Hetrombopag for the management of chemotherapy-induced thrombocytopenia in patients with advanced solid tumors: a multicenter, randomized, double-blind, placebo-controlled, phase II study.

Background: Chemotherapy-induced thrombocytopenia (CIT) increases the risk of bleeding, necessitates chemotherapy dose reductions and delays, and negatively impacts prognosis. Objectives: This study aimed to evaluate the efficacy and safety of hetrombopag for the management of CIT in patients with advanced solid tumors. Design: A multicenter, randomized, double-blind, placebo-controlled, phase II study. Methods: Patients with advanced solid tumors who experienced a chemotherapy delay of ⩾7 days due to thrombocytopenia (platelet count <75 × 109/L) were randomly assigned (1:1) to receive oral hetrombopag at an initial dose of 7.5 mg once daily or a matching placebo. The primary endpoint was the proportion of treatment responders, defined as patients resuming chemotherapy within 14 days (platelet count ⩾100 × 109/L) and not requiring a chemotherapy dose reduction of ⩾15% or a delay of ⩾4 days or rescue therapy for two consecutive cycles. Results: Between 9 October 2021 and 5 May 2022, 60 patients were randomized, with 59 receiving ⩾1 dose of assigned treatment (hetrombopag/placebo arm, n = 28/31). The proportion of treatment responders was significantly higher in the hetrombopag arm than in the placebo arm [60.7% (17/28) versus 12.9% (4/31); difference of proportion: 47.6% (95% confidence interval (CI): 26.0-69.3); odds ratio = 10.44 (95% CI: 2.82-38.65); p value (nominal) based on the Cochran-Mantel-Haenszel: <0.001)]. During the double-blind treatment period, grade 3 or higher adverse events (AEs) occurred in 35.7% (10/28) of patients with hetrombopag and 38.7% (12/31) of patients on placebo. The most common grade 3 or higher AEs were decreased neutrophil count [35.7% (10/28) versus 35.5% (11/31)] and decreased white blood cell count [17.9% (5/28) versus 19.4% (6/31)]. Serious AEs were reported in 3.6% (1/28) of patients with hetrombopag and 9.7% (3/31) of patients with placebo. Conclusion: Hetrombopag is an effective and well-tolerated alternative for managing CIT in patients with solid tumors. Trial registration: ClinicalTrials.gov identifier: NCT03976882.

Neurons upregulate PD-L1 via IFN/STAT1/IRF1 to alleviate damage by CD8+ T cells in cerebral malaria.

BACKGROUND: Cerebral malaria (CM) is the most lethal complication of malaria, and survivors usually endure neurological sequelae. Notably, the cytotoxic effect of infiltrating Plasmodium-activated CD8+ T cells on cerebral microvasculature endothelial cells is a prominent feature of the experimental CM (ECM) model with blood-brain barrier disruption. However, the damage effect of CD8+ T cells infiltrating the brain parenchyma on neurons remains unclear. Based on the immunosuppressive effect of the PD-1/PD-L1 pathway on T cells, our previous study demonstrated that the systemic upregulation of PD-L1 to inhibit CD8+ T cell function could effectively alleviate the symptoms of ECM mice. However, it has not been reported whether neurons can suppress the pathogenic effect of CD8+ T cells through the PD-1/PD-L1 negative immunomodulatory pathway. As the important inflammatory factor of CM, interferons can induce the expression of PD-L1 via different molecular mechanisms according to the neuro-immune microenvironment. Therefore, this study aimed to investigate the direct interaction between CD8+ T cells and neurons, as well as the mechanism of neurons to alleviate the pathogenic effect of CD8+ T cells through up-regulating PD-L1 induced by IFNs. METHODS: Using the ECM model of C57BL/6J mice infected with Plasmodium berghei ANKA (PbA), morphological observations were conducted in vivo by electron microscope and IF staining. The interaction between the ECM CD8+ T cells (immune magnetic bead sorting from spleen of ECM mice) and primary cultured cortical neurons in vitro was observed by IF staining and time-lapse photography. RNA-seq was performed to analyze the signaling pathway of PD-L1 upregulation in neurons induced by IFNß or IFNγ, and verified through q-PCR, WB, IF staining, and flow cytometry both in vitro and in vivo using IFNAR or IFNGR gene knockout mice. The protective effect of adenovirus-mediated PD-L1 IgGFc fusion protein expression was verified in ECM mice with brain stereotaxic injection in vivo and in primary cultured neurons via viral infection in vitro. RESULTS: In vivo, ECM mice showed infiltration of activated CD8+ T cells and neuronal injury in the brain parenchyma. In vitro, ECM CD8+ T cells were in direct contact with neurons and induced axonal damage, as an active behavior. The PD-L1 protein level was elevated in neurons of ECM mice and in primary cultured neurons induced by IFNß, IFNγ, or ECM CD8+ T cells in vitro. Furthermore, the IFNß or IFNγ induced neuronal expression of PD-L1 was mediated by increasing STAT1/IRF1 pathway via IFN receptors. The increase of PD-L1 expression in neurons during PbA infection was weakened after deleting the IFNAR or IFNGR. Increased PD-L1 expression by adenovirus partially protected neurons from CD8+ T cell-mediated damage both in vitro and in vivo. CONCLUSION: Our study demonstrates that both type I and type II IFNs can induce neurons to upregulate PD-L1 via the STAT1/IRF1 pathway mediated by IFN receptors to protect against activated CD8+ T cell-mediated damage, providing a targeted pathway to alleviate neuroinflammation during ECM.

Experiencing art creation as a therapeutic intervention to relieve anxiety - a case study of a university's ceramic art course.

Background: University students are anxiety prone. Due to their changing their social roles, the proportion of university students with anxiety is relatively high. In this study, using the simple random sampling, we surveyed 53 university students, including sophomores, juniors, and seniors. Aims: This paper examines the relationship between art creation and anxiety. Methods: This study uses the Self-Assessment Anxiety Scale (SAS). The test form measures the presence and extent of their anxiety problems through a series of questions. We tested the effects of an art creation process on SAS scores and suggest best practices for course settings and teaching methods for art-related subjects. Results: Art therapy intervention reduced anxiety. The most effective technique was found to be slapping the clay board during the creation process. Other actions relieved anxiety as well. Results suggest that the art creation process is an application of art therapy effective in relieving anxiety in university students. Conclusion: Key actions in the process of creating art are closely related to the treatment approaches used in art therapy interventions. This has the potential to not only improve mental health, but also to promote the health and well-being of students. Implications for future research: Rapid societal changes increasing competition for employment creates work and life pressures. University students face challenges with learning, peer competition, and employment, often resulting in anxiety. A diversified curriculum can alleviate anxiety through proper curricular planning and design. Based on this, the university's arts courses should be able to study how to improve and optimize the existing teaching and learning outcomes and can be integrated with the university's general education curriculum planning. Through appropriate teaching content and learning methods, the courses of university general education can play a role in reducing students' anxiety and promote physical and mental health, thus contributing to sustainable development of the society.

Preparation of multifunctional ceramic foams for sound absorption, waterproofing, and antibacterial applications.

Using porous materials for sound absorption is an effective approach to alleviating noise pollution, although their hydrophilic properties potentially cause concerns regarding public safety and health risks. This work provides a facile strategy for establishing a multifunctional ceramic system by using sponges as the sintering template, adjusting the pore structure of ceramic foams by varying the ceramic slurry weights and fluorinating the sintered ceramic foams via hydrolysis and condensation processes to provide low surface energy. The obtained porous ceramic foams demonstrate sound-absorbing, waterproof, and antibacterial properties. The results reveal that the increase in ceramic slurry weight decreases the pore size and porosity due to the formation of more compact structures, and the decrease in porosity compromises the sound absorption performance. In the middle-range sound frequency, the maximum sound absorption coefficient reached 0.92. In addition, the fluorination of the rough ceramic surfaces endows the ceramic foams with waterproof properties, which enables them to float on water and display the silver mirror phenomenon. In addition, due to the waterproof property reducing the contact area between the ceramic surface and the bacterial suspension, as well as the lipophilic fluorine chain disrupting the bacterial structures, these ceramic foams exhibited antibacterial rates above 95%. In addition, the mechanisms underlying the sound-absorbing, waterproof, and antibacterial properties of these porous ceramic foams are elucidated. Therefore, this work provides a facile approach to developing a multifunctional ceramic system. Their practical features make these ceramic foams more significant in the field of noise reduction.

Real world experience with camrelizumab in patients with advanced non-small cell lung cancer: a prospective multicenter cohort study (NOAH-LC-101).

Background: Camrelizumab has shown promising survival benefits in treatment-naïve advanced non-small cell lung cancer (NSCLC) patients when used in combination with chemotherapy. However, its effectiveness and safety outside the clinical trial setting are largely unknown. Therefore, we conducted NOAH-LC-101, a prospective multicenter cohort study, to investigate the real-world effectiveness and safety of camrelizumab on a large cohort of advanced NSCLC patients in daily clinical practice. Methods: All consecutive patients aged ≥18 years with confirmed advanced NSCLC scheduled for camrelizumab treatment were screened for inclusion at 43 hospitals in China. The primary outcome was progression-free survival (PFS). The secondary outcomes included overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety. Results: Between August 2019 and February 2021, 403 patients were included. The median age of participants was 65 years (range, 27-87 years). There were 57 (14.1%) participants with an Eastern Cooperative Oncology Group performance status (ECOG PS) of ≥2. Most participants received camrelizumab in the second or later lines (68.7%) and plus chemotherapy (64.8%). The median PFS was 12.6 [95% confidence interval (CI): 10.7-17.0] months and median OS was 22.3 months [95% CI: 19.3-not reached (NR)]. The ORR was 28.8% (95% CI: 24.4-33.5%) and DCR was 79.9% (95% CI: 75.7-83.7%). Adverse events of any grade occurred in 348 (86.4%) participants. No new safety signals were identified. Reactive cutaneous capillary endothelial proliferation was observed in 75 (18.6%) patients, all of which were grade 1-2. Conclusions: This study demonstrates the effectiveness and safety of camrelizumab in a large sample of real-world NSCLC patients. The results are generally consistent with those previously reported in pivotal clinical trials. This study supports the clinical use of camrelizumab in a broader patient population (ChiCTR1900026089).

Transcription factor NFE2L3 promotes the proliferation of esophageal squamous cell carcinoma cells and causes radiotherapy resistance by regulating IL-6.

OBJECTIVE: To scrutinize the impact of overexpression and interference of NFE2L3 on radiosensitivity of esophageal squamous cell carcinoma cells (ESCC) and its downstream mechanism and to assess whether NFE2L3 expression alters in vivo radiosensitivity of ESCC by developing a subcutaneous tumor model in mice. METHODS: Through RNA-Seq, we compared the differentially expressed genes between the ECA-109R cell line and its parent ECA-109 cell line. The differentially expressed genes were selected and verified by qRT-PCR. Transfection of ESCC cell lines with NFE2L3 inhibitor or mimic lentivirus constructs was done to study the activity of NFE2L3. To assess the effect of NFE2L3 on cellular growth and proliferation, clonogenic survival assay, EdU incorporation assay, and CCK-8 assay were done after irradiation. To probe how many irradiated DNA double-strand breaks were produced, the corresponding intensity of γ-H2AX foci were detected by immunofluorescence. Apoptotic cells were assayed by flow cytometry assay after irradiation; To investigate the downstream genes of NFE2L3, we knocked NFE2L3, and RNA-Seq was used to find out the downstream genes. qRT-PCR and western blot ensued to score associated protein profiles. The in vivo ESCC cell radiosensitivity was scrutinized by nude mouse xenograft models. RESULTS: The differential genes between ECA-109R cells and its parent ECA-109 cells were compared by qRT-PCR to unveil a significant increase in NFE2L3 expression. Functional analysis indicated that NFE2L3 increased radioresistance in ESCC cells. Then, through high-throughput sequencing and bioinformatics analysis, IL-6 was found to be a hub gene that played a role downstream of NFE2L3 and was verified by qRT-PCR, western blot, and double luciferase reporter gene experiment. NFE2L3 could regulate ESCC cell radiosensitivity via the IL-6-STAT3 signaling pathway, and downregulation of IL-6 expression could reverse the effects of highly expressed NFE2L3. In vivo tumor xenograft experiments confirmed that NFE2L3 affects the sensitivity to radiation therapy. CONCLUSION: NFE2L3 can affect the radiosensitivity of ESCC cells through IL-6 transcription and IL-6/STAT3 signaling pathway. This makes NFE2L3 a putative target to regulate ESCC cell radiosensitivity.

Toripalimab plus chemotherapy in treatment-naïve, advanced esophageal squamous cell carcinoma (JUPITER-06): A multi-center phase 3 trial.

Platinum-based chemotherapy is the standard first-line treatment for advanced esophageal squamous cell carcinoma (ESCC). In this phase 3 study (ClinicalTrial.gov: NCT03829969), 514 patients with treatment-naïve advanced ESCC were randomized (1:1) to receive toripalimab or placebo in combination with paclitaxel plus cisplatin (TP) every 3 weeks for up to 6 cycles, followed by toripalimab or placebo maintenance. At the prespecified final analysis of progression-free survival (PFS), a significant improvement in PFS is observed for the toripalimab arm over the placebo arm (hazard ratio [HR] = 0.58; 95% CI, 0.46-0.74; p < 0.0001). The prespecified interim analysis of overall survival (OS) also reveals a significant OS improvement for patients treated with toripalimab plus TP over placebo plus TP (HR = 0.58; 95% CI, 0.43-0.78; p = 0.0004). The incidences of grade ≥3 treatment-emergent adverse events are similar between the two arms. Toripalimab plus TP significantly improves PFS and OS in patients with treatment-naïve, advanced ESCC, with a manageable safety profile.

Research Progress and Development Direction of Filling Cementing Materials for Filling Mining in Iron Mines of China.

Backfill mining is the only way to realize no-waste mining and create green mines, but complicated backfill mining technology, high mining costs, and low-production capacity greatly restrict its application in low-quality iron mines. To reduce the cost of iron ore backfill mining, a large number of low-cost green backfill cementing materials have been developed in China over the past 10 years. This paper first introduces the research and development of green cementitious materials using solid waste. Then, it points out the key technologies in the development of green filling cementing materials, reveals the hydration mechanism of green cementing materials through microscopic analysis and research, and optimizes the ratio of green cementing materials based on an orthogonal test. Finally, the development direction of green filling cementing materials is put forward: combining technology development with the filling mining method and filling process; taking the development route from technology to products and from products to commodities. To reduce the cost of filling mining and pursue the economic benefits of filling mining, a demonstration mine of tailings and green cementing materials is taken as the breakthrough point to comprehensively promote the development of iron ore full solid-waste filling mining technology and achieve its large-scale promotion and application.

Efficacy and safety of a novel anti-HER2 therapeutic antibody RC48 in patients with HER2-overexpressing, locally advanced or metastatic gastric or gastroesophageal junction cancer: a single-arm phase II study.

BACKGROUND: Current treatment options for human epidermal growth factor receptor 2 (HER2)-overexpressing gastric cancer at third-line have shown limited clinical benefit. Further, there is no specific treatment for HER2 immunohistochemistry (IHC) 2+ and fluorescence in-situ hybridization-negative patients. Here, we report the efficacy and safety of a novel anti-HER2 antibody RC48 for patients with HER2-overexpressing, advanced gastric or gastroesophageal junction cancer. METHODS: Patients with HER2-overexpressing (IHC 2+ or 3+), locally advanced or metastatic gastric or gastroesophageal junction cancer who were under at least second-line therapy were eligible and received RC48 2.5 mg/kg alone every 2 weeks. The primary endpoint was the objective response rate (ORR) assessed by an independent review committee. Secondary endpoints included progression-free survival (PFS), overall survival (OS), duration of response, time to progression, disease control rate, and safety. RESULTS: Of 179 patients screened, 125 were eligible and received RC48 treatment. The ORR was 24.8% (95% confidence interval [CI]: 17.5%-33.3%). The median PFS and OS were 4.1 months (95% CI: 3.7-4.9 months) and 7.9 months (95% CI: 6.7-9.9 months), respectively. The most frequently reported adverse events were decreased white blood cell count (53.6%), asthenia (53.6%), hair loss (53.6%), decreased neutrophil count (52.0%), anemia (49.6%), and increased aspartate aminotransferase level (43.2%). Serious adverse events (SAEs) occurred in 45 (36.0%) patients, and RC48-related SAEs were mainly decreased neutrophil count (3.2%). Seven patients had adverse events that led to death were not RC48-related. CONCLUSIONS: RC48 showed promising activity with manageable safety, suggesting potential application in patients with HER2-overexpressing, advanced gastric or gastroesophageal junction cancer who have previously received at least two lines of chemotherapy.

Comparison of Clinical Efficacy of Neoadjuvant Chemoradiation Therapy Between Lower and Higher Radiation Doses for Carcinoma of the Esophagus and Gastroesophageal Junction: A Systematic Review.

PURPOSE: Neoadjuvant concurrent chemoradiation therapy (nCRT) plus surgery has been a standard treatment for locoregionally advanced esophageal cancer and carcinoma of the gastroesophageal junction (EC/GEJ), but the optimal preoperative radiation dose is still unclear. We performed this systematic review to explore the treatment efficacy and toxicity of different radiation dose levels and find an optimal dose-fractionation strategy in EC/GEJ patients receiving nCRT. METHODS AND MATERIALS: Embase and Ovid Medline were searched for articles involving cases of operable squamous and adenocarcinoma of the esophagus and GEJ in which patients received nCRT up to a dose of 50.4 Gy in 28 fractions that were published until July 2019, when the search was performed. Physical dose distributions were converted to biologically equivalent doses (BEDs), which were described in units of gray (alpha/beta). Pooled rates of overall survival (OS), progression-free survival (PFS), failure patterns, and toxicities were compared between lower-dose radiation therapy (LDRT; BED ≤48.85 Gy10) and higher-dose radiation therapy (HDRT; BED >48.85 Gy10) for patients treated with nCRT. RESULTS: A total of 110 studies with 7577 EC/GEJ patients receiving nCRT were included in this pooled analysis. Both the PFS and OS rates of patients receiving LDRT were significantly higher than those of patients receiving HDRT. Patients receiving LDRT had improved safety regarding treatment-related adverse events and lower distant failure rates than patients receiving HDRT. Utilization of modern radiation therapy (RT) techniques, including 3-dimensional conformal RT and intensity modulated RT, was associated with improved oncologic outcomes compared with 2-dimensional methods. Subgroup analysis showed that EC/GEJ patients receiving conventionally fractionated radiation to a dose of 40.0 to 41.4 Gy in 20-23 fractions showed improved OS compared with those receiving radiation above this dose. CONCLUSIONS: Based on the limited data, nCRT using BED ≤48.85 Gy10 was suitable for locoregionally advanced, resectable EC/GEJ. A total dose of 40.0 to 41.4 Gy in 20 to 23 fractions using modern RT techniques might provide the optimal therapeutic ratio.

Effectiveness and Safety of Apatinib in Patients with Advanced or Metastatic Adenocarcinoma of Stomach or Gastroesophageal Junction: A Prospective Observation Study.

BACKGROUND: Apatinib showed promising efficacy in the treatment of advanced or metastatic gastric cancer (mGC) in previous clinical studies. However, the real-world data are limited, and this study aimed to assess the effectiveness and safety of apatinib for the treatment of advanced or mGC in this setting. METHODS: In this prospective observational study, progression-free survival (PFS), overall survival (OS), overall response rate (ORR), disease control rate (DCR) and treatment-related adverse events (AEs) were recorded and evaluated. Univariate and multivariate analyses were conducted to explore potential biomarkers which might be related to the effectiveness. RESULTS: A total of 321 mGC patients from 47 centers in China were enrolled between July 1, 2015, and March 1, 2018. Thirty-two patients achieved partial response, 155 patients achieved stable disease, and 115 patients had progressive disease, and no CR was achieved, illustrating an ORR of 10.60% and a DCR of 61.92%. The median PFS and OS were 4.0 and 8.2 months, respectively. Multivariate Cox analysis showed that the potential biomarkers associated with longer PFS were combination regimens plus taxel/docetaxel, and apatinib initial dosage ≥500mg, occurrence of AEs of leukopenia, and hand-foot syndrome. Main AEs were proteinuria (17.1%), hypertension (15.9%), and handfoot syndrome (8.7%). CONCLUSION: The present prospective observational study showed favorable effectiveness and safety of apatinib in real-world patients with advanced or metastatic GC in China. (A prospective, multi-center, non-intervention study of apatinib in the treatment of advanced gastric cancer-Trial Registry Number: ChiCTR-OPN-15006601).

Clinical efficacy of irinotecan plus raltitrexed chemotherapy in refractory esophageal squamous cell cancer.

Our retrospective study assessed the efficacy and safety of irinotecan plus raltitrexed in esophageal squamous cell cancer (ESCC) patients who were previously treated with multiple systemic therapies. Between January 2016 and December 2018, records of 38 ESCC patients who underwent irinotecan plus raltitrexed chemotherapy after at least one line of chemotherapy were reviewed. Efficacy assessment was performed every two cycles according to the RECIST version 1.1. A total of 95 cycles of chemotherapy were administered, and the median course was 3 (range 2-6). There was no treatment-related death. Nine patients had partial response, 21 had stable disease and eight had progressive disease. The overall objective response rate was 23.68% (9/38) and the disease control rate was78.94% (30/38). After a median follow-up of 18.5 months, the median progression-free survival and overall survival were 105 and 221 days, respectively. There were five patients (13.15%) with grade 3/4 leukopenia, three patients (7.89%) with grade 3/4 neutropenia and one patient (2.63%) with grade 3/4 diarrhea. The combination of irinotecan plus raltitrexed was effective for pretreated ESCC patients. Further studies are needed to determine the optimal dose of the two drugs.

Mortality from heart disease following radiotherapy in esophageal carcinoma: a retrospective cohort study in US SEER cancer registry.

BACKGROUND: Recently, multiple studies have focused on cardiac toxicity induced by radiation, particularly in patients with breast carcinoma. However, in most circumstances, the radiation intensity is much higher for the heart in patients with esophageal carcinoma. This study aimed to investigate whether cardiac toxicity is related to radiation and distinguish the types of patients who are more susceptible to cardiac death. METHODS: We analyzed 8,210 esophageal cancer survivors who were involved in the US Surveillance Epidemiology and End Results (SEER) cancer program. Descriptive statistics were used to demonstrate the disease characteristics in radiation therapy (RT) and non-RT groups. Cox hazard proportional regression and Kaplan-Meier method were applied to determine independent risk factors of cardiac death. RESULTS: The most important risk factors determining heart death were age (HR, 14.297; 95% CI: 9.174-22.283) and radiation (HR, 1.952; 95% CI: 1.684-2.263). The radiotherapy performed in the middle (HR, 1.872; 95% CI: 1.464-2.395) and lower thoracic segment of the esophagus (HR, 1.539; 95% CI: 1.464-1.772) was associated with an increased risk of cardiogenic death, which occurred since the first year after diagnosis. Compared with RT in postoperative group (HR, 0.48; 95% CI, 0.37-0.62), patients in preoperative group had a significantly increased survival rate. CONCLUSIONS: Cardiogenic death is closely related to RT in esophageal cancer patients. Age, radiation sequence and tumor sites are key factors influencing the cardiac death risk induced by radiotherapy. Early detection and prevention are necessary for the high-risk population.

The benefit of taxane-based therapies over fluoropyrimidine plus platinum (FP) in the treatment of esophageal cancer: a meta-analysis of clinical studies.

PURPOSE: Fluoropyrimidine plus platinum (FP) is currently the standard treatment for esophageal cancer (EC). In recent years, taxane-based chemotherapy has also been used and has shown good efficacy in EC. This study aims to investigate the advantages of taxane-based over FP chemotherapy, as well as discuss its drawbacks, in the treatment of EC. PATIENTS AND METHODS: A literature search was done for studies comparing clinical outcomes between taxane-based and FP chemotherapy in EC. Pooled analyses were performed to compare the efficacy and grade 3/4 adverse events in patients who received neoadjuvant chemotherapy (NACT), neoadjuvant chemoradiotherapy (NACRT), or definitive chemoradiotherapy (dCRT). Subgroup analyses were also conducted in esophageal squamous cell carcinoma (ESCC). RESULTS: Thirty-one studies with a total of 3,912 patients were included in the analysis. Better long-term survival was found in patients who received taxane-based NACT (progression-free survival (PFS): pooled HR=0.58, P=0.0008; and overall survival (OS): pooled HR=0.50, P<0.00001) and dCRT (PFS: pooled HR=0.75, P<0.0001). In NACRT, taxane-based treatment and FP showed similar efficacy. In ESCC patients, taxane-based treatment showed better OS (NACT: pooled HR=0.57, P=0.02; NACRT: pooled HR=0.51, P=0.03; and dCRT: pooled HR=0.73, P<0.0001) than FP chemotherapy. Furthermore, taxane-based therapy also showed a better short-term response (complete response (CR), objective response rate (ORR), disease control rate (DCR), or pathologic complete response (pCR). However, taxane-based therapy was significantly correlated with a higher incidence of grade 3/4 leukopenia, neutropenia, and diarrhea. CONCLUSION: Compared to FP, taxane-based therapy produced better clinical response and outcomes in EC patients receiving NACT or dCRT, and in all types of therapy in patients with ESCC. Taxane-based treatment is associated with more frequent toxicity.

Apoptosis-promoting effect of rituximab-conjugated magnetic nanoprobes on malignant lymphoma cells with CD20 overexpression.

BACKGROUND: Cancer targeting nanoprobes with precisely designed physicochemical properties may show enhanced pharmacological targeting and therapeutic efficacy. As a widely used commercialized antibody, rituximab has been in clinical use for three decades and has lengthened or even saved thousands of lives. However, many people cannot benefit from rituximab treatment because of drug resistance or side effects. METHODS: In this study, a 13-nm rituximab-conjugated magnetic nanoparticle was developed as a therapeutic nanoprobe targeting CD20 overexpressing malignant lymphoma cells to enhance the treatment effects of rituximab. The magnetic cores (2,3-dimercaptosuccinicacid modified Fe3O4 nanoparticles, Fe3O4@DMSA) of the nanoprobes with an average diameter of 6.5 nm were synthesized using a co-precipitation method. Rituximab was then conjugated on the surface of Fe3O4@DMSA using a cross-linking agent (carbodiimide/N-hydroxysulfosuccinimide sodium salt). Based on theoretical calculations, approximately one antibody was coupled with one nanoparticle, excluding the multivalent antibody effect. RESULTS: Cell targeting experiments and magnetic resonance (MR) signal and T2 measurements showed that the Fe3O4@DMSA@Ab nanoprobes have specific binding affinity for CD20-positive cells. Compared to rituximab and Fe3O4@DMSA, Fe3O4@DMSA@Ab nanoprobes significantly reduced cell viability and promoted Raji cell apoptosis. Initiating events of apoptosis, including increased intracellular calcium and reactive oxygen species, were observed in nanoprobe-treated Raji cells. Nanoprobe-treated Raji cells also showed the most drastic decrease in mitochondrial membrane potential and Bcl-2 expression, compared to rituximab and Fe3O4@DMSA-treated Raji cells. CONCLUSION: These results indicate that Fe3O4@DMSA@Ab nanoprobes have the potential to serve as MRI tracers and therapeutic agents for CD20-positive cells.

Systematic Assessment of the Toxicity and Potential Mechanism of Graphene Derivatives In Vitro and In Vivo.

Graphene is a two-dimensional crystal that is stripped from pristine graphite and made of single layer of carbon atoms. Containing numerous functional groups, graphene derivatives (GDs) could be easily modified and have aroused great attention for potential applications in biomedicine. However, pristine graphene and graphene oxide (GO) could arouse cell and animal toxicity. To screen GDs with high biocompatibility applied for biomedicine, general comparison was performed about the toxicities of six GDs with diverse types of surface modification, size, and redox state, including GO, reduced GO (rGO), graphene quantum dot (GQD), aminated GQD (GQD-NH2), carboxyl GQD (GQD-COOH), and graphene oxide quantum dot (GOQD). In contrast, it was found that large particle size, oxidation state, high concentration, and long exposure time were unfavorable factors affecting the cell viability. We further explored the mechanism of different toxicity, which could be contribute to cell membrane destruction by sharpened edges of GDs (LDH release, hemolysis), ROS production, immuno-inflammatory responses, and activation of apoptotic pathways (IKK/IκBα/NF-κB and BAX/BCL-2). Overall, our combined data primarily explored the related biochemical and molecular mechanism underlying the biological behaviors and toxicity of GDs, and we also identified GQD, GQD-NH2, GQD-COOH, and GOQD could be safely used for biomedical application as drug carriers.

MicroRNA-365 suppresses cell growth and invasion in esophageal squamous cell carcinoma by modulating phosphoserine aminotransferase 1.

BACKGROUND: A number of studies have indicated that expression of miRNA-365 (miR-365) is suppressed in various cancers, suggesting its cancer-suppressive role. In the present investigation, we evaluated the regulation and character of miR-365 in human esophageal squamous cell carcinoma (ESCC). PATIENTS AND METHODS: The tumor tissues and adjacent nontumor tissue samples were collected from 30 patients having ESCC, and the expression levels of miR-365 were studied by quantitative real-time polymerase chain reaction (PCR). MTT and cell invasion by Matrigel assay were done to study the effect of miR-365 on proliferation and metastasis of ESCC cells. An in vivo tumor model was generated by inoculating ESCC cells subcutaneously into BALB nude mice. A study of various biomarkers such as quantitative polymerase chain reaction (qPCR), luciferase activity assay, and Western blot was done to confirm the targets of miR-365. RESULTS: In tumor tissues, a significant downregulation of miR-365 was observed versus the nontumor adjacent tissues and ESCC cells versus the selected esophageal endothelial cells. It was observed that higher expression levels of miR-365 inhibited the cell invasion, colony formation, growth in esophageal cancer cell lines in vitro, and tumor development in vivo. The study of biomarkers suggests involvement of phosphoserine aminotransferase 1 (PSAT1) as a favorable target for miR-365, and its abnormal expression inverted the miR-365-arbitrated suppression of invasion, viability, and epithelial-mesenchymal transition in esophageal cancer cells. A negative correlation existed with expression of miR-365 and PSAT1 in human esophageal cancer tissue samples. CONCLUSION: The study established that miR-365 exhibits tumor-suppressive action via regulating the levels of PSAT1 and leads to invasion and progressiveness of esophageal cancer.

PEGylated mBPEI-rGO nanocomposites facilitate hepotocarcinoma treatment combining photothermal therapy and chemotherapy.

Despite chemotherapy has been widely used for tumor therapy, the serious side effect is still a major challenge. Recently, two dimensional nanomaterial-based drug delivery systems have attracted wide concern due to their high drug loading and low side effect. In addition, some kinds of nanomaterials can directly act as a photosensitizer to induce cancer destruction. In this study, we developed a drug delivery system of mixture of high/low molecular weight branched polyethylenimine-polyethylene glycol-reduced graphene oxide (mBPEI-PEG-rGO) using reduced graphene oxide as matrix. A model drug of doxorubicin (DOX) was loaded on the nanocomposites with the efficiency of 81% and the release rate of more than 50% at acidic environment. In vitro experiments indicated that mBPEI-PEG-rGO-DOX with enhanced stability and biocompatibility efficiently delivered and released DOX into cells mainly through micropinocytosis and killed SMMC-7721 cells by inducing reactive oxygen species (ROS) and cell apoptosis. Furthermore, in vivo experiments indicated that the combination of intratumoral injection of mBPEI-PEG-rGO-DOX and local laser irradiation nearly ablated hepatocarcinoma. In conclusion, this new drug delivery system provided an alternative for combinational photothermal and chemotherapy against hepatocarcinoma.

What is the optimal radiation dose for non-operable esophageal cancer? Dissecting the evidence in a meta-analysis.

The standard radiation dose 50.4 Gy with concurrent chemotherapy for localized inoperable esophageal cancer as supported by INT-0123 trail is now being challenged since a radiation dose above 50 Gy has been successfully administered with an observable dose-response relationship and insignificant untoward effects. Therefore, to ascertain the treatment benefits of different radiation doses, we performed a meta-analysis with 18 relative publications. According to our findings, a dose between 50 and 70 Gy appears optimal and patients who received ≥ 60 Gy radiation had a significantly better prognosis (pooled HR = 0.78, P = 0.004) as compared with < 60 Gy, especially in Asian countries (pooled HR = 0.75, P = 0.003). However, contradictory results of treatment benefit for ≥ 60 Gy were observed in two studies from Western countries, and the pooled treatment benefit of ≥ 60 Gy radiation was inconclusive (pooled HR = 0.86, P = 0.64). There was a marginal benefit in locoregional control in those treated with high dose (> 50.4/51 Gy) radiation when compared with those treated with low dose (≤ 50.4/51 Gy) radiation (pooled OR = 0.71, P = 0.06). Patients that received ≥ 60 Gy radiation had better locoregional control (OR = 0.29, P = 0.001), and for distant metastasis control, neither the > 50.4 Gy nor the ≥ 60 Gy treated group had any treatment benefit as compared to the groups that received ≤ 50.4 Gy and < 60 Gy group respectively. Taken together, a dose range of 50 to 70 Gy radiation with CCRT is recommended for non-operable EC patients. A dose of ≥ 60 Gy appears to be better in improving overall survival and locoregional control, especially in Asian countries, while the benefit of ≥ 60 Gy radiation in Western countries still remains controversial.