Marine Cytotoxin Santacruzamate A Derivatives as Potent HDAC1-3 Inhibitors and Their Synergistic Anti-Leukemia Effects with Venetoclax.

Acute myeloid leukemia (AML) is a hematologic malignancy characterized by infiltration of the blood and bone marrow, exhibiting a low remission rate and high recurrence rate. Current research has demonstrated that class I HDAC inhibitors can downregulate anti-apoptotic proteins, leading to apoptosis of AML cells. In the present investigation, we conducted structural modifications of marine cytotoxin Santacruzamate A (SCA), a compound known for its inhibitory activity towards HDACs, resulting in the development of a novel series of potent class I HDACs hydrazide inhibitors. Representative hydrazide-based compound 25c exhibited concentration-dependent induction of apoptosis in AML cells as a single agent. Moreover, 25c exhibited a synergistic anti-AML effect when combined with Venetoclax, a clinical Bcl-2 inhibitor employed in AML therapy. This combination resulted in a more pronounced downregulation of anti-apoptotic proteins Mcl-1 and Bcl-xL, along with a significant upregulation of the pro-apoptotic protein cleaved-caspase3 and the DNA double-strand break biomarker γ-H2AX compared to monotherapy. These results highlighted the potential of 25c as a promising lead compound for AML treatment, particularly when used in combination with Venetoclax.

Analysis of the risk factors for intraoperative acute diffuse brain swelling in patients with isolated traumatic acute subdural haematomas.

BACKGROUND: The purpose of this retrospective study was to investigate the risk factors for intraoperative acute diffuse brain swelling in patients with isolated traumatic acute subdural haematomas (ASDH). METHODS: A total of 256 patients who underwent decompressive craniectomy for isolated traumatic ASDH between April 2013 and December 2020 were included. We evaluated the risk factors for intraoperative acute diffuse brain swelling using a multivariate logistic regression analysis. RESULTS: The incidence of intraoperative acute diffuse brain swelling in patients with isolated traumatic ASDH was 21.88% (56/256). Dilated pupils (OR = 24.78), subarachnoid haemorrhage (OR = 2.41), and the time from injury to surgery (OR = 0.32) were independent risk factors for intraoperative acute diffuse brain swelling, while no independent associations were observed between these risk factors and sex, age, the mechanism of injury, the Glasgow Coma Scale score, site of haematoma, thickness of haematoma, midline shift and the status of the basal cistern, although the mechanism of injury, the Glasgow Coma Scale score and the status of the basal cistern were correlated with the incidence of intraoperative acute diffuse brain swelling in the univariate analyses. CONCLUSIONS: This study identified the risk factors for intraoperative acute diffuse brain swelling in patients with isolated traumatic ASDH. An increased risk of intraoperative acute diffuse brain swelling occurs in patients with bilaterally dilated pupils, subarachnoid haemorrhage and a shorter time from injury to surgery. These findings should help neurosurgeons obtain information before surgery about intraoperative acute diffuse brain swelling in patients with isolated traumatic ASDH.

A systematic review of radiomics in osteosarcoma: utilizing radiomics quality score as a tool promoting clinical translation.

OBJECTIVES: To assess the methodological quality and risk of bias in radiomics studies investigating diagnosis, therapy response, and survival of patients with osteosarcoma. METHODS: In this systematic review, literatures on radiomics in osteosarcoma were included and assessed for methodological quality through the radiomics quality score (RQS). The risk of bias and concern of application was assessed using the Quality Assessment of Diagnostic Accuracy Studies tool. A meta-analysis of studies focusing on predicting osteosarcoma response to neoadjuvant chemotherapy was performed. RESULTS: Twelve radiomics studies exploring osteosarcoma were identified, and five were included in meta-analysis. The RQS reached an average of 20.4% (6.92 of 36) with good inter-rater agreement (ICC 0.95, 95% CI 0.85-0.99). Four studies validated results with an internal dataset, none of which used external dataset; one study was prospectively designed, and another one shared part of the dataset. The risk of bias and concern of application were mainly related to index test aspect. The meta-analysis showed a diagnostic odds ratio of 43.68 (95%CI 13.5-141.31) for predicting response to neoadjuvant chemotherapy with high heterogeneity and low methodological quality. CONCLUSIONS: The overall scientific quality of included studies is insufficient; however, radiomics remains a promising technology for predicting treatment response, which might guide therapeutic decision-making and related to prognosis. Improvements in study design, validation, and open science needs to be made to demonstrate the generalizability of findings and to achieve clinical applications. Widespread application of RQS, pre-trained RQS scoring procedure, and modification of RQS in response to clinical needs are necessary. KEY POINTS: • Limited radiomics studies were established in osteosarcoma with mean RQS of 20.4%, commonly due to unvalidated results, retrospective study design, and absence of open science. • Meta-analysis of radiomics studies predicting osteosarcoma response to neoadjuvant chemotherapy showed high diagnostic odds ratio 43.68, while high heterogeneity and low methodological quality were the main concerns. • A previously trained data extraction instrument allowed reaching moderate inter-rater agreement in RQS applications, while RQS still needs improvement to become a wide adaptive tool in reviews of radiomics studies, in routine self-check before manuscript submitting and in study design.

Design, synthesis and biological evaluation of hybrid of ubenimex-fluorouracil for hepatocellular carcinoma therapy.

In our previous study, we discovered a ubenimex-fluorouracil (5FU) conjugates BC-02, which displays significant in vivo anti-tumor activity, however, the instability of BC-02 in plasma limits its further development as a drug candidate. Herein, we designed and synthesized four novel ubenimex-5FU conjugates by optimizing the linkers between ubenimex and 5FU based on BC-02. Representative compound 20 is more stable than BC-02 in human plasma and displays about 100 times higher CD13 inhibitory activity than the positive control ubenimex. Meanwhile, the antiproliferative activity of 20 was comparable with 5FU in vitro. The preliminary mechanism study indicated that compound 20 exhibited significant anti-invasion and anti-angiogenesis activities in vitro. Furthermore, compound 20 obviously inhibits tumor growth and metastasis in vivo and prolong the survival time of tumor-bearing mice. Our study may have an important implication reference for the design of more druglike mutual prodrug, and compound 20 can be used as a lead compound for further design and development.

Management of subdural effusion and hydrocephalus following decompressive craniectomy for posttraumatic cerebral infarction in a patient with traumatic brain injury: a case report.

BACKGROUND: Subdural effusion with hydrocephalus (SDEH) is a rare complication of traumatic brain injury, especially following decompressive craniectomy (DC) for posttraumatic cerebral infarction. The diagnosis and treatment are still difficult and controversial for neurosurgeons. CASE PRESENTATION: A 45-year-old man developed traumatic cerebral infarction after traumatic brain injury and underwent DC because of the mass effect of cerebral infarction. Unfortunately, the complications of traumatic subdural effusion (SDE) and hydrocephalus occurred in succession following DC. Burr-hole drainage and subdural peritoneal shunt were performed in sequence because of the mass effect of SDE, which only temporarily improved the symptoms of the patient. Cranioplasty and ventriculoperitoneal shunt were performed ultimately, after which SDE disappeared completely. However, the patient remains severely disabled, with a Glasgow Outcome Scale of 3. CONCLUSIONS: It is important for neurosurgeons to consider the presence of accompanying hydrocephalus when treating patients with SDE. Once the diagnosis of SDEH is established and the SDE has no mass effect, timely ventriculoperitoneal shunt may be needed to avoid multiple surgical procedures, which is a safe and effective surgical method to treat SDEH.

[Molecular mechanism of Bupleuri Radix and Scutellariae Radix drug pair for depression based on integrative pharmacology platform of traditional Chinese medicine].

Xiaochaihu decoction is a classic prescription of traditional Chinese medicine. Modern research has proved its anti-depression effect. However, its pharmacological mechanism for anti-depression effect is difficult to be unveiled because of the complexity of compound Chinese medicines. Bupleuri Radix and Scutellariae Radix is the core drug pair of Xiaochaihu decoction. In this research, Bupleuri Radix and Scutellariae Radix were analyzed by the integrative pharmacology platform to study its molecular mechanism for anti-depression. One hundred and sixteen active ingredients were predicted, 62 for Bupleuri Radix, mainly including saikosaponins, acids, alcohols, and 54 for Scutellariae Radix, mainly including flavonoids and glycosides. Its anti-depression effect was relevant to 118 core targets, including 22 known disease targets, such as serotonin receptor(HTR2C), activating transcription factor(ATF1, ATF2), δ opioid receptor(OPRD1), µ opioid receptor (OPRM1), κ opioid receptor(OPRK1), inositol monophosphatase(IMPA1), Toll-like receptor 4 (TLR4), histamine H1 receptor(HRH1), neurotrophic factor tyrosine kinase receptor1 (NTRK1), Glycogen synthetase kinase 3ß(GSK3ß), etc. The antidepressant effect involved positive regulation of transcription from RNA polymerase Ⅱ promoter, transcription factor binding, cytosol, transcriptional regulation of DNA template, enzyme binding, endocrine system, nervous system, neurotrophin signaling pathway, cell growth and death, signal transduction, thyroid hormone signaling pathway and other related biological processes and metabolic pathways. This study provides a scientific evidence for further study of the anti-depression mechanism of this drug pair.

A Molecular Signature of Two Long Non-Coding RNAs in Peripheral Blood Predicts Acute Renal Allograft Rejection.

BACKGROUND/AIMS: Acute rejection (AR) is a major complication post renal transplantation, with no widely-accepted non-invasive biomarker. This study aimed to explore the expression profiles of long non-coding RNAs (lncRNAs) in the peripheral blood (PB) of renal transplant recipients and their potential diagnostic values. METHODS: The genome-wide lncRNA expression profiles were analyzed in 150 PB samples from pediatric and adult renal transplant (PRTx and ARTx) cohorts. The diagnostic performance of differentially expressed lncRNA was determined using receiver operator characteristic curve, with area under the curve (AUC) and 95% confidential interval (CI). Finally, a risk score was constructed with logistical regression model. RESULTS: A total of 162 lncRNAs were found differentially expressed in PRTx cohort, while 163 in ARTx cohort. Among these identified lncRNAs, 23 deregulated accordingly in both cohorts, and could distinguish AR recipients from those without AR. Finally, a risk score with two most significant lncRNAs (AF264622 and AB209021) was generated and exhibited excellent diagnostic performance in both PRTx (AUC:0.829, 95% CI:0.735-0.922) and ARTx cohorts (AUC: 0.889, 95% CI: 0.817-0.960). CONCLUSION: A molecular signature of two lncRNAs in PB could serve as a novel non-invasive biomarker for the diagnosis of AR in both pediatric and adult renal transplant recipients.

[Expression of AXL enhances docetaxel-resistance of prostate cancer cells].

OBJECTIVE: To explore the effect of the AXL expression on the chemosensitivity of prostate cancer PC-3 and DU145 cells to docetaxel and possible mechanisms. METHODS: Using Western blot, we examined the expressions of the AXL protein, p-AXL and Gas6 in the docetaxel-resistant PC-3 (PC-3-DR) and DU145 (DU145-DR) cells stimulated with gradually increased concentrations of docetaxel. We transfected the PC-3 and DU145 cells with negative NC ShRNA and AXL-ShRNA, respectively, which were confirmed to be effective, detected the proliferation, apoptosis and cycle distribution of the cells by CCK8, MTT and flow cytometry after treated with the AXL-inhibitor MP470 and/or docetaxel, and determined the expression of the ABCB1 protein in the PC-3-DR and DU145-DR cells after intervention with the AXL-inhibitor R428 and/or docetaxel. RESULTS: The expression of the AXL protein in the PC-3 and DU145 cells was significantly increased after docetaxel treatment (P <0.05). The expressions AXL and p-AXL were remarkably higher (P <0.05) while that of Gas6 markedly lower (P <0.05) in the PC-3 and DU145 than in the PC-3-DR and DU145-DR cells. The inhibitory effect of docetaxel on the proliferation and its enhancing effect on the apoptosis of the PC-3 and DU145 cells were significantly decreased at 48 hours after AXL transfection (P <0.05). MP470 obviously suppressed the growth and promoted the apoptosis of the PC-3-DR and DU145-DR cells, with a higher percentage of the cells in the G2/M phase when combined with docetaxel than used alone (P <0.05). R428 markedly reduced the expression of ABCB1 in the PC-3-DR and DU145-DR cells, even more significantly in combination with docetaxel than used alone (P <0.05). CONCLUSIONS: The elevated expression of AXL enhances the docetaxel-resistance of PC-3 and DU145 prostate cancer cells and AXL intervention improves their chemosensitivity to docetaxel, which may be associated with the increased cell apoptosis in the G2/M phase and decreased expression of ABCB1.

MicroRNA expression profiles in muscle-invasive bladder cancer: identification of a four-microRNA signature associated with patient survival.

Bladder cancer ranks the second most common genitourinary tract cancer, and muscle-invasive bladder cancer (MIBC) accounts for approximately 25 % of all bladder cancer cases with high mortality. In the current study, with a total of 202 treatment-naïve primary MIBC patients identified from The Cancer Genome Atlas dataset, we comprehensively analyzed the genome-wide microRNA (miRNA) expression profiles in MIBC, with the aim to investigate the relationship of miRNA expression with the progression and prognosis of MIBC, and generate a miRNA signature of prognostic capabilities. In the progression-related miRNA profiles, a total of 47, 16, 3, and 84 miRNAs were selected for pathologic T, N, M, and histologic grade, respectively. Of the eight most important progression-related miRNAs, four (let-7c, mir-125b-1, mir-193a, and mir-99a) were significantly associated with survival of patients with MIBC. Finally, a four-miRNA signature was generated and proven as a promising prognostic parameter. In summary, this study identified the specific miRNAs associated with the progression and aggressiveness of MIBC and a four-miRNA signature as a promising prognostic parameter of MIBC.

Monomeric C-reactive protein is associated with severity and prognosis of decompensated hepatitis B cirrhosis.

C-reactive protein (CRP) is an acute-phase protein produced by the liver in response to infection and during chronic inflammatory disorders. Systemic inflammation is a major driver of cirrhosis progression from the compensated to the decompensated stage. Previous studies have shown that pentameric CRP (pCRP) to be a weak predictor of disease severity and prognosis in patients with decompensated hepatitis B cirrhosis, with it being only helpful for identifying patients with a higher short-term risk of death under certain conditions. Accumulating evidence indicates that pCRP dissociates to and acts primarily as the monomeric conformation (mCRP) at inflammatory loci, suggesting that mCRP may be a potentially superior disease marker with higher specificity and relevance to pathogenesis. However, it is unknown whether mCRP and anti-mCRP autoantibodies are associated with disease severity, or progression in decompensated hepatitis B cirrhosis. In this study, we evaluated the serum levels of mCRP and anti-mCRP autoantibodies in patients with decompensated cirrhosis of hepatitis B and their association with disease severity and theoretical prognosis. The results showed that patients with high mCRP and anti-mCRP autoantibody levels had more severe liver damage and that coagulation function was worse in patients with high anti-mCRP autoantibodies. Analysis of the correlation between pCRP, mCRP and anti-mCRP autoantibody levels with Model for End-Stage Liver Disease (MELD), Albumin-Bilirubin (ALBI), and Child-Turcotte-Pugh (CTP) prognostic scores showed that mCRP was the most strongly correlated with MELD score, followed by anti-mCRP autoantibodies; conversely, pCRP was not significantly correlated with prognostic score. Therefore, mCRP and anti-mCRP autoantibodies may be more advantageous clinical indicators than pCRP for evaluating the pathological state of decompensated hepatitis B cirrhosis.

A new genetic diagnosis strategy for paroxysmal kinesigenic dyskinesia: Targeted high-throughput detection of PRRT2 gene c.649 locus.

BACKGROUND: Paroxysmal kinesigenic dyskinesia (PKD) is the most prevalent kind type of paroxysmal Dyskinesia, characterized by recurrent and transient episodes of involuntary movements. Most PKD cases were attributed to the proline-rich transmembrane protein 2 (PRRT2) gene, in which the c.649 region is a hotspot for known mutations. Even though some patients with PKD have been genetically diagnosed using whole-exome sequencing (WES) and Sanger sequencing, there are still cases of missed diagnoses due to the limitations of sequencing technology and analytic methods on throughput. METHODS: Patients meeting the diagnosis criteria of PKD with negative results of PRRT2-Sanger sequencing and WES were included in this study. Mutation screening and targeted high-throughput sequencing were performed to analyze and verify the sequencing results of the potential mutations. RESULTS: Six patients with PKD with high mutation ratios of c.649dupC were screened using our targeted high-throughput sequencing from 26 PKD patients with negative results of PRRT2-Sanger sequencing and WES (frequency = 23.1%), which compensated for the comparatively shallow sequencing depth and statistical flaws in this region. Compared with the local normal population and other patients with PKD, the mutation ratios of c.649dupC of these six patients with PKD were much higher and also had truncated protein structures and differentially altered mRNA expression. CONCLUSION: Based on the above studies, we emphasize the routine targeted high-throughput sequencing of the c.649 site in the PRRT2 gene in so-called genetic-testing-negative patients with PKD, and manually calculate the deletion and duplication mutations depth and ratios to lower the rate of clinical misdiagnosis.

Induction of jasmonate signalling regulators MaMYC2s and their physical interactions with MaICE1 in methyl jasmonate-induced chilling tolerance in banana fruit.

MYC2, a basic helix-loop-helix (bHLH) transcription factor, is a key regulator in the activation of jasmonate (JA) response. However, the molecular details of MYC2 involving in methyl jasmonate (MeJA)-induced chilling tolerance of fruit remain largely unclear. In the present work, two MYC2 genes, MaMYC2a and MaMYC2b, and one homolog of the inducer of the C-repeat-binding factor (CBF) gene, MaICE1 were isolated and characterized from banana fruit. MaMYC2s and MaICE1 were found to be all localized in the nucleus. In addition, the proline-rich domain (PRD) and the acidic domain (AD) in the N-terminus were important for the transcriptional activation of MaMYC2 in yeast cells. Unlike MaICE1's constitutive expression, MaMYC2a and MaMYC2b were induced rapidly following MeJA treatment during cold storage. Moreover, protein-protein interaction analysis confirmed that MaMYC2s interacted with MaICE1. The expression of ICE-CBF cold-responsive pathway genes including MaCBF1, MaCBF2, MaCOR1, MaKIN2, MaRD2 and MaRD5 was also significantly induced by MeJA. Taken together, our work provides strong evidence that MaMYC2 is involved in MeJA-induced chilling tolerance in banana fruit through physically interacting and likely functionally coordinating with MaICE1, revealing a novel mechanism for ICE1 in response to cold stress as well as during development of induced chilling tolerance.

Comparison of the effects of stepwise intracranial decompression and decompressive craniectomy in the treatment of severe traumatic brain injury: A randomized controlled trial.

BACKGROUND: To compare the effects of stepwise intracranial decompression (SID) and decompressive craniectomy (DC) on severe traumatic brain injury. METHODS: This prospective randomized study was conducted at The Third Affiliated Hospital of Soochow University. Ninety two patients were divided into 2 groups according to the random number table method. The study group received SID, whereas the control group received DC. The surgical time and intraoperative bleeding of the 2 groups of patients were recorded, neurological function and glasgow coma score before and after treatment in both groups, incidence of complications, prognostic situation, and levels of brain oxygen metabolism indicators before and after treatment. RESULTS: Among the 92 patients who agreed, 46 were assigned to the study and control groups, and 6 patients were excluded. Finally, 86 patients were analyzed, including 43 in the study group and 43 in the control group. After treatment, the glasgow coma score scores of the 2 groups increased compared to before treatment; the study group had a higher score, The National Institutes of Health Stroke Scale score decreased compared to before treatment, and the study group had a lower score (P < .05). The incidence of complications in the study group (4.65%) was significantly lower than that in the control group (18.60%) (P < .05). The good prognosis rate of the research group (41.86%) was significantly higher than that of the control group (16.28%) (P < .05). CONCLUSION: Compared with DC, using SID to treat severe traumatic brain injury can shorten surgical time and reduce intraoperative bleeding, more effectively improve patients neurological function and consciousness state, reduce the incidence of complications, and regulate brain oxygen metabolism status, which is beneficial for improving prognosis and ensuring a good outcome of the disease.

Design, synthesis, and biological evaluation of novel HDAC/CD13 dual inhibitors for the treatment of cancer.

Aminopeptidase N (APN/CD13) plays a role in tumors progression, but its inhibitor lacks cytotoxicity and is used as an adjuvant drug in cancer treatment. Histone deacetylases (HDACs) are a type of epigenetic targets, and HDAC inhibitors are cytotoxic and exhibit synergistic effects with other anticancer agents. Herein, a novel series of HDAC/CD13 dual inhibitors were rationally designed and synthesized to combine the anti-metastasis and anti-invasion of CD13 inhibitor with the cytotoxic of HDAC inhibitor. The representative compound 12 exhibited more potent inhibitory activity against human CD13, HDAC1-3, and antiproliferative activity than positive controls bestatin and SAHA. Compound 12 effectively induced apoptosis in MV4-11 cells, while arresting A549 cells in G2/M phase. Moreover, 12 exhibited significantly better anti-metastasis and anti-invasion effects than mono-inhibitors 32 and 38, indicating that it is a promising anti-cancer agent for further investigation.

Safety and environmental impact control of cross passage construction in soft soil strata using tunnel boring machine method.

The construction of cross passages using the tunnel boring machine (TBM) method represents an emerging construction technique with numerous advantages. However, owing to the scarcity of application instances, the safety control methodologies and the regulatory patterns concerning environmental impacts remain inconclusive. In this study, a cross passage excavated using the TBM method-the first of its kind in the Tianjin area-was investigated. We identified the key risk control measures for the construction and analysed the TBM operating parameters, monitored ground and building settlements, and monitored mainline tunnel deformations and mechanical responses, revealing the ground and tunnel structure deformation patterns. The following conclusions are drawn. (1) The ground surrounding the cross-passage break-out opening was stabilised by performing secondary grouting and small-range freezing, and the break-in opening was excavated using a completely enclosed steel sleeve. These measures prevented water and sand inflows during the excavation of the break-out and break-in openings in the silt and silty sand strata. (2) The torsional moment of the cutter disc was large during the break-out phase. Break-out mainline tunnel displacement monitoring data indicated that the thrust had a significant effect on the mainline tunnel during the break-out phase. (3) The TBM tunnelling caused ground loss. The ground settlement exhibited a U-shaped distribution along the cross-passage axis, with the maximum settlement being 10 mm. (4) During the break-out phase, the deformation of the break-out mainline tunnel exhibited a duck-egg-shaped distribution. The clearance convergence of the break-out mainline tunnel was within ± 4, and the clearance convergence of the break-in mainline tunnel was controlled within ± 1 mm.

[Phenotypic differences of stroma cells in benign and malignant human prostate tissues].

OBJECTIVE: To analyze the stroma changes of benign and malignant human prostate tissues. METHODS: For the identification of stroma cells phenotype in human prostate cancer and benign prostate hyperplasia tissues, Masson method and immunohistochemical analysis of α-smooth muscle actin (α-SMA), desmin, and vimentin were performed. The relative volume of intratumor stroma (0%, Grade 0; 1% - 33%, Grade 1; 34% - 66%, Grade 2; 67% - 100%, Grade 3) were quantified and analyzed in local and advanced prostate cancer tissues. RESULTS: Stroma myofibroblasts in prostate cancer were stained green by Masson staining and showed a co-expression of α-SMA and vimentin without an expression of desmin. It was significantly different from smooth muscle cells in benign prostate hyperplasia stained red and co-expressing a-SMA and desmin. Statistical analysis showed that high stroma volume (Grade 2/3) in advanced prostate cancer were significantly higher than that in an early stage of prostate cancer (83% vs 55%, P < 0.05). CONCLUSION: Significant phenotypic differences of stroma cells existed in benign and malignant human prostate tissues. A high expression of myofibroblasts in advanced prostate cancer may play an important role in cancer progression. And its clinical significance should raise a high alert.

First-in-Class Hydrazide-Based HDAC6 Selective Inhibitor with Potent Oral Anti-Inflammatory Activity by Attenuating NLRP3 Inflammasome Activation.

In this study, we report the first highly selective HDAC6 inhibitor with hydrazide as the zinc-binding group (ZBG), which displays superior pharmacokinetic properties to the current hydroxamic acid inhibitors. Structure-activity relationship study reveals that ethyl group substituent hydrazide-based ZBG and cap group with more substantial rigidity and larger volume increase the HDAC6 selectivity of designed compounds. Representative inhibitor 35m exhibits potent HDAC6 inhibitory activity with an IC50 value of 0.019 µM. To our surprise, 35m establishes significant improvement in the pharmacokinetic property with much higher AUC0-inf (10292 ng·h/mL) and oral bioavailability (93.4%) than hydroximic acid-based HDAC6 inhibitors Tubastatin A and ACY-1215. Low-dose 35m remarkably decreases LPS-induced IL-1ß release both in vitro and in vivo by blocking the activation of NLRP3, indicating that 35m can be a potential orally active therapeutic agent for the treatment of NLRP3-related diseases.

Machine Learning for Structure Determination in Single-Particle Cryo-Electron Microscopy: A Systematic Review.

Recently, single-particle cryo-electron microscopy (cryo-EM) has become an indispensable method for determining macromolecular structures at high resolution to deeply explore the relevant molecular mechanism. Its recent breakthrough is mainly because of the rapid advances in hardware and image processing algorithms, especially machine learning. As an essential support of single-particle cryo-EM, machine learning has powered many aspects of structure determination and greatly promoted its development. In this article, we provide a systematic review of the applications of machine learning in this field. Our review begins with a brief introduction of single-particle cryo-EM, followed by the specific tasks and challenges of its image processing. Then, focusing on the workflow of structure determination, we describe relevant machine learning algorithms and applications at different steps, including particle picking, 2-D clustering, 3-D reconstruction, and other steps. As different tasks exhibit distinct characteristics, we introduce the evaluation metrics for each task and summarize their dynamics of technology development. Finally, we discuss the open issues and potential trends in this promising field.

The coexistence of recurrent pituitary adenoma and meningioma: case report.

The coexistence of pituitary adenoma and meningioma is very rare. Here, we present a case of recurrent non-functioning pituitary adenoma and temporal lobe meningioma in a patient without previous irradiation. A 73-year-old woman underwent a right-sided craniotomy of pituitary adenoma for visual deficits 30 years ago. She presented again with a 2-year history of lack of alertness, confusion and visual deficits. Brain magnetic resonance imaging (MRI) demonstrated a recurrent pituitary adenoma and a left temporal lobe tumour. The patient underwent a left frontotemporal craniotomy. After the surgery, the patient showed improvement in neurological symptoms. The histology of the sellar region tumour revealed that it was a pituitary adenoma, and the histology of the temporal lobe tumour demonstrated that it was a meningioma of transitional type. The coexistence of pituitary adenoma and meningioma is a very rare surgical entity, especially in a patient with recurrent pituitary adenoma. Although this co-occurrence is rare, more cases and additional studies are necessary to explain these unusual findings.

Abnormal increase of miR-4262 promotes cell proliferation and migration by targeting large tumor suppressor 1 in gliomas.

BACKGROUND: miRNA was recently detected as tumor suppressor or inducer in various cancers including gliomas. Due to the abnormal expression of miR-4262 in glioma cancer, we supposed that miR-4262 made efforts in proliferation and migration in glioma cancer. METHODS: CCK-8, Transwell migration Assay and Wound-healing assay were appraisal assays for cell proliferation and migration. qRT-PCR and western blot were performed to test the expression of miR-4262, MMP2, MMP13 and LATS1 in glioma cancers tissues and cancer cells. The targeting detection between miR-4262 and LATS1 was detected by luciferase reporter assay. RESULTS: miR-4262 expression was dramatically higher in glioma tumor tissues than in para-tumor control. Inhibition of miR-4262 in glioma cancer cells prominently inhibited cell proliferation and migration. Mechanically, downregulation of miR-4262 inhibited expression of matrix metalloproteinase (MMP) -2, -13. In addition, miR-4262 directly and negatively modulated expression of large tumor suppressor 1 (LATS1). Moreover, we discovered that overexpression of LATS1 could reverse the effects of miR-4262 on cell proliferation and migration, as well as the production of MMP-2, -13. CONCLUSIONS: In glioma cancer, miR-4262 regulated cell proliferation and migration mediated by LATS1. This indicated that miR-4262 is a tumor inducer in glioma cancer and may be a feasible target for glioma therapy.