Rapid response in relapsed follicular lymphoma to novel anti-CD19 CAR-T therapy with pseudo-progression and cytomegalovirus infection: A case report.

CD19-directed chimeric antigen receptor (CAR) T cell therapy has been shown to achieve a considerably durable response in patients with refractory or relapsed B cell non-Hodgkin lymphomas. Most of these CARs were generated by lentivirus. With the exception of Yescarta and Tecartus, few patients with relapsed-/refractory- lymphoma have been treated clinically with a CARs using retroviral vector (RV). Here, we reported a relapsed/refractory grade 2 follicular lymphoma patient with multiple chemotherapy failures, and was treated with a novel CD19 CAR-T cell manufactured from a RV. After tumor burden was reduced with Obinutuzumab and Duvelisib, the patient was infused novel CD19 CAR-T cells at a dose of 3 × 106 cells/ kg. Then he experienced a rapid response and achieved almost complete remission by day 26. Only grade 2 CRS, bilateral submaxillary lymph node enlargement and cytomegalovirus (CMV) infection occurred without neurotoxicity, and the patient's condition improved after a series of symptomatic treatments. In addition, CAR copy number peaked at 532,350 copies/µg on day 15 and continued to expand for 5 months. This may be the first case report of RV preparation of novel CD19 CAR-T cells for direct treatment of recurrent follicular lymphoma. We will observe its long-term efficacy and conduct trials in more patients in the future.

NONO promotes gallbladder cancer cell proliferation by enhancing oncogenic RNA splicing of DLG1 through interaction with IGF2BP3/RBM14.

Gallbladder cancer (GBC) is a highly malignant and rapidly progressing tumor of the human biliary system, and there is an urgent need to develop new therapeutic targets and modalities. Non-POU domain-containing octamer-binding protein (NONO) is an RNA-binding protein involved in the regulation of transcription, mRNA splicing, and DNA repair. NONO expression is elevated in multiple tumors and can act as an oncogene to promote tumor progression. Here, we found that NONO was highly expressed in GBC and promoted tumor cells growth. The dysregulation of RNA splicing is a molecular feature of almost all tumor types. Accordingly, mRNA-seq and RIP-seq analysis showed that NONO promoted exon6 skipping in DLG1, forming two isomers (DLG1-FL and DLG1-S). Furthermore, lower Percent-Spliced-In (PSI) values of DLG1 were detected in tumor tissue relative to the paraneoplastic tissue, and were associated with poor patient prognosis. Moreover, DLG1-S and DLG1-FL act as tumor promoters and tumor suppressors, respectively, by regulating the YAP1/JUN pathway. N6-methyladenosine (m6A) is the most common and abundant RNA modification involved in alternative splicing processes. We identified an m6A reader, IGF2BP3, which synergizes with NONO to promote exon6 skipping in DLG1 in an m6A-dependent manner. Furthermore, IP/MS results showed that RBM14 was bound to NONO and interfered with NONO-mediated exon6 skipping of DLG1. In addition, IGF2BP3 disrupted the binding of RBM14 to NONO. Overall, our data elucidate the molecular mechanism by which NONO promotes DLG1 exon skipping, providing a basis for new therapeutic targets in GBC treatment.

BFGF attenuates aortic valvular interstitial cell calcification by inhibiting endoplasmic reticulum stress-mediated apoptosis.

The potential protective effect of basic fibroblast growth factor (BFGF) on the cardiovascular system has been proposed previously, however, its effect on calcific aortic valve disease (CAVD) and underlying mechanisms have not been elucidated. The valvular interstitial cell (VIC) were isolated from porcine aortic valve leaflets. To investigate the effect of BFGF on osteogenic differentiation of VIC, the osteogenic induced medium (OIM) and BFGF were added. The protein expression level was detected by Western blot, and apoptosis was determined by flow cytometry. The effect of BFGF on CAVD process in vivo was assessed by a rat CAVD model, which was identified by echocardiography and Alizarin red staining. The expression level of BFGF in the aortic valve and serum were significantly upregulated in CAVD patients compared to control group. In addition, exogenous BFGF injection attenuates CAVD process in vivo. The protein markers of osteogenic differentiation, endoplasmic reticulum stress (ERS), and apoptosis were significantly upregulated by culture with OIM. On the contrary, the aforementioned proteins were suppressed after adding 100 ng/mL of BFGF. Inhibition of PI3K/Akt and ERK1/2 pathways by specific inhibitors abolished the protective effect of BFGF. In conclusion, BFGF could alleviate the VIC calcification by inhibiting ERS-mediated apoptosis, which is partly regulated by activation of the PI3K/Akt and ERK1/2 signaling pathways. BFGF may provide a potential avenue for CAVD therapy.

Spontaneous Pancreatic Hemorrhage: Successful Conservative Management in Two Cases.

BACKGROUND Spontaneous pancreatic and peripancreatic hemorrhage (SPH) is a rare subtype of spontaneous retroperitoneal hemorrhage. With diverse clinical manifestations and no specific presentations, early diagnosis of SPH becomes challenging. Patient-specific underlying causes and vital signs guide the SPH treatment approach. CASE REPORT Case 1: A 39-year-old man reported unexplained hypogastralgia at the emergency department (ED). An abdominal MRI revealed a mixed hematoma and cystic lesions between the pancreatic head and descending duodenum, attributed to ruptured mucinous cystic neoplasms. Extensive hematoceles were identified around the liver and abdominal pelvis on an enhanced CT scan. After undergoing fasting, rehydration, proton pump inhibitor and somatostatin intravenous injections, and peritoneal puncture, his condition improved. He was discharged nine days post-admission. Case 2: A 44-year-old man arrived at the ED with back pain and right upper quadrant pain. Enhanced CT indicated peritoneal fluid and a hematoma between the pancreatic head and descending duodenum. He initially received conservative treatment. However, on the eighth day, he reported recurrent abdominal pain. Follow-up CT showed an enlarged hematoma and gastric content accumulation. The patient was fasted and put on parenteral nutrition, and by the 37th day of hospitalization, he had fully recovered and was discharged. Both patients, having stable hemodynamics, fully recovered following conservative management, with no surgical intervention required. CONCLUSIONS Given its varied clinical presentations, SPH can easily be misdiagnosed. However, successful conservative management can lead to full recovery, as demonstrated in these case reports.

Primary malignant melanoma of the cervix: A comprehensive analysis of case reports in the Chinese population.

PURPOSE: Malignant melanoma is a tumor generated from the basal melanocytes of human epidermis. Primary malignant melanoma of the cervix (PMMC) is derived from cervical melanocytes. It is an uncommon disease, mostly occurring in perimenopausal women. PMMC has a bad prognosis and lacks a defined protocol or treatment standards. The aim of this study was to analyze the impact of different surgical procedures and different adjuvant treatment modalities on their prognosis and to find risk factors for their prognosis by integrating published case report data based on the Chinese population. METHODS AND RESULTS: This study included 165 patients with PMMC in the Chinese population. We used the Kaplan-Meier method to build the survival curve, and the log-rank test to examine the variations among the subgroups. Prognostic factors were examined utilizing the Cox proportional hazards regression model. We found that patients who underwent radical hysterectomy-based surgery, those who underwent lymphadenectomy, and those who underwent other treatments in addition to surgery had significantly better survival rates. The overall analysis, showed that age, and FIGO Stage II, III, and IV, increased the risk of death. Moreover, radical hysterectomy (RH), total hysterectomy (TAH), lymphadenectomy, and adjuvant therapy were correlated with a decreased mortality risk. CONCLUSION: After summarizing the current data, we recommend radical hysterectomy, and lymphadenectomy treatment for patients with PMMC. For patients who had already undergone surgery, other treatment options had a positive effect on prognosis. For patients who had already undergone surgery, other treatment options had a positive effect on prognosis; therefore patient-specific treatment options need to be further discussed.

Effect of individualized comfortable nursing on prognosis of vacuum sealing drainage in patients with orthopedic trauma.

To explore the effect of individualized comfortable nursing on prognosis of vacuum sealing drainage (VSD) in patients with orthopedic trauma. 110 patients with orthopedic trauma VSD were randomly divided into the control group and the observation group, with 55 patients in each group receiving routine care and comfortable care. The wound healing time, visual analog scale, quality of life score, the level of inflammatory factors, the incidence of complications, and patient satisfaction were compared between the 2 groups. The average time of wound healing in the observation group was significantly lower than that in the control group (P < .01). The satisfaction rate in the observation group was significantly higher than that in the control group (P = .029). Meanwhile, the results showed that visual analog scale and quality of life scores in the observation group was significantly improved than that of the control group after receiving intervention (P < .05). After receiving intervention, the levels of TNF-α and IL-6 of patients in both groups were decreased, and the levels of TNF-α and IL-6 in the observation group were significantly decreased than those in the control group. Moreover, the incidence rate of adverse reaction in the observation group was significantly lower than that in the control group (P < .01). Comfortable nursing can reduce the wound healing time, the postoperative pain level, the incidence of complications, and improve patient satisfaction, which is of great significance for the prognosis of VSD in patients with orthopedic trauma.

Abscisic acid plays a key role in the mechanism of photosynthetic and physiological response effect of Tetrabromobisphenol A on tobacco.

The toxicity of bromide to animals and microorganisms has been widely studied, but the mechanism by which bromide toxicity affects plants is rarely studied. This study used the bromophenol compound Tetrabromobisphenol A (TBBPA) as a representative of bromide to explore the physiological and molecular response mechanism of tobacco leaves to TBBPA. In addition, physiological determination, transcriptomics, weighted gene co-expression network analysis (WGCNA) analysis, and random forest prediction model were conducted. The findings from this study indicated that TBBPA limited the photoreaction process by destroying the light-catching antenna protein of tobacco leaves, the activity of the photosystem reaction centers (PSII and PSI), and the linear electron transport efficiency. TBBPA also reduced the rate of the Calvin-Benson cycle by inhibiting the activities of gene such as Rubisco, PGK, and TPI, and finally destroyed the photosynthesis process. Although cyclic electron transport was enhanced under stress conditions, it could not reverse the damage caused by TBBPA on photosynthesis. TBBPA exposure resulted in the accumulation of reactive oxygen species (ROS) in tobacco leaves, and the activities of Superoxide dismutase (SOD), Ascorbate peroxidase (APX), and Glutathione peroxidase (GPX) and their coding genes were significantly down-regulated. Although POD activity and proline (Pro) content were increased, they were insufficient to remove excess O2·- free radicals to relieve ROS stress. WCGNA and random forest models predicted that the damage of TBBPA to the above processes in tobacco was closely related to the increase in abscisic acid (ABA) content. TBBPA affects the Calvin cycle by inducing ABA signal transduction and stomatal closure, which leads to a series of chain reactions, such as electron transport chain obstruction, excess of ROS, decrease in chlorophyll synthesis, and photosystem reaction center damage.

Development and validation of a nomogram model for cancer-specific survival of patients with poorly differentiated thyroid carcinoma: A SEER database analysis.

Background: This study aimed to establish and validate an accurate prognostic model, based on demographic and clinical parameters, for predicting the cancer-specific survival (CSS) of patients with poorly differentiated thyroid carcinoma (PDTC). Materials and methods: Patients diagnosed with PDTC between 2004 to 2015 were obtained from the Surveillance, Epidemiology, and End Results (SEER) database. Randomly split the data into training and validation sets. Kaplan-Meier analysis with the log-rank test was performed to compare the survival distribution among cases. Univariate and multivariate Cox proportional hazards regression analyses were used to identify independent prognostic factors, which were subsequently utilized to construct a nomogram for predicting the 5- and 10-year cancer-specific survival of patients with PDTC. The discriminative ability and calibration of the nomogram model were assessed using the concordance index and calibration plots, respectively. In addition, we performed a decision curve analysis to assess the clinical value of the nomogram. Simultaneously, we compared the predictive performance of the nomogram model against that of the American Joint Committee on Cancer (AJCC) T-, N-, M-stage. Results: A total of 970 eligible patients were randomly assigned to either a training cohort (n = 679) or a validation cohort (n = 291). The Kaplan-Meier analysis revealed that there were no significant differences in cumulative survival based on the race, radiation, and marital status of patients. The stepwise Cox regression model showed that the model was optimal when the following five variables were included: age, tumor size, T-, N-, and M-stage. A nomogram was developed as a graphical representation of the model and exhibited good calibration and discriminative ability in the study. Compared to the T-, N-, and M-stage, the C-index of nomogram (training group: 0.807, validation group: 0.802), the areas under the receiver operating characteristic curve of the training set (5-year AUC: 0.843, 10-year AUC:0.834) and the validation set (5-year AUC:0.878, 10-year AUC:0.811), and the calibration plots of this model all exhibited better performance. At last, compared with T-, N-, and M-stage, the decision curve analysis indicated that the nomogram had excellent clinical net benefit. Conclusions: The nomogram developed by us can accurately predict the CSS of PDTC patients. It can help clinicians determine appropriate treatment strategies for poorly differentiated thyroid carcinoma patients.

Neuromedin U promotes human type 2 immune responses.

Type 2 immunity mediates the immune responses against parasites and allergic stimuli. Evidence from studies of cell lines and animals implies that neuromedin U (NmU) acts as a pro-inflammatory mediator of type 2 inflammation. However, the role of NmU in human type 2 immunity remains unclear. Here we investigated the expression of NmU in human blood and airways, and the expression of NmU receptors by human immune cells in blood and lung tissue. We detected human NmU (hNmU-25) in blood and airways with higher concentrations in the latter. NmU receptor 1 (NmUR1) was expressed by most human immune cells with higher levels in type 2 cells including type 2 T helpers, type 2 cytotoxic T cells, group-2 innate lymphoid cells and eosinophils, and was upregulated in lung-resident and activated type 2 cells. We also assessed the effects of NmU in these cells. hNmU-25 elicited type 2 cytokine production by type 2 lymphocytes and induced cell migration, including eosinophils. hNmU-25 also enhanced the type 2 immune response to other stimuli, particularly prostaglandin D2. These results indicate that NmU could contribute to the pathogenic processes of type 2 immunity-mediated diseases in humans via its pro-inflammatory effects on type 2 lymphocytes and eosinophils.

A dual-positive charges strategy for sensitive and quantitative detection of mitochondrial SO2 in cancer cells and tumor tissue.

Mitochondrial sulfur dioxide (SO2) correlates with various activities of the development and progression of cancer. However, the specific biological function of mitochondrial SO2 in cancerous cells remains amphibolous. Therefore, it is of great significance and urgency to develop a rapid and accurate method to monitor the dynamic fluctuations of mitochondrial SO2 in cancer cells and tumor tissue. Herein, in this work, we introduce a "dual-positive charges" strategy for simultaneously enhancing the sensitivity and mitochondrial targeting ability of SO2 detection in cancer cells for the first time. For proof of concept, the dual positive charged probe DCP was rationally designed and synthesized based on chromenoquinoline fluorophore. Correspondingly, we also synthesized single positive charged SO2 probe MCP as controls. As expected, the detection limit of dual positive charged DCP for SO2 detection was 0.06 µM, which was 7-fold lower than that of the single positive charged probe MCP. Besides, DCP showed a higher mitochondrial co-localization coefficient in cancer cells and it could distinguish cancer cells (HeLa) and normal cells (L929) in co-incubated system. In a word, the evidence suggested that the implementation of dual-positive charges strategy greatly improved the sensitivity to SO2 response and the specificity of mitochondrial targeting in cancer cells. Finally, DCP was successfully applied to monitor SO2 fluctuation in cancer cells, tumor tissue and living zebrafish. Thus, this work provides a powerful tool to investigate the role of mitochondrial SO2 in cancer and other related diseases.

Comprehensive analysis of tumor mutation burden and immune microenvironment in prostate cancer.

PURPOSE: Prostate adenocarcinoma (PRAD) is a high incidence of malignant tumor of the urinary system and the second most common male cancer in the world. Immune checkpoint inhibitor (ICIS) therapy is becoming a new hope for cancer treatment. METHODS: To realize the possibility of PRAD patients benefiting from ICIS treatment, we analyzed the mutation spectrum of all PRAD patients, calculated the TMB of each PRAD patient, and divided the patients into high TMB group and low TMB group. Differentially expressed genes (DEGs) between the two groups were identified and path analysis was carried out. The immune cell infiltration of each PRAD patient was evaluated and survival analysis was performed to explore the effect of immune cell infiltration on the prognosis. RESULTS: We found that high TMB was associated with better survival outcomes, with higher TMB scores in young patients, T2 and N0 patients. 28 hub genes were screened by the overlap between 229 DEGs and immune-related genes. T cells CD8 and CD4 memory activated in the high TMB group were higher than those in the low TMB group, while Mast cells resting in the low TMB group were higher than that in the high TMB group. High neutrophil infiltration is associated with poor prognosis in patients with PRAD. Finally, from the immune genes used to construct the prognostic risk model of TMB, it is found that CHP2 and NRG1 are independent prognostic factors of PRAD. CONCLUSIONS: This study provides new insights into the immune microenvironment and potential immunotherapy of PRAD.

Rational engineering of biomimetic flavylium fluorophores for regulating the lysosomal and mitochondrial localization behavior by pH-induced structure switch and application to fluorescence imaging.

Mitochondria and lysosomes, as the important subcellular organelles, play vital roles in cell metabolism and physiopathology. However, there is still no general method to precisely regulate the lysosomal and mitochondrial localization behavior of fluorescent probes except by selecting specific targeting groups. Herein, we proposed a pH-induced structure switch (pHISS) strategy to solve this tricky puzzle. For the proof-of-concept, we have rationally designed and synthesized a series of cationic flavylium derivatives FL-1-9 with tunable pH-induced structure switch through adjusting the electron-donating ability of the substituents. As expected, the co-localization imaging experiments revealed that the lysosomal and mitochondrial localization behavior of FL-1-9 dyes is closely related to their pHISS ability. It is noteworthy that FL cationic dyes with strong electron-donors are not prone to pHISS and can be well enriched in mitochondria, while FL cationic dyes with weak electron-donors are highly susceptible to pHISS and display an unusual lysosome-targeting capability. This also provided a feasible strategy for lysosomal localization without basic groups and presented new application options for some flavylium dyes previously thought to be less stable. Furthermore, FL cationic dyes with medium electron-donor exhibit certain localization abilities both in mitochondria and lysosomes. Finally, through a detailed study of pH-induced structure switch and exploiting the pH inertia brought by the strong electron-donors, a novel NIR ratiometric fluorescent probe with large wavelength-shift was constructed for monitoring mitochondrial H2S in living cells, tumor tissues and living mice, highlighting the value of the pHISS strategy in precisely regulating organelle targeting and constructing corresponding organelle targeting probes.

Differences Between Cancer-Specific Survival of Patients With Anaplastic and Primary Squamous Cell Thyroid Carcinoma and Factors Influencing Prognosis: A SEER Database Analysis.

Purpose: Anaplastic thyroid carcinoma (ATC) and primary squamous cell carcinoma of the thyroid (PSCCTh) have similar histological findings and are currently treated using the same approaches; however, the characteristics and prognosis of these cancers are poorly researched. The objective of this study was to determine the differences in characteristics between ATC and PSCCTh and establish prognostic models. Patients and Methods: All variables of patients with ATC and PSCCTh, diagnosed from 2004-2015, were retrieved from the Surveillance, Epidemiology, and End Results Program (SEER) database. Percentage differences for categorical data were compared using the Chi-square test. Kaplan-Meier curves, log-rank test, and Cox-regression for survival analysis, and C-index value was used to evaluate the performance of the prognostic models. Results: After application of the inclusion and exclusion criteria, a total of 1164 ATC and 124 PSCCTh patients, diagnosed from 2004 to 2015, were included in the study. There were no differences in sex, ethnicity, age, marital status, or percentage of proximal metastases between the two cancers; however, radiotherapy, chemotherapy, incidence of surgical treatment, and presence of multiple primary tumors were higher in patients with ATC than those with PSCCTh. Further cancer-specific survival (CSS) of patients with PSCCTh was better than that of patients with ATC. Prognostic factors were not identical for the two cancers. Multivariate Cox model analysis indicated that age, sex, radiotherapy, chemotherapy, surgery, multiple primary tumors, marital status, and distant metastasis status are independent prognostic factors for CSS in patients with ATC, while for patients with PSCCTh, the corresponding factors are age, radiotherapy, multiple primary tumors, and surgery. The C-index values of the two models were both > 0.8, indicating that the models exhibited good discriminative ability. Conclusion: Prognostic factors influencing CSS were not identical in patients with ATC and PSCCTh. These findings indicate that different clinical treatment and management plans are required for patients with these two types of thyroid cancer.

Numerical Investigation into the Gas Production from Hydrate Deposit under Various Thermal Stimulation Modes in a Multi-Well System in Qilian Mountain.

The primary objective of this study was to investigate the energy recovery performance of the permafrost hydrate deposit in the Qilian Mountain at site DK-2 using depressurization combined with thermal injection by the approach of numerical simulation. A novel multi-well system with five horizontal wells was applied for large-scale hydrate mining. The external heat is provided by means of water injection, wellbore heating, or the combinations of them through the central horizontal well, while the fluids are extracted outside from the other four production wells under constant depressurization conditions. The injected water can carry the heat into the hydrate deposit with a faster rate by thermal convection regime, while it also raises the local pressure obviously, which results in a strong prohibition effect on hydrate decomposition in the region close to the central well. The water production rate is always controllable when using the multi-well system. No gas seepage is observed in the reservoir due to the resistance of the undissociated hydrate. Compared with hot water injection, the electric heating combined with normal temperature water flooding basically shows the same promotion effect on gas recovery. Although the hydrate regeneration is more severe in the case of pure electric heating, the external heat can be more efficiently assimilated by gas hydrate, and the efficiency of gas production is best compared with the cases involving water injection. Thus, pure wellbore heating without water injection would be more suitable for hydrate development in deposits characterized by low-permeability conditions.

Sensitive Detection of Single-Nucleotide Polymorphisms by Solid Nanopores Integrated With DNA Probed Nanoparticles.

Single-nucleotide polymorphisms (SNPs) are the abundant forms of genetic variations, which are closely associated with serious genetic and inherited diseases, even cancers. Here, a novel SNP detection assay has been developed for single-nucleotide discrimination by nanopore sensing platform with DNA probed Au nanoparticles as transport carriers. The SNP of p53 gene mutation in gastric cancer has been successfully detected in the femtomolar concentration by nanopore sensing. The robust biosensing strategy offers a way for solid nanopore sensors integrated with varied nanoparticles to achieve single-nucleotide distinction with high sensitivity and spatial resolution, which promises tremendous potential applications of nanopore sensing for early diagnosis and disease prevention in the near future.

Liver fibrosis promotes immune escape in hepatocellular carcinoma via GOLM1-mediated PD-L1 upregulation.

Immune checkpoint blockade is considered a breakthrough in cancer treatment. However, with the low response rates and therapeutic resistance of patients with hepatocellular carcinoma (HCC), the challenges facing the application of this treatment are tremendous. Liver fibrosis is a key driver of tumor immune escape, the underlying mechanism has never been clarified. This study sought to explore the role of liver fibrosis in regulating tumor-infiltrating lymphocytes (TILs) and inducing tumor immunosuppression. Ninety-nine fixed HCC tissue samples were used to analyze the association between liver fibrosis and immune escape using immunohistochemistry. In HCC patients, low FIB-4 values and high CD8+ T cell infiltration were correlated with prolonged survival. Elevated expression of immune checkpoints and attenuated antitumor immunity were observed in CCl4-induced mice liver fibrosis models and human fibrotic livers compared to control group. GOLM1 levels were increased in livers of patients with fibrosis and mice in response to CCl4-induced liver fibrosis. CD8+ T cell infiltrations were significantly decreased and PD-L1 expression was significantly increased in tumor tissues from hepatocyte-specific GOLM1 transgenic mice (Alb/GOLM1 mice) inducing chemical carcinogenesis compared to their corresponding control WT mice. GOLM1 induced PD-L1 expression via EGFR pathway activation. EGFR inhibitors, especially together with anti-PD-L1 therapy, improved the efficacy of immunotherapy in HCC. These findings illustrate the importance of liver fibrosis-induced immunosuppression as a tumor-promoting mechanism. GOLM1, which is highly upregulated in the fibrotic liver, regulates tumor microenvironmental immune escape via the EGFR/PD-L1 signaling pathway. EGFR blockade may bolster the efficacy of immune checkpoint inhibitors for HCC treatment.

Phenotypic and Cellular Characteristics of a Stromal Vascular Fraction/Extracellular Matrix Gel Prepared Using Mechanical Shear Force on Human Fat.

The retention of fat-derived grafts remains a challenge for regenerative medicine. Fat aspirates from patients undergoing liposuction were prepared into standard Coleman fat grafts or further isolated using mechanical shear force to prepare a stromal vascular fraction (SVF)/extracellular matrix (ECM) gel. The retention rate of the SVF/ECM gel was significantly higher than that of the Coleman fat at 3, 14, 28, and 60 days following transplantation on the backs of nude mice. The viscosity of the fat was directly proportional to the shearing force. Although the mechanical isolation did not affect the total number of cells, it significantly decreased the number of living cells. Flow cytometry showed a greater number of mesenchymal stem cells, supra-adventitial (SA)-adipose stromal cells (ASCs), and adipose-derived stem cells but a lower number of endothelial progenitor cells in the SVF/ECM gel than in the Coleman fat. Thus, mechanical isolation of fat can increase the pluripotency of adipocytes, which can improve graft retention in cell therapy.

Case Report: A Case of Sintilimab-Induced Cystitis/Ureteritis and Review of Sintilimab-Related Adverse Events.

Immune checkpoint inhibitors (ICIs) have been proven to be beneficial in multiple advanced malignancies. However, the widespread use of ICIs also occurred with various immune-related adverse events (irAEs). Here, we first report a case of sintilimab-related cystitis/ureteritis. A 53-year-old man with driver gene-negative pulmonary adenocarcinoma (cT1cN3M1c, Stage IVB) was being treated with sintilimab in combination of paclitaxel-albumin and bevacizumab as second-line treatment. He was hospitalized for haematuria, pollakiuria, painful micturition and low back pain after three courses. Urinalysis showed red blood cells (RBCs) and white blood cells (WBCs) were obviously increased, and serum creatinine (sCr) level was also significantly elevated. Urine culture and cytology were both negative, and cystoscopy revealed diffused redness of bladder mucosa. Urinary ultrasonography showed mild hydronephrosis and dilated ureter. The patient was diagnosed as immunotherapy-related cystitis/ureteritis after a multidisciplinary team (MDT) meeting. Once the diagnosis was made, corticosteroid therapy was given, which rapidly resolved the patient's symptoms and signs. Computer tomography angiography (CTA) and CT urography (CTU) was conducted after sCr level was back to normal and demonstrated ureter dilation and hydroureter. Once symptoms relieved, bladder biopsy was performed and confirmed the bladder inflammation. The patient was subsequently switched to maintenance dose of methylprednisolone and tapered gradually. Since sintilimab has been used in advanced malignancies, we first reported a rare case of sintilimab-induced cystitis/ureteritis and summarized sintilimab-related adverse events to improve the assessment and management of irAEs.

Neuromedin U: potential roles in immunity and inflammation.

Since the discovery of neuromedin U (NmU) from porcine spinal cord in 1985, this neuropeptide has been subsequently identified in many other species with multiple physiological and pathophysiological roles detected, ranging from smooth muscle contraction, feeding, energy balance to tumorigenesis. Intriguingly, NmU is also emerging to play pro-inflammatory roles involving immune cell activation and cytokine release in a neuron-dependent or neuron-independent manner. The NmU-mediated inflammatory responses have already been observed in worm infection, sepsis, autoimmune arthritis and allergic animal models. In this review, we focus on the roles of NmU in immunity and inflammation by highlighting the interactions between NmU and immune cells, summarizing the signalling mechanism involved in their reactions and discussing its potential contributions to inflammatory diseases.

CEG 2.0: an updated database of clusters of essential genes including eukaryotic organisms.

Essential genes are key elements for organisms to maintain their living. Building databases that store essential genes in the form of homologous clusters, rather than storing them as a singleton, can provide more enlightening information such as the general essentiality of homologous genes in multiple organisms. In 2013, the first database to store prokaryotic essential genes in clusters, CEG (Clusters of Essential Genes), was constructed. Afterward, the amount of available data for essential genes increased by a factor >3 since the last revision. Herein, we updated CEG to version 2, including more prokaryotic essential genes (from 16 gene datasets to 29 gene datasets) and newly added eukaryotic essential genes (nine species), specifically the human essential genes of 12 cancer cell lines. For prokaryotes, information associated with drug targets, such as protein structure, ligand-protein interaction, virulence factor and matched drugs, is also provided. Finally, we provided the service of essential gene prediction for both prokaryotes and eukaryotes. We hope our updated database will benefit more researchers in drug targets and evolutionary genomics. Database URL: http://cefg.uestc.cn/ceg.