The BRD4 Inhibitor dBET57 Exerts Anticancer Effects by Targeting Superenhancer-Related Genes in Neuroblastoma.

Neuroblastoma (NB) is the most common solid tumor of the neural crest cell origin in children and has a poor prognosis in high-risk patients. The oncogene MYCN was found to be amplified at extremely high levels in approximately 20% of neuroblastoma cases. In recent years, research on the targeted hydrolysis of BRD4 to indirectly inhibit the transcription of the MYCN created by proteolysis targeting chimaera (PROTAC) technology has become very popular. dBET57 (S0137, Selleck, TX, USA) is a novel and potent heterobifunctional small molecule degrader based on PROTAC technology. The purpose of this study was to investigate the therapeutic effect of dBET57 in NB and its potential mechanism. In this study, we found that dBET57 can target BRD4 ubiquitination and disrupt the proliferation ability of NB cells. At the same time, dBET57 can also induce apoptosis, cell cycle arrest, and decrease migration. Furthermore, dBET57 also has a strong antiproliferation function in xenograft tumor models in vivo. In terms of mechanism, dBET57 targets the BET protein family and the MYCN protein family by associating with CRBN and destroys the SE landscape of NB cells. Combined with RNA-seq and ChIP-seq public database analysis, we identified the superenhancer-related genes TBX3 and ZMYND8 in NB as potential downstream targets of dBET57 and experimentally verified that they play an important role in the occurrence and development of NB. In conclusion, these results suggest that dBET57 may be an effective new therapeutic drug for the treatment of NB.

Giant tumor resection under ultrasound-guided nerve block in a patient with severe asthma: A case report.

BACKGROUND: General anesthesia in critically ill patients is associated with increased risk of complications. Nerve block anesthesia is an alternative, but could be challenging in cases with surgical field that involves multiple dermatomes. CASE SUMMARY: We report resection of a giant lipoma in the left shoulder and upper back under supraclavicular brachial plexus block plus T3-4 paravertebral block in an older patient with severe asthma. A 70-year-old patient presented with a slow-growing giant mass (25, 15 and 5 cm in length, width and depth, respectively) that extended from the lateral side of the left scapula to the axillary midline, and from the T5 thoracic vertebra intercostal to the mid-medial section of the left upper arm. He had sharp intermittent pain over the mass for the past 7 d. The patient also had severe bronchial asthma for the past 8 years. A pulmonary function test revealed only 20% of the predicted forced expiratory volume in 1 second (FEV1, 0.49 L). After controlling asthma with glucocorticoid, the tumor was resected under ultrasound-guided supraclavicular brachial plexus block and T3-4 paravertebral block. The surgery was completed without incident. CONCLUSION: Ultrasound-guided regional nerve block is a viable alternative for patients with poor cardiopulmonary function undergoing shoulder, back and axillary surgery.

Potential application value of PET/computed tomography in retroperitoneal leiomyosarcoma and a literature review.

OBJECTIVE: To analyze the fluorine-18 fludeoxyglucose PET/computed tomography (18F-FDG PET/CT) findings of retroperitoneal leiomyosarcoma (RLMS) and the role of this method in differentiating between benign and malignant masses and classifying the malignant degree to improve the understanding of this rare disease. METHODS: Eight leiomyomas (A group), 13 RLMSs (B group), and 20 postoperative recurrence/metastasis RLMSs (C group) were enrolled. PET/CT features of B group were analyzed. The differences of metabolic parameters between three groups were compared, receiver operating characteristic (ROC) curve analysis was performed to group A and B, and correlation analysis was performed to subgroup B. RESULTS: (1) The RLMS patients were more likely to be female, and PET/CT showed a high degree of heterogeneous metabolism in the soft tissue mass. (2) The standardized uptake value (SUV) of RLMS were significantly higher than those of benign leiomyomas (P < 0.05). The area under the ROC curve was 0.909, the sensitivity and specificity for diagnosing RLMS were 0.923 and 0.750, respectively, The SUVmax and SUVstd of primary RLMS were moderately associated with the Ki67 index. The mean SUVmax in the G1, G2 and G3 subgroups increased successively (4.15 ± 0.35, 6.47 ± 0.83, and 10.13 ± 4.29, respectively). (3) Primary RLMS was characterized by local invasion, but hematogenous metastasis and lymph node metastasis were rare. Postoperative recurrence/metastasis of RLMS was characterized by local recurrence and hematogenous metastasis, but lymph node metastasis was rare. CONCLUSION: PET/CT has potential value in the preoperative staging, benign and malignant differentiation, malignant degree classification and postoperative follow-up of RLMS.

Prediction of Histologic Subtype and FNCLCC Grade by SUVmax Measured on 18F-FDG PET/CT in Patients with Retroperitoneal Liposarcoma.

This study aimed to evaluate the usefulness of maximum standardized uptake value (SUVmax) on 18F-fluorodeoxyglucose positron emission tomography with computed tomography (18F-FDG PET/CT) in differentiating the subtypes and tumor grades of retroperitoneal liposarcoma (RPLS). The data of RPLS patients who underwent surgical resection from November 2013 to December 2019 at the sarcoma center of our institute were reviewed. The demographics, clinical features, and SUVmax of 84 patients who underwent preoperative 18F-FDG PET/CT scans were analyzed. Of these, 19 patients (22.6%) were with well-differentiated liposarcoma (WDLPS), 60 patients (71.4%) were with dedifferentiated liposarcoma (DDLPS), and 5 patients (6.0%) were with pleomorphic liposarcoma (PMLPS). The median SUVmax of WDLPS, DDLPS, and PMLPS groups was 2.8 (IQR: 1.9-3.2), 6.2 (IQR: 4.1-11.3), and 4.5 (IQR: 4.0-7.4). The ROC curve suggested 3.8 as an approximate cutoff value of SUVmax for distinguishing WDLPS and non-WDLPS (sensitivity = 0.769; specificity = 0.895). The median SUVmax for FNCLCC Grades 1, 2, and 3 of RPLS was 2.5 (IQR: 1.9-3.2), 4.5 (IQR: 3.2-6.7), and 9.0 (IQR: 6.0-13.3). The ROC curves suggest that SUVmax of ≤3.8 and >5.3 can be used for predicting FNCLCC Grades 1 and 3, respectively. The result showed that 18F-FDG PET/CT exhibited high sensitivity and specificity for identifying the subtypes and FNCLCC grades of RPLS. Additionally, 18F-FDG PET/CT might be a useful complementary imaging modality for guiding suitable biopsy location of RPLS.

Functional magnetic resonance imaging and immunohistochemical study of hypothalamic function following oral glucose ingestion in rats.

BACKGROUND: The hypothalamus plays a central role in the regulation of metabolism by sensing metabolic demands and releasing regulatory neurotransmitters. This study investigated the response of the hypothalamus to glucose ingestion in rats by blood oxygen level-dependent functional magnetic resonance imaging (BOLD-fMRI) and immunohistochemical techniques to determine the role of the hypothalamus in glyco-regulation during disturbances in carbohydrate metabolism. METHODS: The signal intensity of the hypothalamus was monitored by fMRI for 60 minutes after oral glucose intake in 48 healthy rats (age 14 months), which included 24 normal weight rats (weighing (365 +/- 76.5) g) and 24 overweight rats (weighing (714 +/- 83.5) g). Then, 12 rats (6 normal, 6 overweight) underwent a repeat fMRI scan after consuming an equivalent amount of water without glucose on a separate day. The procedure for fMRI with water intake was the same as for glucose ingestion. fMRI data was processed using time cluster analysis and intensity averaging method. After fMRI, the expression of neuropeptide Y (NPY) and 5-hydroxytryptamine (5-HT) in the hypothalamus of all rats was determined by immunohistochemistry. Positive cells for NPY or 5-HT were counted. RESULTS: There was a transient, but significant, decrease in fMRI signal intensity in all rats (mean (3.12 +/- 0.78)%) in the hypothalamus within 19.5 - 25.5 minutes of oral glucose ingestion. In overweight rats, the decrease in signal intensity in response to the glucose ingestion was more markedly attenuated than that observed in normal weight rats ((2.2 +/- 1.5)% vs (4.2 +/- 0.7)% inhibition, t = 2.12, P < 0.05). There was no significant response in the hypothalamus after oral water ingestion. The percentage of NPY positive cells in obese rats were slightly lower than those in control group (21% vs 23%, t = 0.71, P > 0.05); but there was no significant difference between the two groups; the percentage of 5-HT positive cells in obese rats were significantly lower than those in the control group (22% vs 31%, t = 3.25, P < 0.01). CONCLUSIONS: There is a transient, but significant, decrease in BOLD signal intensity in the hypothalamus following glucose ingestion, which is similar to that observed in humans. The response of the hypothalamus to glucose ingestion was different in overweight and normal weight rats. The percentage of NPY positive cells in obese rats were lower than those in the control group, although this difference was not statistically significant. The percentage of 5-HT positive cells in obese rats was significantly lower than those in the control group.

Differentiation between malignant and benign ovarian tumors by magnetic resonance imaging.

OBJECTIVE: To determine the magnetic resonance (MR) imaging findings of an ovarian mass which are most predictive of malignancy and assess the value of intravenous gadolinium administration in the characterization of an ovarian mass. METHODS: Totally 74 consecutive patients with a clinically or sonographically indeterminate adnexal mass underwent MR imaging, of whom 59 had subsequent surgical resection of 70 adnexal masses. These 59 patients formed the study population. MR imaging studies were prospectively and independently reviewed by a senior and a junior radiologist. The senior radiologist also reevaluated the studies in a blind fashion after a minimum 6 months interval. The sensitivity, specificity, positive predictive value, and negative predictive value of contrast-enhanced and unenhanced MR imaging were evaluated. RESULTS: The most predictive MR imaging findings for malignancy were presence of vegetations in a cystic lesion and presence of necrosis in a solid lesion. The odds ratio was even higher when the ancillary finding of peritoneal metastasis or ascites was present. Contrast media contributed significantly to lesion characterization. Total 70 ovarian masses were detected by contrast-enhanced MR imaging including 37 malignant ovarian masses and 33 benign ovarian masses with 87% (61/70) accuracy, 86% (32/37) sensitivity, 88% (29/33) specificity, 89% (32/36) positive predictive value, and 85% (29/34) negative predictive value, whereas 70 ovarian masses were detected by unenhanced MR imaging with 74% (52/70) accuracy, 73% (27/37) sensitivity, 76% (25/33) specificity, 77% (27/35) positive predictive value, and 71% (25/35) negative predictive value. There were significant differences in accuracy (P < 0.01), sensitivity (P < 0.01), specificity (P < 0.01) between contrast-enhanced and unenhanced MR imaging. CONCLUSION: Contrast-enhanced MR imaging is highly accurate in detection and characterization of complex adnexal masses.