a nomogram based on two cytokines including IL-4 and TNF-α to predict OS of breast cancer and investigated their correlation with blood test indicators.