Incidence and risk factors for potential drug-drug interactions in outpatients receiving opioid analgesics.

BACKGROUND: Opioids are the most frequently used drugs to treat pain in cancer patients. However opioid analgesics can cause adverse effects and potential drug-drug interaction. RESEARCH DESIGN AND METHODS: This cross-sectional retrospective study analyzed pDDI in 1839 patients with opioid analgesics in a large comprehensive hospital in China from January 1 to 31 December 2022. Three drug interaction databases were used to screen for pDDI including Drugs (U.S.A.), Medscape (U.S.A.), and Drug Assistant of Dingxiangyuan (China). RESULTS: The prevalence of pDDIs among 1839 patients was around 41.27% of 759 patients, and 564 patients (74.31%) with pDDIs were diagnosed with tumor. Further, the total of 275 various pDDIs combinations were identified. The combination of oxycodone with morphine had the most frequent occurrence of 229 times, and its adverse effects mainly related to exacerbate central respiratory depression. While, gender, tumor, number of diagnoses, and the variety of opioid analgesics used were independent risk factors for pDDIs. CONCLUSIONS: Outpatients taking opioid analgesics had a higher incidence of pDDIs. As consequently, optimized monitoring and management of patients taking opioid analgesics is recommended in order to ensure patient medication safety.

The global landscape of immune-derived lncRNA signature in colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) is a highly heterogeneous cancer. This heterogeneity has an impact on the efficacy of immunotherapy. Long noncoding RNAs (lncRNAs) have been found to play regulatory functions in cancer immunity. However, the global landscape of immune-derived lncRNA signatures has not yet been explored in colorectal cancer. METHODS: In this study, we applied DESeq2 to identify differentially expressed lncRNAs in colon cancer. Next, we performed an integrative analysis to globally identify immune-driven lncRNA markers in CRC, including immune-associated pathways, tumor immunogenomic features, tumor-infiltrating immune cells, immune checkpoints, microsatellite instability (MSI) and tumor mutation burden (TMB). RESULTS: We also identified dysregulated lncRNAs, such as LINC01354 and LINC02257, and their clinical relevance in CRC. Our findings revealed that the differentially expressed lncRNAs were closely associated with immune pathways. In addition, we found that RP11-354P11.3 and RP11-545G3.1 had the highest association with the immunogenomic signature. As a result, these signatures could serve as markers to assess immunogenomic activity in CRC. Among the immune cells, resting mast cells and M0 macrophages had the highest association with lncRNAs in CRC. The AC006129.2 gene was significantly associated with several immune checkpoints, for example, programmed cell death protein 1 (PD-1) and B and T lymphocyte attenuator (BTLA). Therefore, the AC006129.2 gene could be targeted to regulate the condition of immune cells or immune checkpoints to enhance the efficacy of immunotherapy in CRC patients. Finally, we identified 15 immune-related lncRNA-generated open reading frames (ORFs) corresponding to 15 cancer immune epitopes. CONCLUSION: In conclusion, we provided a genome-wide immune-driven lncRNA signature for CRC that might provide new insights into clinical applications and immunotherapy.

LCP1 knockdown in monocyte-derived macrophages: mitigating ischemic brain injury and shaping immune cell signaling and metabolism.

Rationale: Ischemic stroke poses a significant health burden with limited treatment options. Lymphocyte Cytosolic Protein 1 (LCP1) facilitates cell migration and immune responses by aiding in actin polymerization, cytoskeletal rearrangements, and phagocytosis. We have demonstrated that the long non-coding RNA (lncRNA) Maclpil silencing in monocyte-derived macrophages (MoDMs) led to LCP1 inhibition, reducing ischemic brain damage. However, the role of LCP1 of MoDMs in ischemic stroke remains unknown. Methods and Results: We investigated the impact of LCP1 on ischemic brain injury and immune cell signaling and metabolism. We found that knockdown of LCP1 in MoDMs demonstrated robust protection against ischemic infarction and improved neurological behaviors in mice. Utilizing the high-dimensional CyTOF technique, we demonstrated that knocking down LCP1 in MoDMs led to a reduction in neuroinflammation and attenuation of lymphopenia, which is linked to immunodepression. It also showed altered immune cell signaling by modulating the phosphorylation levels of key kinases and transcription factors, including p-PLCg2, p-ERK1/2, p-EGFR, p-AKT, and p4E-BP1 as well as transcription factors like p-STAT1, p-STAT3, and p-STAT4. Further bioinformatic analysis indicated that Akt and EGFR are particularly involved in fatty acid metabolism and glycolysis. Indeed, single-cell sequencing analysis confirmed that enrichment of fatty acid and glycolysis metabolism in Lcp1high monocytes/macrophages. Furthermore, Lcp1high cells exhibited enhanced oxidative phosphorylation, chemotaxis, migration, and ATP biosynthesis pathways. In vitro experiments confirmed the role of LCP1 in regulating mitochondrial function and fatty acid uptake. Conclusions: These findings contribute to a deeper understanding of LCP1 in the context of ischemic stroke and provide valuable insights into potential therapeutic strategies targeting LCP1 and metabolic pathways, aiming to attenuating neuroinflammation and lymphopenia.

The influence of radiation-induced bystander effect in osteoblasts mediated by plasma-derived extracellular vesicles (EVs).

OBJECTIVES: Head and neck tumor patients may develop post-radiotherapy diseases after radiotherapy treatment. And radiotherapy can elicit radiation-induced bystander effect, wherein extracellular vesicles (EVs) play a crucial role. For normal parts of the body that have not been directly irradiated, the effect of EVs on them needs to be further explored. This study aims to investigate the functions of plasma-derived EVs in regulating normal osteoblasts during radiation-induced bystander effects. METHODS AND MATERIALS: Rat plasma-derived EVs were isolated and identified firstly, followed by an evaluation of their intracellular biological effects on normal osteoblasts in vitro. Transcriptome sequencing analysis and confirmations were performed to identify potential mechanisms. RESULTS: Irradiated plasma-derived EVs were found to enhance osteoblast proliferation, migration, and cell cycle progression, concurrently suppressing the expression of osteogenesis-related genes and proteins. Furthermore, these EVs attenuated the expression of osteogenesis and oxidative stress resistance related genes, while upregulating the PI3K-AKT pathway and intracellular reactive oxygen species in osteoblasts. CONCLUSIONS: Irradiated plasma-derived EVs could alter the biological effects in osteoblasts, which is closely associated with the levels of GPX1 and the PI3K-AKT signaling pathway. This suggests that plasma-derived EVs serve as a crucial factor contributing to radiation-induced bystander effect in osteoblasts.

A ScWIP5 gene confers fall armyworm resistance by reducing digestive enzyme activities in sugarcane.

BACKGROUND: The fall armyworm, Spodoptera frugiperda, is one of the most dangerous pests to various crops. As the most crucial sugar crop, sugarcane is also constantly threatened by these pests. Plant wound-induced proteinase inhibitors (WIP) are natural defense proteins that play important roles in the defense system against insect attack. Breeding for resistance would be the best way to improve the variety characteristics and productivity of sugarcane. Screening and verification for potential plant endogenous insect-resistant genes would greatly improve the insect-resistant breeding progress of sugarcane. RESULTS: A sugarcane WIP5 gene (ScWIP5) was up-regulated 536 times after insect feeding treatment on previous published transcriptome databases. ScWIP5 was then cloned and its potential role in sugarcane resistance to fall armyworm evaluated by construction of transgenic Nicotiana benthamiana. The toxicity of ScWIP5 transgenic N. benthamiana to fall armyworm showed lower weight gain and higher mortality compared to wild-type N. benthamiana feeding group. Furthermore, the concentration of JA and NbAOC, NbAOS, and NbLOX from the Jasmin acid biosynthesis pathway was significantly induced in ScWIP5 transgenic N. benthamiana compared to the control. In addition, digestive enzyme actives from the insect gut were also evaluated, and trypsin and cathepsin were significantly lower in insects fed with ScWIP5 transgenic N. benthamiana. CONCLUSION: These results indicate that ScWIP5 might enhance insect resistance by increasing JA signal transduction processes and reducing insect digestive enzyme activities, thus impacting insect growth and development. © 2023 Society of Chemical Industry.

A pilot study of multi-antigen stimulated cell therapy-I plus camrelizumab and apatinib in patients with advanced bone and soft-tissue sarcomas.

BACKGROUND: Cell-based  immunotherapy shows the therapeutic potential in sarcomas, in addition to angiogenesis-targeted tyrosine kinase inhibitor (TKI) and immune checkpoint inhibitor (ICI). Multi-antigen stimulated cell therapy-I (MASCT-I) technology is a sequential immune cell therapy for cancer, which composes of multiple antigen-loaded dendritic cell (DC) vaccines followed by the adoptive transfer of anti-tumor effector T-cells. METHODS: In this phase 1 study, we assessed MASCT-I plus camrelizumab (an ICI against PD-1) and apatinib (a highly selective TKI targeting VEGFR2) in patients with unresectable recurrent or metastatic bone and soft-tissue sarcoma after at least one line of prior systemic therapy. One MASCT-I course consisted of 3 DC subcutaneous injections, followed by 3 active T cell infusions administered 18-27 days after each DC injection. In schedule-I group, 3 DC injections were administered with a 28-day interval in all courses; in schedule-II group, 3 DC injections were administered with a 7-day interval in the first course and with a 28-day interval thereafter. All patients received intravenous camrelizumab 200 mg every 3 weeks and oral apatinib 250 mg daily. RESULTS: From October 30, 2019, to August 12, 2021, 19 patients were enrolled and randomly assigned to schedule-I group (n = 9) and schedule-II group (n = 10). Of the 19 patients, 11 (57.9%) experienced grade 3 or 4 treatment-related adverse events. No treatment-related deaths occurred. Patients in schedule-II group showed similar objective response rate (ORR) with those in schedule-I group (30.0% versus 33.3%) but had higher disease control rate (DCR; 90.0% versus 44.4%) and longer median progression-free survival (PFS; 7.7 versus 4.0 months). For the 13 patients with soft-tissue sarcomas, the ORR was 30.8%, DCR was 76.9%, and median PFS was 12.9 months; for the 6 patients with osteosarcomas, the ORR was 33.3%, the DCR was 50.0%, and median PFS was 5.7 months. CONCLUSIONS: Overall, MASCT-I plus camrelizumab and apatinib was safe and showed encouraging efficacy in advanced bone and soft-tissue sarcoma, and schedule-II administration method was recommended. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04074564.

Ganoderma lucidum polysaccharide peptide (GLPP) attenuates rheumatic arthritis in rats through inactivating NF-κB and MAPK signaling pathways.

BACKGROUND: Not many drugs with fewer side effects are available for the treatment of rheumatoid arthritis (RA). Ganoderma lucidum polysaccharide peptide (GLPP) has good immunomodulatory effects, but whether it is effective in managing RA is not clear. PURPOSE: This study was conducted to examine the anti-RA activity and possible mechanisms of GLPP in collagen-induced arthritis (CIA) rats. METHODS: Male Wistar rats were intradermally injected with bovine type II collagen in the tail base to establish the CIA model and were orally administered 100 or 200 mg/kg GLPP for 35 days. Paw thickness, clinical arthritis scores, gait analysis, organ index determination, blood cell counts, micro-CT imaging and pathological staining were performed on the rats. Liver and kidney function were measured by commercial kits, and antibody levels were measured by ELISA kits. RA-related protein levels were detected by Western blotting. RESULTS: GLPP effectively alleviated CIA symptoms and reduced immune organ indexes, antibody levels and systemic organ injury. GLPP decreased the protein expression of tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6, matrix metalloproteinase (MMP)2, MMP9, MMP13, BCL-2, OPN, ß-Catenin, and hypoxia inducible factor (HIF)-1α and increased the protein expression of BAX in the joint tissues of CIA rats. Moreover, GLPP decreased the phosphorylation levels of p65, IκB-α and ERK1/2. CONCLUSION: GLPP effectively alleviated RA symptoms in CIA rats by inhibiting the NF-κB and MAPK pathways. This study suggests a promising therapeutic effect of mushroom-derived polysaccharide peptides on RA.

COVID-19 vaccination effectiveness and safety in vulnerable populations: a meta-analysis of 33 observational studies.

Background: Even 3 years into the COVID-19 pandemic, questions remain about how to safely and effectively vaccinate vulnerable populations. A systematic analysis of the safety and efficacy of the COVID-19 vaccine in at-risk groups has not been conducted to date. Methods: This study involved a comprehensive search of PubMed, EMBASE, and Cochrane Central Controlled Trial Registry data through 12 July 2022. Post-vaccination outcomes included the number of humoral and cellular immune responders in vulnerable and healthy populations, antibody levels in humoral immune responders, and adverse events. Results: A total of 23 articles assessing 32 studies, were included. The levels of IgG (SMD = -1.82, 95% CI [-2.28, -1.35]), IgA (SMD = -0.37, 95% CI [-0.70, -0.03]), IgM (SMD = -0.94, 95% CI [-1.38, -0.51]), neutralizing antibodies (SMD = -1.37, 95% CI [-2.62, -0.11]), and T cells (SMD = -1.98, 95% CI [-3.44, -0.53]) were significantly lower in vulnerable than in healthy populations. The positive detection rates of IgG (OR = 0.05, 95% CI [0.02, 0.14]) and IgA (OR = 0.03, 95% CI [0.01, 0.11]) antibodies and the cellular immune response rates (OR = 0.20, 95% CI [0.09, 0.45]) were also lower in the vulnerable populations. There were no statistically significant differences in fever (OR = 2.53, 95% CI [0.11, 60.86]), chills (OR = 2.03, 95% CI [0.08, 53.85]), myalgia (OR = 10.31, 95% CI [0.56, 191.08]), local pain at the injection site (OR = 17.83, 95% CI [0.32, 989.06]), headache (OR = 53.57, 95% CI [3.21, 892.79]), tenderness (OR = 2.68, 95% CI [0.49, 14.73]), and fatigue (OR = 22.89, 95% CI [0.45, 1164.22]) between the vulnerable and healthy populations. Conclusion: Seroconversion rates after COVID-19 vaccination were generally worse in the vulnerable than healthy populations, but there was no difference in adverse events. Patients with hematological cancers had the lowest IgG antibody levels of all the vulnerable populations, so closer attention to these patients is recommended. Subjects who received the combined vaccine had higher antibody levels than those who received the single vaccine.

Cancer-keeper genes as therapeutic targets.

Finding cancer-driver genes has been a central theme of cancer research. We took a different perspective; instead of considering normal cells, we focused on cancerous cells and genes that maintained abnormal cell growth, which we named cancer-keeper genes (CKGs). Intervening CKGs may rectify aberrant cell growth, making them potential cancer therapeutic targets. We introduced control-hub genes and developed an efficient algorithm by extending network controllability theory. Control hub are essential for maintaining cancerous states and thus can be taken as CKGs. We applied our CKG-based approach to bladder cancer (BLCA). All genes on the cell-cycle and p53 pathways in BLCA were identified as CKGs, showing their importance in cancer. We discovered that sensitive CKGs - genes easily altered by structural perturbation - were particularly suitable therapeutic targets. Experiments on cell lines and a mouse model confirmed that six sensitive CKGs effectively suppressed cancer cell growth, demonstrating the immense therapeutic potential of CKGs.

China special issue on gastrointestinal tumors-Regulatory-immunoscore-A novel indicator to guide precision adjuvant chemotherapy in colorectal cancer.

Novel biomarkers are essential to improve the treatment efficacy and overall survival of stage II and III colorectal cancer (CRC), allowing for personalized treatment decisions. Here, the densities of CD8+ and FOXP3+ T cells in the tumor and invasive margin were processed by immunohistochemistry and digital pathology to form a scoring system named regulatory-Immunoscore (RIS). Cox proportional hazards regression models were used to determine the risk factors associated with time to recurrence. Harrell's concordance index and the time-dependent area under the curve were used to assess model performance. A total of 1213 stage I-III DNA mismatch repair-proficient colorectal cancer (pMMR CRC) patients were randomly assigned to a training set (n = 642) and a validation set (n = 571). From the Cox multivariable analysis, the association of RIS with survival was independent of patient age, sex and anatomy-based tumor risk parameters (P < .0001). For stage II patients, chemotherapy was significantly associated with better recurrence time in patients with low (95% confidence interval [CI]: 0.11-0.54, P = .001) and intermediate (95% CI = 0.25-0.57, P < .001) RIS values. In stage III patients treated with adjuvant chemotherapy, a treatment duration of 6 or more months was significantly associated with better recurrence time in patients with intermediate RIS values (95% CI = 0.38-0.90, P = .016) when compared with duration under 6 months. Therefore, these findings suggest that RIS is reliable for predicting recurrence risk and treatment responsiveness for patients with stage I-III pMMR CRC.

Vitamin D ameliorates insulin resistance-induced osteopenia by inactivating the nucleotide-binding oligomerization domain-like receptor protein 3 inflammasome.

Objective: Osteoporosis (OP) can be considered a chronic complication of type 2 diabetes mellitus (T2DM). Aberrant activation of the nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome is associated with the pathogenesis of various inflammation-related diseases, e.g., T2DM and OP. Vitamin D affects the inflammatory pathway and inhibits an excessive inflammatory response. The current study investigated the inter-relationship between vitamin D and inflammasome activation in T2DM. Method: Hepatocellular carcinoma (HepG2) cells and bone marrow stromal cells (BMSCs) were treated with Conditioned Medium of bone marrow mesenchymal stem cells after VitD treatment (CM-VitD), as well as phosphoinositide 3-kinase (PI3K) specific agonist, 740Y-P, or the PI3K specific inhibitor, LY294002, respectively, or both. 40 Eight-week-old female Sprague Dawley rats were selected and established as a DM model. The rats were injected with CM-VitD, as well as the 740Y-P specific agonist, or the LY294002 inhibitor, respectively, or both. A quantitative reverse transcription polymerase chain reaction and western blotting were conducted to evaluate the expression of messenger ribonucleic acid and protein in the RUX2 gene, alkaline phosphatase (ALP), OsteoPontiN (OPN), peroxisome proliferator-activated receptor gamma (PPARγ), fatty acid-binding protein 4 (FABP4), protein kinase B (AKT), PI3K, NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), caspase-1, interleukin (IL)-1 beta (ß), IL-18, and tumor necrosis factor alpha (TNF-α) in the BMSCs and liver tissue of rats. Enzyme-linked immunosorbent assay was used to detect the concentration of inflammatory factors in the cell supernatant and serum of rats. Results: An isolated co-culture of HepG2/insulin-resistance cells and BMSCs promoted the adipogenic transformation of the latter and inhibited the transformation of BMSCs into osteogenesis. The PI3K specific agonist, 740Y-P, significantly increased the expression of PI3K, AKT, NLRP3, ASC and Caspase-1 while the PI3K specific inhibitor, LY294002, does the opposite. Additionally, CM-VitD reduced the expression of NLRP3, ASC, caspase-1, IL-1ß, and IL-18 in BMSCs and rat liver via the PI3K/AKT pathway. Conclusion: Vitamin D can inhibit the inflammatory response induced by T2DM and promote the osteogenesis of BMSCs, which may play a key role in the treatment of type 2 diabetes patients with OP.

Correction: ThC2@C82 versus Th@C84: unexpected formation of triangular thorium carbide cluster inside fullerenes.

[This corrects the article DOI: 10.1039/D2SC04846A.].

First-in-Maintenance Therapy for Localized High-Grade Osteosarcoma: An Open-Label Phase I/II Trial of the Anti-PD-L1 Antibody ZKAB001.

PURPOSE: We investigated the safety and preliminary efficacy of anti-PD-L1 antibody (ZKAB001) as maintenance therapy for localized patients with high-grade osteosarcoma to reduce the risk of recurrence and metastasis. PATIENTS AND METHODS: This open-label Phase I/II study was divided into dose-escalation Phase I and expansion Phase II. Phase I used a 3+3 design with ZKAB001 at three escalating doses ranging: 5, 10, 15 mg/kg every 2 weeks in 9 patients with localized high-grade osteosarcoma and Phase II tested 10 mg/kg in 12 patients for up to 24 cycles. Primary endpoints were safety and tolerability assessed using CTCAE4.0.3. RESULTS: Between October 2018 and 2019, 21 eligible patients were enrolled and accepted ZKAB001 treatment: 9 in the dose-escalation phase, and 12 in expansion phase. Six patients with disease progression withdrew from this study and follow-up is ongoing. The MTD was not defined in Phase I. All doses had a manageable safety profile. The recommended dose in Phase II was set at 10 mg/kg. Most frequent immune-related adverse events were thyroiditis (76.2%) and dermatitis (42.9%). Only 1 (4.8%) of 21 patients had a Grade 3 skin rash. The median 3-year event-free survival (EFS) and overall survival (OS) were not established; however, 24-month EFS was 71.4% (95% confidence interval, 47.2-86.0) and 2-year OS was 100%. Preliminary efficacy data showed EFS benefits in patients with PD-L1 positive or an MSI-H sub-population. CONCLUSIONS: Switching to maintenance using ZKAB001 showed an acceptable safety profile and provided preliminary evidence of clinical activity in localized patients with osteosarcoma.

A L833V/H835L EGFR variant lung adenocarcinoma with skin metastasis: A case report and literature review.

The co-occurrence of two or more rare variants, known as compound variants, is rare in non-small cell lung carcinoma with epidermal growth factor receptor (EGFR) variants, and the compound variant L833V/H835L in exon 21 of EGFR is extremely rare. There is very little evidence regarding its treatment. Herein, we report a case of an advanced lung adenocarcinoma patient with cutaneous metastases. Next generation sequencing detected a combination variant of EGFR exon 21 L833V/H835L. To our surprise, our patient had almost complete remission of skin symptoms after 1 month of oral gefitinib (250 mg/d qd) treatment with less skin toxicity. At the time of this report submission, the last CT scan confirmed that the patient had achieved partial response. To date, the patient has achieved a remarkable result with a progression-free survival of 18 + months. The presentation of this case and a literature review suggest that tailored therapeutic interventions are available for this subset of patients.

Tumor-on-a-chip: Perfusable vascular incorporation brings new approach to tumor metastasis research and drug development.

The extracellular matrix interacts with cancer cells and is a key factor in the development of cancer. Traditional two-dimensional models cannot mimic the natural in situ environment of cancer tissues, whereas three-dimensional (3D) models such as spherical culture, bioprinting, and microfluidic approaches can achieve in vitro reproduction of certain structures and components of the tumor microenvironment, including simulation of the hypoxic environment of tumor tissue. However, the lack of a perfusable vascular network is a limitation of most 3D models. Solid tumor growth and metastasis require angiogenesis, and tumor models with microvascular networks have been developed to better understand underlying mechanisms. Tumor-on-a-chip technology combines the advantages of microfluidics and 3D cell culture technology for the simulation of tumor tissue complexity and characteristics. In this review, we summarize progress in constructing tumor-on-a-chip models with efficiently perfused vascular networks. We also discuss the applications of tumor-on-a-chip technology to studying the tumor microenvironment and drug development. Finally, we describe the creation of several common tumor models based on this technology to provide a deeper understanding and new insights into the design of vascularized cancer models. We believe that the tumor-on-a-chip approach is an important development that will provide further contributions to the field.

Reactivity of Formaldehyde during 4-Hydroxy-2-butanone Synthesis in Supercritical State.

4-Hydroxy-2-butanone, an important intermediate for vitamin A and fragrances, is usually produced by aldol condensation of acetone and formaldehyde. Noncatalytic synthesis of 4-hydroxy-2-butanone in supercritical state, which was fast and had high production yield, was widely applied. Previous research on 4-hydroxy-2-butanone synthesis in the supercritical state focused on the formation and dehydration of 4-hydroxy-2-butanone while ignoring side reactions involving formaldehyde, which were studied in this paper. A reaction pathway of 4-hydroxy-2-butanone supercritical synthesis containing formaldehyde side reactions was proposed. The cross-disproportionation of formaldehyde and formic acid was found to be the main consumption of formic acid. The effects of initial formaldehyde and formic acid mass fractions in the feed on side reactions were studied. Based on the experiments conducted from 523.15 K to 563.15 K and 17 MPa, a kinetic model was suggested. The relative deviations between experimental and simulated data were less than 10%.

There is a Good Consistency Between Reflux Symptom Score-12 and Reflux Symptom Index in Chinese Population.

OBJECTIVE: To investigate the consistency between the Reflux Symptom Score-12 (RSS-12) and Reflux Symptom Index (RSI) in Chinese people. METHODS: Patients with symptoms of LPR from the outpatient otorhinolaryngology-head and neck surgery clinic were included. All included patients completed the RSS-12 and RSI. The patient with RSS-12>11 or RSI>13 suggested possible LPR. For the patients with RSI >13 or RSS-12>11, they were treated using diet recommendations and were prescribed a twice-daily pantoprazole for 12 weeks. The consistency between the RSS-12 and RSI was compared with the weighted Cohen's kappa statistic. RESULTS: A total of 258 patients were included. The mean scores for RSS-12 and RSI were 13.21±17.31 and 12.86±6.15, respectively. The positive rate of LPR was 17.44% based on the RSI, and 24.42% based on the RSS-12. The kappa value between the RSS-12 and RSI was 0.736 (P < 0.001). Following 12 weeks of treatment, there was a significant reduction in both RSI and RSS-12. Based on the RSI, 73% of patients had a good treatment response, whereas according to the RSS-12, 85% of patients had a good treatment response. CONCLUSION: There is a good consistency between RSS-12 and RSI, meaning that the RSS-12 is a feasible LPR initial screening tool. The RSS-12 provides a more comprehensive evaluation of reflux symptoms and treatment effect than RSI in patients with LPR.

Multiple-dose up-titration study to evaluate the pharmacokinetics, safety and antitumor activity of apatinib in advanced gastric adenocarcinoma.

Background and purpose: The objective of this study was to investigate the pharmacokinetics, safety, and antitumor activity of apatinib, a vascular endothelial growth factor receptor 2 inhibitor, in advanced gastric adenocarcinoma or gastroesophageal junction adenocarcinoma and evaluate the effect of dose titration on dosage optimization for individual patients. Methods: Patient with advanced gastric adenocarcinoma progressed after at least one line of chemotherapy were enrolled. Apatinib was given orally once daily starting at 500 mg for 14 days, then up-titrated to 750 mg for 14 days, and then proceeded to a maximum dose of 850 mg. Dose up-titration determination was based on toxicity. The 28-day treatment cycles continued until disease progression, intolerable toxicities, withdrawal of consent, or investigator' decision. Results: A total of 60 patients were enrolled, with 17, 18, and 25 patients receiving a maximum dose of 500 mg, 750 mg, and 850 mg, respectively. The pharmacokinetic parameters varied considerably, with the interpatient coefficient of variation for steady state areas under the plasma concentration time curve (AUCss) and the mean maximum concentration of both > 50%. During 500 mg and 750 mg dosing stage, drug exposures in patients with a maximum dosage of 850 mg were lower than in those not titrated to 850 mg. Patients with total gastrectomy exhibited significantly lower AUCss than patients with partial or no gastrectomy (p = 0.004 and 0.032, respectively). Toxicities were tolerable, and disease control rate was 39.5% (95% CI 25.0%-55.6%). Conclusions: Apatinib dose titration based on toxicity could be used in clinical practice to provide optimal dosage for individual patients. Clinical Trial registration: https://clinicaltrials.gov/ct2/show/NCT02764268?term=NCT02764268&draw=2&rank=1, NCT02764268.

ThC2@C82 versus Th@C84: unexpected formation of triangular thorium carbide cluster inside fullerenes.

Synthesis of the first thorium-containing clusterfullerenes, ThC2@C s (6)-C82 and ThC2@C2(5)-C82, is reported. These two novel actinide fullerene compounds were characterized by mass spectrometry, single-crystal X-ray diffraction crystallography, UV-vis-NIR spectroscopy, and theoretical calculations. Crystallographic studies reveal that the encapsulated ThC2 clusters in both C s (6)-C82 and C2(5)-C82 feature a novel bonding structure with one thorium metal center connected by a C[triple bond, length as m-dash]C unit, forming an isosceles triangular configuration, which has not been hitherto observed for endohedral fullerenes or for solid phase thorium carbides. Electronic structure calculations assign a formal electronic structure of [Th4+(C2)2-]2+@[C82]2-, with pronounced donation bonding from (C2)2- to Th4+, secondary backbonding from the fullerene to thorium and Th-C double bond character in both compounds. This work presents a new family of endohedral fullerenes, MC2@C2n-2, being unexpected isomers of MC2n , and provides broader understanding of thorium bonding.

The Combination of Anlotinib and Gemcitabine/Docetaxel in Patients with Metastatic Osteosarcoma Who Have Failed Standard Chemotherapy.

Purpose: The options for the second-line treatment of metastatic osteosarcoma are still limited. Anlotinib is a multi-kinase inhibitor which has shown promising efficacy and good tolerability in various cancer types. This retrospective study was conducted to evaluate the efficacy and safety of anlotinib combined with gemcitabine/docetaxel (GD) in patients with metastatic osteosarcoma who have failed first-line chemotherapy. Patients and Methods: The data of patients who received anlotinib combined with GD or GD were collected. The primary endpoint was progression-free survival. Secondary endpoints included objective response rate and safety. Results: From July 2013 to November 2020, a total of 32 patients were enrolled, 13 received anlotinib combined with GD and 19 received GD. Median PFS was 9.0 months (95% CI 6.7-39.1) in the combination group and 5.0 months (95% CI 1.2-6.7) in the chemotherapy group. ORR were 38.4% and 15.8%, DCR were 69.2% and 38.1% in the combination and chemotherapy group, respectively. The most common adverse events included fatigue (78.9% in the combination group vs 69.2% in the chemotherapy group), hypertension (46.2% vs 10.5%), diarrhea (38.5% vs 21.1%), hypothyroidism (38.5% vs 15.8%), neutropenia (23.1% vs 36.8%) and AST elevation (30.8% vs 21.1%). The most common grade 3 or worse adverse events included hand-foot reaction (7.7% vs 5.3%), hypothyroidism (15.4% vs 0), neutropenia (0 vs 10.5%). Conclusion: The combination of anlotinib and GD showed favorable efficacy with manageable toxicities compared with GD in the second-line treatment for metastatic osteosarcoma. This combination therapy deserves further investigations in patients with osteosarcoma.