Adaptive resistance of tumor cells to anti-vascular endothelial growth factor therapy: A reversible phenomenon.

Vascular endothelial growth factor (VEGF) inhibition is an essential targeted strategy for malignant tumors, but its efficacy is severely constrained by drug resistance. The traditional view holds that the target of VEGF inhibition is endothelial cells, and thus compensatory angiogenesis is considered the main mechanism of drug resistance. In this study, we found that tumor cells themselves could develop acquired resistance to VEGF therapy, indicating an independent resistance mechanism apart from angiogenesis. Notably, this acquired resistance was temporary, disappearing completely four days after discontinuing exposure to the drug in vitro. Our findings suggest that tumor cells may also be targets of VEGF inhibition, and their response to treatment should not be overlooked in contributing to drug resistance.

Plasma extracellular vesicles proteomics in meningioma patients.

Tumor derived Extracellular vesicles (EVs) in circulating system may contain tumor-specific markers, and EV detection in body fluids could become an important tool for early tumor diagnosis, prognosis assessment. Meningiomas are the most common benign intracranial tumors, few studies have revealed specific protein markers for meningiomas from patients' body fluids. In this study, using proximity labeling technology and non-tumor patient plasma as a control, we detected protein levels of EVs in plasma samples from meningioma patients before and after surgery. Through bioinformatics analysis, we discovered that the levels of EV count and protein count in meningioma patients were significantly higher than those in healthy controls, and were significantly decreased postoperatively. Among EV proteins in meningioma patients, the levels of MUC1, SIGLEC11, E-Cadherin, KIT, and TASCTD2 were found not only significantly elevated than those in healthy controls, but also significantly decreased after tumor resection. Moreover, using publicly available GEO databases, we verified that the mRNA level of MUC1, SIGLEC11, and CDH1 in meningiomas were significantly higher in comparison with normal dura mater tissues. Additionally, by analyzing human meningioma specimens collected in this study, we validated the protein levels of MUC1 and SIGLEC11 were significantly increased in WHO grade 2 meningiomas and were positively correlated with tumor proliferation levels. This study indicates that meningiomas secret EV proteins into circulating system, which may serve as specific markers for diagnosis, malignancy predicting and tumor recurrent assessment.

TMEM52B Isoforms P18 and P20 Differentially Promote the Oncogenesis and Metastasis of Nasopharyngeal Carcinoma.

Transmembrane protein 52B (TMEM52B), a newly identified tumor-related gene, has been reported to regulate various tumors, yet its role in nasopharyngeal carcinoma (NPC) remains unclear. Transcriptomic analysis of NPC cell lines reveals frequent overexpression of TMEM52B, and immunohistochemical results show that TMEM52B is associated with advanced tumor stage, recurrence, and decreased survival time. Depleting TMEM52B inhibits the proliferation, migration, invasion, and oncogenesis of NPC cells in vivo. TMEM52B encodes two isoforms, TMEM52B-P18 and TMEM52B-P20, differing in their N-terminals. While both isoforms exhibit similar pro-oncogenic roles and contribute to drug resistance in NPC, TMEM52B-P20 differentially promotes metastasis. This functional discrepancy may be attributed to their distinct subcellular localization; TMEM52B-P18 is confined to the cytoplasm, while TMEM52B-P20 is found both at the cell membrane and in the cytoplasm. Mechanistically, cytoplasmic TMEM52B enhances AKT phosphorylation by interacting with phosphoglycerate kinase 1 (PGK1), fostering NPC growth and metastasis. Meanwhile, membrane-localized TMEM52B-P20 promotes E-cadherin ubiquitination and degradation by facilitating its interaction with the E3 ubiquitin ligase NEDD4, further driving NPC metastasis. In conclusion, the TMEM52B-P18 and TMEM52B-P20 isoforms promote the metastasis of NPC cells through different mechanisms. Drugs targeting these TMEM52B isoforms may offer therapeutic benefits to cancer patients with varying degrees of metastasis.

Active control of an electromagnetically induced transparency analogue in a coupled dual bound states in the continuum system integrated with graphene.

Electronically induced transparency (EIT) is a coherent optical phenomenon that induces interference within atoms, allowing certain specific frequencies of light to pass through atomic media without being absorbed. However, EIT systems face challenges related to narrow transparency windows and precise control of slow light. We propose an interference structure based on a coupled dual bound states in the continuum (BIC) system to emulate the EIT-like effect. By integrating quasi-BIC (bright mode) with BIC (dark mode), our design successfully achieves an EIT-like effect in a narrow bright mode with a full width at half maximum (FWHM) of less than 1 nm. Its notable features are the bright mode's wide tunability achieved through structural parameter adjustment and a significant group delay of up to 14.43 ps. Additionally, integrating graphene into the BIC structure introduced a form of active tunability akin to the EIT-like effect. We numerically calculate the coupling structure, and its intrinsic mechanism is analyzed. Analysis based on coupled-mode theory confirms that this active modulation primarily stems from changes in the BIC structure's loss. Due to its special frequency selectivity and insensitivity to the polarization of the light source, this narrow-band EIT-like structure is particularly suitable for high-precision optical sensing and spectroscopy. The significant group delay of this structure enhances the interaction between light and matter, improving the accuracy and efficiency of optical signal control and data transmission, opening up new avenues for slow light applications and making significant progress in the development of active tunable optical switches and modulators.

Reversibly reconfigurable GSST metasurface for broadband beam steering and achromatic focusing in the long-wave infrared.

Active optical metasurfaces promise compact, lightweight, and energy-efficient optical systems with unprecedented performance. Chalcogenide phase-change material Ge2Sb2Se4Te1 (GSST) has shown tremendous advantages in the design of mid-infrared active metasurfaces. However, most of the GSST-based active metasurfaces can only work efficiently within a narrow frequency range. Furthermore, their design flexibility and reversible switching capability are severely restricted by the melting of GSST during re-amorphization. Here, we propose broadband, reversibly tunable, GSST-based transmissive metasurfaces operating in the long-wave infrared spectrum, where the GSST micro-rods are cladded by refractory materials. To accurately evaluate the performance of the proposed metasurfaces, two figures of merits are defined: FOMΦ for the evaluation of wavefront matching, and FOMop for the assessment of the overall performance incorporating both wavefront modulation efficiency and switching contrast ratio. For the proof of concept, two meta-devices are numerically presented: a multifunctional deflector that offers continuous beam steering and long-wave pass filtering simultaneously, and a large-area (1 cm × 1 cm) broadband (11-14 µm) varifocal metalens with the ability of achromatic imaging (12.5-13.5 µm). In particular, the metalens features high FOMop values over 16 dB in the achromatic band, with the average focusing efficiency approximating 70% (60%) in amorphous (crystalline) state and a spectral switching contrast ratio surpassing 25 dB. Our design scheme provides an additional degree of freedom for dynamic modulation and offers a novel approach for achieving high-efficiency mid-infrared compact optical devices.

TCR repertoire landscape reveals macrophage-mediated clone deletion in endotoxin tolerance.

BACKGROUND: Endotoxin tolerance (ET) is a protective mechanism in the process of sepsis, septic shock, and their sequelae including uncontrolled inflammation. Accumulating evidence has shown that peripheral T cells contribute to the induction of ET. However, what and how T-cell development contributes to ET inductions remain unclear. METHODS: Mice were intraperitoneally injected with LPS at a concentration of 5 mg/kg to establish an LPS tolerance model and were divided into two groups: a group examined 72 h after LPS injection (72-h group) and a group examined 8 days after LPS injection (8-day group). Injection of PBS was used as a control. We performed high-throughput sequencing to analyze the characteristics and changes of CD4+SP TCRß CDR3 repertoires with respect to V direct to J rearrangement during the ET induction. Moreover, the proportion and proliferation, as well as surface molecules such as CD80 and CD86, of F4/80+ macrophages were analyzed using FCM. Furthermore, ACT assay was designed and administered by the tail vein into murine LPS-induced mouse model to evaluate the role of F4/80+ macrophages on the development of CD4+SP thymocytes in ET condition. RESULTS: We found that the frequency and characteristics of the TCRß chain CDR3 changed obviously under condition of ET, indicating the occurrence of TCR rearrangement and thymocyte diversification. Moreover, the absolute numbers of F4/80+ macrophages, but not other APCs, were increased in thymic medulla at 72-h group, accompanied by the elevated function-related molecules of F4/80+ macrophages. Furthermore, adoptively transferred OVA332-339 peptide-loaded macrophages into Rag-1-/- mice induced the clone deletion of OVA-specific CD4+SP, thereby ameliorating the pathology in lung tissue in LPS challenge. CONCLUSIONS: These data reveal that the frequency and characteristics of the TCRß chain CDR3 undergo dynamic programming under conditions of LPS tolerance. Furthermore, the peripheral macrophages may be a key factor which carry peripheral antigen to thymic medulla and affect the negative selection of T-cell population, thereby contributing to the formation of ET. These results suggest that the clone selection in thymus in ET may confer protection against microbial sepsis.

C12orf59 Promotes Esophageal Squamous Cell Carcinoma Progression via YAP-Mediated Epithelial-Mesenchymal Transition.

C12orf59 is a novel gene widely expressed in diverse normal human tissues. Aberrant expression of C12orf59, which is involved in tumor progression, has been reported in a few types of cancer. However, its expression and biological function in esophageal squamous cell carcinoma (ESCC) remain largely unclear. Here, we found that the mRNA and protein levels of C12orf59 were prominently higher in both tumor tissues and most ESCC cell lines. Functionally, C12orf59 overexpression promoted ESCC cell proliferation, migration and invasion, whereas C12orf59 depletion worked oppositely. Mechanistically, C12orf59 exerted its oncogenic function through the induction of epithelial-mesenchymal transition (EMT) of ESCC cells, which relied on Yes-associated protein (YAP) dephosphorylation and nuclear translocation. Constitutively active YAP further facilitated cell migration, invasion and EMT induced by enforced C12orf59 overexpression. On the contrary, increased cell motility and EMT caused by enforced C12orf59 overexpression were dramatically repressed upon YAP inactivation by verteporfin. Thus, we conclude that YAP activation driven by C12orf59 contributes to the malignancy of ESCC through EMT and that targeting drugs for C12orf59 combined with YAP inhibitor may be a potential therapeutic strategy for ESCC.

The Clinical Relevance and Tumor Promoting Function of C19orf10 in Kidney Renal Clear Cell Carcinoma.

Kidney renal clear cell carcinoma (KIRC) is the most common primary renal neoplasms. Currently, there are few molecular indicators and therapeutic targets that can be used in diagnostic and prognostic assessment. In this study, we identified the C19orf10 expression in KIRC specimens and explored the diagnostic and prognostic value of C19orf10 in KIRC using TCGA and CPTAC database. Loss-of- and gain-of- function of C19orf10 was performed to investigate the roles of C19orf10 on KIRC cell viability, proliferation, migration and invasion via CCK-8, Edu incorporation and Transwell assays respectively. C19orf10 was overexpressed in KIRC tissues and the elevated C19orf10 expression was closely associated with clinicopathological characteristics of KIRC including histological grade, TNM stage, metastatic status. Silencing C19orf10 significantly suppressed the viability, proliferation, migration and invasion ability, while overexpression of C19orf10 promoted the progression and malignant phenotype in KIRC cells. Furthermore, C19orf10 exerted its carcinogenic function by regulating ZO-1 and PTEN/Akt signaling pathway. Moreover, the Kaplan-Meier survival analysis, Cox regression analysis and receiver operating curve analysis showed that patients with C19orf10 overexpression have poor survival time. C19orf10 could discriminate KIRC patients with high-risk from low-risk. Taken together, C19orf10 contributes to KIRC development via ZO-1 and PTEN/Akt signaling pathway and C19orf10 could serve as a potential diagnostic and prognostic candidate and therapeutic target of KIRC.

Identifying clinical risk factors correlate with suicide attempts in patients with first episode major depressive disorder.

BACKGROUND: Major depressive disorder (MDD) is the most common mental disorder associated with suicide attempts. When a patient first visits the clinic, clinicians are often expected to make concrete diagnose about acute suicidal risk. However, the timeliness of suicide attempts correlates with patients with MDD has not been tested. METHODS: We divided 1718 first-episode and untreated MDD outpatients into those who did not have suicide attempts (non-attempts), recent suicide attempters (≤14 days before assessment) and long - dated suicide attempters (> 30 days before assessment). Positive Symptom Scale of Positive and Negative Syndrome Scale (PANSS), the 17-item Hamilton Depression Scale, 14 - item Hamilton Anxiety Scale, and clinical global impression of severity scale (CGI-S) was assessed. Body mass index, some glycolipid metabolism and thyroid hormone parameters were measured. A gradient-boosted decision trees statistical model was used to generate equally weighted classification for distinguishing recent and long - dated suicide attempters from non-attempts. RESULTS: The classifier identified higher excitement, hostility, anxiety, depression symptoms and higher free thyroxine (FT4) as risk factors for recent suicide attempters with an estimated accuracy of 87% (sensitivity, 59.1%; specificity, 61.2 %). For long - dated suicide attempters' risk factors, single status, higher anxiety and hostility symptoms, higher LDLC and lower BMI, the estimated accuracy was 88% (sensitivity, 52.8%; specificity, 49.6%). CONCLUSIONS: Risk factors for suicide attempt among patients with MDD can be identified by integrating demographic, clinical, and biological variables as early as possible during the first time see a doctor.

PAPP-A functions as a tumor suppressor and is downregulated in renal cell carcinoma.

Pregnancy-associated plasma protein A (PAPP-A) is a proteolytic enzyme produced by the placenta. The expression and role of PAPP-A in renal cell carcinoma (RCC) remain elusive. The aim of this study was to investigate the role and the molecular mechanisms of PAPP-A in RCC. Initially, we evaluated the expression of PAPP-A in samples from patients with RCC and cell lines by quantitative PCR, western blot and immunohistochemical staining, and examined the role of PAPP-A in RCC cells by cell viability, colony formation and Transwell assays. Next, we investigated the molecular mechanisms regulating the tumor suppressor function of PAPP-A. Our results demonstrated that PAPP-A is expressed at low levels in RCC tissues and cells. Clinical data analysis revealed a significant correlation between PAPP-A expression and RCC-related death (P < 0.0115). Overexpression of PAPP-A inhibited viability, proliferation, migration and invasion of RCC cells. Furthermore, PAPP-A overexpression significantly increased phosphorylation of c-Jun N-terminal kinase and decreased the expression of cyclin D1, phosphorylated glycogen synthase kinase-3ß and ß-catenin. This study is the first to report that downregulation of PAPP-A is associated with poor prognosis in patients with RCC. In conclusion, PAPP-A may serve as a novel prognostic marker and potentially as a therapeutic target in patients with RCC.

Topologically protected plasmon mode with ultrastrong field localization in a graphene-based metasurface.

Graphene plasmons, the electromagnetic waves coupled to charge excitations in a graphene sheet, have attracted great interest because of their intriguing properties, such as electrical tunability, long plasmon lifetime, and high degree of spatial confinement. They may enable the manufacture of novel optical devices with extremely high speed, low driving voltage, low power consumption and compact sizes. In this paper, we propose a graphene-based metasurface which can support a topologically protected graphene plasmon mode with the ability of ultrastrong field localization. We show that such a plasmonic metasurface, constructed by depositing a graphene sheet on a periodic silicon substrate, would exhibit different bandgap topological characteristics as the filling factor of the periodic substrate changes. By setting suitable Fermi levels of graphene at two different areas of the metasurface, topological interface plasmon modes can be excited, resulting in over 8 orders of magnitude enhancement of the plasmon intensity. The topologically protected plasmon mode is robust against the perturbation of the structural parameters, and its frequency can be tuned by adjusting the gate-voltage on the graphene sheet. This highly integrated platform could provide a pathway for low-power and actively controllable nonlinear optics.

mTORC2/Rac1 Pathway Predisposes Cancer Aggressiveness in IDH1-Mutated Glioma.

Isocitrate dehydrogenase (IDH) mutations are common genetic abnormalities in lower grade gliomas. The neomorphic enzyme activity of IDH mutants leads to tumor formation through epigenetic alteration, dysfunction of dioxygenases, and metabolic reprogramming. However, it remains elusive as to how IDH mutants regulate the pathways associated with oncogenic transformation and aggressiveness. In the present study, by using unbiased transcriptomic profiling, we showed that IDH1 mutations result in substantial changes in the gene sets that govern cellular motility, chemotaxis, and invasion. Mechanistically, rapamycin-insensitive companion of mammalian target of rapamycin (Rictor)/Ras-related C3 botulinum toxin substrate 1 (Rac1) signaling plays an essential role in the motility and proliferation of IDH1-mutated cells by prompting cytoskeleton reorganization, lamellipodia formation, and enhanced endocytosis. Targeting the Rictor/Rac1 pathway suppresses IDH1-mutated cells by limiting endocytosis and cell proliferation. Overall, our findings indicate a novel metabolic reprogramming mechanism of IDH1-mutated cells by exploiting metabolites from the extracellular milieu. Targeting the Rictor/Rac1 pathway could be an alternative therapeutic strategy for IDH1-mutated malignancies.

MicroRNA­124 negatively regulates chloride intracellular channel 1 to suppress the migration and invasion of liver cancer cells.

The dysregulation of microRNAs (miRNAs) is associated with the development and progression of a variety of cancers, including liver cancer. Aberrant expression of miRNA (miR)­124 has been demonstrated in liver cancer, but its functional mechanism in liver cancer is still largely unknown. Metastasis of liver cancer is one of the most common causes of mortality. The present study showed that miR­124 inhibited the proliferation, migration and invasion of liver cancer cells. Furthermore, chloride intracellular channel 1 (CLIC1) was identified as a novel target of miR­124 in liver cancer cells. Overexpression of miR­124 reduced CLIC1 expression at both the protein and mRNA levels in liver cancer cells. Downregulation of CLIC1 decreased the migration and invasion of liver cancer cells without affecting cell proliferation. Taken together, these results showed that CLIC1 is a critical target for miR­124­mediated inhibitory effects on cell migration and invasion. Thus, miR­124 or suppression of CLIC1 may have diagnostic value and therapeutic potential for the treatment of human liver cancer.

Combination of PARP inhibitor and temozolomide to suppress chordoma progression.

Chordoma, a malignant bone cancer, is highly resistant to conventional therapeutic approaches; this greatly limits radio- and chemotherapeutic options and disease management. In the present study, we investigated three patient-derived chordoma cell lines to elucidate the molecular mechanism of resistance to therapeutics. An in vitro high-throughput chemical screening assay and an in vivo xenograft model were used to identify novel chemosensitizers for chordoma. We found that patient-derived chordoma cell lines recapitulated disease phenotypes, which were highlighted by robust resistance to medical therapy manifested as lack of DNA damage accumulation. Mechanistically, the PARP DNA repair pathway was found to play a central role in this resistance. Chemical screening confirmed that PARP inhibitors could strikingly enhance temozolomide (TMZ) therapy in chordoma cells. Combining the FDA-approved PARP inhibitor, olaparib, with chemotherapeutics not only potentiated DNA damage accumulation, cell cycle arrest, and apoptosis in vitro but also suppressed chordoma xenograft expansion in vivo. We conclude that combining PARP inhibition with TMZ could be an effective therapeutic approach for the clinical management of chordoma. KEY MESSAGES: The PARP DNA repair pathway enhances chemoresistance in chordoma cells. Combining PARP inhibitors with genotoxic agents induces chordoma cell cytotoxicity. PARP inhibitor combining with temozolomide suppresses growth of chordoma in vivo.

Lanthanum chloride induces neuron damage by activating the nuclear factor-kappa B signaling pathway in activated microglia.

Lanthanum is a rare earth element which can have adverse effects on the central nervous system (CNS). However, the mechanisms of these effects are not fully understood. The activated microglia plays an important role in the pathogenesis of neurodegenerative diseases and thus could be involved in mediating the toxic effects of lanthanum on the CNS. Nuclear factor-kappa B (NF-κB) is a critical nuclear factor which regulates the expression of inflammatory mediators in the activated microglia. This study investigated the effects of lanthanum chloride (LaCl3) on the NF-κB signaling pathway and explored the relationship between the microglia activation and neuron damage induced by La in vitro. The results showed that BV2 microglial cells treated with 0, 0.05, 0.1 or 0.2 mM LaCl3 could up-regulate the expression of Iba1 protein, a marker of microglia activation, and of p-IKKαß and p-IκBα in a dose-dependent manner. La could also increase the translocation of the NF-κB p65 subunit from the cytosol into the nucleus, and then elevate the production of NO, TNF-α, IL-1ß, IL-6 and MCP-1 by BV2 microglial cells. In a neuron-microglia co-culture system, BV2 microglia treated with LaCl3 resulted in a significant increase of the rates of neuron apoptosis. Conversely, the pre-treatment with PDTC (an inhibitor of the NF-κB signaling pathway) could inhibit the release of inflammatory cytokines and reduce the number of apoptotic neurons caused by La. These findings suggested that the neuron injury induced by LaCl3 might be related to the abnormal activation of microglia, which could remarkably increase the expression and release of pro-inflammatory cytokines via activating the NF-κB signaling pathway.

Targeting IDH1-Mutated Malignancies with NRF2 Blockade.

BACKGROUND: Neomorphic IDH1 mutations disrupt the redox balance by promoting reactive oxygen species (ROS) production. However, the mechanism by which IDH1-mutant cells maintain ROS homeostasis remains elusive. It is also not known whether reprogrammed ROS homeostasis establishes targetable vulnerability in IDH1-mutated cancers. METHODS: We investigated ROS homeostasis in wild-type (GSC827, GSC923, GSC627, and GSC711) and IDH1-mutated cells (IDH1R132C- and IDH1R132H-transduced U87, U251; MGG152, and TS603 cells). We analyzed the stability and transcriptional activity of NRF2 in IDH1-mutated cells. The oxidative DNA damage was analyzed using NRF2-targeting small interfering RNA. Moreover, we evaluated the effect of the NRF2 inhibitor brusatol in an IDH1-mutated subcutaneous xenograft nude mouse model (control group, n = 5; brusatol-treated group, n = 6). All statistical tests were two-sided. RESULTS: We showed that IDH1-mutated cells develop a dependency on the NRF2 antioxidative pathway. Genetic or pharmacologic blockade of NRF2 not only disrupted ROS homeostasis (mean [SD] ROS levels increased by 317 [42.1]%, P = .001, in IDH1R132C and by 286. 5 [48.7]%, P = .003, in IDH1R132H cells) but also enhanced oxidative DNA damage and decreased proliferation of IDH1-mutated cells. Brusatol selectively suppressed IDH1-mutated cancer progression in vivo (mean [SD] final tumor volume was 761.6 [391.6] mm3 in the control and 246.2 [215] mm3 in the brusatol-treated group, P = .02). CONCLUSIONS: IDH1 mutation reprograms ROS homeostasis in cancer cells, which leads to dependency on the NRF2 antioxidant pathway for ROS scavenging. NRF2 blockade might be a novel therapeutic approach to treat malignancies with IDH1 mutation.

Inhibition of Hsp70 Suppresses Neuronal Hyperexcitability and Attenuates Epilepsy by Enhancing A-Type Potassium Current.

The heat shock protein 70 (Hsp70) is upregulated in response to stress and has been implicated as a stress marker in temporal lobe epilepsy (TLE). However, whether Hsp70 plays a pathologic or protective role in TLE remains unclear. Here we report a deleterious role of Hsp70 in kainic acid (KA)-induced seizures. Hsp70 expression is upregulated in a KA model of TLE, and silencing or inhibition of Hsp70 suppresses neuronal hyperexcitability and attenuates acute or chronic epilepsy by enhancing A-type potassium current in hippocampal neurons. Hsp70 upregulation leads to proteosomal degradation of Kv4-KChIP4a channel complexes primarily encoding neuronal A-type current. Furthermore, Hsp70 directly binds to the N terminus of auxiliary KChIP4a and targets Kv4-KChIP4a complexes to proteasome. Taken together, our findings reveal a role of Hsp70 in the pathogenesis of epilepsy through degradation of Kv4-KChIP4a complexes, and pharmacological inhibition of Hsp70 may represent therapeutic potential for epilepsy or hyperexcitability-related neurological disorders.

Conditioned medium from overly excitatory primary astrocytes induced by La3+ increases apoptosis in primary neurons via upregulating the expression of NMDA receptors.

Lanthanum (La) can accumulate in the brain and impair learning and memory. However, the underlying mechanism of La-induced neurotoxicity has remained elusive. Under physiological conditions, it has been reported that moderately excitatory astrocytes play an important role in the regulation of neuronal signals and synaptic plasticity. However, under pathological conditions, overly excitatory astrocytes can release excess excitatory transmitters, such as glutamate (Glu) and d-serine, and induce the over-activation of NMDA receptors (NMDAR) in neurons, ultimately leading to neuronal excitotoxicity. To date, limited work has been performed with respect to whether La can induce neuronal excitotoxicity by inducing astrocytes to become overexcited. In this study, in vitro models of primary culture rat cortical astrocytes and neurons were established. First, the astrocytes were treated with 0.125 mM, 0.25 mM and 0.5 mM lanthanum chloride (LaCl3) for 24 h, and the supernatants were collected as a conditioned medium (CM) which is denoted as CM (La3+); then, the neurons were treated with CM (La3+) for 48 h. The results illustrate that LaCl3 treatment significantly upregulated the mRNA and protein expression levels of metabotropic glutamate receptor 5 (mGLUR5), phospholipase C (PLC), connexin 43 (Cx43) and Cx30, increased the concentrations of inositol trisphosphate (IP3) and [Ca2+]i, and promoted the synthesis and release of Glu and d-serine in astrocytes. Moreover, the CM (La3+) could increase the mRNA and protein expression levels of NMDAR subunits (NR1, NR2A, NR2B), the concentration of [Ca2+]i and the rate of apoptosis in neurons. Furthermore, after removal of La, CM (La-free) had a similar effect on neurons which could be antagonized by MK-801, DCKA and DAAO. These results suggest that the neuron apoptosis induced by La is closely related to the excessive release of Glu and d-serine from overly excitatory astrocytes.

Double-barreled gun: Combination of PARP inhibitor with conventional chemotherapy.

DNA repair pathways are evolutionarily conserved molecular mechanisms that maintain the integrity of genomic DNA. In cancer therapies, the integrity and activity of DNA repair pathways predict therapy resistance and disease outcome. Members of the poly (ADP-ribose) polymerase (PARP) family initiate and organize the biologic process of DNA repair, which counteracts many types of chemotherapies. Since the first development in approximately 3 decades ago, PARP inhibitors have greatly changed the concept of cancer therapy, leading to encouraging improvements in tumor suppression and disease outcomes. Here we summaries both pre-clinical and clinical findings of PARP inhibitors applications, particularly for combination therapies.

Targeting NAD+/PARP DNA Repair Pathway as a Novel Therapeutic Approach to SDHB-Mutated Cluster I Pheochromocytoma and Paraganglioma.

Purpose: Cluster I pheochromocytomas and paragangliomas (PCPGs) tend to develop malignant transformation, tumor recurrence, and multiplicity. Transcriptomic profiling suggests that cluster I PCPGs and other related tumors exhibit distinctive changes in the tricarboxylic acid (TCA) cycle, the hypoxia signaling pathway, mitochondrial electron transport chain, and methylation status, suggesting that therapeutic regimen might be optimized by targeting these signature molecular pathways.Experimental Design: In the present study, we investigated the molecular signatures in clinical specimens from cluster I PCPGs in comparison with cluster II PCPGs that are related to kinase signaling and often present as benign tumors.Results: We found that cluster I PCPGs develop a dependency to mitochondrial complex I, evidenced by the upregulation of complex I components and enhanced NADH dehydrogenation. Alteration in mitochondrial function resulted in strengthened NAD+ metabolism, here considered as a key mechanism of chemoresistance, particularly, of succinate dehydrogenase subunit B (SDHB)-mutated cluster I PCPGs via the PARP1/BER DNA repair pathway. Combining a PARP inhibitor with temozolomide, a conventional chemotherapeutic agent, not only improved cytotoxicity but also reduced metastatic lesions, with prolonged overall survival of mice with SDHB knockdown PCPG allograft.Conclusions: In summary, our findings provide novel insights into an effective strategy for targeting cluster I PCPGs, especially those with SDHB mutations. Clin Cancer Res; 24(14); 3423-32. ©2018 AACR.