Association of NUDT15 gene polymorphism with adverse reaction, treatment efficacy, and dose of 6-mercaptopurine in patients with acute lymphoblastic leukemia: a systematic review and meta-analysis.

6-mercaptopurine (6-MP) serves as the backbone in the maintenance regimens of acute lymphoblastic leukemia (ALL). We aimed to evaluate the influence of NUDT15 gene polymorphism on the risk of myelosupression, hepatotoxicity and interruption of 6-MP, as well as treatment efficacy and dose of 6-MP in ALL patients. A total of 24 studies with 3,374 patients were included in this meta-analysis. We found 9-fold higher risk of 6-MP induced leukopenia (odds ratio [OR] =9.00, 95% confidence interval [CI]: 3.73-21.74) and 2.5-fold higher risk of 6-MP-induced neutropenia (OR=2.52, 95% CI: 1.72-3.69) for NUDT15 c.415C>T variant carriers in the dominant model. Moreover, we found that the dose intensity of 6-MP in ALL patients with one NUDT15 c.415C>T variant alleles (CT) was 19% less than that in wild-type patients (CC) (mean differences: 19.43%, 95% CI: -25.36 to -13.51). The tolerable dose intensity of 6-MP in NUDT15 c.415C>T homozygote variant (TT) and heterozygote variant (CT) carriers was 49% and 15% less than that in wild-type patients, respectively. The NUDT15 c.415C>T variant group (CT+TT) had seven times (OR=6.98, 95% CI: 2.83-17.22) higher risk of developing 6-MP intolerance than the CC group. However, NUDT15 c.415C>T polymorphism did not appear significantly associated with hepatotoxicity, treatment interruption or relapse incidence. We concluded that NUDT15 c.415C>T was a good predictor for 6-MP-induced myelosuppression in ALL patients. The dose intensity of 6-MP in ALL patients with NUDT15 c.415C>T variants was significantly lower than that in wild-type patients. This research provided a basis for further investigation into relations between NUDT15 gene and adverse reaction, treatment efficacy and dose intensity of 6-MP.

Nonreciprocal coupling modulated difference-sideband generation in a double-cavity optomechanical system.

We theoretically study the difference-sideband generation in a double-cavity optomechanical system with nonreciprocal coupling. Beyond the conventional linearized description of optomechanical interactions, we derive analytical expressions for the efficiency of difference-sideband generation by using a perturbation method. Here we investigate bistable behaviors of the system and show the difference-sideband generation modulated by the nonreciprocal coupling strength between the two cavities. We find that the nonreciprocal coupling strength can not only affect the bistability of the system but also lead to different efficiencies of difference-sideband generation at low power. To achieve high efficiency of difference-sideband generation, we give the optimal matching conditions under different parameter mechanisms. Especially as the power increases, we find new matching conditions with remarkable difference-sideband generation emerging, which is attribute to the strong coherence between the cavity field and the mechanical oscillator. Furthermore, a feasible scheme to obtain difference-sideband generation by employing multiple adjustable variables is proposed. Our results may find applications in nonreciprocal optical frequency combs and communications, and provide a potential method for precision measurements and on-chip manipulation of light transmission.

The efficacy and safety of roxadustat for anemia in patients with dialysis-dependent chronic kidney disease: a systematic review and meta-analysis.

BACKGROUND: This meta-analysis aims to assess the efficacy and safety of roxadustat in treating anemia patients with dialysis-dependent (DD) chronic kidney disease (CKD). METHODS: We comprehensively searched 5 databases for randomized controlled trials (RCTs) investigating roxadustat for anemia in DD-CKD patients. RevMan 5.0 was used to extract and synthesize data for meta-analysis. RESULTS: Ten different RCTs (9 studies) and 5698 DD-CKD patients with anemia were included. Our findings revealed that when compared to the erythropoiesis-stimulating agents (ESAs) group, the roxadustat group showed increased hemoglobin levels [MD (Mean Difference) 0.25 g/dL (95%CI 0.14 g/dL to 0.36 g/dL), p < 0.00001] and improved iron-utilization by increasing serum iron [MD 1.85 µmol/L], total iron binding capacity [MD 35.73 µg/dL], transferrin saturation [MD 1.19%], and transferrin level [MD 0.40 g/L]. In addition, we found that roxadustat significantly decreased the low-density lipoprotein-cholesterol [MD -0.39 mmol/L] and total cholesterol [MD -0.6 mmol/L]. In patients with a C-reactive protein level that exceeds the upper limit of the normal range, hemoglobin levels were higher for roxadustat than for ESAs [MD 0.39 g/dL]. Treatment-emergent adverse events, treatment-emergent serious adverse events, and major adverse cardiovascular events were not significantly different between the two groups. CONCLUSIONS: The hemoglobin levels of DD-CKD patients were significantly increased and not affected by the inflammatory state after roxadustat treatment. Roxadustat also improved iron utilization, and it was not associated with higher treatment-emergent adverse events, treatment-emergent serious adverse events, and major adverse cardiovascular events when compared to ESAs.

"Sandwich Therapy"-Immunotherapy Plus Concurrent Chemoradiotherapy for Advanced Esophagogastric Junction Carcinoma: Report of Two Cases and Literature Review.

Introduction: Esophagogastric junction (EGJ) carcinomas develop in the transition zone between the esophagus and stomach. The incidence of EGJ carcinoma has steadily increased over the past few decades. Most patients are first diagnosed at an advanced stage, which renders them ineligible for surgery. Current methods for the treatment of advanced EGJ carcinoma include surgery, chemotherapy, local palliative therapy, and supportive care; however, none of these treatment methods has provided satisfactory therapeutic effects when used alone. Case Report: We report two cases of patients with EGJ carcinoma who were sequentially treated with immunotherapy plus induction chemotherapy, followed by immunotherapy plus concurrent chemoradiotherapy and maintenance immunotherapy. Both patients achieved extended overall survival times with good quality of life with this new therapeutic approach. Conclusion: Immunotherapy plus chemoradiotherapy may therefore be a reasonable option for treatment of selected EGJ carcinoma patients. However, well-designed trials for the acquisition of additional evidence are required to validate the findings in this study.

Survival Risk Analysis of Small Cell Lung Cancer Patients with Pre-Existing Type 2 Diabetes Mellitus: A Single-Center Retrospective Cohort Study.

Purpose: We aimed to investigate the clinicopathological characteristics and survival risk factors in small cell lung cancer (SCLC) patients with preexisting type 2 diabetes mellitus (preDM). Patients and Methods: All patients with SCLC admitted to our hospital between January 2013 and August 2018 were followed up until August 2020 and retrospectively analyzed. Clinical characteristics of SCLC patients with and without preDM were extracted. Cox proportional hazards models were conducted to identify potential independent prognostic factors. Results: Of 628 eligible individuals, 88 individuals had preDM. preDM was independently significantly associated with distant metastasis in all SCLC patients (p =0.016, OR=1.80, 95% CI 1.11-2.91), while preDM did not affect the outcome of SCLC patients (p=0.803, HR=1.04, 95% CI 0.79-1.36) by multivariate analysis. In the preDM group, the median overall survival (OS) was shorter in the insulin group than in the non insulin group (13.93 months versus 21.77 months, p=0.024). Multivariate analysis identified that insulin treatment was an independent unfavorable factor associated with OS (p =0.009, HR=2.10, 95% CI 1.19-3.64). In addition, poorer performance status (PS) and liver metastasis were also independent unfavorable prognostic factors (all p<0.01), while thoracic therapy significantly improved OS and decreased mortality risk in diabetic patients with SCLC (p<0.05). Conclusion: preDM may promote distant metastasis of SCLC while it is insulin therapy and not preDM which adversely affects the prognosis of SCLC patients. These findings indicate that enhancing blood glucose control and reducing insulin analog use may be essential to the improvement of the long-term survival of the diabetic population with SCLC.

First-Line Anlotinib Combined with Stereotactic Body Radiation Therapy for an Octogenarian with Pulmonary Carcinosarcoma.

Pulmonary carcinosarcoma (PC) is a rare and highly malignant type of non-small cell lung cancer (NSCLC) that is insensitive to radiotherapy and chemotherapy and has a poor prognosis. Here, we report a case of an 88-year-old patient with inoperable PC and a history of cerebral infarction who was treated with first-line anlotinib combined with stereotactic body radiation therapy (SBRT). The therapeutic response has sustained for 10 months. Our work suggests that SBRT combined with anlotinib may be a safe and effective treatment strategy for octogenarians with PC.

Efficacy and Drug Resistance Analysis of ALK Inhibitors in Combination with Stereotactic Body Radiation Therapy for Treating Lung Squamous Carcinoma Patient Harboring EML4-ALK Rearrangement.

EML4-ALK rearrangement is common in lung adenocarcinoma. The ALK inhibitors remarkably inhibit lung adenocarcinoma and reveal long-term beneficial effects in several patients. Advanced genetic testing technology reveals that EML4-ALK rearrangement has been observed in patients with lung squamous cell carcinoma. In the present study, we report a case of a 53-year-old patient with EML4-ALK rearranged in lung squamous carcinoma; PET/CT scan revealed brain and multiple bone metastases. First-line ALK-TKI combined with local stereotactic body radiation therapy indicated progression-free survival of 9 months. After progressive disease, treatment was switched to lorlatinib, with little efficacy and a total overall survival of 11 months. The emergence of drug resistance revealed that the genetic test result was EML4-ALK fusion (V3a/b variants), indicating a poor prognosis. In this study, we analyzed the treatment efficacy of ALK inhibitors and provided a research basis for the treatment of EML4-ALK rearranged in lung squamous cell carcinoma patients.

Development of the First Value Assessment Index System for Off-Label Use of Antineoplastic Agents in China: A Delphi Study.

OBJECTIVE: To develop the first value assessment index system for off-label use of antineoplastic agents in China. METHODS: A modified two-round Delphi method was employed to establish consensus within a field to reach agreement via a questionnaire or doing interview among a multidisciplinary panel of experts by collecting their feedback to inform the next round, exchanging their individual knowledge, experience, and opinions anonymously, and resolving uncertainties. RESULTS: Expert's positive coefficient was 94.74% in the first round and 100.00% in the second round. In the first round, expert's authority coefficient for a majority of 61 indicators was ≥ 0.80 (85.2%, ranging from 0.70 to 0.89, mean=0.84) and coefficient of variation for all the 61 indicators was ≥ 22% (ranging from 11.67% to 21.74%, mean=17.4%). In two rounds, the mean expert's authority coefficient raised to 0.85 (ranging from 0.75 to 0.90), and coefficient of variation for all indicators was < 20% (ranging from 10.49% to 19.71%, mean=15.97%). The P-values of Kendall's W test were all < 0.001 for each round. At the end of two rounds, W-value for concordance was 0.395 (χ2=347.494, P<0.0001). The final value assessment index system comprised of eight domains, 21 subdomains, and 56 indicators. The weight and combination weight of each domain were 0.4211 for therapeutic value, 0.1678 for source and type of evidence, 0.0961 for public feedback/comments, 0.0894 for novelty in drug discovery, 0.0689 for grading of evidence recommendation, 0.0578 for consistency of evidence results, 0.0561 for disease burden, and 0.0428 for ratio of composition/integration. CONCLUSION: Use of Delphi method to develop the proposed value assessment index system was found scientific and credible. This value assessment index system is highly appropriate for off-label use of antineoplastic agents in China.

Atezolizumab-induced psoriasis in a patient with metastatic lung cancer-a case report.

Immune checkpoint inhibitors, now FDA-approved, are being increasingly used for diverse cancer types. Dermatological complications are most frequent immune-related adverse events during immune checkpoints inhibitors therapies. There is no case reporting psoriasis exacerbation from Asia until now. We present a case of a 53-year-old Chinese man with non-small cell lung cancer (NSCLC) who presented with severe psoriasis at about two weeks after atezolizumab initiation. A skin punch biopsy was performed which revealed these were hyperkeratosis with IL-17A expression positive and confirmed the diagnosis of psoriasis. Atezolizumab was discontinued. Psoriasis was treated with flumethasone ointment every 12 hours and desloratadine 5 mg once daily for 2 weeks instead of phototherapies and improved completely over the next 2 months. He received chemotherapy in 4 cycles and radiotherapy and remained stable disease until December, 2019. Oncologists should pay attention to potential psoriasis exacerbation when patients use anti-programmed death ligand 1 (anti-PD-L1), especially who had a personal psoriasis-related history.

The effect of EDTA root conditioning on periodontal surgery outcome: A meta-analysis.

OBJECTIVE: Chemical root conditioning is a procedure to remove the smear layer, which influences periodontal healing. The purpose of this study was to determine the effect of using ethylenediaminetetraacetic acid (EDTA) as a root conditioning agent on periodontal surgery outcomes. METHOD AND MATERIALS: The databases searched from their earliest records to February 2015 included Pubmed, Embase, the Cochrane library, and ISI Web of Science. Quality assessment of the methodologies of all the included studies and data was performed with Review Manager software. Probing depth (PD) and clinical attachment level (CAL) were analyzed using inverse variance. RESULTS: The evaluation of the three articles that met the inclusion criteria showed that the differences between the EDTA groups and the control groups were not statistically significant (6 months PD: mean difference [MD] = -0.15 mm, Z = 1.09, P = .27; CAL: MD = 0.15 mm, Z = 0.89, P = .37). CONCLUSION: EDTA was not able to significantly improve the PD and CAL. A positive outcome of using EDTA as a root conditioning agent was not evident. Thus, future research should focus on EDTA in combination with other drugs or a better alternative drug to EDTA.

[Determination of oxaprozin in human plasma with high performance liquid chromatography (HPLC) and its application].

The present research was aimed to develop a high performance liquid chromatography (HPLC) method to determine oxaprozin in plasma and to evaluate the bioavailability of two oxaprozin enteric coated tablets. A C18 column was used to separate the plasma after protein precipitation and the mobile phase was methanol-12. 5mmol/L ammonium acetate buffer solution (pH=3.0)(71:29). The calibration curve was linear in the concentration range of 0. 50-70. 56 microg . mL-1, and the intra and inter-day RSDs were less than 12. 33% and 10. 42% respectively. A single dose of 0. 4 g reference preparation or test preparation of oxaprozin enteric coated tablets was administered to 20 healthy volunteers according to a randomized crossover study. AUC0-->264h were (4 917. 44 +/- 629. 57) microg . h . mL-1 and (4 604. 30+/-737. 83) microg . h . mL-1, respectively; Cmax were (52. 34+/-7. 68) microg . mL-1 and (48. 66+/-4. 87) microg . mL-1, respectively; Tmax were (18. 70+/-2.27) h and (19. 30+/-1. 63) h, respectively; The relative bioavailability of test preparation was 94.0% +/- 13. 7%. The method is simple, rapid and selective for oxaprozin determination. There is no significant difference in the main pharmacokinetic parameters between the test formulation and reference formulation and the two formulations are in bioequivalence.

[Bioequivalence research of cyclosporin soft capsules].

This paper is aimed to study the bioavailability and bioequivalence of Cyclosporin Soft Capsules (test preparation and reference preparation) in Chinese healthy volunteers. A high performance liquid chromatography-ultraviolet (HPLC-UV) method for determining the concentration of Cyclosporin A in human whole blood was developed and methodological validated. In accordance with the randomized two-period self crossover study, 24 volunteers received a single oral dose of 400 mg of test preparation or reference preparation. Multiple blood samples were collected post dose and then the concentration of Cyclosporin A in human whole blood samples was determined using the validated assay. The pharmacokinetic parameters including AUC0-t, Cmax, Tmax, and T1/2 were calculated using the non-compartmental method. The bioequivalence of the two preparations was evaluated. After receiving single dose of 400 mg of Cyclosporine A, the pharmacokinetic parameters of T1/2, Cmax, Tmax, and AUC0-t, of Cyclosporin A were (10.114 +/- 6.329) h and (9.717 +/- 4.076) h, (2021.235 +/- 298.581) ng x ml(-1) and (1992.192 +/- 1286.923) ng x ml(-1) (1.729 +/- 0.361) h and (1.813 +/- 0.323) h, (9824.811 +/- 1633.026) ng x h x ml(-1) and (10316.514 +/- 1395.955) ng x h x ml(-1) for test preparation and reference preparation, respectively. The statistical results suggested that these parameters were comparable between the two preparations. The results showed that the test preparation was bioequivalent with the reference preparation in healthy volunteers.

[In vitro study on two kind of recombinant adeno-associated virus-mediated transfection efficiency with enhanced green fluorescent protein into rats osteoblasts].

OBJECTIVE: To compare the transfection efficiency of two kind of recombinant adeno-associated virus-mediated transfection to rats osteoblasts with enhanced green fluorescent protein and assess the feasibility of it as a vector for gene therapy of osteoblast lesions. METHODS: The osteoblasts of rats were isolated, cultured and identified with type I collagen staged digestion method. According to different multiplicity of infection (MOI) (MOI = 1 x 10(3), 1 x 10(4), 1 X 10(4), 5 x 10(5)), rAAV-EGFP was transfected into osteoblasts with rAAV only and rAAV-ADV co-transfection respectively. The expression of EGFP along with the transfection time was observed under inverted fluorescence microscope. The transfection efficiency and fluorescence intensity was evaluated by flow cytometry. The best MOI value was analysed and the cell growth curves were obtained according to the best MOI value to evaluate the toxic effects of rAAV-EGFP. RESULTS: The cultured cells possessed the biological behaviors of osteoblasts. The transfection efficiency of the rAAV was increased with the increasing of MOI. The EGFP expression reached the maximum on day 5 in ADV(-) group, the transfection efficiency of rAAV2/6-EGFP and rAAV2/9-EGFP was 90.2% and 66.1% respectively when MOI was 1 x 10(5) and no significant increase was observed when MOI was 5 x 10(5). In ADV(+) group, EGFP expression reached its maximum on day 3, the transfection efficiency of rAAV2/6-EGFP and rAAV2/9-EGFP was 47.6% and 30.5% respectively when MOI was 5 x 10(5). And no significant biologic effects on the cyto-activity was observed. CONCLUSION: The transfection efficiency of two kind of virus vectors was both very high and rAAV2/6's is higher than that of rAAV2/9. This suggested the potential of rAAV-EGFP as a safe and efficient vector for gene therapy.