EPIC-1042 as a potent PTRF/Cavin1-caveolin-1 interaction inhibitor to induce PARP1 autophagic degradation and suppress temozolomide efflux for glioblastoma.

BACKGROUND: Temozolomide (TMZ) treatment efficacy in glioblastoma is determined by various mechanisms such as TMZ efflux, autophagy, base excision repair (BER) pathway, and the level of O6-methylguanine-DNA methyltransferase (MGMT). Here, we reported a novel small-molecular inhibitor (SMI) EPIC-1042 (C20H28N6) with the potential to decrease TMZ efflux and promote PARP1 degradation via autolysosomes in the early stage. METHODS: EPIC-1042 was obtained from receptor-based virtual screening. Co-immunoprecipitation and pull-down assays were applied to verify the blocking effect of EPIC-1042. Western blotting, co-immunoprecipitation, and immunofluorescence were used to elucidate the underlying mechanisms of EPIC-1042. In vivo experiments were performed to verify the efficacy of EPIC-1042 in sensitizing glioblastoma cells to TMZ. RESULTS: EPIC-1042 physically interrupted the interaction of PTRF/Cavin1 and caveolin-1, leading to reduced secretion of small extracellular vesicles (sEVs) to decrease TMZ efflux. It also induced PARP1 autophagic degradation via increased p62 expression that more p62 bound to PARP1 and specially promoted PARP1 translocation into autolysosomes for degradation in the early stage. Moreover, EPIC-1042 inhibited autophagy flux at last. The application of EPIC-1042 enhanced TMZ efficacy in glioblastoma in vivo. CONCLUSION: EPIC-1042 reinforced the effect of TMZ by preventing TMZ efflux, inducing PARP1 degradation via autolysosomes to perturb the BER pathway and recruitment of MGMT, and inhibiting autophagy flux in the later stage. Therefore, this study provided a novel therapeutic strategy using the combination of TMZ with EPIC-1042 for glioblastoma treatment.

Gastrointestinal stromal tumors arising in the perianal and perineal region: Two case reports and literature review.

INTRODUCTION AND IMPORTANCE: Gastrointestinal stromal tumor (GIST) is rare because of its variable clinical incidence reported (from 0.4 to 2/100,000 per year) in the literature, mainly occurs primarily in the stomach and small intestine. GISTs in the perianal and perineal regions have been reported in a few pieces of literature. GIST located in the perianal and perineal regions may be misdiagnosed and missed due to atypical symptoms. We report two cases of GIST in rare sites and hope to reduce the occurrence of such events through a review of the relevant literature. CASE DESCRIPTION: We reported two cases of GIST located in the perianal and perineal regions with different symptoms. One case underwent an emergency procedure to stop bleeding and resect the mass, and the other case was discovered during the physical examination and slowly grew in the follow-up. Following the completion of the relevant examination, the patient underwent surgical resection. Both cases were finally diagnosed as GIST by immunohistochemistry. CLINICAL DISCUSSION AND CONCLUSION: Due to atypical clinical symptoms of perianal and perineal GIST, definitive diagnosis depends on pathology and immunohistochemistry, which can lead to misdiagnosis and missed diagnosis. Surgical resection is the preferred option for localized masses. Surgical resection of GIST located in the perianal and perineal regions requires an appropriate surgical approach based on the patients' actual condition, taking into account the protection of anal function and complete resection of the mass. Masses located in perianal and perineal region should be taken seriously by clinicians.

ROS-triggered cycle amplification effect: A prodrug activation nanoamplifier for tumor-specific therapy.

Selective in situ activation of prodrugs or generation of bioactive drugs is an important approach to reducing the side effects of chemotherapy. Herein, a tailored ROS-activable prodrug nanomedicine (Cu-SK@DTC-PPB) was developed as the prodrug activation nanoamplifier for highly selective antitumor therapy. Cu-SK@DTC-PPB was rationally constructed by the diethyldithiocarbamate (DTC) prodrug DTC-PPB and the nanoscale coordinated framework Cu-SK based on copper and the ROS generator shikonin (SK). Cu2+, SK and DTC were kept in the inactive state in the fabricated Cu-SK@DTC-PPB. In the presence of ROS within tumors, DTC-PPB can be activated to release less cytotoxic DTC, which can rapidly chelate Cu2+ from the Cu-SK framework to synthesize highly cytotoxic Cu(DTC)2 and induce SK to release in a cascade. The released SK can generate ROS to increase the intracellular ROS level, further activating DTC-PPB to release more DTC. That is, Cu-SK@DTC-PPB can undergo a self-amplifying positive feedback loop to induce numerous bioactive Cu(DTC)2 formation and SK release triggered by a small amount of ROS within the tumor microenvironment, which endows the transformation of "less toxic-to-high toxic" and thus significantly improve its selectivity towards tumors. Therefore, this study provides a new strategy of prodrug activation for tumor therapy with high efficiency and low toxicity. STATEMENT OF SIGNIFICANCE: Owing to the striking difference in ROS level between cancer cells and normal cells, ROS-responsive prodrugs are regarded as a promising approach for tumor-specific therapy. However, the stability and responsiveness of prodrugs are hard to balance. Preferable sensitivity may cause premature activation while favorable stability may lead to incomplete prodrug activation and insufficient active drug release. This study provides a tailored ROS-responsive prodrug activation nanoamplifier with favorable stability and effective prodrug activation capacity. The nanoamplifier can undergo a self-amplifying positive feedback loop to achieve numerous bioactive drugs generation in situ under ROS triggers within the tumor microenvironment, showing the enhanced antitumor therapeutic effect. Thus, this study provides a new strategy for prodrug activation and tumor-specific therapy.

A Stimuli-Responsive Small-Molecule Metal-Carrying Prochelator: A Novel Prodrug Design Strategy for Metal Complexes.

Selective activation of prodrugs is an important approach to reduce the side effects of disease treatment. We report a prodrug design concept for metal complexes, termed "metal-carrying prochelator", which can co-carry a metal ion and chelator within a single small-molecule compound and remain inert until it undergoes a specifically triggered intramolecular chelation to synthesize a bioactive metal complex in situ for targeted therapy. As a proof-of-concept, we designed a H2 O2 -responsive small-molecule prochelator, DPBD, based on the strong chelator diethyldithiocarbamate (DTC) and copper. DPBD can carry Cu2+ (DPBD-Cu) and respond to elevated H2 O2 levels in tumor cells by releasing DTC, which rapidly chelates Cu2+ from DPBD-Cu affording a DTC-copper complex with high cytotoxicity, realizing potent antitumor efficacy with low systemic toxicity. Thus, with its unique intramolecularly triggered activation mechanism, this concept based on a small-molecule metal-carrying prochelator can help in the prodrug design of metal complexes.

Recurrent bleeding after rubber band ligation diagnosed as mild hemophilia B: a case report and literature review.

BACKGROUND: Hemophilia is a recessive hemorrhagic disease relevant to X chromosome. In mild hemophilia cases, spontaneous bleeding is rare and the blood clotting function is normal, but severe bleeding may occur after trauma or surgery. Therefore, missed diagnosis of hemophilia before operation may contribute to bleeding after hemorrhoid operation. CASE PRESENTATION: A 21-year-old male was hospitalized in the anorectal department because of repeated bleeding after hemorrhoid surgery. Despite several suture hemostasis procedures, the patient still suffered from recurrent bleeding. He had no family history of hemophilia or bleeding tendency, and had not been diagnosed with hemophilia before this admission. The diagnosis of mild hemophilia B was made after further examination of coagulation indexes. By using frozen plasma and coagulation factor complex to supplement coagulation factors, the patient's bleeding was stopped and he was discharged after 23 days in hospital. During the follow-up, lower-than-normal coagulation factors were still found in him, but no bleeding occurred again. CONCLUSIONS: The undiagnosed patient with mild hemophilia B has an increased risk of bleeding after hemorrhoid surgery because of the consumption of coagulation factors. This case report aims to address the importance of hemophilia screening before operation and reduce the risk of postoperative bleeding. For patients with recurrent bleeding after hemorrhoid surgery, hemophilia should be further excluded. Wound bleeding may recur in hemophilia patients after suture hemostasis. Therefore, prompt supplementation of coagulation factors is needed to help stop bleeding once the diagnosis of hemophilia is made.

Glutathione-responsive copper-disulfiram nanoparticles for enhanced tumor chemotherapy.

Disulfiram (DSF), a familiar FDA-approved drug used for alcohol withdrawal, has recently been verified with potent antitumor therapeutic effect by generating Cu(DTC)2, which is the complex of its metabolite diethyldithiocarbamate (DTC) and copper. However, its poor tumor selectivity and insufficient endogenous Cu2+ concentration within tumor site largely hinders the application of DSF-based antitumor therapy. Therefore, a GSH-responsive coordination nanoparticles (Cu-IXZ@DSF) was established as a copper carrier to achieve synchronous but separate delivery of Cu2+ and DSF without antitumor ability, further to realize selectively triggered tumor in situ Cu(DTC)2 generation for antitumor therapy. A widely-used proteasome inhibitor ixazomib (IXZ) was chosen as ligands and Cu2+ was used as coordination nodes to form nanosized Cu-IXZ@DSF. The DSF encapsulated in Cu-IXZ@DSF could be reduced to DTC by intracellular GSH, which could contend for Cu2+ and realize in situ high toxic Cu(DTC)2 generation. Meanwhile, the chelation could lead to the disassembly of Cu-IXZ@DSF and release of IXZ to eventually achieve tumor specific "transformation from low toxicity to high toxicity" chemotherapy. The results of in vitro and in vivo experiments demonstrated that the as-prepared nanoplatform Cu-IXZ@DSF showed good biosafety and excellent antitumor effect via endoplasmic reticulum stress (ERS) as well as reactive oxygen species (ROS) generation pathway. Therefore, this nanocarrier provides an inspiring strategy with specific-triggered antitumor Cu(DTC)2 generation for DSF-based chemotherapy with high therapeutic effect and biosafety and showing great potential of treating cancer.

Homography-Based Minimal-Case Relative Pose Estimation With Known Gravity Direction.

In this paper, we propose a novel approach to two-view minimal-case relative pose problems based on homography with known gravity direction. This case is relevant to smart phones, tablets, and other camera-IMU (Inertial measurement unit) systems which have accelerometers to measure the gravity vector. We explore the rank-1 constraint on the difference between the euclidean homography matrix and the corresponding rotation, and propose an efficient two-step solution for solving both the calibrated and semi-calibrated (unknown focal length) problems. Based on the hidden variable technique, we convert the problems to the polynomial eigenvalue problems, and derive new 3.5-point, 3.5-point, 4-point solvers for two cameras such that the two focal lengths are unknown but equal, one of them is unknown, and both are unknown and possibly different, respectively. We present detailed analyses and comparisons with the existing 6- and 7-point solvers, including results with smart phone images.

Prevalence of recessive infection of pathogens of hand, foot, and mouth disease in healthy people in China: A meta-analysis.

BACKGROUND: To analyze the prevalence of latent infection of pathogens of hand, foot, and mouth disease (HFMD) in Chinese healthy population and its influencing factors, so as to provide reference for the prevention and control of HFMD. METHODS: A systematic literature searching about the incidence of latent infection of HFMD was conducted in Chinese and English databases. The inclusion and exclusion criteria of the retrieved literature were established. The qualified literatures were screened and the data were extracted. The pooled rate and its 95% confidence interval was used to assess the latent infection rate of HFMD pathogens in healthy Chinese population, and subgroup analysis was conducted based on gender and age. All statistical analyses were performed using the STATA version 12.0 software. RESULTS: A total of 31 literatures were included in this meta-analysis. The recessive infection rate of HFMD pathogens reported in the literature of Chinese healthy people ranged from 4.59% to 44.12%. The results of meta-analysis showed that the latent infection rate of human enteroviruses (HEVs) in healthy Chinese population was 17.5% (14.9-20.1%), among which, the latent infection rates of EV-A71, CV-A16, and other HEVs were 3.3% (2.2-4.4%), 1.7% (1.0-2.5%), and 15.1% (11.1-17.1%), respectively. The latent infection rates of HEVs in healthy men and women in China were 16.7% (12.9-20.4%) and 14.4% (10.8-18.0%), respectively. The latent infection rates of HEVs in the healthy population aged 0 to 5 years and over 5 years were 24.4% (20.4-28.5%) and 9.4% (6.5-12.2%), respectively. Meta regression showed that the factors affecting the latent infection rate of HEVs in Chinese healthy population included sampling period, sampling area, and study population. CONCLUSION: The latent infection rate of HEVs is high in healthy people in China, but it is mainly caused by other enteroviruses. The latent infection rate of HEVs in male was higher than that of female and was greater in people aged 0 to 5 than that of aged over 5 years. Limited by the quantity and quality of the included studies, more high-quality studies are needed for further verification in the future.

Association of Glutathione S-Transferase M1 null genotype with inflammatory bowel diseases: A systematic review and meta-analysis.

BACKGROUND: Ulcerative colitis (UC) and Crohn disease (CD) are the 2 main types of inflammatory bowel diseases (IBDs). Several studies have been conducted to investigate the association of Glutathione S-Transferase M1 (GSTM1) null genotype with UC and CD, but the results are inconsistent. Here, we performed a meta-analysis to clarify this controversy based on relative large sample size. METHODS: A systematic article searching was conducted in the PubMed, EMBASE, SCOPUS, WOS, ProQuest, Chinese National Knowledge Infrastructure (CNKI), and Chinese Wanfang databases up to August 31, 2019. Meta-analysis results were synthesized by using crude odds ratio (OR) with its 95% confidence interval (CI). Heterogeneity, sensitivity analysis, subgroup analysis, and publication bias were assessed by using STATA 11.0 software. RESULTS: A total of 15 relevant studies including 4353 IBDs patients (1848 CD cases, 2505 UC cases) and 5413 controls were included in this meta-analysis. Totally, we found a significant association between GSTM1 null genotype and risk to IBDs in the overall populations (OR = 1.37, 95%CI = 1.13-1.65, P = .001). Stratified by ethnicity, we found a significant association between GSTM1 null genotype and risk to IBDs in the Asian population (OR = 2.54, 95%CI = 2.15-3.00, P = .001), but not in the Caucasian population. Stratified by disease type, we found a significant association between GSTM1 null genotype with CD in the Asian population (OR = 2.37, 95%CI = 1.11-5.06, P = .026), and with UC in the Asian (OR = 2.48, 95%CI = 1.93-3.20, P = .001) population. In addition, funnel plot and Egger linear regression test suggests no publication bias in all genetic models. CONCLUSION: GSTM1 null genotype is associated with susceptibility to IBD, UC, and CD in the Asian population. Further well-designed studies are still needed to confirm these findings.

Parameter identification of fractional order linear system based on Haar wavelet operational matrix.

Fractional order systems can be more adequate for the description of dynamical systems than integer order models, however, how to obtain fractional order models are still actively exploring. In this paper, an identification method for fractional order linear system was proposed. This is a method based on input-output data in time domain. The input and output signals are represented by Haar wavelet, and then fractional order systems described by fractional order differential equations are transformed into fractional order integral equations. Taking use of the Haar wavelet operational matrix of the fractional order integration, the fractional order linear system can easily be converted into a system of algebraic equation. Finally, the parameters of the fractional order system are determined by minimizing the errors between the output of the real system and that of the identified system. Numerical simulations, involving integral and fractional order systems, confirm the efficiency of the above methodology.

Urinary TNF-α and NGAL are correlated with the progression of nephropathy in patients with type 2 diabetes.

The aim of this study was to investigate the correlation of the proinflammatory marker tumor necrosis factor-α (TNF-α) and the tubular marker neutrophil gelatinase-associated lipocalin (NGAL) with the progression of the early stage of type 2 diabetic nephropathy (DN). Baseline levels of urinary TNF-α and NGAL were measured in 63 non-diabetic controls and 201 patients with type 2 diabetes and different albuminuria statuses. The patients with diabetes (n=125) with normo- or microalbuminuria were subsequently followed-up for 28 (25-32) months, with routine measurements of creatinine and urinary albumin excretion (UAE). It was observed that baseline levels of urinary TNF-α and NGAL were significantly elevated and correlated with the severity of albuminuria in patients with diabetes. During the follow-up, the urinary levels of TNF-α and NGAL were observed to be significantly correlated with a rapid decline in the estimated glomerular filtration rate (eGFR). Following adjustment for other progression promoters, including albuminuria, TNF-α remained a significant predictor of eGFR decline. These results suggest that inflammation is important in the pathogenesis of DN and indicate that TNF-α may be used as an independent predictor for the progression of DN at the early stage.