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.

The Emerging Roles of CIB1 in Cancer.

Calcium and integrin-binding protein 1 (CIB1) is an EF-hand calcium binding protein, which is involved in many cellular processes, including calcium signaling, cell survival and proliferation, cell migration, cell adhesion and apoptosis. A number of studies have found that CIB1 is ubiquitously expressed and is related to various human diseases, such as cancer, Alzheimer's disease (AD), cardiac hypertrophy and male infertility. The mechanism of CIB1 in human diseases is still not clear, although multiple functions of CIB1 are modulated by interacting with numerous interacting partners. As a calcium binding protein, the roles of CIB1 in calcium signaling by binding calcium or modulating some key modulators, such as calcineurin, integrin, inositol 1,4,5-trisphosphate receptor (IP3R) and taste 1 receptor member 2 (TAS1R2). The tumor promoting mechanisms of CIB1 have been described in different aspects, including promoting tumor cell cycle and proliferation, inhibiting tumor cell apoptosis, and mediating tumor cell migration and angiogenesis. In addition, multiple functions of CIB1, such as neural development, taste or gustation functions, and virus infection are also elucidated. These recent advances have significantly expanded our understanding of the knowledge of CIB1 and highlighted the potential mechanisms of CIB1 in tumor progression.

Colorimetric aptasensor for progesterone detection based on surfactant-induced aggregation of gold nanoparticles.

This paper proposes an aptasensor for progesterone (P4) detection in human serum and urine based on the aggregating behavior of gold nanoparticles (AuNPs) controlled by the interactions among P4-binding aptamer, target P4 and cationic surfactant hexadecyltrimethylammonium bromide (CTAB). The aptamer can form an aptamer-P4 complex with P4, leaving CTAB free to aggregate AuNPs in this aptasensor. Thus, the sensing solution will turn from red (520 nm) to blue (650 nm) in the presence of P4 because P4 aptamers are used up firstly owing to the formation of an aptamer-P4 complex, leaving CTAB free to aggregate AuNPs. However, in the absence of P4, CTAB combines with aptamers so that AuNPs still remain dispersed. Therefore, this assay makes it possible to detect P4 not only by absorbance measurement but also through naked eyes. By monitoring the variation of absorbance and color, a CTAB-induced colorimetric assay for P4 detection was established with a detection limit of 0.89 nM. Besides, the absorbance ratio A650/A520 has a linear correlation with the P4 concentration of 0.89-500 nM. Due to the excellent recoveries in serum and urine, this biosensor has great potential with respect to the visual and instrumental detection of P4 in biological fluids.

[A clinical analysis of 40 cases of primary and secondary pulmonary lymphoma].

OBJECTIVE: To investigate the clinical manifestations, pathological types, treatment and prognosis of primary pulmonary lymphoma (PPL) and secondary pulmonary lymphoma (SPL). METHODS: The clinical data of 40 cases of PPL or SPL diagnosed from 2003 to 2013 in the Chinese PLA General Hospital were retrospectively analyzed. All cases were diagnosed via lung biopsy or surgical biopsy. RESULTS: There were 24 male and 16 female patients, aging from 15 to 84 years, including 10 patients with PPL and 30 with SPL. The main clinical manifestations of PPL were cough and chest pain, but 4 patients were asymptomatic. Chest CT showed lung mass in 8 patients and patchy opacities in 3. ¹8F-FDG PET/CT showed that the SUV(max) of lung lesions was 3.96-6.70 with a median value of 4.50. The pathological types of all PPL cases were non-Hodgkin lymphoma (NHL), and 4 patients were treated with surgery combined with chemotherapy, and 3 patients were treated with surgery alone. The main clinical manifestations of SPL were cough, superficial lymph node enlargement and fever, but 8 patients were asymptomatic. The chest CT revealed pleural effusions in 20, mediastinal and hilar lymph node enlargement in 14, patch opacities in 13 and multiple nodules in 6 patients. In addition to pulmonary involvement, PET/CT examination confirmed that cervical lymph nodes, thyroid, stomach and pancreas were also involved. The SUV(max) was from 2.40 to 19.60, with a median value of 5.70. Twenty-one cases of SPL were NHL and 9 were Hodgkin lymphomas (HL). Of these patients with SPL, 14 were treated with chemotherapy alone, 8 chemotherapy combined with radiotherapy, and 2 surgery combined with chemotherapy. The one-year survival rate of PPL was 100%, compared with 93.3% of SPL. The shortest survival time of PPL was 13 months, compared with 2 months of SPL. CONCLUSIONS: There were differences in the radiological features, pathological types and treatment between PPL and SPL. The chest CT manifestations of PPL were mainly lung masses, while those of SPL were mainly pleural involvement and mediastinal and hilar lymph node enlargement. The pathological type of PPL was all NHL while that of 9 cases of SPL was HL. Patients with PPL were mainly treated with surgical therapy, but SPL mainly with chemotherapy. PET/CT examination may be helpful for the diagnosis and staging of lung lymphoma. Since the misdiagnosis rate of pulmonary lymphoma was high, diagnosis must rely on lung tissue biopsy and immunohistochemistry. Compared with PPL, the prognosis of SPL is poorer.