Concurrent fabry disease and immunoglobulin a nephropathy: a case report.

BACKGROUND: Fabry disease (FD) is an X-linked, hereditary dysfunction of glycosphingolipid storage caused by mutations in the GLA gene encoding alpha-galactosidase A enzyme. In rare cases, FD may coexist with immunoglobulin A nephropathy (IgAN). We describe a case of concurrent FD, IgAN, and dilated cardiomyopathy-causing mutations in the TTN and BAG3 genes, which has not been reported previously. CASE PRESENTATION: A 60-year-old female patient was admitted with a one-week history of facial and lower-limb edema, two-year history of left ventricular hypertrophy and sinus bradycardia, and recurring numbness and pain in three lateral digits with bilateral thenar muscle atrophy. Renal biopsy revealed concurrent FD (confirmed via an alpha-galactosidase A enzyme assay, Lyso-GL-3 quantification, and GLA gene sequencing) and IgAN. Heterozygous mutations in the TTN (c.30,484 C > A;p.P10162T) and BAG3 (c.88 A > G;p.I30V) genes were observed. The patient reported that two of her brothers had undergone kidney transplantation; one died suddenly at 60 years of age, and the other required a cardiac pacemaker. The 35-year-old son of the patient was screened for the GLA gene mutation and found to be positive for the same mutation as the patient. The patient was administered oral losartan (50 mg/day). Enzyme replacement therapy was refused due to financial reasons. Her renal and cardiac functions were stable yet worth closely monitoring during follow-up. CONCLUSION: The family history of patients with concurrent heart and renal diseases should be assessed in detail. Genetic testing and histological examinations are essential for diagnosing FD with IgAN.

Gαi1/3 mediate Netrin-1-CD146-activated signaling and angiogenesis.

Netrin-1 binds to the high-affinity receptor CD146 to activate downstream signaling and angiogenesis. Here, we examine the role and underlying mechanisms of G protein subunit alpha i1 (Gαi1) and Gαi3 in Netrin-1-induced signaling and pro-angiogenic activity. In mouse embryonic fibroblasts (MEFs) and endothelial cells, Netrin-1-induced Akt-mTOR (mammalian target of rapamycin) and Erk activation was largely inhibited by silencing or knockout of Gαi1/3, whereas signaling was augmented following Gαi1/3 overexpression. Netrin-1 induced Gαi1/3 association with CD146, required for CD146 internalization, Gab1 (Grb2 associated binding protein 1) recruitment and downstream Akt-mTOR and Erk activation. Netrin-1-induced signaling was inhibited by CD146 silencing, Gab1 knockout, or Gαi1/3 dominant negative mutants. Netrin-1-induced human umbilical vein endothelial cell (HUVEC) proliferation, migration and tube formation were inhibited by Gαi1/3 short hairpin RNA (shRNA), but were potentiated by ectopic Gαi1/3 overexpression. In vivo, intravitreous injection of Netrin-1 shRNA adeno-associated virus (AAV) significantly inhibited Akt-mTOR and Erk activation in murine retinal tissues and reduced retinal angiogenesis. Endothelial knockdown of Gαi1/3 significantly inhibited Netrin1-induced signaling and retinal angiogenesis in mice. Netrin-1 mRNA and protein expression were significantly elevated in retinal tissues of diabetic retinopathy (DR) mice. Importantly, silence of Netrin-1, by intravitreous Netrin-1 shRNA AAV injection, inhibited Akt-Erk activation, pathological retinal angiogenesis and retinal ganglion cells degeneration in DR mice. Lastly, Netrin-1 and CD146 expression is significantly increased in the proliferative retinal tissues of human proliferative diabetic retinopathy patients. Together, Netrin-1 induces CD146-Gαi1/3-Gab1 complex formation to mediate downstream Akt-mTOR and Erk activation, important for angiogenesis in vitro and in vivo.

[A preliminary study on the role of V-domain Ig suppressor of T cell activation in juvenile idiopathic arthritis]. / Tç»†èƒžæ´»åŒ–å ç–«çƒè›‹ç™½æŠ‘åˆ¶Våž‹ç»“æž„åŸŸåœ¨å¹¼å¹´ç‰¹å‘æ€§å ³èŠ‚ç‚Žä¸­ä½œç”¨çš„åˆæ­¥ç ”ç©¶.

OBJECTIVES: To study the expression of V-domain Ig suppressor of T cell activation (VISTA) in peripheral blood of children with juvenile idiopathic arthritis (JIA) and its role in the pathogenesis of JIA. METHODS: In this prospective study, peripheral blood was collected from 47 children with different subtypes of JIA and 10 healthy children. Flow cytometry was used to measure the expression levels of VISTA, interferon-γ (IFN-γ), and tumor necrosis factor-α (TNF-α) on CD14+ mononuclear cells, CD4+ T lymphocytes, and CD8+ T lymphocytes. RESULTS: The children with JIA had a significantly lower expression level of VISTA than the healthy children (P<0.05). There was a significant difference in the expression of VISTA between the children with different subtypes of JIA, with the lowest expression level in those with systemic JIA (P<0.05). There was also a significant difference in the expression of VISTA between different immune cells, with a significantly higher expression level on the surface of monocytes (P<0.05). Correlation analysis showed that VISTA was negatively correlated with the expression of IFN-γ and TNF-α on CD4+ T cells (r=-0.436 and -0.382 respectively, P<0.05), CD8+ T cells (r=-0.348 and -0.487 respectively, P<0.05), and CD14+ mononuclear cells (r=-0.582 and -0.603 respectively, P<0.05). CONCLUSIONS: The insufficient expression of VISTA may be associated with the pathogenesis of JIA, and enhancing the immunomodulatory effect of VISTA might be one option for the treatment of JIA in the future.

Collagenous gastritis in a young Chinese woman: A case report.

BACKGROUND: Collagenous gastritis (CG) is a rare condition whose pathogenesis may be related to immune abnormalities. We report a case of CG from China. CASE SUMMARY: A 24-year-old woman presented with recurrent abdominal distension and discomfort for 3 mo. Upper gastrointestinal endoscopy found diffuse nodular elevation-depression changes in the mucosa of the entire gastric corpus. Endoscopic ultrasound showed predominant involvement of the lamina propria and submucosa, and computed tomography imaging showed mild enhancement of the gastric wall. Pathological histology revealed that the thickness of the subepithelial collagen band was about 40 µm, and the Masson trichrome staining result was positive and the Congo red staining result was negative. This case is consistent with the child-adolescent type of CG. CONCLUSION: Serum pepsinogen I, pepsinogen II, pepsinogen I/II ratio, and gastrin-17 may be potential non-invasive monitoring markers. Currently, treatments for CG vary, and the likely prognosis is unknown. Individual cases of gastric cancer in patients with CG have been reported.

The bevacizumab plus oxaliplatin-based chemotherapy regimen is more suitable for metastatic colorectal cancer patients with a history of schistosomiasis: a clinical retrospective analysis.

Background: The basic platelet counts of schistosomiasis patients are low. If it does not meet the requirements for chemotherapy, the patient's treatment will not be carried out, which directly affects their prognosis. Therefore the impact of treatment on platelet counts is critically important. The effects of bevacizumab plus oxaliplatin-based chemotherapy and bevacizumab plus irinotecan-based chemotherapy regimens on platelets are different but have not been determined. In order to find a more suitable plan for metastatic colorectal cancer (mCRC) patients with a history of schistosomiasis, we conducted a retrospective analysis of mCRC patients and evaluated the impact of bevacizumab on their platelets. Methods: The medical records of all mCRC patients with a history of schistosomiasis who received oxaliplatin-based chemotherapy or irinotecan-based chemotherapy as first-line treatment for no less than 4 cycles, with or without bevacizumab from September 1, 2017, to June 30, 2019, in Kunshan Hospital were reviewed. Six-month cumulative incidence rates of splenomegaly and thrombocytopenia of chemotherapy with and without bevacizumab groups, oxaliplatin-based chemotherapy with and without bevacizumab groups, irinotecan-based chemotherapy with and without bevacizumab groups were compared from the first cycle until the completion of chemotherapy using Kaplan-Meier analysis and Log-rank test. Results: Evaluable splenic enlargement and thrombocytopenia results were obtained from 153 mCRC patients. The 6-month cumulative incidence rates of splenomegaly (23.3% vs. 55%; P=0.01) and that of thrombocytopenia (43.8% vs. 57.5%; P=0.40) were lower in the bevacizumab group than the non-bevacizumab group, however there were no statistical differences for the rates of thrombocytopenia. For patients treated with oxaliplatin, the rates of splenomegaly (19.5% vs. 66.7%; P=0.01) and thrombocytopenia (31.7% vs. 77.2%; P=0.02) were lower in the bevacizumab-treated cohort than that in the non-bevacizumab cohort. When stratified for irinotecan, there were no statistical differences in the frequency of splenomegaly between the two groups. However, the rates of thrombocytopenia were higher in the bevacizumab-treated cohort than that in the non-bevacizumab cohort (59.4% vs. 8.7%; P=0.01). Conclusions: The bevacizumab plus oxaliplatin-based chemotherapy regimen is safer for mCRC patients with a history of schistosomiasis, especially for patients with a lower platelet count.

SOMCL-19-133, a novel, selective, and orally available inhibitor of NEDD8-activating enzyme (NAE) for cancer therapy.

Inhibition of the NEDD8-activating enzyme (NAE), the key E1 enzyme in the neddylation cascade, has been considered an attractive anticancer strategy with the discovery of the first-in-class NAE inhibitor, MLN4924. In this study, we identified SOMCL-19-133 as a highly potent, selective, and orally available NAE inhibitor, which is an analog to AMP. It effectively inhibited NAE with an IC50 value of 0.36 nM and exhibited more than 2855-fold selectivity over the closely related Ubiquitin-activating enzyme (UAE). It is worth noting that treatment with SOMCL-19-133 prominently inhibited Cullin neddylation and delayed the turnover of a panel of Cullin-RING ligases (CRLs) substrates (e.g., Cdt1, p21, p27, and Wee1) at lower effective concentrations than that of MLN4924, subsequently caused DNA damage and Chk1/Chk2 activation, and thus triggered cell cycle arrest and apoptosis. Moreover, SOMCL-19-133 exhibited potent antiproliferative activity against a broad range of human tumor cell lines (mean IC50 201.11 nM), which was about 5.31-fold more potent than that of MLN4924. In vivo, oral delivery treatments with SOMCL-19-133, as well as the subcutaneous injection, led to significant tumor regression in mouse xenograft models. All of the treatments were well tolerated on a continuous daily dosing schedule. Compared with MLN4924, SOMCL-19-133 had a 5-fold higher peak plasma concentration, lower plasma clearance, and a 4-fold larger area under the curve (AUClast). In conclusion, SOMCL-19-133 is a promising preclinical candidate for treating cancers owing to its profound in vitro and in vivo efficacy and favorable pharmacokinetic properties.

Prognostic Nutritional Index Predicts Outcome of PD-L1 Negative and MSS Advanced Cancer Treated with PD-1 Inhibitors.

Purpose: Tumor mutational burden (TMB), microsatellite instability-high (MSI-H), and expression of programmed death ligand-1 (PD-L1) have emerged as predictive biomarkers for responsiveness to immune checkpoint inhibitors (ICIs) in several cancer types. However, for patients with negative PD-L1 expression, or microsatellite stability (MSS), some cases may experience favorable response to immunotherapy, and there is currently a lack of good relevant predictors. We tried to introduce several peripheral blood markers for predicting treatment outcome and immune-related adverse events (irAEs) in PD-L1 negative and MSS patients. Methods: A retrospective study of 142 PD-L1 negative and MSS patients was carried out. The association of peripheral blood markers including lactate dehydrogenase (LDH), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), albumin-to-globulin ratio (AGR), prognostic nutrition index (PNI), and other factors with clinicopathological characters and prognosis were assessed by Cox regression and Kaplan-Meier methods. Results: Lower level of PNI and poor performance status (ECOG score of 2) was correlated with significantly shorter overall survival (OS) and worse outcome of ICIs. The multivariate analysis revealed that PNI (for OS HR = 0.465, 95% CI: 0.236-0.916, p = 0.027; for PFS HR = 0.493, 95% CI: 0.251-0.936, p = 0.031) and ECOG score (for OS HR = 4.601, 95% CI: 2.676-7.910, p < 0.001; for PFS HR = 2.830, 95% CI: 1.707-4.691, p < 0.001) were independent prognostic factors for OS and PFS. NLR was related to the onset of irAEs. Conclusions: Pretreatment level of PNI and NLR, beyond PD-L1 expression and MSS, can improve the predictive accuracy for immunotherapy outcomes and has the potential to expand the candidate pool of patients for treatment with ICIs.

Human umbilical cord-derived mesenchymal stem cells promote repair of neonatal brain injury caused by hypoxia/ischemia in rats.

Administration of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) is believed to be an effective method for treating neurodevelopmental disorders. In this study, we investigated the possibility of hUC-MSCs treatment of neonatal hypoxic/ischemic brain injury associated with maternal immune activation and the underlying mechanism. We established neonatal rat models of hypoxic/ischemic brain injury by exposing pregnant rats to lipopolysaccharide on day 16 or 17 of pregnancy. Rat offspring were intranasally administered hUC-MSCs on postnatal day 14. We found that polypyrimidine tract-binding protein-1 (PTBP-1) participated in the regulation of lipopolysaccharide-induced maternal immune activation, which led to neonatal hypoxic/ischemic brain injury. Intranasal delivery of hUC-MSCs inhibited PTBP-1 expression, alleviated neonatal brain injury-related inflammation, and regulated the number and function of glial fibrillary acidic protein-positive astrocytes, thereby promoting plastic regeneration of neurons and improving brain function. These findings suggest that hUC-MSCs can effectively promote the repair of neonatal hypoxic/ischemic brain injury related to maternal immune activation through inhibition of PTBP-1 expression and astrocyte activation.

[Establishment of A Mouse Model of Hematopoietic Stem Cell Transplantation Infected with Respiratory Syncytial Virus].

OBJECTIVE: To establish a mouse model of respiratory syncytial virus (RSV) infection after hematopoietic stem cell transplantation, so as to lay the foundation for future research on RSV infection and related complications after hematopoietic stem cell transplantation. METHODS: Bone marrow cells and spleen cells were transplanted to C57BL/6 mice after myeloablative treatment to establish a mouse model of allogeneic hematopoietic stem cell transplantation. The chimerism rate was detected by flow cytometry 3 and 7 weeks after transplantation. The transplanted mice were infected with RSV by nasal drops. The lung tissues were collected 5 days after infection for identification of infection, and lung tissues were analyzed for pathology 2 weeks and 2 months after infection. RESULTS: The chimerism rate was > 90% at 3 and 7 weeks after transplantation. Successful infection was detected 5 days after RSV infection, and there were severe and persistent pathological changes in the lung tissues of the mice 2 weeks and 2 months after infection. CONCLUSION: RSV infection in stable chimeric mice after hematopoietic stem cell transplantation can cause significantly persistent lung disease, which lays foundation for the prevention and treatment of RSV infection and the mechanism of later bronchiolitis obliterans after hematopoietic stem cell transplantation.

Comparison of Radiation Dose and Image Quality Between Split-Filter Twin Beam Dual-Energy Images and Single-Energy Images in Single-Source Contrast-Enhanced Chest Computed Tomography.

OBJECTIVE: To compare image quality and radiation dose of split-filter TwinBeam dual-energy (SF-TBDE) with those of single-energy images (SECT) in the contrast-enhanced chest computed tomography (CT). METHODS: Two hundred patients who underwent SF-TBDE (n = 100) and SECT (n = 100) contrast-enhanced chest scanning were retrospectively analyzed. The contrast-to-noise ratio (CNR) and figure of merit (FOM)-CNR of 5 structures (lung, aorta, pulmonary artery, thyroid, and erector spinae) were calculated and subjectively evaluated by 2 independent radiologists. Radiation dose was compared using volume CT dose index and size-specific dose estimate. RESULTS: The CNR and FOM-CNR of lung and erector spinae in SF-TBDE were higher than those of SECT (P < 0.001). The differences in the subjective image quality between the 2 groups were not significant (P = 0.244). Volume CT dose index and size-specific dose estimate of SF-TBDE were lower than those of SECT (6.60 ± 1.56 vs 7.81 ± 3.02 mGy, P = 0.001; 9.25 ± 1.60 vs. 10.55 ± 3.54; P = 0.001). CONCLUSIONS: The SF-TBDE CT can provide similar image quality at a lower radiation dose compared with SECT.

LncRNA PINK1-AS promotes Gαi1-driven gastric cancer tumorigenesis by sponging microRNA-200a.

Gastric cancer (GC) is one of the leading causes of human mortality around the world. We have previously shown that Gαi1 (the inhibitory subunit 1 of the heterotrimeric guanine nucleotide-binding protein) recruitment to ligand-activated receptor tyrosine kinases (RTKs) is essential for signaling. Testing its role in GC cancer-promoting functions, we found that Gαi1 is upregulated in human GC, correlating with poor overall survival. In established and primary human GC cells, Gαi1 shRNA (small hairpin RNA) or knockout produced significant anti-GC cell activity, proliferation and migration was inhibited, and apoptosis was activated. Conversely, ectopic Gαi1 overexpression promoted proliferation and migration of GC cells in vitro. By examining the tumor-suppressive miRNA microRNA-200a (miR-200a), we found that miR-200a directly silenced Gαi1 to induce anti-GC cell activity. The expression of miR-200a was downregulated in human GC, correlating with upregulation of a novel miR-200a-targeting long non-coding RNA (LncRNA), PINK1 (PTEN Induced Kinase 1)-AS. RNA immunoprecipitation, RNA-pull down, and RNA fluorescence in situ hybridization assays confirmed that PINK1-AS directly binds to miR-200a. Silencing PINK1-AS in GC cells led to miR-200a accumulation, Gαi1 downregulation, and inhibition of GC cell progression in vitro, whereas PINK1-AS upregulation produced the converse results. Significantly, anti-GC cell activity induced by PINK1-AS shRNA was ameliorated by the expression of miR-200a antisense or the 3'-UTR (untranslated region)-depleted Gαi1. In vivo, the growth of subcutaneous MGC-803 xenografts in nude mice was inhibited by PINK1-AS shRNA, but accelerated by PINK1-AS overexpression. Patient-derived GC xenograft growth in nude mice was largely inhibited after intratumoral injection of PINK1-AS shRNA lentivirus. In conclusion, PINK1-AS promotes Gαi1-driven GC progression by sponging miR-200a.

Renal failure and hepatitis following ingestion of raw grass carp gallbladder: A case report.

BACKGROUND: Fish gallbladder has long been used as a folk remedy in Asian countries. Multiple organ damage after ingestion of fish gallbladder resulting in near mortality has been known to us. Here, we describe a case of acute renal failure (ARF) and hepatitis due to grass carp gallbladder poisoning and review the literature. CASE SUMMARY: A previously healthy, 50-year-old woman was admitted to our hospital with a 2-d history of generalized abdominal pain and repeated vomiting following ingestion of two raw grass carp gallbladders in an attempt to alleviate her cough. She developed anuria on day 4 with markedly elevated serum creatinine, urea, bilirubin, alanine aminotransferase, and aspartate aminotransferase. Based on thorough evaluation of her history and prompt biochemical investigations, we diagnosed her with ARF and hepatitis secondary to fish gallbladder poisoning. Her renal biopsy revealed acute tubular necrosis, following which she underwent six sessions of conventional hemodialysis due to renal failure. Supportive treatment with gastric mucosal protectant and liver protectant was administered for targeted organ protection. The patient's liver function gradually recovered, and serum creatinine was 164 mmol/L at discharge on day 24. Over a follow-up period of 2 wk, her renal function completely recovered. CONCLUSION: Physicians should be mindful of toxic complications of raw grass carp gallbladder ingestion and we should promote awareness to reduce incidences of food poisoning.

Glycogen synthase kinase 3ß inhibition synergizes with PARP inhibitors through the induction of homologous recombination deficiency in colorectal cancer.

Monotherapy with poly ADP-ribose polymerase (PARP) inhibitors results in a limited objective response rate (≤60% in most cases) in patients with homologous recombination repair (HRR)-deficient cancer, which suggests a high rate of resistance in this subset of patients to PARP inhibitors (PARPi). To overcome resistance to PARPi and to broaden their clinical use, we performed high-throughput screening of 99 anticancer drugs in combination with PARPi to identify potential therapeutic combinations. Here, we found that GSK3 inhibitors (GSK3i) exhibited a strong synergistic effect with PARPi in a panel of colorectal cancer (CRC) cell lines with diverse genetic backgrounds. The combination of GSK3ß and PARP inhibition causes replication stress and DNA double-strand breaks, resulting in increased anaphase bridges and abnormal spindles. Mechanistically, inhibition or genetic depletion of GSK3ß was found to impair the HRR of DNA and reduce the mRNA and protein level of BRCA1. Finally, we demonstrated that inhibition or depletion of GSK3ß could enhance the in vivo sensitivity to simmiparib without toxicity. Our results provide a mechanistic understanding of the combination of PARP and GSK3 inhibition, and support the clinical development of this combination therapy for CRC patients.

Serum level of interleukin-35 as a potential prognostic factor for gastric cancer.

AIMS: Interleukin-35 (IL-35), a novel anti-inflammatory cytokine, has recently been implicated in tumor development, progression, and survival. However, the relationship between serum IL-35 levels and gastric cancer (GC) is inconclusive. Here, we performed this study to clarify the role of serum level of IL-35 in GC patients. METHODS: We enrolled 180 GC patients and 170 healthy controls and used enzyme-linked immunosorbent assay to detect serum IL-35 levels. The clinical relevance between IL-35 and clinical pathology parameters was assessed. Univariate and multivariate logistic regressions were used to determine the feasibility of IL-35 as a clinical biomarker. RESULTS: We observed that serum IL-35 levels were significantly higher in GC patients (17.559 ± 13.266 pg/mL) than in healthy controls (8.077 ± 3.801 pg/mL, P < .001). High serum IL-35 levels were significantly associated with clinical stage (P = .048) and Helicobacter pylori (HP) infection (P < .001). The Kaplan-Meier survival analysis indicated that patients in the high-IL-35 group had poor overall survival (OS) and progression-free survival (PFS) (median OS: 26.0 vs 36.0 months, P < .001; median PFS: 18.0 vs.26.0 months, P = .044). Multivariate analyses demonstrated that serum IL-35 was an independent prognostic factor for GC (OS: hazard ratio [HR] = 1.031 [95% CI, 1.017-1.045], P < .001; PFS: HR = 1.029 [95% CI, 1.015-1.043], P < .001). CONCLUSIONS: High serum IL-35 levels are associated with poor disease prognosis in GC patients, and it may be become a new and promising biomarker for prognosis of gastric cancer.

GDC-0349 inhibits non-small cell lung cancer cell growth.

Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related human mortality with a clear need for new therapeutic intervention. GDC-0349 is a potent and selective ATP-competitive mTOR inhibitor. In A549 cells and primary human NSCLC cells, GDC-0349 inhibited cell growth, proliferation, cell cycle progression, migration and invasion, while inducing significant apoptosis activation. Although GDC-0349 blocked Akt-mTORC1/2 activation in NSCLC cells, it also exerted cytotoxicity in Akt1-knockout A549 cells. Furthermore, restoring Akt-mTOR activation by a constitutively-active Akt1 only partially attenuated GDC-0349-induced A549 cell apoptosis, indicating the existence of Akt-mTOR-independent mechanisms. In NSCLC cells GDC-0349 induced sphingosine kinase 1 (SphK1) inhibition, ceramide accumulation, JNK activation and oxidative injury. Conversely, N-acetylcysteine, the JNK inhibitor and sphingosine 1-phosphate alleviated GDC-0349-induced NSCLC cell apoptosis. In vivo, daily oral administration of GDC-0349 potently inhibited NSCLC xenograft growth in mice. Akt-mTOR in-activation, SphK1 inhibition, JNK activation and oxidative stress were detected in NSCLC xenograft tissues with GDC-0349 administration. In summary, GDC-0349 inhibits NSCLC cell growth via Akt-mTOR-dependent and Akt-mTOR-independent mechanisms.

The therapeutic effect of the BRD4-degrading PROTAC A1874 in human colon cancer cells.

A1874 is a novel BRD4-degrading proteolysis targeting chimera (PROTAC). In primary colon cancer cells and established HCT116 cells, A1874 potently inhibited cell viability, proliferation, cell cycle progression, as well as cell migration and invasion. The BRD4-degrading PROTAC was able to induce caspase and apoptosis activation in colon cancer cells. Furthermore, A1874-induced degradation of BRD4 protein and downregulated BRD-dependent genes (c-Myc, Bcl-2, and cyclin D1) in colon cancer cells. Significantly, A1874-induced anti-colon cancer cell activity was more potent than the known BRD4 inhibitors (JQ1, CPI203, and I-BET151). In BRD4-knockout colon cancer cells A1874 remained cytotoxic, indicating the existence of BRD4-independent mechanisms. In addition to BRD4 degradation, A1874 cytotoxicity in colon cancer cells was also associated with p53 protein stabilization and reactive oxygen species production. Importantly, the antioxidant N-acetyl-cysteine and the p53 inhibitor pifithrin-α attenuated A1874-induced cell death and apoptosis in colon cancer cells. In vivo, A1874 oral administration potently inhibited colon cancer xenograft growth in severe combined immuno-deficient mice. BRD4 degradation and p53 protein elevation, as well as apoptosis induction and oxidative stress were detected in A1874-treated colon cancer tissues. Together, A1874 inhibits colon cancer cell growth through both BRD4-dependent and -independent mechanisms.

p38γ overexpression promotes osteosarcoma cell progression.

Osteosarcoma (OS) is the most common primary bone malignancy in the adolescent population. Recent studies demonstrate that p38 gamma (p38γ) phosphorylates retinoblastoma (Rb) to promote cyclin expression, cell-cycle entry and tumorigenesis. Studying the potential function of p38γ in human OS, we show that p38γ mRNA and protein expression are significantly elevated in OS tissues and OS cells, whereas its expression is relatively low in normal bone tissue and in human osteoblasts/osteoblastic cells. Knockdown of p38γ in established (U2OS) and primary human OS cells potently inhibited cell growth, proliferation, migration and invasion, while promoting cell apoptosis. Furthermore, CRISPR/Cas9-induced p38γ knockout inhibited human OS cell progression in vitro. Conversely, ectopic overexpression of p38γ in primary human OS cells augmented cell growth, proliferation and migration. Signaling studies show that retinoblastoma (Rb) phosphorylation and cyclin E1/cyclin A expression were decreased following p38γ shRNA knockdown and knockout, but increased after ectopic p38γ overexpression. Collectively, these results show that p38γ overexpression promotes human OS cell progression.

A carbon nanomaterial derived from a nanoscale covalent organic framework for photothermal therapy in the NIR-II biowindow.

Herein, we report a microporous carbon nanomaterial that was generated from a nanoscale covalent organic framework precursor via a simple pyrolysis approach. The obtained carbon-based nanoparticles possessed a broad NIR absorption capacity and exhibited a high level of photothermal conversion ability (η = 50.6%) in the NIR-II biowindow. Its excellent PTT antitumor efficiency was fully evidenced by in vitro and in vivo experiments under 1064 nm laser irradiation.

The therapeutic value of SC66 in human renal cell carcinoma cells.

The PI3K-AKT-mTOR cascade is required for renal cell carcinoma (RCC) progression. SC66 is novel AKT inhibitor. We found that SC66 inhibited viability, proliferation, migration and invasion of RCC cell lines (786-O and A498) and patient-derived primary RCC cells. Although SC66blocked AKT-mTORC1/2 activation in RCC cells, it remained cytotoxic in AKT-inhibited/-silenced RCC cells. In RCC cells, SC66 cytotoxicity appears to occur via reactive oxygen species (ROS) production, sphingosine kinase 1inhibition, ceramide accumulation and JNK activation, independent of AKT inhibition. The ROS scavenger N-acetylcysteine, the JNK inhibitor (JNKi) and the anti-ceramide sphingolipid sphingosine-1-phosphate all attenuated SC66-induced cytotoxicity in 786-O cells. In vivo, oral administration of SC66 potently inhibited subcutaneous 786-O xenograft growth in SCID mice. AKT-mTOR inhibition, SphK1 inhibition, ceramide accumulation and JNK activation were detected in SC66-treated 786-O xenograft tumors, indicating that SC66 inhibits RCC cell progression through AKT-dependent and AKT-independent mechanisms.