Neoadjuvant Camrelizumab Plus Platinum-Based Chemotherapy vs Chemotherapy Alone for Chinese Patients With Resectable Stage IIIA or IIIB (T3N2) Non-Small Cell Lung Cancer: The TD-FOREKNOW Randomized Clinical Trial.

Importance: The benefit of neoadjuvant camrelizumab plus chemotherapy for resectable stage IIIA or IIIB non-small cell lung cancer (NSCLC) remains unknown. Objective: To assess the efficacy and safety of neoadjuvant camrelizumab plus chemotherapy vs chemotherapy alone for patients with resectable stage IIIA or IIIB NSCLC. Design, Setting, and Participants: In this randomized phase 2 clinical trial conducted at 2 hospitals in China, patients aged 18 to 70 years with resectable stage IIIA or IIIB (T3N2) NSCLC were enrolled between April 7, 2020, and January 12, 2022. Interventions: Patients were randomly assigned to receive 3 cycles of camrelizumab (200 mg) plus chemotherapy (nab-paclitaxel, 130 mg/m2, and platinum [cisplatin, 75 mg/m2; carboplatin, area under the curve, 5; or nedaplatin, 100 mg/m2]) or chemotherapy alone, followed by surgery after 4 to 6 weeks. Main Outcomes and Measures: The primary end point was the pathologic complete response (pCR) rate. Secondary end points included the major pathologic response (MPR) rate, objective response rate (ORR), event-free survival (EFS), and safety. Disease-free survival (DFS, defined as the time from surgery to disease recurrence or death from any cause) was analyzed post hoc. Efficacy was assessed on a modified intention-to-treat basis. Results: Ninety-four Chinese patients were randomized, and 88 (93.6%; median age, 61 years [IQR, 54-65 years]; 74 men [84.1%]) received allocated neoadjuvant treatment (43 received camrelizumab plus chemotherapy, and 45 received chemotherapy alone). Among these 88 patients, the pCR rate was 32.6% (14 of 43; 95% CI, 19.1%-48.5%) with camrelizumab plus chemotherapy vs 8.9% (4 of 45; 95% CI, 2.5%-21.2%) with chemotherapy alone (odds ratio, 4.95; 95% CI, 1.35-22.37; P = .008). The MPR rates were 65.1% (95% CI, 49.1%-79.0%) with camrelizumab plus chemotherapy and 15.6% (95% CI, 6.5%-29.5%) with chemotherapy alone. The radiographic ORRs were 72.1% (95% CI, 56.3%-84.7%) with camrelizumab plus chemotherapy and 53.3% (95% CI, 37.9%-68.3%) with chemotherapy alone. With a median follow-up of 14.1 months (IQR, 9.2-20.9 months), the median EFS and DFS were not reached in either group. The most common neoadjuvant treatment-related adverse events of grade 3 or higher were decreased white blood cell count (6 of 43 [14.0%] in the camrelizumab plus chemotherapy group vs 2 of 45 [4.4%] in the chemotherapy group) and decreased neutrophil count (3 of 43 [7.0%] in the camrelizumab plus chemotherapy group vs 5 of 45 [11.1%] in the chemotherapy group). No treatment-related deaths were reported. Conclusions and Relevance: This randomized clinical trial found that among patients with resectable stage IIIA or IIIB (T3N2) NSCLC, camrelizumab plus chemotherapy, compared with chemotherapy alone, significantly improved the pCR rate with manageable toxic effects. Trial Registration: ClinicalTrials.gov Identifier: NCT04338620.

Heterogeneity and Clinical Effect of Epidermal Growth Factor Receptor in Primary Lung and Brain Metastases of Nonsmall Cell Lung Cancer.

INTRODUCTION: This study aimed to analyze the heterogeneity in epidermal growth factor receptor (EGFR) gene mutation and its impact on clinical outcomes in primary tumor and corresponding brain metastasis (BM) in nonsmall cell lung cancer (NSCLC). MATERIALS AND METHODS: Primary pulmonary tumors and paired BMs of 27 NSCLC patients were surgically removed. All brain lesions were histologically confirmed as metastatic NSCLC. EGFR gene mutation status was detected by using amplification refraction mutation system. McNemar test was performed to compare EGFR mutation status between lung primary tumors and metastatic brain tumors and Kappa test was performed to quantify the agreement between the two. RESULTS: Of the 27 patients, nine cases were found to have EGFR mutations in BMs and 10 had a positive EGFR mutation status in primary lung tumor tissue. The rate of consistency of the matched tumor was 24/27 (88.9%). Among the three cases presenting EGFR mutational heterogeneity, two patients harbored an EGFR mutation in the primary tumor but not in the BMs; meanwhile, the last patient demonstrated the opposite pattern. Compared to patients with consistent EGFR mutations, patients with inconsistent mutations showed better outcomes. Further analysis revealed that the two patients whose EGFR mutant-type primary tumor progressed to wild-type cerebral metastatic tumor had longer overall survival than the patient whose EGFR wild-type primary tumor progressed to mutant-type brain metastatic tumor. CONCLUSIONS: Heterogeneity of EGFR mutation status was observed between primary NSCLC and paired BM. Patients possessing a wild-type EGFR mutation in BM might have better outcomes, especially those with transition from mutant to wild-type.

Regulation of CD18 stability by SIGIRR-modulated ubiquitination: new insights into the relationship between innate immune response and acute lung injury.

Inappropriate accumulation of alveolar macrophages (AMs) and subsequent excessive production of immune responses play critical roles in the pathogenesis of acute lung injury (ALI), but the core negative regulators governing innate signalling in AMs are ill defined. We have previously shown that single immunoglobin IL-1 receptor-related protein (SIGIRR), a negative regulator of IL-1 receptor and Toll-like receptor signalling, inhibits lipopolysaccharide (LPS)-induced inflammatory responses in AMs. To address the biological relevance of SIGIRR in vivo, we generated a murine ALI model via intratracheal instillation of LPS. Intriguingly, SIGIRR expression was observed to be decreased in resident and recruited macrophages during ALI. This decrease was associated with parallel induction in CD18 protein levels in LPS-challenged lung tissues. Through intranasal injection of SIGIRR lentiviral particles studies, we showed that the overexpression of SIGIRR attenuated recruitment of macrophages and neutrophils, decreased production of inflammatory cytokines and ameliorated pathological changes in lungs. Whilst exploring the basis for this phenotype, SIGIRR was found to be coexpressed with CD18 in AMs, and SIGIRR potentiated the instability of CD18 protein via enhancement of its ubiquitination and proteasome degradation. Conversely, by using CD18-/- mice, we further observed that CD18 deletion completely abolished the therapeutic effects of overexpression of SIGIRR on LPS-induced ALI. Mover, overexpression of CD18 in AMs promoted adhesion to ECM components, enhanced TLR4-mediated inflammasome activation and thereby potentiated IL-1ß production. These data collectively identify SIGIRR/CD18 as a key negative regulatory circuit maintaining innate immune homeostasis in AMs along the pathogenesis of ALI.

Tislelizumab combined with chemotherapy as neoadjuvant therapy for surgically resectable esophageal cancer: A prospective, single-arm, phase II study (TD-NICE).

BACKGROUND: Clinical benefit of neoadjuvant immunotherapy in resectable esophageal squamous cell carcinoma (ESCC). remains unclear. This study evaluated the efficacy and safety of the programmed death 1 (PD-1) inhibitor tislelizumab combined with chemotherapy as neoadjuvant therapy in patients with resectable ESCC. METHODS: Treatment-naïve patients were enrolled and eligible patients received 3 cycles of neoadjuvant therapy with tislelizumab, carboplatin, and nab-paclitaxel. The primary endpoint was surgery patients major pathological response (MPR). Subgroup analysis was stratified by tumor downstaging, circumferential resection margin (CRM), PD-ligand 1 (PD-L1) expression, and tumor mutation burden (TMB). Safety was assessed by adverse events (AEs) and postoperative complications. RESULTS: Between September 2020 and March 2021, 45 patients were enrolled. Thirty-six (80.0%) of 45 patients underwent surgery, and 29 (80.5%) underwent successful R0 resection. MPR and pathological complete response (pCR) for surgery patients were 72.0% and 50.0%, respectively. Intention to treatment (ITT) patients MPR and PCR were 57.5% and 40%. Downgrading occurred in 75% of 36 patients. MPR and pCR were identified to be associated with tumor downstaging and CRM but not PD-L1 expression or TMB. TPS levels in MPR and pCR group were significantly higher than that in Non-MPR and Non-pCR group, respectively. Treatment-related AEs of grade 3-4 and immune-related AEs occurred in 42.2% and 22.2% of 45 patients, respectively, and postoperative complications occurred in 77.8% of 36 patients. No treatment-related surgical delay or death occurred. No associations between gene mutation and pathological efficacy were observed. CONCLUSIONS: Tislelizumab plus chemotherapy as neoadjuvant therapy demonstrates promising antitumor activity for resectable ESCC with high rates of MPR, pCR, and R0 resection, as well as acceptable tolerability.

Wandering rod: form lumbar spine into left pleural cavity with nerve irritated symptoms.

Spinal instrumented rod migrating from the surgical site to another remote site in the body is rare. Some cases result in organ or blood vessel injury. Most reported cases were asymptomatic until the finally injuries were generated. We report a unique case of spinal implant failure in which the rod moved from lumbar spine into chest 13 years post lumbar instrumentation. The migrated rod caused no damage to the organs in the pleural cavity but did cause an atypical pleural irritation syndrome which seemed to correlate with the mechanical irritation caused by the rod. These atypical symptoms of rod migration have not been reported previously.

Negative Effects of SIGIRR on TRAF6 Ubiquitination in Acute Lung Injury In Vitro.

In this study, the effects of single immunoglobin IL-1 receptor-related protein (SIGIRR) on tumor necrosis factor- (TNF-) receptor-associated factor 6 (TRAF6) ubiquitination in acute lung injury (ALI) were evaluated in both alveolar epithelial cells and alveolar macrophage cells in vitro. Our results found that SIGIRR negatively regulated TRAF6 ubiquitination and such SIGIRR inhibition could enhance the TRAF6 expression in both alveolar epithelial cells (AECs) and alveolar macrophage cells (AMCs). SIGIRR knockdown may increase NF-κB activity via TRAF6 regulation by the classical but not the nonclassical NF-κB signaling pathway. Such modulation between TRAF6 and SIGIRR could affect cytokine secretion and exacerbate the immune response; the IL-8, NFKB1, and NFKBIA mRNA levels were reduced after SIGIRR overexpression. The current study reveals the molecular mechanisms of the negative regulatory roles of SIGIRR on the innate immune response related to the LPS/TLR-4 signaling pathway and provides evidence for strategies to clinically treat inflammatory diseases.

Rare paraneoplastic erythroderma associated with ectopic neuron-specific enolase deposition in basal cells.

The cutaneous symptom of the paraneoplastic erythroderma can be the only symptom of a malignancy. Although many cases associated with malignancies have been reported, the pathogenesis of cancer related erythroderma is still unclear. Herein we presented a patient with large cell neuroendocrine carcinoma (LCNEC) of the lung and contemporary severe erythroderma. The patient suffered from skin erythema and scaling all over the body and the cutaneous lesions recovered completely after 3 weeks of surgery. Strong expression of neuron-specific enolase (NSE, 2+ positive) was found in both primary cancer and basal cells of the preoperative skin. Three months later, postoperative skin biopsy presented nearly normal skin tissues, accompanied with a negative expression of NSE. Nine months after surgery, cancer recurred in the liver and brain with the first symptom of skin erythema and scaling. The pathology of liver biopsy tissues illustrated the LCNEC and 3+ positive expression of NSE. The skin biopsy tissues showed 2+ positive stain of NSE. Evaluation after two cycles of chemotherapy showed marked improvement in erythroderma and reduction of tumor volume. However, the patient experienced recurrent worsening of erythroderma when chemotherapy was terminated due to severe myelosuppression. Eleven months after surgery, the patient died of cancer cachexia and multiple organ failure. To our knowledge, this was the first case of paraneoplastic erythroderma associated with LCNEC of lung. Furthermore, we firstly discovered that the deposition of NSE in basal cells might be a crucial pathogenic factor of erythroderma.

Three-Dimensional Printing PEEK Implant: A Novel Choice for the Reconstruction of Chest Wall Defect.

BACKGROUND: The purpose of this study is to use 3-dimensional printing (3DP) polyetheretherketone (PEEK) implants for skeletal reconstructions after wide excision of chest wall. 3DP PEEK implants were expected to provide a better physiological simulation than traditional ones because of a closer elastic modulus to cortical bone and similar biomechanical properties. METHODS: Eighteen patients (mean age 44.5 years), comprising 6 males and 12 females, underwent adequate radical wide excision for tumors and chest wall reconstruction using 3DP PEEK implants. Surgical data, which include patient demographic characteristics, implant preparation parameters, and preoperative and postoperative pulmonary function test results, were collected and analyzed. RESULTS: Ten patients with rib tumors and 8 patients with sternum tumors were selected for the study. The mean chest wall defect size was 173.6 ± 151.5 cm2 (range, 55 to 625 cm2). The mean weight of a single 3DP PEEK rib and sternum was 28 g and 104 g, respectively. The flexural and tensile strength of PEEK implants were 141 ± 7 MPa and 89 ± 3 MPa, respectively. Preoperative and postoperative pulmonary function tests revealed that mean forced vital capacity was from 2.79 ± 0.68 L to 2.40 ± 0.70 L with a reduction of 14.0% (p < 0.001). No side effects were observed 6 to 12 months after the operation. CONCLUSIONS: These findings suggest that 3DP PEEK implant is a safe and effective alternative in the reconstruction of chest wall defects. The pulmonary function of the patient may be preserved effectively after surgery.

[Research Status of the Skeletalre Construction of Chest Wall].

Chest wall defect may be caused by many factors such as the resection of tumor and trauma, and the reconstruction of bone-defection is still the key point of thoracic surgery. With the development of material science, more and more new materials have been used in medical practice, which makes huge progress in the surgery of chest wall. However, none of these materials satisfy all the practical needs of the reconstruction. Recently, with the development of the capacity of computer, 3D-printing technology has been gradually used in clinical work, and the idea of individual treatment has been accepted by more and more people. The weakness of these materials may be solved by the new material and the application of individual treatment, which could also make great advance in chest wall surgery. This article will make a summary of the research on the reconstruction of chest wall.
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The chimeric ubiquitin ligase SH2-U-box inhibits the growth of imatinib-sensitive and resistant CML by targeting the native and T315I-mutant BCR-ABL.

Chronic myeloid leukemia (CML) is characterized by constitutively active fusion protein tyrosine kinase BCR-ABL. Although the tyrosine kinase inhibitor (TKI) against BCR-ABL, imatinib, is the first-line therapy for CML, acquired resistance almost inevitably emerges. The underlying mechanism are point mutations within the BCR-ABL gene, among which T315I is notorious because it resists to almost all currently available inhibitors. Here we took use of a previously generated chimeric ubiquitin ligase, SH2-U-box, in which SH2 from the adaptor protein Grb2 acts as a binding domain for activated BCR-ABL, while U-box from CHIP functions as an E3 ubiquitin ligase domain, so as to target the ubiquitination and degradation of both native and T315I-mutant BCR-ABL. As such, SH2-U-box significantly inhibited proliferation and induced apoptosis in CML cells harboring either the wild-type or T315I-mutant BCR-ABL (K562 or K562R), with BCR-ABL-dependent signaling pathways being repressed. Moreover, SH2-U-box worked in concert with imatinib in K562 cells. Importantly, SH2-U-box-carrying lentivirus could markedly suppress the growth of K562-xenografts in nude mice or K562R-xenografts in SCID mice, as well as that of primary CML cells. Collectively, by degrading the native and T315I-mutant BCR-ABL, the chimeric ubiquitin ligase SH2-U-box may serve as a potential therapy for both imatinib-sensitive and resistant CML.

Upregulation of microrna-451 increases the sensitivity of A549 cells to radiotherapy through enhancement of apoptosis.

BACKGROUND: As radioresistance of non-small cell lung cancers (NSCLC) is one of the main causes of failure in radiotherapy, we examined whether micro ribonucleic acid (miR-451) could function as a potential radiosensitizer of NSCLC and the related mechanism. METHODS: Radioresistant NSCLC cell line A549 was transfected with pre-miR-451 or a scrambled control. The miR-451 messenger RNA level, colony-forming ability, apoptosis, and phosphatase and tensin homolog (PTEN) protein level of 549 cells were examined by real-time polymerase chain reaction, clonogenic assay, flow cytometry analysis, and Western blot. RESULTS: Upregulation of miR-451 enhanced the suppressive effects of irradiation on the colony-forming ability of A549 cells. The apoptosis and PTEN expression of A549 cells post-irradiation were also enhanced by upregulation of miR-451. CONCLUSIONS: Upregulation of miR-451 sensitized radioresistant NSCLC A549 cells to irradiation through the enhancement of apoptosis. The activation of PTEN post-irradiation was possibly correlated with the radiosensitization of A549 cells induced by miR-451 overexpression.

Pulmonary resident neutrophils regulate the production of GM-CSF and alveolar macrophages.

Alveolar macrophages exist in the lung airspaces, and their differentiation and function are considerably regulated by the microenvironment. In this study, we examine the important role of resident neutrophil/IL-23/granulocyte/macrophage colony-stimulating factor (GM-CSF) axis in the development and preferential phenotype of alveolar macrophages under physiological conditions. Using CD18-deficient (CD18(-/-) ) mice, we show a correlation between increased granulopoiesis and enhanced alveolar macrophage development in an IL-23- and GM-CSF-dependent manner. The apoptotic neutrophils could inhibit the secretion of IL-23 from alveolar macrophages, which is important for the production of GM-CSF, and depletion of neutrophils disrupted the regulation of IL-23 and GM-CSF. This study reveals a mechanism for the regulation of the local alveolar macrophage population and function by neutrophil apoptosis in the circulatory system.

Tracheal suspension by using 3-dimensional printed personalized scaffold in a patient with tracheomalacia.

The major methods are used to fix or stabilize the central airways and major bronchi with either anterior suspension and/or posterior fixation for severe tracheomalacia (TM). Many support biomaterials, like mesh and sternal plate, can be used in the surgery. But there are no specialized biomaterials for TM which must be casually fabricated by the doctors in operation. Three dimensional printing (3DP) has currently untapped potential to provide custom, protean devices for challenging and life-threatening disease processes. After meticulous design, we created a polycaprolactone (PCL) scaffold for a female patient with TM, which would support for at least 24 months, to maintain the native lumen size of collapsed airways. Using 4-0 Polyglactin sutures, we grasped and suspended the malacic trachea into the scaffold. A remarkable improvement can be observed in the view of bronchoscope and chest CT after surgery. In the narrowest cavity of malacic trachea, the inner diameter increased from 0.3 to 1.0 cm, and the cross sectional area increased 4-5 times. The patient felt an obvious relief of dyspnea after surgery. In a word, the 3DP PCL scaffold can supply a personalized tool for suspending the malacic trachea in the future.

Chimeric ubiquitin ligases inhibit non-small cell lung cancer via negative modulation of EGFR signaling.

Targeting epidermal growth factor receptor (EGFR) represents a promising therapeutic strategy for non-small cell lung cancers (NSCLC). The ubiquitin-proteasome system (UPS) is a major pathway that mediates protein degradation. To target the degradation of EGFR, we generated two artificial ubiquitin ligases, which are composed of an EGFR-binding domain, i.e., the SH2 domain from growth factor receptor binding protein 2 (Grb2), and an ubiquitin ligase catalytic domain, i.e., the RING domain from Cbl or the U-box domain from CHIP. When the chimeric ubiquitin ligases were introduced into lung cancer SPC-A1 cells, they effectively associated with EGFR, promoted its ubiquitination and degradation, and as a result, blocked the downstream PI3K-Akt signal pathway. Moreover, cell proliferation and invasion were inhibited, the sensitivity to docetaxel-induced apoptosis was enhanced and the tumorigenicity was suppressed. In conclusion, negative modulation of EGFR signaling by the chimeric ubiquitin ligases can inhibit malignancy of SPC-A1 cells and sensitize these cells to chemotherapy, thus it may be applied to targeted therapy for NSCLC.

Sea-urchin-like Au nanocluster with surface-enhanced raman scattering in detecting epidermal growth factor receptor (EGFR) mutation status of malignant pleural effusion.

Somatic mutations in the epidermal growth factor receptor (EGFR) gene are common in patients with lung adenocarcinomas and are associated with sensitivity to the small-molecule tyrosine kinase inhibitors (TKIs). For 10%-50% of the patients who experienced malignant pleural effusion (MPE), pathological diagnosis might rely exclusively on finding lung cancer cells in the MPE. Current methods based on polymerase chain reaction were utilized to test EGFR mutation status of MPE samples, but the accuracy of the test data was very low, resulting in many patients losing the chance of TKIs treatment. Herein, we synthesized the sea-urchin-like Au nanocluster (AuNC) with an average diameter of 92.4 nm, composed of 15-nm nanopricks. By introducing abundant sharp nanopricks, the enhancement factor of AuNC reached at 1.97 × 10(7). After capped with crystal violet (CV), polyethylene glycol, and EGFR mutation specific antibody, the AuNC-EGFR had excellent surface-enhanced Raman scattering (SERS) activity and EGFR mutation targeted recognition capability in lung cancer cells. Characteristic SERS signal at 1617 cm(-1) of CV was linear correlation with the number of H1650 cells, demonstrating the minimum detection limit as 25 cells in a 1-mL suspension. The gold mass in single H1650 cells exposed to AuNC-E746_750 for 2 h ranged from 208.6 pg to 231.4 pg, which approximately corresponded to 56-62 AuNCs per cell. Furthermore, SERS was preclinically utilized to test EGFR mutation status in MPE samples from 35 patients with lung adenocarcinoma. Principal component analysis (PCA) and the support vector machine (SVM) algorithm were constructed for EGFR mutation diagnostic analysis, yielding an overall accuracy of 90.7%. SERS measurement based on sea-urchin-like AuNC was an efficient method for EGFR mutation detection in MPE, and it might show great potential in applications such as predicting gene typing of clinical lung cancer in the near future.

Potassium channel ether à go-go1 is aberrantly expressed in human liposarcoma and promotes tumorigenesis.

The ether à go-go1 (Eag1) channel is overexpressed in a variety of cancers. However, the expression and function of Eag1 in liposarcoma are poorly understood. In the present study, the mRNA expression of Eag1 in different adipose tissue samples was examined by real-time PCR. Then, the protein expression of Eag1 in 131 different adipose tissues from 109 patients was detected by immunohistochemistry. Next, the associations between Eag1 expression and clinicopathological features of liposarcoma were analyzed. In addition, the effects of Eag1 on liposarcoma cell proliferation and cycle were evaluated by CCK-8, colony formation, xenograft mouse model, and flow cytometry, respectively. Finally, the activation of p38 mitogen-activated protein kinase (MAPK) was detected by Western blot analysis to explain the detailed mechanisms of oncogenic potential of Eag1 in liposarcoma. It was found that Eag1 was aberrantly expressed in over 67% liposarcomas, with a higher frequency than in lipoma, hyperplasia, inflammation, and normal adipose tissues. However, Eag1 expression was not correlated with clinicopathological features of liposarcoma. Eag1 inhibitor imipramine or Eag1-shRNA significantly suppressed the proliferation of liposarcoma cells in vitro and in vivo, accompanying with accumulation of cells in the G1 phase. These results suggest that Eag1 plays an important role in regulating the proliferation and cell cycle of liposarcoma cells and might be a potential therapeutic target for liposarcoma.

TC-1 overexpression promotes cell proliferation in human non-small cell lung cancer that can be inhibited by PD173074.

Thyroid cancer-1 (TC-1), a natively disordered protein, is widely expressed in vertebrates and overexpressed in many kinds of tumors. However, its exact role and regulation mechanism in human non-small cell lung cancer (NSCLC) are still unclear. In the present study, we found that TC-1 is highly expressed in NSCLC and that its aberrant expression is strongly associated with NSCLC cell proliferation. Exogenous TC-1 overexpression promotes cell proliferation, accelerates the cell G1-to-S-phase transition, and reduces apoptosis in NSCLC. The knockdown of TC-1, however, inhibits NSCLC cell proliferation, cycle transition, and apoptosis resistance. Furthermore, we also demonstrated that PD173074, which functions as an inhibitor of the TC-1 in NSCLC, decreases the expression of TC-1 and inhibits TC-1 overexpression mediated cell proliferation in vitro and in vivo. Nevertheless, the inhibition function of PD173074 on NSCLC cell proliferation was eliminated in cells with TC-1 knockdown. These results suggest that PD173074 plays a significant role in TC-1 overexpression mediated NSCLC cell proliferation and may be a potential intervention target for the prevention of cell proliferation in NSCLC.

Engineered ubiquitin ligase PTB-U-box targets insulin/insulin-like growth factor receptor for degradation and coordinately inhibits cancer malignancy.

The type 1 insulin-like growth factor receptor (IGF-1R) is a promising target for cancer therapy with antibodies and small molecule tyrosine kinase inhibitors (TKIs) which have been actively tested clinically. Evidences have demonstrated that insulin receptor (IR), which is implicated in tumorigenesis, conveys resistance to IGF-1R targeted therapy. This provided the compelling rationale for co-targeting IGF-1R and IR. Herein we have developed an approach to simultaneously down-regulate IGF-1R and IR in protein levels. By generating and screening several engineered ubiquitin ligases, we have identified that, PTB-U-box, which is composed of an IGF-1R/IR-binding domain and a functional E3 ubiquitin ligase domain, binds activated IGF-1R/IR and targets their ubiquitination and degradation. When ectopically expressed in HepG2 and HeLa cells, PTB-U-box inhibits cell proliferation and invasion, increases chemo-sensitivity, as well as interrupts glucose metabolism. Finally, intratumoral injection of adenovirus carrying PTB-U-box dramatically retards the growth of HepG2 xenograft. Therefore, well-designed engineered ubiquitin ligase represents an effective therapeutic strategy for the treatment of the cancers with co-expressed IGF-1R/IR.

Silencing of Ether à go-go 1 by shRNA inhibits osteosarcoma growth and cell cycle progression.

Recently, a member of the voltage-dependent potassium channel (Kv) family, the Ether à go-go 1 (Eag1) channel was found to be necessary for cell proliferation, cycle progression and tumorigenesis. However, the therapeutic potential of the Eag1 channel in osteosarcoma remains elusive. In the present study, a recombinant adenovirus harboring shRNA against Eag1 was constructed to silence Eag1 expression in human osteosarcoma MG-63 cells. We observed that Eag1-shRNA inhibited the proliferation and colony formation of MG-63 cells due to the induction of G1 phase arrest. Moreover, in vivo experiments showed that Eag1-shRNA inhibited osteosarcoma growth in a xenograft nude mice model. In addition, selective inhibition of Eag1 significantly decreased the expression levels of cyclin D1 and E. Taken together, our data suggest that the Eag1 channel plays a crucial role in regulating the proliferation and cell cycle of osteosarcoma cells, and represents a new and effective therapeutic target for osteosarcoma.