K6-linked SUMOylation of BAF regulates nuclear integrity and DNA replication in mammalian cells.

Barrier-to-autointegration factor (BAF) is a highly conserved protein in metazoans that has multiple functions during the cell cycle. We found that BAF is SUMOylated at K6, and that this modification is essential for its nuclear localization and function, including nuclear integrity maintenance and DNA replication. K6-linked SUMOylation of BAF promotes binding and interaction with lamin A/C to regulate nuclear integrity. K6-linked SUMOylation of BAF also supports BAF binding to DNA and proliferating cell nuclear antigen and regulates DNA replication. SENP1 and SENP2 catalyze the de-SUMOylation of BAF at K6. Disrupting the SUMOylation and de-SUMOylation cycle of BAF at K6 not only disturbs nuclear integrity, but also induces DNA replication failure. Taken together, our findings demonstrate that SUMOylation at K6 is an important regulatory mechanism that governs the nuclear functions of BAF in mammalian cells.

CC1007, a small molecular compound, suppresses multiple myeloma via upregulation of Nur77.

BACKGROUND: Multiple myeloma (MM) is a hematological malignancy of plasma cells characterized by the production of monoclonal immunoglobulin protein. Despite significant advances in the treatment of MM, it remains an incurable disorder owing to its resistance to chemotherapy and refractory nature. Inhibitors of histone deacetylases (HDACIs) have been identified as promising therapeutic drugs for cancer treatment. At present, numerous HDACIs are under study for the treatment of MM in monotherapy or in conjunction with other agents. OBJECTIVES: In the present study, we investigated the anti-MM effect of CC1007, which was designed to indirectly inhibit class IIa HDACs by binding to myocyte enhancer factor-2 (MEF2) and blocking the targets regulated by the HDAC-MEF2 complex. DESIGN: The effect of CC1007 on human MM cell lines, namely U266 and MM1.S, and CD138+ cells collected from the bone marrow of patients with MM was evaluated. METHODS: The cells were subjected to growth-inhibition assay, apoptosis assay, cell cycle analysis, real-time PCR, western blotting, immunofluorescence, co-immunoprecipitation, ChIP assay, and siRNA transfection. Statistical differences were compared using two-tailed t tests or one-way analysis of variance followed by the Bonferroni post hoc test. RESULTS: CC1007 inhibited the proliferation of MM cell lines and primary MM cells and induced their apoptosis and cell cycle arrest. Furthermore, CC1007 decreased the expression of MEF2C and HDAC7, thereby disturbing their interaction and promoting the overexpression of Nur77, a target of MEF2C. The overexpression of Nur77 and its translocation from the nucleus to the cytoplasm resulted in its binding to B-cell lymphoma 2 on the mitochondrial surface, thereby inducing the release of cytochrome C and activating the mitochondrial apoptotic pathway. CONCLUSIONS: Since CC1007 demonstrates remarkable anti-MM effect on MM cells, it may be a promising drug for the treatment of MM.

Patched1-ArhGAP36-PKA-Inversin axis determines the ciliary translocation of Smoothened for Sonic Hedgehog pathway activation.

The Sonic Hedgehog (Shh) pathway conducts primarily in the primary cilium and plays important roles in cell proliferation, individual development, and tumorigenesis. Shh ligand binding with its ciliary membrane-localized transmembrane receptor Patched1 results in the removal of Patched1 from and the translocation of the transmembrane oncoprotein Smoothened into the cilium, leading to Shh signaling activation. However, how these processes are coupled remains unknown. Here, we show that the Patched1-ArhGAP36-PKA-Inversin axis determines the ciliary translocation of Smoothened. We find that Patched1 interacts with and stabilizes the PKA negative regulator ArhGAP36 to the centrosome. Activating the Shh pathway results in the removal of ArhGAP36 from the mother centriole and the centrosomal PKA accumulation. This PKA then phosphorylates Inversin and promotes its interaction with and the ciliary translocation of Smoothened. Knockdown of Inversin disrupts the ciliary translocation of Smoothened and Shh pathway activation. These findings reveal a regulatory molecular mechanism for the initial step of Shh pathway activation.

The Plk1 kinase negatively regulates the Hedgehog signaling pathway by phosphorylating Gli1.

Hedgehog (Hh) signaling is a highly conserved cell signaling pathway important for cell life, development and tumorigenesis. Increasing evidence suggests that the Hh signaling pathway functions in certain phases of the cell cycle. However, the coordination between Hh signaling and cell cycle control remains poorly understood. Here, we show that polo-like kinase-1 (Plk1), a critical protein kinase regulating many processes during the cell cycle, also regulates Hh signaling by phosphorylating and inhibiting Gli1, a downstream transcription factor of the Hh signaling pathway. Gli1 expression increases along with Hh signaling activation, leading to upregulation of Hh target genes, including cyclin E, during the G1 and S phases. Gli1 is phosphorylated at S481 by Plk1, and this phosphorylation facilitates the nuclear export and binding of Gli1 with its negative regulator Sufu, leading to a reduction in Hh signaling activity. Inhibition of Plk1 kinase activity led to Gli1 maintaining is role in promoting downstream gene expression. Collectively, our data reveal a novel mechanism regarding the crosstalk between Hh signaling and cell cycle control.

Automatic evaluation of vertex structural defects on the anode surface of a low-light-level image intensifier based on proposed individual image processing strategies.

In the process of microchannel plate (MCP) making and physicochemical treatment of a low-light-level (LLL) image intensifier, multifilament fixed pattern noise, also known as structural defects, is one of the most common defects in the anode surface. The appearance of this defect will seriously affect the imaging quality of an image intensifier, so it should be found in time before delivery. The traditional evaluation method of this defect relies on subjective judgment, and the disadvantage is that the division of the dense defect area and the measurement of defect gray difference (GD) are not standardized. To address this problem, an automatic evaluation method of vertex structural defects of an LLL image intensifier based on proposed individual image processing strategies is presented, which provides a digital evaluation scheme for such defects. This method is composed of two parts: quasi-circular defect detection and defect GD calculation. The first part is composed of coarse detection and fine detection. Coarse detection is to scan the anode surface and take the two ends of a pair of adjacent line segments with a large gradient sum and opposite gray change direction as the defect boundaries; fine detection is to establish the image patch from defect boundaries, extract the edge segment from the image patch, and judge whether it conforms to the shape of a circle. In order to substantiate the performance of the quasi-circular defect detection strategy, two relevant techniques are used as comparison. One is based on a Gaussian filter, and the other is based on a fixed-size window template. The comparison results show that our method, to the best of our knowledge, has the best detection performance for vertex structural defects. The second part consists of region of interest (ROI) cropping, secondary defect detection, shortest distance sequence establishment, effective distance extraction, triplet set construction, and triplet GD calculation. First, the location histogram of defects is established to cut ROI; then, the secondary defect detection is performed to extract more vertex structural defects from ROI; after that, the shortest distance sequence of defects is constructed, and the effective distances are extracted by using the structural features of multifilament. Finally, the triplet set is generated according to the effective distance, and the triplet GD is calculated based on the gray information near the triplet baseline. The GD of vertex structural defects corresponds to the maximum GD of triplets. So as to verify the effectiveness of vertex defect GD calculation strategy, several image tubes with different degrees of such defects are used for experiments, and the subjective evaluation method is used as comparison. The experimental results substantiate that this method is superior to the subjective method in locating ROI accurately and calculating defect GD quantitatively. In general, the automatic evaluation method can be regarded as an effective evaluation scheme for vertex structural defects of an LLL image intensifier.

Postmitotic annulate lamellae assembly contributes to nuclear envelope reconstitution in daughter cells.

In higher eukaryotic cells, the nuclear envelope (NE) is composed of double nuclear membranes studded with nuclear pore complexes (NPCs) and undergoes dynamic disassembly and reassembly during the cell cycle. However, how the NE and NPC reassemble remains largely unclear. Here, using HeLa, HEK293, and Drosophila cells, along with immunofluorescence microscopy and transmission EM methods, we found that postmitotic annulate lamellae (AL) assembly contributes to NE and NPC assembly. We observed that the AL are parallel membrane-pair stacks and possess regularly spaced AL pore complexes (ALPCs) that are morphologically similar to the NPCs. We found that the AL assemble in the cytoplasm during mitotic exit simultaneously with NE re-formation in daughter cells. Then, the assembled AL either bound the decondensing chromatin to directly transform into the NE or bound and fused with the outer nuclear membrane to join the assembling NE. The AL did not colocalize with sheet and tubular endoplasmic reticulum (ER) marker proteins on the ER or the lamin B receptor-localized membrane in the cytoplasm, suggesting that postmitotic AL assembly occurs independently of the chromatin and ER. Collectively, our results indicate that postmitotic AL assembly is a common cellular event and an intermediate step in NE and NPC assembly and in NE expansion in higher eukaryotic cells.

Effect of Comorbidity on Outcomes of Patients with Advanced Non-Small Cell Lung Cancer Undergoing Anti-PD1 Immunotherapy.

BACKGROUND Comorbidities are reportedly related to the survival of patients with non-small cell lung cancer (NSCLC). The purpose of this study was to explore the impact of comorbidity, assessed by the Charlson comorbidity index (CCI) and the simplified comorbidity scores (SCS) on clinical outcomes of patients with NSCLC treated with immune checkpoint inhibitors. MATERIAL AND METHODS Sixty-six patients with NSCLC who received programmed cell death protein 1 (PD1) inhibitors in our institution in the past 2 years were enrolled in this retrospective study. Data on comorbidity (CCI and SCS) and clinical outcomes, including progression-free survival (PFS), immunotherapy responses, and immunotherapy-related adverse events, were analyzed. RESULTS The disease control rate was obviously higher among patients in the CCI <1 group than the CCI ≥1 group (P<0.001), but were similar between the SCS <8 group and SCS ≥8 group (P=0.585). The median PFS in the CCI <1 group was 271.0 days (95% CI: 214.3-327.7 days) compared with 232.0 days (95% CI: 66.2-397.8 days) for the CCI ≥1 group (P=0.0084). However, the median PFS showed no difference between the groups with SCS <8 at 271.0 days (95% CI: 138.7-403.3 days) versus SCS ≥8 at 222.0 days (95% CI: 196.2-247.8 days), P=0.2106). The incidence of adverse events was similar among patients with high versus low comorbidity indexes (CCI: 35.8% versus 23.6%, P=0.286, respectively; and SCS: 28.0% versus 29.3%, respectively, P=0.912). CONCLUSIONS The comorbidity burden might be a predictor for survival in patients with NSCLC undergoing PD1 inhibitor immunotherapy.

[Mechanisms for inhibitory effect of ALDH2 on doxorubicin-induced cytotoxicity in C2C12 myogenic cell line].

OBJECTIVE: To investigate the mechanisms for inhibitory effect of aldehyde dehydrogenase 2 (ALDH2) on doxorubicin (DOX)-induced cytotoxicity in C2C12 myogenic cell line.
 METHODS: Cell apoptosis was evaluated by flow cytometry and the activity of capase-3/7. The relative content of reactive oxygen species (ROS) and 4-hydroxynonenal (4-HNE) were detected by chemical fluorometric enzyme immunoassay. The protein and mRNA expression of ALDH2, Bcl-2, NADPH oxidase 2 (NOX2) and the cytoplasmic subunit p-p47PHOX were evaluated by Western blot and quantitative PCR, respectively. 
 RESULTS: Overexpression of ALDH2 attenuated DOX-induced cell toxicity (increase in apoptosis and inhibition of proliferation), which were reversed by downregulation of ALDH2. Overexpression of ALDH2 reduced p47PHOX phosphorylation levels, and suppressed activation of NOX2 and ROS production, which were reversed by downregulation of ALDH2. Moreover, apocynin, an inhibitor of NOX, reduced the cytotoxicity of DOX concomitantly with a decrease in phosphorylation of p47PHOX, ROS production and caspase-3/7 activity, and an increase in the activity and expression of ALDH2. 
 CONCLUSION: DOX-induced cytotoxicity is related to increase of intracellular oxidative stress, which is involved in unregulation of NOX2 and downregulation of ALDH2. Activation of ALDH2 could exert cytoprotection via inhibiting NOX2-dependent ROS production.

Mitotic ER-mitochondria contact enhances mitochondrial Ca2+ influx to promote cell division.

Cell division is tightly regulated and requires an expanded energy supply. However, how this energy is generated remains unclear. Here, we establish a correlation between two mitochondrial Ca2+ influx events and ATP production during mitosis. While both events promote ATP production during mitosis, the second event, the Ca2+ influx surge, is substantial. To facilitate this Ca2+ influx surge, the lamin B receptor (LBR) organizes a mitosis-specific endoplasmic reticulum (ER)-mitochondrial contact site (ERMCS), creating a rapid Ca2+ transport pathway. LBR acts as a tether, connecting the ER Ca2+ release channel IP3R with the mitochondrial VDAC2. Depletion of LBR disrupts the Ca2+ influx surge, reduces ATP production, and postpones the metaphase-anaphase transition and subsequent cell division. These findings provide insight into the mechanisms underlying mitotic energy production and supply required for cell proliferation.

Vascular endothelial growth factor levels in diabetic peripheral neuropathy: a systematic review and meta-analysis.

Objective: Vascular endothelial growth factors (VEGFs, including VEGF-A, VEGF-B, VEGF-C, VEGF-D and PLGF) have important roles in the development and function of the peripheral nervous system. Studies have confirmed that VEGFs, especially VEGF-A (so called VEGF) may be associated with the diabetic peripheral neuropathy (DPN) process. However, different studies have shown inconsistent levels of VEGFs in DPN patients. Therefore, we conducted this meta-analysis to evaluate the relationship between cycling levels of VEGFs and DPN. Methods: This study searched 7 databases, including PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), VIP Database, WanFang Database, and Chinese Biomedical Literature (CBM), to find the target researches. The random effects model was used to calculate the overall effect. Results: 14 studies with 1983 participants were included, among which 13 studies were about VEGF and 1 was VEGF-B, so only the effects of VEGF were pooled. The result showed that there were obviously increased VEGF levels in DPN patients compared with diabetic patients without DPN (SMD:2.12[1.34, 2.90], p<0.00001) and healthy people (SMD:3.50[2.24, 4.75], p<0.00001). In addition, increased circulating VEGF levels were not associated with an increased risk of DPN (OR:1.02[0.99, 1.05], p<0.00001). Conclusion: Compared with healthy people and diabetic patients without DPN, VEGF content in the peripheral blood of DPN patients is increased, but current evidence does not support the correlation between VEGF levels and the risk of DPN. This suggests that VEGF may play a role in the pathogenesis and repairment of DPN.

Corrigendum: Vascular endothelial growth factor levels in diabetic peripheral neuropathy: a systematic review and meta-analysis.

[This corrects the article DOI: 10.3389/fendo.2023.1169405.].

Immune infiltration and drug specificity analysis of different subtypes based on functional status in angioimmunoblastic T-cell lymphoma.

Angioimmunoblastic T-cell lymphoma (AITL) is a subtype of peripheral T-cell lymphoma (PTCL) strongly correlated with worse clinical outcomes. However, the role of characteristic pathway-related genes in patients with AITL (e.g., subtype typing and pathogenesis) remains unknown. In this study, we intended to understand the potential role and prognostic value of characteristic pathways in AITL and identified a model for subtype identification based on pathway-related functional status. Transcriptomic (RNA-seq) data were obtained from the Gene Expression Omnibus database for three sets of tumor tissues from AITL patients. AITL was divided into three clusters based on the pathway profile of patients and the best clustering k = 3, and differentially expressed genes (DEGs) in the three clusters were analyzed. The top 45 important variables associated with characteristic pathways, such as Huntington's disease, VEGF signaling pathway, nucleotide excision repair, ubiquitin-mediated proteolysis, purine metabolism, olfactory transduction, etc., were used to construct a subtype identification model. The model was experimentally validated and proved to possess good predictive efficacy. In addition, pathway-related subtype typing was significantly associated with different immune cell infiltration in AITL. Further analysis revealed that the drug IC50 values predicted also differed markedly among the different subtypes, thus further identifying some subtype-specific drugs. Our study indicates a potential role of characteristic pathways in AITL staging for the first time, provides novel insights for future research targeting AITL, and points to potential therapeutic options for patients with different subtypes of AITL.

Identification and validation of 5-methylcytosine-associated genes in diffuse large B-cell lymphoma.

5-methylcytosine modifications play a significant role in carcinogenesis; however, studies exploring 5-methylcytosine-related genes in diffuse large B-cell lymphoma patients are lacking. In this study, we aimed to understand the potential role and clinical prognostic impact of 5-methylcytosine regulators in diffuse large B-cell lymphoma and identify a prognostic biomarker based on 5-methylcytosine-associated genes. Gene expression profiles and corresponding clinical information of diffuse large B-cell lymphoma patients and normal controls were obtained from The Cancer Genome Atlas, Gene Expression Omnibus, and Genotype-Tissue Expression databases. Diffuse large B-cell lymphoma was divided into three clusters according to the 5-methylcytosine regulators, and differentially expressed genes were screened among the three clusters. Univariate Cox and Lasso-Cox regression analyses were used to screen prognostic genes and construct a prognostic risk model. Kaplan-Meier curve analysis, univariate and multivariate Cox regression analyses, and time-dependent receiver operator characteristic curve analysis were used to evaluate prognostic factors. GSVA was used to enrich potential pathways associated with 5-methylcytosine modification patterns. SsGSEA and CIBERSORT were used to assess immune cell infiltration. Six 5-methylcytosine-related genes (TUBB4A, CD3E, ZNF681, HAP1, IL22RA2, and POSTN) were used to construct a prognostic risk model, which was proved to have a good predictive effect. In addition, univariate and multivariate Cox regression risk scores were independent prognostic factors for diffuse large B-cell lymphoma. Further analysis showed that the 5-methylcytosine risk score was significantly correlated with immune cell infiltration and immune checkpoint of diffuse large B-cell lymphoma. Our study reveals for the first time a potential role for 5-methylcytosine modifications in diffuse large B-cell lymphoma, provides novel insights for future studies on diffuse large B-cell lymphoma, and offers potential prognostic biomarkers and therapeutic targets for patients with diffuse large B-cell lymphoma.

Targeting EZH2 prevents the occurrence and mitigates the development of Sjögren's syndrome in mice.

OBJECTIVE: We analyzed RNA-SEQ data and found that EZH2 gene expression in salivary glands (SGs) of Sjögren's syndrome (SS) patients was up-regulated and correlated with pathological injury. In this study, we sought to determine if inhibiting EZH2 would ameliorate SS-like disease in NOD/Ltj (NOD) mice. METHODS: We analyzed RNA-SEQ data of SGs of patients with SS from data obtained from the GEO database to explore the correlation between EZH2 gene expression and the progression of SS. Inhibition of EZH2 in the NOD mice was achieved by intraperitoneal administration of GSK343 using both a preventative and a therapeutic model. The effects of GSK343 on SGs secretion and pathological damage, as well as the levels and functions of T cells, B cells, Myeloid-derived suppressor cells (MDSCs), and other immune cells were evaluated. RESULTS: The expression levels of the gene encoding EZH2 in the SGs of SS patients were significantly higher than the non-SS sicca patients, and the expression levels were positively correlated with the severity of the SGs pathological damage. GSK343 treatment significantly increased the salivary flow rate and pathological damage of the SGs in the NOD mice compared to the control mice. In addition, GSK343 significantly inhibited the number and pro-inflammatory-factor secretion of CD4+ and CD8+ T cells and inhibited the increase in the Th1/Th2 cell ratio caused by SS. RNA-SEQ data also showed that EZH2 inhibited several inflammatory pathways during the pathogenesis of SS. CONCLUSIONS: EZH2 expression was up-regulated in the submandibular gland tissue of SS patients.Inhibition of EZH2 alleviated SS-like disease in NOD mice, suggesting that EZH2 might be a potential target for the clinical treatment of SS.

Proteomic profiling of plasma exosomes from patients with B-cell acute lymphoblastic leukemia.

We aimed to comprehensively investigate the proteomic profile and underlying biological function of exosomal proteins associated with B-cell acute lymphoblastic leukemia. Exosomes were isolated from plasma samples collected from five patients with B-ALL and five healthy individuals, and their protein content was quantitatively analyzed by liquid chromatography with tandem mass spectrometry. A total of 342 differentially expressed proteins were identified in patients with B-ALL. The DEPs were mainly associated with protein metabolic processes and protein activity regulation and were significantly enriched in the Notch and autophagy pathways. Furthermore, we found that ADAM17 and ATG3 were upregulated in patients with B-ALL and enriched in the Notch and autophagy pathways, respectively. Further western blot analysis of exosomes collected from additional 18 patients with B-ALL and 10 healthy controls confirmed that both ADAM17 and ATG3 were overexpressed in exosomes derived from patients with B-ALL (p < 0.001). The areas under the curves of ADAM17 and ATG3 were 0.989 and 0.956, respectively, demonstrating their diagnostic potential. In conclusion, ADAM17 and ATG3 in plasma-derived exosomes may contribute to the progression of B-ALL by regulating the Notch and autophagy pathways. Hence, these proteins may represent valuable diagnostic biomarkers and therapeutic targets for B-ALL.

Icaritin induces cellular senescence by accumulating the ROS production and regulation of the Jak2/Stat3/p21 pathway in imatinib-resistant, chronic myeloid leukemia cells.

In patients with chronic myelogenous leukemia (CML), resistance to tyrosine kinase inhibitor (TKI) therapy, like imatinib, can cause death, progression to accelerated phase or blast crises, and the need for maintenance treatment. Icaritin is an active component of the genus Epimedium, a traditional Chinese herbal medicine. Icaritin has been shown to notably inhibit the growth of CML cells. To explore the potential mechanisms of inhibiting growth and inducing cell senescence in imatinib-resistant CML cells by icaritin, MTT assays were used to assess the cell viability. The apoptosis and cell cycle arrest were evaluated using flow cytometry. The SA-ß-Gal staining and the intracellular reactive oxygen species (ROS) production were measured using flow cytometry to detect the senescent cells. qRT-PCR was conducted to assess the expression of the cell cycle-associated proteins, and western blotting was used to analyze the expressions of the JAK2 and STAT3 phosphorylation proteins. The results showed that icaritin inhibited cell growth and induced cell senescence in imatinib-resistant CML cells, which is associated with the regulation of the JAK2/STAT3/P21 axis and accompanied by the accumulation of ROS. Our data suggest that icaritin is a promising therapeutic strategy for the treatment of imatinib-resistant patients with CML.

B-cell acute lymphoblastic leukemia-related microRNAs: uncovering their diverse and special roles.

B-cell acute lymphoblastic leukemia (B-ALL) is a common type of hematologic malignancy characterized by the uncontrolled growth of immature B lymphocytes. Genomics, transcriptomics, and proteomics at different levels contribute to early diagnosis and can thereby provide better treatment for cancer. MicroRNAs (miRNAs) are conducive to the diagnosis and treatment of patients with B-ALL. Moreover, evidence suggests that runaway miRNAs and exosomes containing miRNA may be involved in the occurrence of B-ALL, which can then be used as potential biomarkers. This review summarizes the role of miRNAs in the pathogenesis, diagnosis, prognosis, and treatment of B-ALL.

Pneumonitis Induced by Immune Checkpoint Inhibitors: From Clinical Data to Translational Investigation.

Immune checkpoint inhibitors (ICIs) have been applied to clinical practice and achieved significant therapeutic benefit in a variety of human malignancies. These drugs not only enhance the body's antitumor immune response but also produce side effects called immune-related adverse events (irAEs). Although checkpoint inhibitor pneumonitis (CIP) has a low clinical incidence, it is likely to cause the delay or termination of immunotherapy and treatment-related death in some severe cases. An increasing number of CIP cases have been reported since 2015, which are attributed to the augmentation of approvals and uses of ICIs, but a comprehensive understanding of CIP is still lacking. This review focuses on the epidemiology, clinical characteristics, treatment strategies, and underlying mechanisms of CIP to strengthen the recognition of pulmonary toxicity among clinicians and researchers.

A small molecular compound CC1007 induces cross-lineage differentiation by inhibiting HDAC7 expression and HDAC7/MEF2C interaction in BCR-ABL1- pre-B-ALL.

Histone deacetylase 7 (HDAC7), a member of class IIa HDACs, has been described to be an important regulator for B cell development and has a potential role in B cell acute lymphoblastic leukemia (B-ALL). CC1007, a BML-210 analog, is designed to indirectly inhibit class IIa HDACs by binding to myocyte enhancer factor-2 (MEF2) and blocking the recruitment of class IIa HDACs to MEF2-targeted genes to enhance the expression of these targets. In this study, we investigated the anticancer effects of CC1007 in breakpoint cluster region-Abelson 1 fusion gene-negative (BCR-ABL1-) pre-B-ALL cell lines and primary patient-derived BCR-ABL1- pre-B-ALL cells. CC1007 had obvious antileukemic activity toward pre-B-ALL cells in vitro and in vivo; it also significantly prolonged median survival time of pre-B-ALL-bearing mice. Interestingly, low dose of CC1007 could inhibit proliferation of BCR-ABL1- pre-B-ALL cells in a time-dependent manner not accompanied by significant cell apoptosis, but along with cross-lineage differentiation toward monocytic lineage. From a mechanistic angle, we showed that HDAC7 was overexpressed in BCR-ABL1- pre-B-ALL cells compared to normal bone marrow samples, and CC1007 could reduce the binding of HDAC7 at the promoters of monocyte-macrophage-specific genes via inhibition of HDAC7 expression and HDAC7:MEF2C interaction. These data indicated that CC1007 may be a promising agent for the treatment of BCR-ABL1- pre-B-ALL.

Clinical Value of Ultrasound-Guided Minimally Invasive Biopsy in the Diagnosis or Treatment of Breast Nodules.

PURPOSE: To explore the clinical value of ultrasound-guided minimally invasive biopsy of breast nodules for diagnosis and treatment of patients with no positive clinical signs on manual breast examination. METHODS: We performed a retrospective review of 136 patients with no signs on breast palpation who underwent ultrasound-guided minimally invasive biopsy. A total of 63 patients underwent breast nodule resection from October 2018 to December 2019 at the General Hospital of Central Theater Command of the People's Liberation Army. Clinical data, including indications for minimally invasive biopsy or resection, pathological and surgical results were retrospectively analyzed. RESULTS: A total of 199 patients were studied; 136 underwent minimally invasive biopsy and 63 underwent resection. No severe surgical complications occurred. Minimally invasive biopsy of breast nodules was superior to resection with respect to operation time, incision length, and postoperative complication rate. CONCLUSION: Ultrasound-guided minimally invasive biopsy of breast nodules is feasible for treatment of patients with negative breast nodules and can achieve accurate diagnosis and satisfactory resection.