Metastasectomy and Stereotactic Body Radiotherapy for Colorectal Cancer With Liver and Lung Oligometastases: A Case Report of Complete Remission in a 96-Year-Old Patient.

We report a rare case of an extremely old colorectal cancer (CRC) patient who had complete remission after liver metastasectomy and stereotactic body radiotherapy (SBRT) to lung oligometastases (OM), with good quality of life and no evidence of recurrence 12 years after the initial diagnosis. An 83-year-old male patient had a right hemicolectomy for stage pT3 pN0 adenocarcinoma of the colon. Soon he was found to have liver metastasis treated with radiofrequency ablation and then liver metastasectomy with clear margins, followed by chemotherapy in the form of FOLFIRI for six months. Six years later, positron emission tomography (PET) showed 1.6 cm OM in the left upper lobe lung. He was not considered a good candidate for surgery. We offered him SBRT 48 Gy in four fractions every other day. The lesion disappeared with no recurrence in the same location on PET and serial computed tomography (CT) scans. Three years later, PET-CT found a new OM in the left lingular lung measuring 1.2 cm. A CT-guided lung biopsy confirmed invasive adenocarcinoma favoring OM from the CRC. SBRT planning failed due to its proximity to the heart. He accepted the longer course of conventional volumetric modulated arc therapy at 60 Gy in 15 fractions with daily cone-beam CT guidance. Again, he tolerated treatment very well with no significant side effects, despite his age. He did not require any chemotherapy or other systemic treatment in the last 11 years, so he did not experience any toxicities related to such treatment. This case is important to show that old age alone should not be considered a contraindication for metastasectomy and SBRT for CRC with liver and lung OM.

The impact of preanalytical variables on the analysis of cell-free DNA from blood and urine samples.

Cell-free DNA (cfDNA), a burgeoning class of molecular biomarkers, has been extensively studied across a variety of biomedical fields. As a key component of liquid biopsy, cfDNA testing is gaining prominence in disease detection and management due to the convenience of sample collection and the abundant wealth of genetic information it provides. However, the broader clinical application of cfDNA is currently impeded by a lack of standardization in the preanalytical procedures for cfDNA analysis. A number of fundamental challenges, including the selection of appropriate preanalytical procedures, prevention of short cfDNA fragment loss, and the validation of various cfDNA measurement methods, remain unaddressed. These existing hurdles lead to difficulties in comparing results and ensuring repeatability, thereby undermining the reliability of cfDNA analysis in clinical settings. This review discusses the crucial preanalytical factors that influence cfDNA analysis outcomes, including sample collection, transportation, temporary storage, processing, extraction, quality control, and long-term storage. The review provides clarification on achievable consensus and offers an analysis of the current issues with the goal of standardizing preanalytical procedures for cfDNA analysis.

PMAIP1 promotes J subgroup avian leukosis virus replication by regulating mitochondrial function.

Avian leukosis virus Subgroup J (ALV-J) exhibits high morbidity and pathogenicity, affecting approximately 20% of poultry farms. It induces neoplastic diseases and immunosuppression. Phorbol-12-myristate-13-acetate-induced protein 1 (PMAIP1), a proapoptotic mitochondrial protein in the B-cell lymphoma-2 (Bcl-2) family, plays a role in apoptosis in cancer cells. However, the connection between the PMAIP1 gene and ALV-J pathogenicity remains unexplored. This study investigates the potential impact of the PMAIP1 gene on ALV-J replication and its regulatory mechanisms. Initially, we examined PMAIP1 expression using quantitative real-time PCR (qRT-PCR) in vitro and in vivo. Furthermore, we manipulated PMAIP1 expression in chicken fibroblast cells (DF-1) and assessed its effects on ALV-J infection through qRT-PCR, immunofluorescence assay (IFA), and western blotting (WB). Our findings reveal a significant down-regulation of PMAIP1 in the spleen, lung, and kidney, coupled with an up-regulation in the bursa and liver of ALV-J infected chickens compared to uninfected ones. Additionally, DF-1 cells infected with ALV-J displayed a notable up-regulation of PMAIP1 at 6, 12, 24, 48, 74, and 108 h. Over-expression of PMAIP1 enhanced ALV-J replication, interferon expression, and proinflammatory factors. Conversely, interference led to contrasting results. Furthermore, we observed that PMAIP1 promotes virus replication by modulating mitochondrial function. In conclusion, the PMAIP1 gene facilitates virus replication by regulating mitochondrial function, thereby enriching our understanding of mitochondria-related genes and their involvement in ALV-J infection, offering valuable insights for avian leukosis disease resistance strategies.

Zimberelimab combined with systemic therapy extended tumor control in post-radiotherapy cervical cancer with brain metastases: A case report.

Out of the total cases of cervical cancer, brain metastases (BMs) are relatively rare, with an estimated incidence rate of 0.63% (range: 0.1%-2.2%). Additionally, BMs prognosis remains poor, and the average patient survival time following a BM diagnosis is 3 to 5 months. Few studies have addressed the effect of programmed cell death-1 inhibitors against BMs in cervical cancer, although they are an established option for recurrent/metastatic disease. Hence, we report a case involving a 54-year-old post-surgery patient with cervical cancer with a body mass index of 19.5 kg/m2 and Eastern Collaborative Oncology Group (ECOG) performance status of 3; the disease recurred with BMs 1 year later. Intensity-modulated radiation therapy concurrent with temozolomide and bevacizumab was initiated, following which zimberelimab immunotherapy combined with anlotinib was administered to extend tumor control. The patient had a progression-free survival duration of 10 months, the tumor response was assessed as a partial response based on the evaluation criteria for solid tumors (RECIST1.1), and the ECOG status improved to 1 after therapy. These findings suggest that immunotherapy-based combination therapy following radiotherapy may be a good choice for patients with cervical cancer and BMs.

Functional analyses of Toxoplasma gondii dihydroorotase reveal a promising anti-parasitic target.

Toxoplasma gondii relies heavily on the de novo pyrimidine biosynthesis pathway for fueling the high uridine-5'-monophosphate (UMP) demand during parasite growth. The third step of de novo pyrimidine biosynthesis is catalyzed by dihydroorotase (DHO), a metalloenzyme that catalyzes the reversible condensation of carbamoyl aspartate to dihydroorotate. Here, functional analyses of TgDHO reveal that tachyzoites lacking DHO are impaired in overall growth due to decreased levels of UMP, and the noticeably growth restriction could be partially rescued after supplementation with uracil or high concentrations of L-dihydroorotate in vitro. When pyrimidine salvage pathway is disrupted, both DHOH35A and DHOD284E mutant strains proliferated much slower than DHO-expressing parasites, suggesting an essential role of both TgDHO His35 and Asp284 residues in parasite growth. Additionally, DHO deletion causes the limitation of bradyzoite growth under the condition of uracil supplementation or uracil deprivation. During the infection in mice, the DHO-deficient parasites are avirulent, despite the generation of smaller tissue cysts. The results reveal that TgDHO contributes to parasite growth both in vitro and in vivo. The significantly differences between TgDHO and mammalian DHO reflect that DHO can be exploited to produce specific inhibitors targeting apicomplexan parasites. Moreover, potential DHO inhibitors exert beneficial effects on enzymatic activity of TgDHO and T. gondii growth in vitro. In conclusion, these data highlight the important role of TgDHO in parasite growth and reveal that it is a promising anti-parasitic target for future control of toxoplasmosis.

Current insights into the oncogenic roles of lncRNA LINC00355.

Long noncoding RNAs (lncRNAs) are a class of nonprotein-coding transcripts that are longer than 200 nucleotides. LINC00355 is a lncRNA located on chromosome 13q21.31 and is consistently upregulated in various cancers. It regulates the expression of downstream genes at both transcriptional and posttranscriptional levels, including eight microRNAs (miR-15a-5p, miR-34b-5p, miR-424-5p, miR-1225, miR-217-5p, miR-6777-3p, miR-195, and miR-466) and three protein-coding genes (ITGA2, RAD18, and UBE3C). LINC00355 plays a role in regulating various biological processes such as cell cycle progression, proliferation, apoptosis, epithelial-mesenchymal transition, invasion, and metastasis of cancer cells. It is involved in the regulation of the Wnt/ß-catenin signaling pathway and p53 signaling pathway. Upregulation of LINC00355 has been identified as a high-risk factor in cancer patients and its increased expression is associated with poorer overall survival, recurrence-free survival, and disease-free survival. LINC00355 upregulation has been linked to several unfavorable clinical characteristics, including advanced tumor node metastasis and World Health Organization stages, reduced Karnofsky Performance Scale scores, increased tumor size, greater depth of invasion, and more extensive lymph node metastasis. LINC00355 induces chemotherapy resistance in cancer cells by regulating five downstream genes, namely HMGA2, ABCB1, ITGA2, WNT10B, and CCNE1 genes. In summary, LINC00355 is a potential oncogene with great potential as a diagnostic marker and therapeutic target for cancer.

Neurophysiology of cerebellar ataxias and gait disorders.

There are numerous forms of cerebellar disorders from sporadic to genetic diseases. The aim of this chapter is to provide an overview of the advances and emerging techniques during these last 2 decades in the neurophysiological tests useful in cerebellar patients for clinical and research purposes. Clinically, patients exhibit various combinations of a vestibulocerebellar syndrome, a cerebellar cognitive affective syndrome and a cerebellar motor syndrome which will be discussed throughout this chapter. Cerebellar patients show abnormal Bereitschaftpotentials (BPs) and mismatch negativity. Cerebellar EEG is now being applied in cerebellar disorders to unravel impaired electrophysiological patterns associated within disorders of the cerebellar cortex. Eyeblink conditioning is significantly impaired in cerebellar disorders: the ability to acquire conditioned eyeblink responses is reduced in hereditary ataxias, in cerebellar stroke and after tumor surgery of the cerebellum. Furthermore, impaired eyeblink conditioning is an early marker of cerebellar degenerative disease. General rules of motor control suggest that optimal strategies are needed to execute voluntary movements in the complex environment of daily life. A high degree of adaptability is required for learning procedures underlying motor control as sensorimotor adaptation is essential to perform accurate goal-directed movements. Cerebellar patients show impairments during online visuomotor adaptation tasks. Cerebellum-motor cortex inhibition (CBI) is a neurophysiological biomarker showing an inverse association between cerebellothalamocortical tract integrity and ataxia severity. Ataxic gait is characterized by increased step width, reduced ankle joint range of motion, increased gait variability, lack of intra-limb inter-joint and inter-segmental coordination, impaired foot ground placement and loss of trunk control. Taken together, these techniques provide a neurophysiological framework for a better appraisal of cerebellar disorders.

Perceptions of Canadian Radiation Oncologists, Medical Physicists, and Radiation Trainees about the Feasibility and Need of Boron Neutron Capture Therapy (BNCT) in Canada: A National Survey.

BACKGROUND: Boron Neutron Capture Therapy (BNCT) is an emerging radiotherapy. There are ongoing efforts to develop a Canadian accelerator-based BNCT center. However, it remains unclear how Canadian radiation oncologists (RO), medical physicists (MP), and their trainees perceive BNCT and its impact on radiation oncology as a discipline. METHODS: A survey was created to explore the knowledge of BNCT, its clinical role, and the support for Canadian research. It was distributed through the Canadian Association of Radiation Oncology (CARO) and the Canadian Organization of Medical Physicists (COMP). RESULTS: We received 118 valid responses from all 10 provinces, from 70 RO (59.3%) and 48 MP (40.7%), including 9 residents. Most knew of BNCT and its indications (60.2%). Although many were unaware of the reasons behind early failures (44.1%), common reasons were a lack of clinical trials and an inaccessibility of neutron sources (42.4%) as well as reactor unsuitability (34.7%). Additionally, 90.6% showed definite (66.9%) or possible (23.7%) support for Canadian BNCT research, while 89% indicated a definite (56.8%) or possible (32.2%) willingness for BNCT referrals. CONCLUSIONS: Most ROs and MPs supported Canadian BNCT research and would refer patients. However, limited awareness and a lack of experiences remain a challenge. Educational sessions are needed to realize this innovative cancer treatment in Canada.

Distributed optical fiber biosensor based on optical frequency domain reflectometry.

In situ acquisition of spatial distribution of biochemical substances is important in cell analysis, cancer detection and other fields. Optical fiber biosensors can achieve label-free, fast and accurate measurements. However, current optical fiber biosensors only acquire single-point of biochemical substance content. In this paper, we present a distributed optical fiber biosensor based on tapered fiber in optical frequency domain reflectometry (OFDR) for the first time. To enhance evanescent field at a relative long sensing range, we fabricate a tapered fiber with a taper waist diameter of 6 µm and a total stretching length of 140 mm. Then the human IgG layer is coated on the entire tapered region by polydopamine (PDA) -assisted immobilization as the sensing element to achieve to sense anti-human IgG. We measure shifts of the local Rayleigh backscattering spectra (RBS) caused by the refractive index (RI) change of an external medium surrounding a tapered fiber after immunoaffinity interactions by using OFDR. The measurable concentration of anti-human IgG and RBS shift has an excellent linearity in a range from 0 ng/ml to 14 ng/ml with an effective sensing range of 50 mm. The concentration measurement limit of the proposed distributed biosensor is 2 ng/ml for anti-human IgG. Distributed biosensing based on OFDR can locate a concentration change of anti-human IgG with an ultra-high sensing spatial resolution of 680 µm. The proposed sensor has a potential to realize a micron-level localization of biochemical substances such as cancer cells, which will open a door to transform single-point biosensor to distributed biosensor.

Schisandrin B Improves the Hypothermic Preservation of Celsior Solution in Human Umbilical Cord Mesenchymal Stem Cells.

BACKGROUND: Human umbilical cord mesenchymal stem cells (hUCMSCs) have emerged as promising therapy for immune and inflammatory diseases. However, how to maintain the activity and unique properties during cold storage and transportation is one of the key factors affecting the therapeutic efficiency of hUCMSCs. Schisandrin B (SchB) has many functions in cell protection as a natural medicine. In this study, we investigated the protective effects of SchB on the hypothermic preservation of hUCMSCs. METHODS: hUCMSCs were isolated from Wharton's jelly. Subsequently, hUCMSCs were exposed to cold storage (4 °C) and 24-h re-warming. After that, cells viability, surface markers, immunomodulatory effects, reactive oxygen species (ROS), mitochondrial integrity, apoptosis-related and antioxidant proteins expression level were evaluated. RESULTS: SchB significantly alleviated the cells injury and maintained unique properties such as differentiation potential, level of surface markers and immunomodulatory effects of hUCMSCs. The protective effects of SchB on hUCMSCs after hypothermic storage seemed associated with its inhibition of apoptosis and the anti-oxidative stress effect mediated by nuclear factor erythroid 2-related factor 2 signaling. CONCLUSION: These results demonstrate SchB could be used as an agent for hypothermic preservation of hUCMSCs.

Semi-Supervised Medical Image Segmentation Guided by Bi-Directional Constrained Dual-Task Consistency.

BACKGROUND: Medical image processing tasks represented by multi-object segmentation are of great significance for surgical planning, robot-assisted surgery, and surgical safety. However, the exceptionally low contrast among tissues and limited available annotated data makes developing an automatic segmentation algorithm for pelvic CT challenging. METHODS: A bi-direction constrained dual-task consistency model named PICT is proposed to improve segmentation quality by leveraging free unlabeled data. First, to learn more unmarked data features, it encourages the model prediction of the interpolated image to be consistent with the interpolation of the model prediction at the pixel, model, and data levels. Moreover, to constrain the error prediction of interpolation interference, PICT designs an auxiliary pseudo-supervision task that focuses on the underlying information of non-interpolation data. Finally, an effective loss algorithm for both consistency tasks is designed to ensure the complementary manner and produce more reliable predictions. RESULTS: Quantitative experiments show that the proposed PICT achieves 87.18%, 96.42%, and 79.41% mean DSC score on ACDC, CTPelvic1k, and the individual Multi-tissue Pelvis dataset with gains of around 0.8%, 0.5%, and 1% compared to the state-of-the-art semi-supervised method. Compared to the baseline supervised method, the PICT brings over 3-9% improvements. CONCLUSIONS: The developed PICT model can effectively leverage unlabeled data to improve segmentation quality of low contrast medical images. The segmentation result could improve the precision of surgical path planning and provide input for robot-assisted surgery.

BRACHY: A Randomized Trial to Evaluate Symptom Improvement in Advanced Non-Small Cell Lung Cancer Treated With External Beam Radiation With or Without High-Dose-Rate Intraluminal Brachytherapy.

PURPOSE: Uncontrolled studies suggest that the addition of high-dose-rate intraluminal brachytherapy (HDRIB) to external beam radiation therapy (EBRT) may improve palliation for patients with advanced non-small cell lung cancer (NSCLC). The purpose of this study was to evaluate the potential clinical benefit of adding HDRIB to EBRT in a multicenter randomized trial. METHODS AND MATERIALS: Patients with symptomatic stage III or IV NSCLC with endobronchial disease were randomized to EBRT (20 Gy in 5 daily fractions over 1 week or 30 Gy in 10 daily fractions over 2 weeks) or the same EBRT plus HDRIB (14 Gy in 2 fractions separated by 1 week). The primary outcome was the proportion of patients who achieved symptomatic improvement in patient-reported overall lung cancer symptoms on the Lung Cancer Symptom Scale (LCSS) at 6 weeks after randomization. Secondary outcomes included improvement in individual symptoms, symptom-progression-free survival, overall survival, and toxicity. The planned sample size was 250 patients based on detection of symptomatic improvement from 40% to 60% with a 2-sided α of .05 and 80% power. RESULTS: A total of 134 patients were randomized over 4.5 years: 67 to each arm. The study closed early owing to slow accrual. The mean age was 69.8 years, and 67% of patients had metastatic disease. At 6 weeks, 19 patients (28.4%) in the EBRT arm and 20 patients (29.9%) in the EBRT plus HDRIB arm experienced an improvement in lung cancer symptoms (P = .84). When limited to patients who completed the LCSS, percentages were 40.4% versus 47.6%, respectively (P = .49). Between group differences in mean change scores (0.3-0.5 standard deviations) in favor of EBRT plus HDRIB were observed for overall symptoms, but only hemoptysis was significantly improved (P = .03). No significant differences were observed in progression-free or overall survival. Grade 3/4 toxicities were similar between groups. CONCLUSIONS: Small to moderate improvements were seen in symptom relief with the combined therapy, but they did not reach statistical significance. Further research is necessary before recommending HDRIB in addition to EBRT for palliation of lung cancer symptoms.

Posterior reversible encephalopathy syndrome after lung transplantation: Risk factors and management.

INTRODUCTION: Posterior reversible encephalopathy syndrome is a rare neurologic complication that can occur under immunosuppressive therapy with CNI after organ transplantation. METHODS: We retrospectively reviewed medical records of 545 patients who underwent lung transplantation between 2012 and 2019. Within this group, we identified 30 patients with neurological symptoms typical of PRES and compared the characteristics of patients who were diagnosed with PRES (n = 11) to those who were not (n = 19). RESULTS: The incidence of PRES after lung transplantation was 2%. Notably, 73% of the patients with PRES were female and the mean age was 39.2. Seizure (82% vs. 21%, p = .002) was the most common neurological presentation. The risk of developing PRES was significantly associated with age (OR = .92, p < .0001) and having cystic fibrosis (CF) (OP = 10.1, p < .0001). Creatinine level (1.9 vs. 1.1 mg/dl, p = .047) and tacrolimus trough level (19.4 vs. 16.5 ng/ml, p = .048) within 1 week prior to neurological symptoms were significantly higher in patients with PRES. CONCLUSION: Renal insufficiency and high tacrolimus levels are associated with PRES. A change of immunosuppressive drug should be done after confirmed PRES diagnosis or immediately in case of severe neurological dysfunction to improve neurological outcomes and minimize the risk of early allograft rejection.

Assessing the Suitability of Chinese Cabbage as an Alternative Host for Spodoptera frugiperda (Lepidoptera: Noctuidae).

When the favored host of an herbivorous insect pest is absent, the availability of alternative host plants can maintain insect pest populations. Spodoptera frugiperda (Lepidoptera: Noctuidae) is a major invasive, polyphagous insect pest in China. To investigate the suitability of Chinese cabbage as an alternative host for S. frugiperda, oviposition preferences and life history traits were determined for S. frugiperda on Chinese cabbage, corn, and winter wheat over three generations. Results showed that S. frugiperda females preferred to lay their eggs on corn compared to winter wheat and Chinese cabbage. The survival rate of S. frugiperda decreased after switching from corn to Chinese cabbage, only 6% of individuals successfully pupated in the third generation. In addition, S. frugiperda reared on Chinese cabbage had lower pupal weight and fecundity. Winter wheat was a good host for S. frugiperda; although the survival rate decreased when S. frugiperda switched from corn to winter wheat in the parental generation, the survival rate increased over the next two generations to be as high as those reared on corn. Chinese cabbage is not a good long-term host for S. frugiperda, but it could maintain the pest population for at least two generations when more suitable host plants are unavailable. These results will inform management strategies for S. frugiperda.

Plasmapheresis compared with conventional treatment for hypertriglyceridemia-induced acute pancreatitis: A systematic review and meta-analysis.

BACKGROUND: The treatment of acute pancreatitis (AP) induced by hypertriglyceridemia (HTG) remains controversial with regard to plasmapheresis vs conventional treatment. We reviewed relevant articles to explore the efficacy of plasmapheresis in the management of HTG-induced AP. METHODS: We systematically reviewed studies that compared plasmapheresis with conventional treatment for HTG-induced AP using three databases: PubMed, Embase, and Cochrane Library, as well as relevant references. The primary outcomes were 24 h triglyceride reduction rate and in-hospital mortality. RESULTS: A total of 791 articles were retrieved. Finally, 15 observational studies (1080 participants) were included, most of which were historical cohort studies. Compared with conventional treatment, plasmapheresis assisted in the reduction of serum triglyceride (TG) levels in the first 24 h after hospital admission (standardized mean difference [SMD]: 0.58; 95% confidence interval [CI]: 0.17 to 0.99; P = 0.005). However, it resulted in increased hospitalization costs (thousand yuan) (weighted mean difference [WMD]: 24.32; 95% CI: 12.96 to 35.68; P < 0.001). With regard to in-hospital mortality, although the mortality rate in the plasmapheresis group was higher than that in the conventional treatment group (relative risk [RR]: 1.74; 95% CI: 1.03 to 2.94; P = 0.038), the result was disturbed by confounding factors as per the subgroup and sensitivity analysis, as well as trial sequential analysis (TSA). No significant differences were found in other outcomes, including systematic complications, local complications, the requirement for surgery, and hospitalization duration. CONCLUSION: The effect of plasmapheresis in HTG-induced AP is not superior to that of conventional treatment, even resulting in a greater economic burden to patients and health care system. High quality randomized control trials are required to obtain a more a definitive understanding of this issue.

The determinants regulating Toxoplasma gondii bradyzoite development.

Toxoplasma gondii is an obligate intracellular zoonotic pathogen capable of infecting almost all cells of warm-blooded vertebrates. In intermediate hosts, this parasite reproduces asexually in two forms, the tachyzoite form during acute infection that proliferates rapidly and the bradyzoite form during chronic infection that grows slowly. Depending on the growth condition, the two forms can interconvert. The conversion of tachyzoites to bradyzoites is critical for T. gondii transmission, and the reactivation of persistent bradyzoites in intermediate hosts may lead to symptomatic toxoplasmosis. However, the mechanisms that control bradyzoite differentiation have not been well studied. Here, we review recent advances in the study of bradyzoite biology and stage conversion, aiming to highlight the determinants associated with bradyzoite development and provide insights to design better strategies for controlling toxoplasmosis.

Bloodless Laparoscopic Partial Splenectomy Assisted by Bipolar Radiofrequency Excision Hemostatic Device.

Among the lymphatic system in the human body, the spleen is the most extensive one and has hematopoietic, hemofiltration, blood storage, and immune functions. As a new method of preserving the spleen, laparoscopic partial splenectomy (LPS) has been increasingly applied in clinical practice with people's deeper insights into minimally invasive treatment and the development of technical equipment. Compared with conventional open splenectomy, LPS can preserve normal spleen tissue as much as possible, decrease the occurrence of complications after total splenectomy, and reduce postoperative hospital stay. The bipolar radiofrequency excision hemostatic device used for LPS can solidify the splenic tissue and close the small blood vessels, which reduces the hemorrhage of the spleen cross-section and clears the operative field, thus achieving the ideal effect of "bloodless partial splenectomy". Therefore, under the premise of strictly mastering the indications and fully understanding the vascular anatomy of the spleen, the application of the bipolar radiofrequency excision hemostatic device in LPS is worthy of clinical promotion.

Melatonin inhibits ESCC tumor growth by mitigating the HDAC7/ß-catenin/c-Myc positive feedback loop and suppressing the USP10-maintained HDAC7 protein stability.

BACKGROUND: Melatonin, a natural hormone secreted by the pineal gland, has been reported to exhibit antitumor properties through diverse mechanisms of action. However, the oncostatic function of melatonin on esophageal squamous cell carcinoma (ESCC) remains elusive. This study was conducted to investigate the potential effect and underlying molecular mechanism of melatonin as single anticancer agent against ESCC cells. METHODS: ESCC cell lines treated with or without melatonin were used in this study. In vitro colony formation and EdU incorporation assays, and nude mice tumor xenograft model were used to confirm the proliferative capacities of ESCC cells. RNA-seq, qPCR, Western blotting, recombinant lentivirus-mediated target gene overexpression or knockdown, plasmids transfection and co-IP were applied to investigate the underlying molecular mechanism by which melatonin inhibited ESCC cell growth. IHC staining on ESCC tissue microarray and further survival analyses were performed to explore the relationship between target genes' expression and prognosis of ESCC. RESULTS: Melatonin treatment dose-dependently inhibited the proliferative ability and the expression of histone deacetylase 7 (HDAC7), c-Myc and ubiquitin-specific peptidase 10 (USP10) in ESCC cells (P < 0.05). The expressions of HDAC7, c-Myc and USP10 in tumors were detected significantly higher than the paired normal tissues from 148 ESCC patients (P < 0.001). Then, the Kaplan-Meier survival analyses suggested that ESCC patients with high HDAC7, c-Myc or USP10 levels predicted worse overall survival (Log-rank P < 0.001). Co-IP and Western blotting analyses further revealed that HDAC7 physically deacetylated and activated ß-catenin thus promoting downstream target c-Myc gene transcription. Notably, our mechanistic study validated that HDAC7/ß-catenin/c-Myc could form the positive feedback loop to enhance ESCC cell growth, and USP10 could deubiquitinate and stabilize HDAC7 protein in the ESCC cells. Additionally, we verified that inhibition of the HDAC7/ß-catenin/c-Myc axis and USP10/HDAC7 pathway mediated the anti-proliferative action of melatonin on ESCC cells. CONCLUSIONS: Our findings elucidate that melatonin mitigates the HDAC7/ß-catenin/c-Myc positive feedback loop and inhibits the USP10-maintained HDAC7 protein stability thus suppressing ESCC cell growth, and provides the reference for identifying biomarkers and therapeutic targets for ESCC.

HMGA1 Promotes Macrophage Recruitment via Activation of NF-κB-CCL2 Signaling in Hepatocellular Carcinoma.

Background: Tumor-associated macrophages (TAMs) are known to generate an immune-suppressive tumor microenvironment (TME) and promote tumor progression. Hepatocellular carcinoma (HCC) is a devastating disease that evolves in the background of chronic inflammatory liver damage. In this study, we aimed to uncover the mechanism by which HCC cells recruit macrophages into the TME. Methods: Bioinformatic analysis was performed to identify differentially expressed genes related to macrophage infiltration. An orthotopic HCC xenograft model was used to determine the role of macrophages in HCC tumor growth. Clodronate liposomes were used to delete macrophages. Western blotting analysis, quantitative real-time PCR, and enzyme-linked immunosorbent assay were performed to determine the underlying mechanisms. Results: The high mobility group A1 (HMGA1) gene was identified as a putative modulator of macrophage infiltration in HCC. Deletion of macrophages with clodronate liposomes significantly abrogated the tumor-promoting effects of HMGA1 on HCC growth. Mechanistically, HMGA1 can regulate the expression of C-C Motif Chemokine Ligand 2 (CCL2), also referred to as monocyte chemoattractant protein 1 (MCP1), which is responsible for macrophage recruitment. Moreover, NF-κB was required for HMGA1-mediated CCL2 expression. Pharmacological or genetic inhibition of NF-κB largely blocked CCL2 levels in HMGA1-overexpressing HCC cells. Conclusions: This study reveals HMGA1 as a crucial regulator of macrophage recruitment by activating NF-κB-CCL2 signaling, proves that HMGA1-induced HCC aggressiveness dependents on the macrophage, and provide an attractive target for therapeutic interventions in HCC.

Study on Increasing the Binding Amount of Rubber and Reinforcing Filler by Adding Aromatic Solvent Oil.

The binding amount of rubber and reinforcing filler directly affects the quality of rubber products. The effect of aromatic solvent oil (S-150) on the binding amount of rubber and reinforcing filler was studied. In order to determine the suitability of rubber after adding S-150, the curing characteristics, physical performance and tensile properties of rubber samples were tested and analyzed. Meanwhile, the microstructure of the composite was analyzed by scanning electron microscopy (SEM). The test results showed that the binding amount of rubber and reinforcing filler was increased after adding S-150. The density and Shore A hardness were decreased. When carbon black was 80 phr, after adding 40 phr of S-150, the rebound resilience of rubber increased by 13% on average, and the elongation at break increased by 88% on average. When white carbon black was between 10-70 phr, after adding 65 phr of S-150, the rebound resilience of rubber increased by 9% on average, and the elongation at break increased by 51% on average. Modulus at 100% and tensile strength were decreased. Meanwhile, it could be judged from the microstructure results that the reticulation space inside the rubber was increased, the agglomerate particles were relatively uniform, and no bubbles or holes were observed. The mechanism that S-150 could increase the binding amount of rubber was analyzed according to the like-dissolves-like principle. This research achievement could lead to improvements in the quality of rubber products and promote their practical application.