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A randomized, phase 1, placebo-controlled trial of APG-157 in oral cancer demonstrates systemic absorption and an inhibitory effect on cytokines and tumor-associated microbes.
Basak, SK, Bera, A, Yoon, AJ, Morselli, M, Jeong, C, Tosevska, A, Dong, TS, Eklund, M, Russ, E, Nasser, H, et al
Cancer. 2020;126(8):1668-1682
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APG-157 is a botanical drug containing multiple polyphenols that delivers the active components to oromucosal tissues near the tumour target. APG-157 slowly disintegrates in the oral cavity over 15 to 20 minutes to release the drug substance. The drug substance is a precise, rational combination of multiple molecules derived from Curcuma longa wherein curcumin is the principal component. The main aim of this study was to determine the pharmacokinetics and safety of the orally delivered pastille (APG-157) when used by normal subjects and patients with cancer. This study is a randomised, double-blind, placebo-controlled trial. A total of 32 subjects were enrolled, and 25 completed the study (13 normal individuals and 12 patients with oral cancer). Results demonstrated that transoral APG-157 treatment leads to systemic absorption of curcumin and its analogs. There was a statistically significant concentration reduction in inflammatory cytokines and Bacteroides species noted in the salivary cells. Pre-treatment and post-treatment tumour samples from patients with cancer demonstrated T-cell recruitment to the tumour microenvironment. Authors conclude that APG-157 is absorbed well, reduces inflammation, and attracts T-cells to the tumour thus, it can be potentially used in combination with immunotherapy drugs. Furthermore, a long-term evaluation of immune checkpoint blockade with and without APG-157 could provide a clear understanding of the usefulness of APG-157 as either an adjuvant or neoadjuvant therapeutic agent for patients with advanced or recurrent head and neck cancer.
Abstract
BACKGROUND Although curcumin's effect on head and neck cancer has been studied in vitro and in vivo, to the authors' knowledge its efficacy is limited by poor systemic absorption from oral administration. APG-157 is a botanical drug containing multiple polyphenols, including curcumin, developed under the US Food and Drug Administration's Botanical Drug Development, that delivers the active components to oromucosal tissues near the tumor target. METHODS A double-blind, randomized, placebo-controlled, phase 1 clinical trial was conducted with APG-157 in 13 normal subjects and 12 patients with oral cancer. Two doses, 100 mg or 200 mg, were delivered transorally every hour for 3 hours. Blood and saliva were collected before and 1 hour, 2 hours, 3 hours, and 24 hours after treatment. Electrocardiograms and blood tests did not demonstrate any toxicity. RESULTS Treatment with APG-157 resulted in circulating concentrations of curcumin and analogs peaking at 3 hours with reduced IL-1β, IL-6, and IL-8 concentrations in the salivary supernatant fluid of patients with cancer. Salivary microbial flora analysis showed a reduction in Bacteroidetes species in cancer subjects. RNA and immunofluorescence analyses of tumor tissues of a subject demonstrated increased expression of genes associated with differentiation and T-cell recruitment to the tumor microenvironment. CONCLUSIONS The results of the current study suggested that APG-157 could serve as a therapeutic drug in combination with immunotherapy. LAY SUMMARY Curcumin has been shown to suppress tumor cells because of its antioxidant and anti-inflammatory properties. However, its effectiveness has been limited by poor absorption when delivered orally. Subjects with oral cancer were given oral APG-157, a botanical drug containing multiple polyphenols, including curcumin. Curcumin was found in the blood and in tumor tissues. Inflammatory markers and Bacteroides species were found to be decreased in the saliva, and immune T cells were increased in the tumor tissue. APG-157 is absorbed well, reduces inflammation, and attracts T cells to the tumor, suggesting its potential use in combination with immunotherapy drugs.
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Pharmaceutical Interventions in Chronic Fatigue Syndrome: A Literature-based Commentary.
Richman, S, Morris, MC, Broderick, G, Craddock, TJA, Klimas, NG, Fletcher, MA
Clinical therapeutics. 2019;41(5):798-805
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Myalgic encephalomyelitis, also known as Chronic Fatigue Syndrome (ME/ CFS), is a disease characterized by an inability to exert oneself physically, often coupled with a combination of other symptoms, including sleep disorders, severe unpredictable pain, and compromised cognitive abilities. The aim of this review was to delineate a number of the more prominent treatments for ME/CFS into different categories and evaluate the methods and results of corresponding drug trials. Results indicate that: • antiviral drugs appear to show limited efficacy in treating ME/CFS over a broad demographic. • there is a lack of clinical research focusing on the use of specific cyclooxygenase-2 inhibitors [analgesic] to treat ME/CFS. • antidepressants may be of use in delivering improvements in the quality of life of patients with ME/CFS. • recalibration of endocrine-immune regulation may be involved in supporting the persistence of ME/CFS and may be responsible at least in part for its resistance to single agent interventions. Authors conclude that there is a great need for larger, longitudinal studies focused on a more clearly defined subset of ME/CFS as well as a greater consideration of potential synergies between interventions and the suitability of combination therapies.
Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disorder characterized by prolonged periods of fatigue, chronic pain, depression, and a complex constellation of other symptoms. Currently, ME/CFS has no known cause, nor are the mechanisms of illness well understood. Therefore, with few exceptions, attempts to treat ME/CFS have been directed mainly toward symptom management. These treatments include antivirals, pain relievers, antidepressants, and oncologic agents as well as other single-intervention treatments. Results of these trials have been largely inconclusive and, in some cases, contradictory. Contributing factors include a lack of well-designed and -executed studies and the highly heterogeneous nature of ME/CFS, which has made a single etiology difficult to define. Because the majority of single-intervention treatments have shown little efficacy, it may instead be beneficial to explore broader-acting combination therapies in which a more focused precision-medicine approach is supported by a systems-level analysis of endocrine and immune co-regulation.
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Human Gut Microbiota and Gastrointestinal Cancer.
Meng, C, Bai, C, Brown, TD, Hood, LE, Tian, Q
Genomics, proteomics & bioinformatics. 2018;16(1):33-49
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In this article the authors review research on the influence of the human gut microbiota on the development and progression of gastrointestinal cancers, and go into significant detail about the molecular mechanisms involved. Helicobacter pylori is a known risk factor for gastric cancer (GC) but other dysbiotic changes in the gut microbiota are also observed in GC. On the other hand, H. pylori is associated with a decreased risk for oesophageal cancer (OC). An increase in gram-negative bacteria is associated with OC, whilst gram-positive bacteria are dominant in a healthy oesophagus. Dietary factors are associated with the risk for colorectal cancer (CRC) and may be due to their effect on the bacterial composition of the bowel. The authors explore possible mechanisms for these links. Although the liver is considered sterile, carcinogenesis can be influenced by the gut microbiota through pathogens and bacterial metabolites which can disturb metabolic pathways and immune responses in the liver. In pancreatic cancer (PC), the gut microbiota may influence carcinogenesis by promoting inflammation. In addition to various lifestyle factors, H. pylori is a risk factor for PC. The authors also review the use of prebiotics, probiotics, synbiotics (a combination of pre- and pro-biotics) and Traditional Chinese Medicine as an adjunct to conventional cancer treatment to reduce side effects, as well as their potential preventive mechanisms.
Abstract
Human gut microbiota play an essential role in both healthy and diseased states of humans. In the past decade, the interactions between microorganisms and tumors have attracted much attention in the efforts to understand various features of the complex microbial communities, as well as the possible mechanisms through which the microbiota are involved in cancer prevention, carcinogenesis, and anti-cancer therapy. A large number of studies have indicated that microbial dysbiosis contributes to cancer susceptibility via multiple pathways. Further studies have suggested that the microbiota and their associated metabolites are not only closely related to carcinogenesis by inducing inflammation and immune dysregulation, which lead to genetic instability, but also interfere with the pharmacodynamics of anticancer agents. In this article, we mainly reviewed the influence of gut microbiota on cancers in the gastrointestinal (GI) tract (including esophageal, gastric, colorectal, liver, and pancreatic cancers) and the regulation of microbiota by diet, prebiotics, probiotics, synbiotics, antibiotics, or the Traditional Chinese Medicine. We also proposed some new strategies in the prevention and treatment of GI cancers that could be explored in the future. We hope that this review could provide a comprehensive overview of the studies on the interactions between the gut microbiota and GI cancers, which are likely to yield translational opportunities to reduce cancer morbidity and mortality by improving prevention, diagnosis, and treatment.
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Effects of alcohol on insulin-like growth factor I and insulin-like growth factor binding protein 3 in postmenopausal women.
Lavigne, JA, Baer, DJ, Wimbrow, HH, Albert, PS, Brown, ED, Judd, JT, Campbell, WS, Giffen, CA, Dorgan, JF, Hartman, TJ, et al
The American journal of clinical nutrition. 2005;81(2):503-7
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Both alcohol and the endocrine hormone insulin-like growth factor (IGF-1) have been linked to increased breast cancer risk. However, the link with breast cancer is stronger in pre-menopausal women but most studies have not distinguished between pre and post-menopausal individuals. This randomly controlled, crossover study looked at how IGF-1 and its major binding protein IGFBP-3 were affected by alcohol in 31 pre-menopausal women, it also considered if levels were affected by the menstrual cycle. The study concluded that there is a link between alcohol and the reduction of IGF-1 but no effect on IGFBP-3 They also found that IGF-1 serum levels significantly increase during the later stages of the menstruation cycle regardless of alcohol intake. Further studies are needed to understand the balance of alcohol intake and how that alters an increase or decrease in breast cancer risk.
Abstract
BACKGROUND Increased circulating insulin-like growth factor I (IGF-I) concentrations, frequently adjusted for IGF binding protein 3 (IGFBP-3), have been associated with increased risk of several types of cancer, including colon, prostate, and breast. Studies have suggested that alcohol may affect IGF-I or IGFBP-3; however, controlled feeding studies to assess alcohol's effects on IGF-I or IGFBP-3 have not been conducted. OBJECTIVE To determine whether chronic, moderate alcohol intake affects serum IGF-I or IGFBP-3 concentrations, we performed a controlled, crossover feeding study. DESIGN Fifty-three postmenopausal women were randomly assigned to consume 0 g (control), 15 g (one drink), or 30 g (2 drinks) alcohol daily for 8 wk and were rotated through the other 2 intake levels in random order. All foods and beverages were provided during the intervention. Individuals were monitored and calories adjusted to maintain constant weight, and serum was collected at the end of each diet period. RESULTS Compared with the effects of 0 g alcohol/d, IGF-I concentrations were nearly unchanged by 15 g alcohol/d (0.8%; 95% CI: -3.2%, 3.5%) but decreased significantly by 4.9% (95% CI: -8.0%, -1.6%) with 30 g alcohol/d. IGFBP-3 concentrations significantly increased by 3.0% (95% CI: 0.4%, 5.6%) with 15 g alcohol/d but did not increase significantly with 30 g/d (1.8%; 95% CI: -0.9%, 4.5%). CONCLUSIONS To our knowledge, this is the first published controlled diet study to find that in postmenopausal women, when weight is kept constant, alcohol consumption reduces the amount of serum IGF-I potentially available for receptor binding. These findings suggest that the effect of alcohol intake should be considered in studies of IGF-I, IGFBP-3, and cancer in postmenopausal women.