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Incorporation of Astragalus polysaccharides injection during concurrent chemoradiotherapy in advanced pharyngeal or laryngeal squamous cell carcinoma: preliminary experience of a phase II double-blind, randomized trial.
Hsieh, CH, Lin, CY, Hsu, CL, Fan, KH, Huang, SF, Liao, CT, Lee, LY, Ng, SK, Yen, TC, Chang, JT, et al
Journal of cancer research and clinical oncology. 2020;(1):33-41
Abstract
PURPOSE Concurrent chemoradiotherapy (CCRT) is one of the standard treatments for patients with advanced head and neck squamous cell carcinoma (HNSCC). However, CCRT may lead to decreased quality of life (QoL) and treatment compliance. This study aimed to determine the effects of PG2 (Astragalus polysaccharides) injection on CCRT-associated adverse events (AEs) and patients' compliance with the CCRT course. METHODS In this phase II double-blind randomized placebo-controlled trial, PG2 injection (sterile powder form) or placebo was administrated three times per week in parallel with CCRT to patients with HNSCC. The chemotherapy regimen included 50 mg/m2 cisplatin every 2 weeks with daily tegafur-uracil (300 mg/m2) and leucovorin (60 mg/day). RESULTS The study was terminated prematurely due to the successful launch of a newly formulated PG2 injection (lyophilized form). A total of 17 patients were enrolled. The baseline demographics and therapeutic compliance were comparable between the CCRT/PG2 and CCRT/placebo groups. During CCRT, severe treatment-associated AEs were less frequent in the CCRT/PG2 group than in the CCRT/placebo group. Furthermore, less QoL fluctuations from the baseline during CCRT were noted in the CCRT/PG2 group than in the CCRT/placebo group, with a significant difference in the pain, appetite loss, and social eating behavior. The tumor response, disease-specific survival and overall survival did not differ between the two groups. CONCLUSION This preliminary study demonstrated PG2 injection exhibited an excellent safety profile, and has potential in ameliorating the deterioration in QoL and the AEs associated with active anticancer treatment among patients with advanced pharyngeal or laryngeal HNSCC under CCRT. Further research in patients with other cancer types or treatment modalities may widen PG2's application in clinical settings.
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The potential role of vitamin D supplementation as a gut microbiota modifier in healthy individuals.
Singh, P, Rawat, A, Alwakeel, M, Sharif, E, Al Khodor, S
Scientific reports. 2020;(1):21641
Abstract
Vitamin D deficiency affects approximately 80% of individuals in some countries and has been linked with gut dysbiosis and inflammation. While the benefits of vitamin D supplementation on the gut microbiota have been studied in patients with chronic diseases, its effects on the microbiota of otherwise healthy individuals is unclear. Moreover, whether effects on the microbiota can explain some of the marked inter-individual variation in responsiveness to vitamin D supplementation is unknown. Here, we administered vitamin D to 80 otherwise healthy vitamin D-deficient women, measuring serum 25(OH) D levels in blood and characterizing their gut microbiota pre- and post- supplementation using 16S rRNA gene sequencing. Vitamin D supplementation significantly increased gut microbial diversity. Specifically, the Bacteroidetes to Firmicutes ratio increased, along with the abundance of the health-promoting probiotic taxa Akkermansia and Bifidobacterium. Significant variations in the two-dominant genera, Bacteroides and Prevotella, indicated a variation in enterotypes following supplementation. Comparing supplementation responders and non-responders we found more pronounced changes in abundance of major phyla in responders, and a significant decrease in Bacteroides acidifaciens in non-responders. Altogether, our study highlights the positive impact of vitamin D supplementation on the gut microbiota and the potential for the microbial gut signature to affect vitamin D response.
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Cognitive impairment and CSF proteome modification after oral bacteriotherapy in HIV patients.
Landi, C, Santinelli, L, Bianchi, L, Shaba, E, Ceccarelli, G, Cavallari, EN, Borrazzo, C, Pinacchio, C, Scagnolari, C, Vullo, V, et al
Journal of neurovirology. 2020;(1):95-106
Abstract
OBJECTIVE To investigate whether a probiotic supplementation to cART patients modifies the cerebrospinal fluid (CSF) proteome and improves neurocognitive impairment. METHODS 26 CSF samples from 13 HIV-positive patients [six patients living with HIV (PLHIV) and seven patients with a history of AIDS (PHAIDS)] were analyzed. All patients underwent to neurocognitive evaluation and blood sampling at baseline and after 6 months of oral bacteriotherapy. Immune phenotyping and activation markers (CD38 and HLA-DR) were evaluated on peripheral blood mononuclear cells (PBMC). Plasma levels of IL-6, sCD14, and MIP-1β were detected, by enzyme-linked immunosorbent assay (ELISA). Functional proteomic analysis of CSF sample was conducted by two-dimensional electrophoresis; a multivariate analysis was performed by principal component analysis (PCA) and data were enriched by STRING software. RESULTS Oral bacteriotherapy leads to an improvement on several cognitive test and neurocognitive performance in both groups of HIV-positive subjects. A reduction in the percentage of CD4+CD38+HLA-DR+ T cells was also observed at peripheral level after the probiotic intake (p = 0.008). In addition, the probiotic supplementation to cART significantly modifies protein species composition and abundance at the CSF level, especially those related to inflammation (β2-microglobulin p = 0.03; haptoglobin p = 0.06; albumin p = 0.003; hemoglobin p = 0.003; immunoglobulin heavy chains constant region p = 0.02, transthyretin p = 0.02) in PLHIV and PHAIDS. CONCLUSIONS Our results suggest that oral bacteriotherapy as a supplement to cART could exert a role in the amelioration of inflammation state at peripheral and CNS level.
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Phase II trial of bevacizumab and sorafenib in recurrent ovarian cancer patients with or without prior-bevacizumab treatment.
Lee, JM, Annunziata, CM, Hays, JL, Cao, L, Choyke, P, Yu, M, An, D, Turkbey, IB, Minasian, LM, Steinberg, SM, et al
Gynecologic oncology. 2020;(1):88-94
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OBJECTIVE To examine whether blocking multiple points of the angiogenesis pathway by addition of sorafenib, a multi-kinase inhibitor against VEGFR2/3, Raf, c-Kit, and PDGFR, to bevacizumab would yield clinical activity in ovarian cancer (OvCa). METHODS This phase II study tested bevacizumab plus sorafenib in two cohorts; bevacizumab-naïve and bevacizumab-exposed patients. Bevacizumab (5 mg/kg IV every 2 weeks) was given with sorafenib 200 mg bid 5 days-on/2 days-off. The primary objective was response rate using a Simon two-stage optimal design. Progression-free survival (PFS) and toxicity were the secondary endpoints. Exploratory correlative studies included plasma cytokine concentrations, tissue proteomics and dynamic contrast-enhanced-magnetic resonance imaging (DCE-MRI). RESULTS Between March 2007 and August 2012, 54 women were enrolled, 41 bevacizumab-naive and 13 bevacizumab-prior, with median 5 (2-9) and 6 (5-9) prior systemic therapies, respectively. Nine of 35 (26%) evaluable bevacizumab-naive patients attained partial responses (PR), and 18 had stable disease (SD) ≥ 4 months. No responses were seen in the bevacizumab-prior group and 7 (54%) patients had SD ≥ 4 months, including one exceptional responder with SD of 27 months. The overall median PFS was 5.5 months (95%CI: 4.0-6.8 months). Treatment-related grade 3/4 adverse events (≥5%) included hypertension (17/54 [31%]; grade 3 in 16 patients and grade 4 in one patient) and venous thrombosis or pulmonary embolism (5/54 [9%]; grade 3 in 4 patients and grade 4 in one patient). Pretreatment low IL8 concentration was associated with PFS ≥ 4 months (p = .031). CONCLUSIONS The bevacizumab and sorafenib combination did not meet the pre-specified primary endpoint although some clinical activity was seen in heavily-pretreated bevacizumab-naive OvCa patients with platinum-resistant disease. Anticipated class toxicities required close monitoring and dose modifications.
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Poor Sensitivity of Fecal Gluten Immunogenic Peptides and Serum Antibodies to Detect Duodenal Mucosal Damage in Celiac Disease Monitoring.
Laserna-Mendieta, EJ, Casanova, MJ, Arias, Á, Arias-González, L, Majano, P, Mate, LA, Gordillo-Vélez, CH, Jiménez, M, Angueira, T, Tébar-Romero, E, et al
Nutrients. 2020;(1)
Abstract
A lifelong gluten-free diet (GFD) is the only current treatment for celiac disease (CD), but strict compliance is complicated. Duodenal biopsies are the "gold standard" method for diagnosing CD, but they are not generally recommended for disease monitoring. We evaluated the sensitivity and specificity of fecal gluten immunogenic peptides (GIPs) to detect duodenal lesions in CD patients on a GFD and compared them with serum anti-tissue transglutaminase (tTG) IgA antibodies. A prospective study was conducted at two tertiary centers in Spain on a consecutive series of adolescents and adults with CD who maintained a long-lasting GFD. Adherence to a GFD and health-related quality of life were scored with validated questionnaires. Mucosal damage graded according to the Marsh-Oberhüber classification (Marsh 1/2/3) was used as the reference standard. Of the 97 patients included, 27 presented duodenal mucosal damage and 70 had normal biopsies (Marsh 0). The sensitivity (33%) and specificity (81%) of GIPs were similar to those provided by the two assays used to measure anti-tTG antibodies. Scores in questionnaires showed no association with GIP, but an association between GIPs and patients' self-reported gluten consumption was found (p = 0.003). GIP displayed low sensitivity but acceptable specificity for the detection of mucosal damage in CD.
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Phase I Study of the Bifunctional Fusion Protein Bintrafusp Alfa in Asian Patients with Advanced Solid Tumors, Including a Hepatocellular Carcinoma Safety-Assessment Cohort.
Doi, T, Fujiwara, Y, Koyama, T, Ikeda, M, Helwig, C, Watanabe, M, Vugmeyster, Y, Kudo, M
The oncologist. 2020;(9):e1292-e1302
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LESSONS LEARNED Bintrafusp alfa had a manageable safety profile and demonstrated preliminary clinical activity in heavily pretreated patients with solid tumors (including hepatocellular carcinoma) with no or limited treatment options. Findings from this study suggest bintrafusp alfa may be a novel therapeutic approach for patients with advanced solid tumors. Additional trials are needed to further explore safety and efficacy of bintrafusp alfa in specific tumor types. BACKGROUND Bintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of transforming growth factor-β (TGF-β) RII receptor (a TGF-β "trap") fused to a human immunoglobulin (Ig) G1 antibody blocking programmed death-ligand 1 (PD-L1). Bintrafusp alfa is designed to neutralize TGF-β signaling by "trapping" and sequestering all TGF-β isoforms, and this trap function is physically linked to PD-L1 blockade in the tumor microenvironment. METHODS NCT02699515 was a phase I, open-label, dose-escalation study of bintrafusp alfa (3, 10, and 20 mg/kg every 2 weeks) in Asian patients with advanced solid tumors, including a hepatocellular carcinoma (HCC) safety-assessment cohort. The primary objective was safety and tolerability; the secondary objective is best overall response. RESULTS As of August 24, 2018, 23 patients (including 9 in the HCC cohort) received bintrafusp alfa. Eight patients experienced treatment-related adverse events (TRAEs). Three patients had grade 3 TRAEs (13.0%; hypoacusis, hyponatremia, hypopituitarism, increased blood creatine phosphokinase, and intracranial tumor hemorrhage); one had grade 4 hyponatremia (4.3%). No treatment-related deaths occurred. In the dose-escalation cohort, two patients had a confirmed partial response, and 3 had stable disease (SD), for an overall response rate of 14.3% and a disease control rate (DCR) of 35.7%. In the HCC cohort, one patient had SD (DCR, 11.1%). A dose-proportional pharmacokinetics profile was observed at doses of >3 mg/kg. CONCLUSION Bintrafusp alfa had a manageable safety profile and preliminary efficacy in heavily pretreated patients with advanced solid tumors, including HCC.
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A 12-week, randomized, double-blind, placebo-controlled, four-arm dose-finding phase 2 study evaluating bexagliflozin as monotherapy for adults with type 2 diabetes.
Halvorsen, YD, Walford, G, Thurber, T, Russell, H, Massaro, M, Freeman, MW
Diabetes, obesity & metabolism. 2020;(4):566-573
Abstract
AIM: To compare the safety and efficacy of bexagliflozin administered as monotherapy at three dosage strengths over a 12-week period to patients with type 2 diabetes who were either naïve to pharmacotherapy or were previously prescribed one oral hypoglycaemic agent and underwent a 6-week period of medication abstinence. METHODS Adults with type 2 diabetes (n = 292) having an HbA1c of between 7.0% and 8.5% were randomized to receive one of three dosage strengths of bexagliflozin (5, 10 or 20 mg) or placebo. The primary endpoint was the change from baseline to week 12 in the %HbA1c. Secondary endpoints included the changes from baseline in fasting plasma glucose (FPG), systolic blood pressure and diastolic blood pressure, body mass and fraction of patients achieving an HbA1c of <7%. RESULTS The mixed model repeated measure estimates of the placebo-adjusted change in %HbA1c from baseline to week 12 for the 5, 10 and 20 mg groups were -0.55% (95% CI: -0.76%, -0.34%, P < 0.0001), -0.68% (95% CI: -0.89%, -0.47%, P < 0.0001) and -0.80% (95% CI: -1.01%, -0.59%, P < 0.0001), respectively. Significant and dose-dependent placebo-adjusted mean reductions from baseline to week 12 in FPG and body mass were observed. The fraction of subjects achieving an HbA1c of <7% was significantly greater in the 20 mg bexagliflozin group. The incidence of adverse events was similar for participants in all active arms (42.3%) compared with the rate measured in those receiving placebo (40.3%). CONCLUSIONS Bexagliflozin confers substantial and dose-dependent benefits on subjects with type 2 diabetes and has an acceptable safety profile. Further evaluation of bexagliflozin for the control of type 2 diabetes in adults is warranted.
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Effects of photobiomodulation on interleukin-10 and nitrites in individuals with relapsing-remitting multiple sclerosis - Randomized clinical trial.
Silva, T, Fragoso, YD, Destro Rodrigues, MFS, Gomes, AO, da Silva, FC, Andreo, L, Viana, A, Teixeira da Silva, DF, Chavantes, MC, Tempestini Horliana, ACR, et al
PloS one. 2020;(4):e0230551
Abstract
OBJECTIVE Investigate the effects of photobiomodulation (PBM) on the expression of IL-10 and nitrites in individuals with Relapsing-Remitting multiple sclerosis (MS), as these biomarkers play a fundamental role in the physiopathology of the disease. The modulation of IL-10 and nitrites through treatment with PBM may be a novel treatment modality for MS. METHODS A randomized, uncontrolled, clinical trial was conducted involving 14 individuals with a diagnosis of Relapsing-Remitting MS and a score of up to 6.0 on the Expanded Disability Status Scale (EDSS). THE PARTICIPANTS WERE RANDOMIZED TO TWO GROUPS Group 1 -PBM in the sublingual region; Group 2 -PBM over the radial artery. Irradiation was administered with a wavelength of 808 nm and output power of 100 mW for 360 seconds twice a week, totaling 24 sessions. Peripheral blood was analyzed for the determination of serum levels of IL-10 and nitrites. RESULTS After treatment with PBM, the expression of IL-10 increased in both the sublingual group (pre-treatment: 2.8 ± 1.4 pg/ml; post-treatment: 8.3 ± 2.4 pg/ml) and the radial artery group (pre-treatment: 2.7 pg/ml ± 1.4; post-treatment: 11.7 ± 3.8 pg/ml). In contrast, nitrite levels were not modulated in the sublingual group (pre-treatment: 65 ± 50 nmol/mg protein; post-treatment: 51 ± 42 nmol/mg protein) or the radial artery group (pre-treatment: 51 ± 16 nmol/mg protein; post-treatment: 42 ± 7 nmol/mg protein). CONCLUSION Treatment with PBM positively modulated the expression of IL-10 but had no effect on nitrite levels. Further studies should be conducted with a larger sample and a control group, as PBM may be a promising complementary treatment for the management of MS. This trial is registered at ClinicalTrials.gov. Identifier: NCT03360487.
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Electroporation technique for joint pain - Pilot feasibility study on TMD patients.
Tartaglia, GM, Gizdulich, A, Farronato, M, Gupta, RJ, Connelly, ST
Clinical and experimental dental research. 2020;(6):642-649
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OBJECTIVE(S): It is well appreciated that traditional analgesic delivery routes used to treat pain associated with temporomandibular disorder (TMD) often have harmful unintended side effects as a consequence of systemic distribution. Further, localized delivery of analgesic medication via intra-articular injections involves a different set of issues limiting their clinical viability. As an option, transdermal analgesic delivery provides for prolonged pain relief and flexibility in dose administration, while limiting systemic exposure and minimizing adverse events. Incorporation of a novel electroporation technique may further increase transdermal drug penetration into synovial tissue/fluid and enhance pain reduction. The present feasibility study compares the effectiveness of an electroporation-enhanced transdermal application of diclofenac sodium to a conventional intra-articular injection of triamcinolone acetonide suspension (corticosteroids) to treat patients with TMD associated pain. METHODS Pre- and post-treatment maximal incisal mouth opening (MIO), pain visual analog scale (VAS) and surface electromyography (EMG) of 22 patients treated with electroporation-enhanced diclofenac and 37 patients treated with corticosteroids injections were collected and analyzed. RESULTS In general, patients treated with electroporation exhibited better results in terms of pain improvement (corrected p-value = .01) compared to the standard treatment, but both methods were similarly effective for improvement of MIO (corrected p-value = .71) and improvement of all EMG indices (corrected p-values ≥ .05). CONCLUSION The enhancing effect of electroporation in transdermal delivery of diclofenac sodium was demonstrated by decreased pain, increase MIO and EMG improvement to normal values. Its analgesic and inflammatory results are comparable with standard treatment offered by corticosteroids.
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Effects of a 14-Day Hydration Intervention on Individuals with Habitually Low Fluid Intake.
Caldwell, AR, Rosa-Caldwell, ME, Keeter, C, Johnson, EC, Péronnet, F, Ganio, MS
Annals of nutrition & metabolism. 2020;:67-68
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BACKGROUND Debate continues over whether or not individuals with low total water intake (TWI) are in a chronic fluid deficit (i.e., low total body water) [1]. When women with habitually low TWI (1.6 ± 0.5 L/day) increased their fluid intake (3.5 ± 0.1 L/day) for 4 days 24-h urine osmolality decreased, but there was no change in body weight, a proxy for total body water (TBW) [2]. In a small (n = 5) study of adult men, there were no observable changes in TBW, as measured by bioelectrical impedance, after increasing TWI for 4 weeks [3]. However, body weight increased and salivary osmolality decreased indicating that the study may have been underpowered to detect changes in TBW. Further, no studies to date have measured changes in blood volume (BV) when TWI is increased. OBJECTIVES Therefore, the purpose of this study was to identify individuals with habitually low fluid intake and determine if increasing TWI, for 14 days, resulted in changes in TBW or BV. METHODS In order to identify individuals with low TWI, 889 healthy adults were screened. Participants with a self-reported TWI less than 1.8 L/day (men) or 1.2 L/day (women), and a 24-h urine osmolality greater than 800 mOsm were included in the intervention phase of the study. For the intervention phase, 15 participants were assigned to the experimental group and 8 participants were assigned to the control group. The intervention period lasted for 14 days and consisted of 2 visits to our laboratory: one before the intervention (baseline) and 14 days into the intervention (14-day follow-up). At these visits, BV was measured using a CO-rebreathe procedure and deuterium oxide (D2O) was administered to measure TBW. Urine samples were collected immediately prior, and 3-8 h after the D2O dose to allow for equilibration. Prior to each visit, participants collected 24-h urine to measure 24-h hydration status. After the baseline visit, the experimental group increased their TWI to 3.7 L for males and 2.7 L for females in order to meet the current Institute of Medicine recommendations for TWI. RESULTS Twenty-four-hour urine osmolality decreased (-438.7 ± 362.1 mOsm; p < 0.001) and urine volume increased (1,526 ± 869 mL; p < 0.001) in the experimental group from baseline, while there were no differences in osmolality (-74.7 ± 572 mOsm; p = 0.45), or urine volume (-32 ± 1,376 mL; p = 0.89) in the control group. However, there were no changes in BV (Fig. 1a) or changes in TBW (Fig. 1b) in either group. CONCLUSIONS Increasing fluid intake in individuals with habitually low TWI increases 24-h urine volume and decreases urine osmolality but does not result in changes in TBW or BV. These findings are in agreement with previous work indicating that TWI interventions lasting 3 days [2] to 4 weeks [3] do not result in changes in TBW. Current evidence would suggest that the benefits of increasing TWI are not related changes in TBW.