Informal institutions and corporate innovation: A Perspective from Red Culture.

Since the 20th century, Red Culture has served as a significant informal institution guiding revolutionary trajectory and developmental course. However, integrating Red Culture into contemporary corporate management and leveraging its constructive influence within today's market-driven economy necessitates comprehensive exploration and thoughtful consideration. This study aims to explore the potential influence of Red Culture on contemporary innovation. Empirical findings reveal substantial and affirmative effects of Red Culture on corporate innovation. Specifically, a heightened Red Culture ambiance correlates with a marked increase in both innovation input and output within corporate. Further investigation underscores Red Culture's pivotal governance role in mitigating strategic manipulation of innovation and research and development practices, especially within the overarching framework of innovation-driven strategies. Moreover, Red Culture synergizes with formal innovation incentive mechanisms, jointly fostering corporate innovation. This study provides micro-level empirical evidence that elucidates the impact of Red Culture on corporate innovation. Additionally, it furnishes valuable policy insights for the practical implementation and enhancement of pertinent Red Culture initiative.

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.

Surgical results for one-stage VII/VIII schwannoma resection and hemihypoglossal-facial neurorrhaphy.

BACKGROUND: This retrospective study evaluated the outcomes of patients undergoing one-stage resection of VII/VIII schwannomas and hemihypoglossal-facial neurorrhaphy via the translabyrinthine approach (TLA). METHODS: The study encompassed ten consecutive patients with unilateral hearing loss (six women, four men, mean age: 49.5 ± 12.1 years) who underwent surgery. The cohort included two patients with vestibular schwannomas (VSs), four with facial nerve schwannomas (FNSs) (two originating from the geniculate ganglion of the facial nerve and two from the cerebellopontine angle), one with VS regrowth, and three with residual VSs. Preoperative facial nerve function, assessed using the House-Brackmann (HB) scale, was Grade V in one and Grade VI in nine patients. The mean preoperative duration of facial paralysis was 7.5 ± 6.9 months. RESULTS: All patients underwent gross total resection. Postoperatively, one patient experienced cerebrospinal fluid leaks, which were successfully managed with lumbar drains and surgical revisions. At follow-up, facial nerve function improved in all patients: HB Grade V to III in one, HB Grade VI to III in one, HB Grade VI to IV in seven, and Grade VI to V in one. No tumor recurrence was observed during the follow-up period (mean duration: 16.6 ± 9.3 months), and no patient had hemilingual atrophy. CONCLUSION: The TLA for one-stage resection of VII/VIII schwannomas and facial nerve reconstruction is effective in treating both regrowth and residual VSs and FNSs in the cerebellopontine angle or petrosal bone in patients with severe preoperative facial palsy. This technique facilitates simultaneous tumor removal and nerve anastomosis, thereby reducing the need for multiple surgical interventions in patients with hearing loss and compromised facial nerve function.

Automated algorithm aided capacity and confidence boost in surgical decision-making training for inferior clivus.

Objective: To assess the impact of automated algorithms on the trainees' decision-making capacity and confidence for individualized surgical planning. Methods: At Chinese PLA General Hospital, trainees were enrolled to undergo decision-making capacity and confidence training through three alternative visual tasks of the inferior clivus model formed from an automated algorithm and given consecutively in three exemplars. The rationale of automated decision-making was used to instruct each trainee. Results: Following automated decision-making calculation in 50 skull base models, we screened out three optimal plans, infra-tubercle approach (ITA), trans-tubercle approach (TTA), and supra-tubercle approach (STA) for 41 (82.00%), 8 (16.00%), and 1 (2.00%) subject, respectively. From September 1, 2023, through November 17, 2023, 62 trainees (median age [range]: 27 [26-28]; 28 [45.16%] female; 25 [40.32%] neurosurgeons) made a decision among the three plans for the three typical models (ITA, TTA, and STA exemplars). The confidence ratings had fine test-retest reliability (Spearman's rho: 0.979; 95% CI: 0.970 to 0.988) and criterion validity with time spent (Spearman's rho: -0.954; 95%CI: -0.963 to -0.945). Following instruction of automated decision-making, time spent (initial test: 24.02 vs. 7.13 in ITA; 30.24 vs. 7.06 in TTA; 34.21 vs. 12.82 in STA) and total hits (initial test: 30 vs. 16 in ITA; 37 vs. 17 in TTA; 42 vs. 28 in STA) reduced significantly; confidence ratings (initial test: 2 vs. 4 in ITA; 2 vs. 4 in TTA; 1 vs. 3 in STA) increased correspondingly. Statistically significant differences (P < 0.05) were observed for the above comparisons. Conclusions: The education tool generated by automated decision-making considers surgical freedom and injury risk for the individualized risk-benefit assessment, which may provide explicit information to increase trainees' decision-making capacity and confidence.

A disease warranting attention from neurosurgeons: primary central nervous system post-transplant lymphoproliferative disorder.

Background: Primary central nervous system post-transplant lymphoproliferative disorder (PCNS-PTLD) is a rare condition, posing diagnostic and treatment challenges, with histological biopsy essential for diagnosis. Standardized treatment protocols are lacking. This disease requires urgent attention due to the increasing number of organ transplant surgeries and the use of immunosuppressive agents. Methods: From 2020 to 2023, our center diagnosed five patients with PCNS-PTLD. We reviewed their clinical records and conducted a comprehensive analysis of 22 literatures on PCNS-PTLD cases following renal transplantation or allogeneic hematopoietic stem cell transplantation (HSCT). Results: Four patients had previously received a kidney transplant, one had undergone allogeneic HSCT. The median time from the last transplant surgery to the diagnosis of PCNS-PTLD differs between kidney transplant (21.5 years) and allogeneic HSCT (9 months). Common symptoms included motor weakness (n = 4), headache (n = 2), confusion (n = 2), and nausea (n = 2), with ring-enhancing (n = 5), typically solitary (n = 3) and supratentorial (n = 3) lesions on imaging. Diagnosis involved robot-assisted stereotactic brain biopsy (n = 4) or craniotomy (n = 1), all showing Epstein-Barr virus and CD20 positivity. Most cases (n = 4) were monomorphic diffuse large B-cell lymphoma. Treatment included rituximab (n = 3), surgical resection (n = 2), zanubrutinib (n = 1), whole-brain radiation (n = 1), and methotrexate (n = 1). At the last follow-up, the median duration of follow-up for all patients was 19 months. During this time, 3 patients had died and 2 patients were still alive. Conclusion: In patients with a history of kidney transplantation or allogeneic HSCT who are on long-term immunosuppressive therapy, any neurological symptoms, particularly the presence of supratentorial ring-enhancing masses in the brain on imaging, whether solitary or multiple, should raise high suspicion for this disease, warranting a timely brain biopsy. Additionally, we found that besides reducing immunosuppressants, zanubrutinib may be a potential, safe, and effective treatment for this condition. Moreover, post-surgical administration of rituximab in conjunction with whole-brain radiotherapy also appears to be a potentially safe and effective approach.

[Analysis of the risk factors for delayed union of extra-articular fractures of the middle and lower third of the tibia treated by locking plate].

OBJECTIVE: To investigate the risk factors for delayed union of extra-articular fractures of the middle and lower third of the tibia treated by locking plate. METHODS: Total of 135 patients of extra-articular fractures of the middle and lower third of the tibia from January 2013 to December 2018 were retrospectively analyzed, including 85 males and 50 females, ranged from 19 to 80 years old. All cases were treated with locking plates. The patients were divided into union group and delayed union group according to the condition of fracture union. The risk factors of delayed healing were determined by univariate analysis of 14 factors that might affect fracture healing first, then the factors with significance were analyzed by binary Logistic regression. RESULTS: There were 13 patients of delayed union, and the rate of delayed union was 9.63%. Univariate analysis showed that delayed union was associated with age, smoking, reduction method, anemia and time of preoperative preparation. Regression analysis showed that age[OR=0.849, 95%CI（0.755, 0.954）, P=0.006], smoking[OR=0.020, 95%CI（0.002, 0.193）, P=0.001], reduction method[OR=23.924, 95%CI（2.210, 258.943）, P=0.009], anemia[OR=0.016, 95%CI（0.001, 0.289）, P=0.005] were the contributory factors for delayed union. CONCLUSION: Young age, smoking, closed reduction and anemia are the risk factors for delayed union of extra-articular fractures of the middle and lower third of the tibia treated by locking plate.

M&A goodwill and corporate technological innovation: The mediating moderating effect of stock pledges.

Identifying whether and how merger and acquisition (M&A) goodwill influences corporate technology innovation is a critical topic in the context of growing M&A activities. Based on the panel data of 2,634 Chinese non-financial listed companies from 2007 to 2019, this paper adopts multiple linear regression and the Bootstrap method to investigate the impact of M&A goodwill on corporate technological innovation and the mechanism through which M&A goodwill affects technological innovation. The results show that: (1) There is a significant negative correlation between M&A goodwill and technological innovation input, with financial constraints acting as the main channels. (2) Non-private corporations enjoy a higher level of financing capacity in terms of debt and equity compared with private corporations, resulting in the absence of the disincentive effect of M&A goodwill on corporate technological innovation inputs, despite the fact that M&A activities also cause massive resource consumption. (3) Stock pledges by controlling shareholders are effective in alleviating the negative impact of M&A goodwill on technological innovation inputs. Furthermore, our results highlight that simple stock pledge measures capture a significant influence of alleviating financing constraints, thereby decreasing the adverse impact of M&A, and hence need to be adequately considered in future M&A and innovation studies. While enriching the literature on the economic consequences of M&A and the research on stock pledge, this paper also provides micro-evidence for an in-depth understanding of the effect of M&A goodwill on technological innovation.

The effective path of green transformation of heavily polluting enterprises promoted by green merger and acquisition-qualitative comparative analysis based on fuzzy sets.

Green merger and acquisition (GMA) is becoming a growing tendency for heavily polluting enterprises in recent years; however, the realization path of green transformation through GMA is still unexplored. Taking 48 Chinese heavily polluting enterprises that had GMA in 2018 as the research object, this paper constructs the "M&A attributes, Organizational characteristics, and External environment" (M-O-E) framework, by using the method of fuzzy-set qualitative comparative analysis (fsQCA) to reveal the configurations of conditions that lead to high levels of green innovation performance. The results show that the high green technology innovation performance after GMA of heavily polluting enterprises is the outcome of multiple antecedents, and no singular antecedent is sufficient for achieving it. Besides, there are three equivalent configurations of conditions to achieve green transformation: professional buyer, internal leading, and internal-external linkage. Among them, the professional buyer configuration highlights that the combination of M&A experience and M&A scale is of great importance, the internal leading configuration emphasizes that the existence of environmental awareness and organizational resources is the core conditions, and the internal-external linkage configuration requires simultaneous efforts of M&A experience and government environmental regulations. Our research contributes to the understanding of green transformation in heavily polluting enterprises from a configurational perspective, and provides a practice-oriented guide to achieve green transformation for the government and heavily polluting enterprises.

Facial Nerve Schwannoma Resection and Nerve Anastomosis in 1 Stage by Translabyrinthine Approach.

Facial nerve schwannomas (FNS) are rare benign tumors that can develop in any segment of the facial nerve. Patients often experience facial palsy and hearing loss after FNS removal or even before surgery.1-3 Double-stage treatment is usually necessary for tumor resection and reconstruction of facial nerve function.4,5Video 1 describes the translabyrinthine approach for resection of the middle-posterior cranial fossa dumbbell FNS and end-to-side hypoglossal-facial nerve anastomosis in 1 stage. The case presented is of a 28-year-old female patient who suffered from right-side hearing loss for 1.5 years, right facial paralysis for 2 months (House-Brackmann grade V), and a right middle-posterior fossa dumbbell FNS extending from the right cerebellopontine angle area and internal auditory canal. Gross total resection of the tumor and hypoglossal-facial nerve end-to-side anastomosis were performed during the same procedure. Postoperative facial nerve function was House-Brackmann grade III at the 6-month follow-up. The patient experienced no postoperative complications. This case demonstrates the advantages of the translabyrinthine approach for middle-posterior fossa dumbbell FNS. This approach helps in achieving tumor resection and nerve anastomosis in 1 stage by avoiding multiple surgical interventions for patients with hearing loss and impaired facial nerve function. The patient consented to surgery and the publication of her images.

The effect of dissolved natural organic matter on adsorption of phenolic compounds on suspended sediments.

Phenolic compounds have caused different degrees of negative impacts in aquatic environment. Amino acids, humic acids and carbohydrates are the three dominant types of dissolved natural organic matter (DNOM) in natural water bodies. In this research, the influences of dissolved natural organic matter (DNOM) on the adsorption behaviors of phenol, 2,4-dichlorophenol (DCP) and 2,4,6-trichlorophenol (TCP) in Weihe River suspended sediment were studied by using DL-alanine, fulvic acid and glucose as the representatives of the three types of DNOM. The results of batch adsorption experiments showed that, without DNOM, Langmuir and Freundlich had good fitting effects on the three phenolic compounds and their maximum adsorption capacities were 21.580, 27.768 and 24.758 mg/kg respectively. The presence of amino acids increased adsorption capacities of the phenol and TCP on suspended sediments by approximately 13.84% and 11.56% respectively. The existence of fulvic acid and glucose positively affected the adsorption of phenol, DCP and TCP on suspended sediment. The isothermal adsorption in the coexistence of different DNOM were more consistent with the nonlinear adsorption. Other influence factors including pH, ionic strength and temperature can influence the adsorption behavior to different extents. The impact of dissolved natural organic matter (DNOM) on adsorption should be fully considered when mastering environmental migration and transformation behaviors of phenolic compounds in water-sediments environment.

First-in-Human Trial of EphA2-Redirected CAR T-Cells in Patients With Recurrent Glioblastoma: A Preliminary Report of Three Cases at the Starting Dose.

Glioblastoma is the most common primary brain malignancy with limited treatment options. EphA2 is a tumor-associated-antigen overexpressed in glioblastoma. Pre-clinical studies have demonstrated the promise of EphA2-redirected CAR T-cells against glioblastoma. We conduct the first-in-human trial of EphA2-redirected CAR T-cells in patients with EphA2-positive recurrent glioblastoma and report the results of three patients enrolled as the first cohort receiving the starting dosage (1×106 cells/kg). A single infusion of EphA2-redirected CAR T-cells was administrated intravenously, with the lymphodepletion regimen consisting of fludarabine and Cyclophosphamide. In two patients, there was grade 2 cytokine release syndrome accompanied by pulmonary edema, which resolved completely with dexamethasone medication. Except that, there was no other organ toxicity including neurotoxicity. In both the peripheral blood and cerebral-spinal-fluid, we observed the expansion of CAR T-cells which persisted for more than four weeks. In one patient, there was a transit diminishment of the tumor. Among these three patients, one patient reported SD and two patients reported PD, with overall survival ranging from 86 to 181 days. At the tested dose level (1×106 cells/kg), intravenously infusion of EphA2-rediretected CAR T-cells were preliminary tolerable with transient clinical efficacy. Future study with adjusted dose and infusion frequency of CAR T-cells is warranted. TRIAL REGISTRATION NUMBERS: NCT03423992.

Outcomes after semisitting and lateral positioning in large vestibular schwannoma surgery: A single-center comparison.

OBJECTIVE: The semisitting position (SSP) and lateral position (LP) in vestibular schwannoma (VS) surgery each have advantages and disadvantages, and which position is superior overall is debatable. Our objective was to determine the optimal position for surgical treatment of VSs with a diameter ≥3 cm. METHODS: We retrospectively evaluated consecutive patients with a large VS treated between January 2010 and July 2020. Patients were grouped by surgical position and analyzed. RESULTS: We enrolled 259 patients (LP group, n = 156; SSP group, n = 103). The resection extent was not significantly different between the SSP (gross-total resection [GTR], n = 89 [88.1%], near-total resection [NTR], n = 10 [9.9%], subtotal resection [STR], n = 2 [2.0%]) and LP (GTR, n = 125 [80.1%]; NTR, n = 24 [15.4%]; STR, n = 7 [4.5%]) groups. The rate of GTR with facial nerve (FN) functional preservation was higher in the SSP group than in the LP group (P = 0.014) at eight days after the operation. However, during follow-up (SSP group median, 31.5 months; LP group median, 19.5 months), there was no significant between-group difference in FN functional preservation. Two patients in the SSP group required conversion to the LP due to severe intraoperative venous air embolism (VAE). CONCLUSION: Compared with the LP, the SSP did not produce significantly better FN outcomes in patients with a large VS. The duration of surgery was significantly longer in SSP cases than in LP cases. Given the risk of VAE associated with the SSP, the selection of the optimal surgical position should be made with caution on an individual basis.

Phenolic compounds in water, suspended particulate matter and sediment from Weihe River in Northwest China.

The distribution and ecological risks of 11 phenolic compounds were studied in Weihe River, Northwest China. The concentrations of phenolic compounds were determined by ultra-high performance liquid chromatography (UPLC). The total concentration of 11 phenolic compounds (∑PC11) ranged from 0.06 to 14.12 µg/L with an average of 5.22 µg/L in water, from 0.92 to 34,885 µg/g with an average of 4,446 µg/g in suspended particulate matter (SPM), and from 3.54 to 34.09 µg/g with an average of 11.09 µg/g in sediment. For individual phenolic compound, the mean concentration of pentachlorophenol was the highest in water (2.65 µg/L) and in SPM (3,865 µg/g), while in sediment the mean concentration of 2,4,6-trichlorophenol was the highest (3.05 µg/g). The total concentration of 5 chlorophenols (∑CP5) was significantly higher than that of 6 non-chlorophenols (∑NCP6) in all three studied compartments. The phenolic compounds in Weihe River were at moderate levels in water and at high levels in sediment. The ecological risk assessment results indicated that phenolic compounds exhibited a high ecological risk in Weihe River water. In most sites, the distribution coefficient (Kd) (SPM) was much higher than Kd (sediment), which probably suggested fresh phenolic compounds input in Weihe River.

Triptolide suppresses IDH1-mutated malignancy via Nrf2-driven glutathione metabolism.

Isocitrate dehydrogenase (IDH) mutation is a common genetic abnormality in human malignancies characterized by remarkable metabolic reprogramming. Our present study demonstrated that IDH1-mutated cells showed elevated levels of reactive oxygen species and higher demands on Nrf2-guided glutathione de novo synthesis. Our findings showed that triptolide, a diterpenoid epoxide from Tripterygium wilfordii, served as a potent Nrf2 inhibitor, which exhibited selective cytotoxicity to patient-derived IDH1-mutated glioma cells in vitro and in vivo. Mechanistically, triptolide compromised the expression of GCLC, GCLM, and SLC7A11, which disrupted glutathione metabolism and established synthetic lethality with reactive oxygen species derived from IDH1 mutant neomorphic activity. Our findings highlight triptolide as a valuable therapeutic approach for IDH1-mutated malignancies by targeting the Nrf2-driven glutathione synthesis pathway.

Targeting NRF2-Governed Glutathione Synthesis for SDHB-Mutated Pheochromocytoma and Paraganglioma.

Succinate dehydrogenase subunit B (SDHB) deficiency frequently occurs in cluster I pheochromocytomas and paragangliomas (PCPGs). SDHB-mutated PCPGs are characterized by alterations in the electron transport chain, metabolic reprogramming of the tricarboxylic cycle, and elevated levels of reactive oxygen species (ROS). We discovered that SDHB-deficient PCPG cells exhibit increased oxidative stress burden, which leads to elevated demands for glutathione metabolism. Mechanistically, nuclear factor erythroid 2-related factor 2 (NRF2)-guided glutathione de novo synthesis plays a key role in supporting cellular survival and the proliferation of SDHB-knockdown (SDHBKD) cells. NRF2 blockade not only disrupted ROS homeostasis in SDHB-deficient cells but also caused severe cytotoxicity by the accumulation of DNA oxidative damage. Brusatol, a potent NRF2 inhibitor, showed a promising effect in suppressing SDHBKD metastatic lesions in vivo, with prolonged overall survival in mice bearing PCPG allografts. Our findings highlight a novel therapeutic strategy of targeting the NRF2-driven glutathione metabolic pathway against SDHB-mutated PCPG.

The contents and release behavior of heavy metals in construction and demolition waste used in freeway construction.

A large volume (more than 4.0 million m3) of treated construction and demolition waste (CDW) is planned to be used in the construction of the Xi'an-Xianyang north loop line freeway in West China. These CDW were preliminarily separated into broken concretes, bricks, and porcelains in the treatment plants. In this study, a total of 190 CDW samples including 80 concretes, 80 bricks, 20 porcelains, and 10 mixed samples were collected from five treatment plants. Five farmland soil samples near treatment plants were collected as controls. The contents of 10 elements including cadmium (Cd), arsenic (As), copper (Cu), nickel (Ni), zinc (Zn), chromium (Cr), lead (Pb), manganese (Mn), silver (Ag), and mercury (Hg) in these samples were measured. The contents of 8 elements (Cu, Ni, Zn, Cr, Pb, Mn, Ag, and Hg) in all CDW samples were qualified for the third-level criterion of the Standard of Soil Environment (GB15618-2008). However, Cd contents in 37 concretes, 34 bricks, 6 porcelain samples, and 4 mixed CDW samples exceeded the national third-level standards (1 mg/kg) in GB15618-2008. And As contents in 28 concretes, 21 bricks, 5 porcelain samples, and 3 mixed CDW samples were higher than the national third-level standards (40 mg/kg). The total exceeding standard rates (ESRs) of Cd and As were 42.6% and 30%, respectively. The leaching tests for Cd and As were also done due to their higher ESRs. The results showed that the release amounts (µg/kg) of Cd and As from CDW were increased with increasing liquid to solid ratio (0.4-10 l/kg) but decreased with increasing pH (4-7). The leached concentrations of Cd and As from four types of CDW samples were both in a descending order: brick, mixed materials, concrete, and porcelain. The measured concentrations (µg/L) of Cd and As in leachate were all lower than second-grade criteria of Standard for Groundwater Quality (GB3838-2002). By comparing the leached concentrations of Cd and As with the value in European criteria (EU Council Decision 2003/33/EC) for hazardous wastes, all the CDW samples should be classified as inert or non-hazardous wastes. Thus, it could be concluded that heavy metals in these CDW would not pollute surrounding soil, surface water, and groundwater environment when applied in freeway construction.

Autocrine BMP4 Signaling Enhances Tumor Aggressiveness via Promoting Wnt/ß-Catenin Signaling in IDH1-mutant Gliomas.

The isocitrate dehydrogenase (IDH1/2) mutations are frequent genetic abnormalities in the majority of WHO grade II/III glioma and secondary GBM. IDH1-mutated (IDH1Mut) glioma exhibits distinctive patterns in cancer biology and metabolism. In the present study, we showed that bone morphogenetic proteins (BMP4) are significantly upregulated in IDH1Mut glioma. Further, we demonstrated that cancer-associated BMP4 is secreted to tumor microenvironment, which enhances the tumor migration and invasion through an autocrine manner. Mechanistically, BMP4 activates its receptor and concomitant SMAD1/5/8 signaling, which potentiates Wnt/ß-catenin signaling by enhancing Frizzled receptor expression. LDN-193189, a selective BMP receptor inhibitor, prolonged the overall survival of mice bearing IDH1-mutated intracranial xenografts by limiting BMP/catenin signaling. These findings demonstrate the pivotal role of BMP4 on tumor aggressiveness in IDH1Mut gliomas, suggesting a possible therapeutic strategy for this type of malignancy.

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.

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.