Placement of a drainage tube in the ileac lumen following laparoscopic appendectomy: A case report and literature review.

RATIONALE: Ileal perforation caused by the insertion of a drainage tube is a rare complication. Hence, the utilization of surgical drains in abdominal surgery remains controversial. At present, there is a trend to reduce the utilization of drains in abdominal surgery, although certain situations may necessitate their application. PATIENT CONCERNS: A 25-year-old Chinese woman presented with a history of right lower abdominal pain persisting for 10 days. Imaging examinations, including abdominal computed tomography and ultrasound, identified low-density lesions measuring 10 × 8 × 8cm3 in the right lower abdomen, which are consistent with perforated appendicitis complicated by a peri-appendiceal abscess. A laparoscopic appendectomy was carried out. On the 5th postoperative day, the drainage fluid changed to a grass-green color (80mL). Imaging with retrograde contrast through the drainage tube revealed that the 26 Fr silicon rubber drainage tube tip was positioned 50cm away from the ileocecal junction within the ileum. Both the ileal and ileocecal regions appeared well-developed. INTERVENTION AND OUTCOMES: Oral intake was suspended, and the patient received antacids, somatostatin, antibiotics, and total parenteral nutrition. On the 19th postoperative day, a follow-up imaging procedure using retrograde contrast through the drainage tube indicated that the tube tip was sealed. The treatment concluded on day 33 postoperatively, and the patient was discharged. DISCUSSION AND CONCLUSION: Ileal perforation due to an abdominal drainage tube following laparoscopic appendectomy constitutes a rare but serious complication. However, due to the adhesion and inflammatory changes around the abscess, laparoscopic dissection becomes a challenging and risky process, and the surgical skills and experiences are particularly important. Removing the abdominal drainage tube promptly based on the characteristics of the drainage fluid is recommended. The findings provide valuable insights for surgeons navigating similar challenges.

Rare retroperitoneal giant sacral schwannoma: A case report.

Schwannomas localized in the sacrum are relatively infrequent, accounting for 1-5% of all spinal axis schwannomas; they present with vague symptoms or are symptomless, so often grow to a considerable size before detection. Sacral schwannomas occasionally present with enormous dimensions, and these tumors are termed giant sacral schwannomas. However, their surgical removal is challenging owing to an abundant vascularity. The present study retrospectively analyzed the clinical and follow-up data of a patient with a giant sacral schwannoma. The patient experienced numbness in the left buttock and lower extremity, with radiating pain in the sole of the foot that had persisted for 3 years. A presacral mass was found by computed tomography examination 6 months after the stool had become thin. A tumor resection was performed using the anterior abdominal approach. A schwannoma was diagnosed by postoperative pathology. The postoperative course was uneventful, with the complete resolution of symptoms during the 21-month clinical follow-up. Overall, the present study reports the case of a giant sacral schwannoma with pelvic pain that was resected without complications and also discusses its successful management. Additionally, the study presents a systematic review of the literature. We consider that the surgical treatment of giant sacral schwannomas with piecemeal subtotal excision can achieve good outcomes, avoiding unnecessary neurological deficits.

Persistent metabolic toxicities following developmental exposure to hexafluoropropylene oxide trimer acid (HFPO-TA): Roles of peroxisome proliferator activated receptor gamma.

BACKGROUND: Hexafluoropropylene oxide trimer acid (HFPO-TA), a perfluorooctanoic acid (PFOA) substitute, exhibited strong affinity and capability to activate peroxisome proliferator activated receptor gamma (PPARγ), a lipid metabolism regulator, suggesting potential to induce metabolic toxicities. METHODS: Fertile chicken eggs were exposed to 0, 0.5, 1 or 2 mg/kg (egg weight) HFPO-TA and incubated until hatch. Serum from 0- and 3- month-old chickens were subjected to liquid chromatography ultra-high resolution mass spectrometry for HFPO-TA concentration, while liver, pancreas and adipose tissue samples were collected for histopathological assessments. In ovo PPARγ reporter and silencing system were established with lentivirus microinjection. qRT-PCR and immunohistochemistry were utilized to evaluate the expression levels of PPARγ downstream genes. RESULTS: In 3-month-old animals developmentally exposed to HFPO-TA, adipose tissue hyperplasia, hepatic steatosis, pancreas islet hypertrophy and elevated serum free fatty acid / insulin levels were observed. Results of reporter assay and qRT-PCR indicated HFPO-TA-mediated PPARγ transactivation in chicken embryo. Silencing of PPARγ alleviated HFPO-TA-induced changes, while PPARγ agonist rosiglitazone mimicked HFPO-TA-induced effects. qRT-PCR and immunohistochemistry revealed that FASN and GPD1 were upregulated following developmental exposure to HFPO-TA in 3-month-old animals. CONCLUSIONS: Developmental exposure to HFPO-TA induced persistent metabolic toxicities in chickens, in which PPARγ played a central role.

Long-term exposure to air pollution and risk of insulin resistance: A systematic review and meta-analysis.

OBJECTIVE: The effects of air pollution on metabolism have become a popular research topic, and a large number of studies had confirmed that air pollution exposure could induce insulin resistance (IR) to varying degrees, but the results were inconsistent, especially for the long-term exposures. The aim of the current study was to further investigate the potential effects of air pollution on IR. METHODS: A systematic review and meta-analysis of four electronic databases, including PubMed, Embase, Web of Science and Cochrane were conducted, searching for relevant studies published before June 10, 2023, in order to explore the potential relationships between long-term exposure to air pollution and IR. A total of 10 studies were included for data analysis, including seven cohort studies and three cross-sectional studies. Four major components of air pollution, including PM2.5 (particulate matter with an aerodynamic diameter of 2.5 µm or less), PM10 (particulate matter with an aerodynamic diameter of 10 µm or less), NO2, and SO2 were selected, and each analyzed for the potential impacts on insulin resistance, in the form of adjusted percentage changes in the homeostasis assessment model of insulin resistance (HOMA-IR). RESULTS: This systematic review and meta-analysis showed that for every 1 µg/m³ increase in the concentration of selected air pollutants, PM2.5 induced a 0.40% change in HOMA-IR (95%CI: -0.03, 0.84; I2 =67.4%, p = 0.009), while PM10 induced a 1.61% change (95%CI: 0.243, 2.968; I2 =49.1%, p = 0.001). Meanwhile, the change in HOMA-IR due to increased NO2 or SO2 exposure concentration was only 0.09% (95%CI: -0.01, 0.19; I2 =83.2%, p = 0.002) or 0.01% (95%CI: -0.04, 0.06; I2 =0.0%, p = 0.638), respectively. CONCLUSIONS: Long-term exposures to PM2.5, PM10, NO2 or SO2 are indeed associated with the odds of IR. Among the analyzed pollutants, inhalable particulate matters appear to exert greater impacts on IR.

Phenotype and function of smooth muscle cells derived from the human normal great saphenous vein in response to hypoxia.

OBJECTIVE: The contribution of hypoxia to the pathophysiology of vascular smooth muscle cells (VSMCs) has not yet been fully elucidated. This study evaluated the effect of hypoxia on the phenotype and function of SMCs derived from the human normal great saphenous veins (NGSVs). METHODS: Fifteen NGSV tissue samples were collected. SMCs were isolated and cultured. Proliferation, migration, adhesion, senescence, and the structure of cytoskeletal filaments in SMCs were observed. mRNA and protein expression of Bax, Bcl-2, caspase-3, matrix metalloproteinases (MMP)-2, MMP-9, tissue inhibitor of metalloproteinases (TIMP)-1, and TIMP-2 was detected by fluorescent quantitative polymerase chain reaction and immunoblotting in the cobalt chloride (CoCl2) and the control groups. RESULTS: A decrease in the number of cytoskeletal filaments was observed. mRNA and protein expression of Bas and caspase-3 was significantly decreased, while the quantity of proliferation, migration, adhesion, senescence, and mRNA and protein expression of Bcl-2, MMP-2, MMP-9, TIMP-1, and TIMP-2 in SMCs in the CoCl2 group were significantly increased compared with the control group. CONCLUSION: Under hypoxic conditions, the phenotype and function of SMCs derived from the human NGSVs were dysregulated, suggesting that VSMCs switch from the contractile phenotype to the secretory or synthetic phenotype, and more dedifferentiate, resulting in extracellular matrix deposition and apoptotic decrease through the intrinsic pathway.

Phosphoproteome reveals long-term potentiation deficit following treatment of ultra-low dose soman exposure in mice.

Soman, a warfare nerve agent, poses a significant threat by inducing severe brain damage that often results in death. Nonetheless, our understanding of the biological changes underlying persistent neurocognitive dysfunction caused by low dosage of soman remains limited. This study used mice to examine the effects of different doses of soman over time. Phosphoproteomic analysis of the mouse brain is the first time to be used to detect toxic effects of soman at such low or ultra-low doses, which were undetectable based on measuring the activity of acetylcholinesterase at the whole-animal level. We also found that phosphoproteome alterations could accurately track the soman dose, irrespective of the sampling time. Moreover, phosphoproteome revealed a rapid and adaptive cellular response to soman exposure, with the points of departure 8-38 times lower than that of acetylcholinesterase activity. Impaired long-term potentiation was identified in phosphoproteomic studies, which was further validated by targeted quantitative proteomics, immunohistochemistry, and immunofluorescence analyses, with significantly increased levels of phosphorylation of protein phosphatase 1 in the hippocampus following soman exposure. This increase in phosphorylation inhibits long-term potentiation, ultimately leading to long-term memory dysfunction in mice.

Penetrating the Blood-Brain Barrier for Targeted Treatment of Neurotoxicant Poisoning by Nanosustained-Released 2-PAM@VB1-MIL-101-NH2(Fe).

It is very important to establish a sustained-release pralidoxime chloride (2-PAM) drug system with brain targeting function for the treatment of neurotoxicant poisoning. Herein, Vitamin B1 (VB1), also known as thiamine, which can specifically bind to the thiamine transporter on the surface of the blood-brain barrier, was incorporated onto the surface of MIL-101-NH2(Fe) nanoparticles with a size of ∼100 nm. Pralidoxime chloride was further loaded within the interior of the above resulted composite by soaking, and a resulting composite drug (denoted as 2-PAM@VB1-MIL-101-NH2(Fe)) with a loading capacity of 14.8% (wt) was obtained. The results showed that the drug release rate of the composite drug was increased in PBS solution with the increase of pH (2-7.4) and a maximum drug release rate of 77.5% at pH 4. Experiments on the treatment of poisoning by gavage with the nerve agent sarin in mice combined with atropine revealed that sustained release of 2-PAM from the composite drug was achieved for more than 72 h. Sustained and stable reactivation of poisoned acetylcholinesterase (AChE) was observed with an enzyme reactivation rate of 42.7% in the ocular blood samples at 72 h. By using both zebrafish brain and mouse brain as models, we found that the composite drug could effectively cross the blood-brain barrier and restore the AChE activity in the brain of poisoned mice. The composite drug is expected to be a stable therapeutic drug with brain targeting and prolonged drug release properties for nerve agent intoxication in the middle and late stages of treatment.

Hexafluoropropylene oxide tetramer acid (HFPO-TeA)-induced developmental toxicities in chicken embryo: Peroxisome proliferator-activated receptor Alpha (PPARα) is involved.

Hexafluoropropylene oxide tetramer acid (HFPO-TeA) is an emerging environmental contaminant, with environmental presence but limited toxicological information. To investigate its potential developmental toxicities, various doses of HFPO-TeA exposure were achieved in chicken embryos via air cell injection, and the exposed embryos were incubated until hatch. Within 24 h of hatch, the hatchling chickens were assessed with electrocardiography and histopathology for toxicological evaluation. For mechanistic investigation, in ovo silencing of PPARα was achieved via lentivirus microinjection, then the morphological/functional endpoints along with protein expression levels of PPARα-regulated genes were assessed. HFPO-TeA exposure in chicken embryo resulted in developmental cardiotoxicity and hepatotoxicity. Specifically, decreased right ventricular wall thickness, increased heart rate and hepatic steatosis were observed, whereas silencing of PPARα resulted in alleviation of observed toxicities. Western blotting for EHHADH and FABPs suggested that developmental exposure to HFPO-TeA effectively increased the expression levels of both targets in hatchling chicken heart and liver tissue samples, while PPARα silencing prevented such changes, suggesting that PPARα and its downstream genes are playing critical roles in HFPO-TeA induced developmental toxicities.

Discovery of Novel PI3Kδ Inhibitors Based on the p110δ Crystal Structure.

PI3Kδ is a key mediator of B-cell receptor signaling and plays an important role in the pathogenesis of certain hematological malignancies, such as chronic lymphocytic leukemia. Idelalisib, which targets PI3Kδ specifically, is the first approved PI3K inhibitor for cancer therapy. Recently, we carried out virtual screening, cell-based assays, adapta kinase assays, and molecular dynamic analysis to discover novel PI3Kδ inhibitors and identified NSC348884 as a lead PI3Kδ inhibitor. NSC348884 had an excellent docking score, potent PI3Kδ-inhibitory activity, antitumor effects on various cancer cell lines, and a favorable binding mode with the active site of PI3Kδ. Moreover, through the structural modification of NSC348884, we further discovered comp#1, which forms H-bonds with both Val828 and Lys779 in the ATP binding pocket of PI3Kδ, with a more favorable conformation binding to PI3Kδ. In addition, we found that N1, N1, N2-trimethyl-N2-((6-methyl-1H-benzo[d]imidazol-2-yl) methyl) ethane-1,2-diamine might be a potential scaffold structure. Thus, the result of this study provides a far more efficient approach for discovering novel inhibitors targeting PI3Kδ.

Cation-Exchangeable Pralidoxime Chloride@bio-MOF-1 as a Treatment for Nerve Agent Poisoning and Sulfur Mustard Skin Poisoning in Animals.

A 2-PAM@bio-MOF-1 composite was prepared by cationic exchange of counter N,N-dimethylammonium cations in the pores of the anionic, biocompatible metal-organic framework (bio-MOF-1) with pralidoxime chloride (2-PAM-Cl) by impregnation. In vitro drug release measurements revealed that the release rate of 2-PAM from 2-PAM@bio-MOF-1 in simulated body fluid (SBF) was more than four-fold higher than that in deionized water, indicating that the presence of endogenous cations in SBF triggered the release of 2-PAM through cation exchange. The release of 2-PAM was rapid within the first 10 h but was much slower over the period of 10-50 h. At room temperature, the maximum release rate of 2-PAM was 88.5% (15 mg of 2-PAM@bio-MOF-1 in 1 mL of SBF), indicating that the drug was efficiently released from the composite MOF in SBF. In simulated gastric fluid, 64.3% of 2-PAM was released from bio-MOF-1 into the simulated gastric fluid after 50h. This suggested that 2-PAM@bio-MOF-1 might be effective for enabling the slow release of 2-PAM in the human body. Indeed, the maximum reactivation rate of acetylcholinesterase in sarin-poisoned mice reached 82.5%. In addition, 2-PAM@bio-MOF-1 demonstrated the ability to adsorb and remove sulfur mustard (HD) in solution and from the skin of guinea pigs.

Enhancing the quantum yield of singlet oxygen: photocatalytic degradation of mustard gas simulant 2-chloroethyl ethyl sulfide catalyzed by a hybrid of polyhydroxyl aluminum cations and porphyrin anions.

By combining the anionic salt meso-tetra(4-carboxyphenyl)porphyrin (TCPP4-) and the Keggin polyoxometalate cation cluster [Al13O4(OH)24(H2O)12]7+ via a simple ion-exchange method, a hybrid (C48H26N4O8)[Al13O4(OH)24(H2O)12]2(OH)10·18H2O (Al13-TCPP) was prepared and thoroughly characterized as a prototype of polyoxometalate-porphyrin hybrids for the photocatalytic degradation of the mustard gas simulant 2-chloroethyl ethyl sulfide (CEES). The experimental results showed that the catalytic degradation rate of CEES in the presence of Al13-TCPP reached 96.16 and 99.01% in 180 and 90 min in methanol and methanol-water solvent mixture (v/v = 1 : 1), respectively. The reaction followed first-order reaction kinetics, and the half-life and kinetic constant in methanol and solvent mixture were 39.8 min, -0.017 min-1 and 14.7 min, -0.047 min-1. Mechanism analysis indicated that under visible light irradiation in air, CEES was degraded through a combination of oxidation and alcoholysis/hydrolysis in methanol and the methanol-water solvent mixture. The superoxide radical (O2˙-) and singlet molecular oxygen (1O2) generated by Al13-TCPP selectively oxidized CEES into a non-toxic sulfoxide. The singlet oxygen capture experiments showed that Al13-TCPP (Φ = 0.236) had a higher quantum yield of singlet oxygen generation than H4TCPP (Φ = 0.135) under visible light irradiation in air. The material Al13-TCPP has good reusability, and the degradation rate of CEES can still reach 98.37% after being recycled five times.

ZSTK474 Sensitizes Glioblastoma to Temozolomide by Blocking Homologous Recombination Repair.

Glioblastoma (GBM) is the most common primary malignant brain tumor in adults. Temozolomide (TMZ) is used as the standard chemotherapeutic agent for GBM but with limited success, and treatment failure is mainly due to tumor resistance. One of the leading causes of TMZ resistance is the upregulation of the DNA repair mechanism. Therefore, targeting the DNA damage response (DDR) is proposed to be an effective strategy to sensitize tumor cells to TMZ. In the present study, we demonstrated that the combined use of the PI3K inhibitor ZSTK474 and TMZ showed synergetic anticancer effects on human GBM cells in vitro and in vivo. The combination treatment led to significantly increased cell apoptosis and DNA double strand breaks (DSBs). In addition, a mechanistic study indicated that TMZ enhanced the homologous recombination (HR) repair efficiency in GBM cells, while ZSTK474 impaired HR repair by blocking the phosphorylation of ATM and the expression of BRCA1/2 and Rad51, thereby sensitizing GBM cells to TMZ. Moreover, TMZ activated the PI3K signaling pathway through upregulation of the PI3K catalytic subunits p110α and p110ß and the phosphorylation of Akt. Meanwhile, ZSTK474 blocked the activity of the PI3K/Akt pathway. Taken together, our findings suggested that the combination of ZSTK474 and TMZ might be a potential therapeutic option for GBM.

Loading and Sustained Release of Pralidoxime Chloride from Swellable MIL-88B(Fe) and Its Therapeutic Performance on Mice Poisoned by Neurotoxic Agents.

Maintaining a long-term continuous and stable reactivator blood concentration to treat organophosphorus nerve agent poisoning using acetylcholinesterase (AChE) reactivator pralidoxime chloride (2-PAM) is very important yet difficult. Because the flexible framework of MIL-88B(Fe) nanoparticles (NPs) can swell in polar solvents, pralidoxime chloride (2-PAM) was loaded in MIL-88B(Fe) NPs (size: ca. 500 nm) by stirring and incubation in deionized water to obtain 2-PAM@MIL-88B(Fe), which had a maximum drug loading capacity of 12.6 wt %. The as-prepared composite was characterized by IR, powder X-ray diffraction (P-XRD), scanning electron microscopy (SEM), ζ-potential, Brunauer-Emmett-Teller (BET), and thermogravimetry/differential thermal analysis (TG/DTA). The results showed that under constant conditions, the maximum drug release rates of 2-PAM@MIL-88B(Fe) in absolute ethanol, phosphate-buffered saline (PBS) solution (pH = 7.4), and PBS solution (pH = 4) at 150 h were 51.7, 80.6, and 67.1%, respectively. This was because the composite showed different swelling behaviors in different solvents. In PBS solution with pH = 2, the 2-PAM@MIL-88B(Fe) framework collapsed after 53 h and released 100% of 2-PAM. For mice after intragastric poisoning with sarin (a neurotoxic agent), an atropine-assisted 2-PAM@MIL-88B(Fe) treatment experiment revealed that 2-PAM@MIL-88B(Fe) continuously released 2-PAM for more than 72 h so that poisoned AChE was continuously and steadily reactivated. The reactivation rate of AChE was 56.7% after 72 h. This composite is expected to provide a prolonged, stable therapeutic drug for the mid- and late-stage treatment of neurotoxic agent poisoning.

Phenotypic and Functional Transformation in Smooth Muscle Cells Derived from a Superficial Thrombophlebitis-affected Vein Wall.

BACKGROUND: Superficial thrombophlebitis (ST) is a frequent pathology, but its exact incidence remains to be determined. This study tested the hypothesis whether relationships exist among smooth muscle cells (SMCs) derived from ST, varicose great saphenous veins (VGSVs), and normal great saphenous veins (GSVs). METHODS: Forty-one samples of ST, VGSVs, and GSVs were collected. SMCs were isolated and cultured. Proliferation, migration, adhesion, and senescence in SMCs from the three vein walls were compared by various methods. Bax, Bcl-2, caspase-3, matrix metalloproteinase-2 (MMP-2), MMP-9, tissue inhibitor of metalloproteinase-1 (TIMP-1), and TIMP-2 messenger RNA (mRNA) and protein expressions were detected by fluorescence quantitative PCR and Western blot. RESULTS: An obvious decrease in cytoskeletal filaments was observed in thrombophlebitic vascular smooth muscle cells (TVSMCs). The quantity of proliferation, migration, adhesion, and senescence in TVSMCs was significantly higher than in varicose vascular smooth muscle cells and normal vascular smooth muscle cells (NVSMCs) (all P < 0.05). Bax and caspase-3 mRNA and protein expression were decreased, while Bcl-2 mRNA and protein expression were increased in the TVSMCs compared with the varicose vascular smooth muscle cells and the NVSMCs (all P < 0.05). MMP-2, MMP-9, TIMP-1, and TIMP-2 mRNA and protein expression were significantly increased in the TVSMCs compared with the VVGSVs and the NVSMCs (all P < 0.05). CONCLUSION: SMCs derived from ST are more dedifferentiated and demonstrate increased cell proliferation, migration, adhesion, and senescence, as well as obviously decreased cytoskeletal filaments. These results suggest that the phenotypic and functional differences could be related to the presence of atrophic and hypertrophic vein segments during the disease course among SMCs derived from ST, VGSVs, and GSVs.

The expression of matrix metalloproteinases and their tissue inhibitors in the vein wall following superficial venous thrombosis.

OBJECTIVES: Superficial venous thrombosis (SVT) is the complications of varicose great saphenous veins (VGSVs), but its pathogenesis remains unclear. This study was designed to measure the changes in expression of matrix metalloproteinases (MMPs) and the tissue inhibitor of metalloproteinases (TIMPs) from SVT, VGSVs, and great saphenous veins (GSVs). METHODS: In the venous walls of the three groups, the expression of MMP-2, MMP-9, TIMP-1, and TIMP-2 proteins, protein-positive expression ratios, mRNA expression, and protein expression were determined by immunohistochemistry, polymerase chain reaction, and western blot. RESULTS: The MMP-2, MMP-9, TIMP-1, and TIMP-2 protein-positive expression ratios, mRNA and protein expression in the SVT group were significantly higher than those in the VGSV and the GSV groups. The corresponding expression in the VGSV group were significantly higher than those in the GSV group. CONCLUSION: Disequilibrium of MMPs and TIMPs in SVT wall occurs due to underlying high hydrostatic pressure and inflammation. These results suggested that MMPs and TIMPs participate in the process of venous wall remodeling.

Hydroxychloroquine synergizes with the PI3K inhibitor BKM120 to exhibit antitumor efficacy independent of autophagy.

BACKGROUND: The critical role of phosphoinositide 3-kinase (PI3K) activation in tumor cell biology has prompted massive efforts to develop PI3K inhibitors (PI3Kis) for cancer therapy. However, recent results from clinical trials have shown only a modest therapeutic efficacy of single-agent PI3Kis in solid tumors. Targeting autophagy has controversial context-dependent effects in cancer treatment. As a FDA-approved lysosomotropic agent, hydroxychloroquine (HCQ) has been well tested as an autophagy inhibitor in preclinical models. Here, we elucidated the novel mechanism of HCQ alone or in combination with PI3Ki BKM120 in the treatment of cancer. METHODS: The antitumor effects of HCQ and BKM120 on three different types of tumor cells were assessed by in vitro PrestoBlue assay, colony formation assay and in vivo zebrafish and nude mouse xenograft models. The involved molecular mechanisms were investigated by MDC staining, LC3 puncta formation assay, immunofluorescent assay, flow cytometric analysis of apoptosis and ROS, qRT-PCR, Western blot, comet assay, homologous recombination (HR) assay and immunohistochemical staining. RESULTS: HCQ significantly sensitized cancer cells to BKM120 in vitro and in vivo. Interestingly, the sensitization mediated by HCQ could not be phenocopied by treatment with other autophagy inhibitors (Spautin-1, 3-MA and bafilomycin A1) or knockdown of the essential autophagy genes Atg5/Atg7, suggesting that the sensitizing effect might be mediated independent of autophagy status. Mechanistically, HCQ induced ROS production and activated the transcription factor NRF2. In contrast, BKM120 prevented the elimination of ROS by inactivation of NRF2, leading to accumulation of DNA damage. In addition, HCQ activated ATM to enhance HR repair, a high-fidelity repair for DNA double-strand breaks (DSBs) in cells, while BKM120 inhibited HR repair by blocking the phosphorylation of ATM and the expression of BRCA1/2 and Rad51. CONCLUSIONS: Our study revealed that HCQ and BKM120 synergistically increased DSBs in tumor cells and therefore augmented apoptosis, resulting in enhanced antitumor efficacy. Our findings provide a new insight into how HCQ exhibits antitumor efficacy and synergizes with PI3Ki BKM120, and warn that one should consider the "off target" effects of HCQ when used as autophagy inhibitor in the clinical treatment of cancer.

BKM120 sensitizes glioblastoma to the PARP inhibitor rucaparib by suppressing homologous recombination repair.

PARP inhibitors have been approved for the therapy of cancers with homologous recombination (HR) deficiency based on the concept of "synthetic lethality". However, glioblastoma (GBM) patients have gained little benefit from PARP inhibitors due to a lack of BRCA mutations. Herein, we demonstrated that concurrent treatment with the PARP inhibitor rucaparib and the PI3K inhibitor BKM120 showed synergetic anticancer effects on GBM U251 and U87MG cells. Mechanistically, BKM120 decreased expression of HR molecules, including RAD51 and BRCA1/2, and reduced HR repair efficiency in GBM cells, therefore increasing levels of apoptosis induced by rucaparib. Furthermore, we discovered that the two compounds complemented each other in DNA damage response and drug accumulation. Notably, in the zebrafish U87MG-RFP orthotopic xenograft model, nude mouse U87MG subcutaneous xenograft model and U87MG-Luc orthotopic xenograft model, combination showed obviously increased antitumor efficacy compared to each monotherapy. Immunohistochemical analysis of tumor tissues indicated that the combination obviously reduced expression of HR repair molecules and increased the DNA damage biomarker γ-H2AX, consistent with the in vitro results. Collectively, our findings provide new insight into combined blockade of PI3K and PARP, which might represent a promising therapeutic approach for GBM.

Combining Two into One: A Dual-Function H5PV2Mo10O40@MOF-808 Composite as a Versatile Decontaminant for Sulfur Mustard and Soman.

Due to the unpredictable nature of a battlefield environment, in the simultaneous degradation of sulfur mustard and nerve agents it is preferable to use just one decontaminant. Herein, the new composite HPVMo@MOF-808 (HPVMo = H5PV2Mo10O40) was deliberately synthesized via a simple impregnation method and thoroughly characterized. The results showed that the decontamination rate of the composites (30-40 mg) with optimal HPVMo loadings for HD (4 µL) and GD (4 µL) under ambient conditions was 97.2% (within 120 min) and 90.8% (within 30 min), respectively. Due to the combinational/synergistic effect of MOF-808 and encapsulated homogeneously dispersed HPVMo, the composite can very efficiently oxidize HD to nontoxic products in a single system, while retaining the inherent excellence of MOF-808 in hydrolytically degrading GD. The decontamination process was found to follow first-order reaction kinetics, and the rate constant and half-life of the composite for HD and GD were 0.0231 min-1, 30.13 min and 0.0795 min-1, 8.72 min, respectively. In addition, experimental results in guinea pigs and Kunming mice used as animal models showed that the composite provided effective skin protection against HD and GD, showing great potential for application in skin decontamination and protection.

A dual-function all-inorganic intercluster salt comprising the polycation ε-[Al13O4(OH)24(H2O)12]7+ and polyanion α-[PMo10V2O40]5- for detoxifying sulfur mustard and soman.

ε-[Al13O4(OH)24(H2O)12]7+, which shares similarity with the phosphotriesterase active site ZnII-OH-ZnII, was specially chosen to interact with the cluster α-PMo10V2O405- to form a new three-dimensional intercluster, which crystallized in the monoclinic space group P21/m with Z = 2, for the decontamination of chemical warfare agents. The experimental results showed that 50 mg of the compound decontaminated 96.4% (within 120 min) and 99.5% (within 40 min) of sulfur mustard (HD) (4 µL) and soman (GD) (4 µL), respectively, in ambient conditions. The decontamination processes followed first-order reaction kinetics with a rate constant and half-life of 0.01234 min-1 and 56.15 min for HD and 0.1198 min-1 and 5.78 min for GD, respectively. It was concluded that the α-PMo10V2O405- moiety was responsible for the catalytic oxidation of HD into non-toxic sulfoxide, while the ε-[Al13O4(OH)24(H2O)12]7+ moiety was responsible for the catalytic hydrolysis of HD and GD into nontoxic hydrolysates. Besides, the compound showed notable efficacy for the decontamination of HD on guinea pig skin and of GD on Kunming mouse skin, indicating high potential for use in human skin protection and treatment.