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Surgical procedures for the symptomatic removal of the gallbladder and the vermiform appendix have been posited to adversely shift the assemblage of the intestinal microbiome increasing the risk of disease. The associated mechanisms have been linked with dysbiosis of the gut microbiota. Cholecystectomy causes changes of bile acid compositions and bile secretion patterns as bile acids interact with the intestinal microbiota in a bidirectional capacity. An appendectomy precludes the further recolonization of the proximal colon with a commensal biofilm that could maintain a stable intestinal microbiome. Epidemiological studies indicate that there is an increased risk of disease rather than causality following a cholecystectomy and appendectomy. This narrative review summarizes studies that report on the role that bile salts and the appendix, contribute to the assemblage of the intestinal microbiome in health and disease.

Graphical abstract, Most COVID-19 cases are mild or asymptomatic and recover well, suggesting that effective immune responses ensue, which successfully eliminate SARS-CoV-2 viruses. However, a small proportion of patients develop severe COVID-19 with pathological immune responses. This indicates that a strong immune system balanced with anti-inflammatory mechanisms is critical for the recovery from SARS-CoV-2 infections. Many vaccines against SARS-CoV-2 have now been developed for eliciting effective immune responses to protect from SARS-CoV-2 infections or reduce the severity of the disease if infected. Although uncommon, serious morbidity and mortality have resulted from both COVID-19 vaccine adverse reactions and lack of efficacy, and further improvement of efficacy and prevention of adverse effects are urgently warranted. Many factors could affect efficacy of these vaccines to achieve optimal immune responses. Dysregulation of the gut microbiota (gut dysbiosis) could be an important risk factor as the gut microbiota is associated with the development and maintenance of an effective immune system response. In this narrative review, we discuss the immune responses to SARS-CoV-2, how COVID-19 vaccines elicit protective immune responses, gut dysbiosis involvement in inefficacy and adverse effects of COVID-19 vaccines and the modulation of the gut microbiota by functional foods to improve COVID-19 vaccine immunisations.

The intestinal microbiota is critical in the ontology of early-life immunity. The intestinal microbiota stimulates immune development through microbial-associated molecular patterns which bind and activate pattern recognition receptors (1). Meanwhile there is codevelopment of numerous antiinflammatory mechanisms that prevent excessive immune responses. Intestinal dysbiosis has been associated with metabolic diseases that occur in adult life. In their elegant study, Leonard et al. (2) report that intestinal dysbiosis is associated with celiac disease (CD) in infants. The mechanism elucidated was linked to adverse shifts of many bacterial metabolites, with a propensity for increased proinflammation over decreased antiinflammatory factors. We posit that the dysregulated interaction between … [↵][1]1To whom correspondence may be addressed. Email: jiezhong_chen{at}medlab.co or luis_vitetta{at}medlab.co. [1]: #xref-corresp-1-1

Summary Coronavirus disease 2019 (Covid‐19), caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection, is now pandemic. While most Covid‐19 patients will experience mild symptoms, a small proportion will develop severe disease, which could be fatal. Clinically, Covid‐19 patients manifest fever with dry cough, fatigue and dyspnoea, and in severe cases develop into acute respiratory distress syndrome (ARDS), sepsis and multi‐organ failure. These severe patients are characterized by hyperinflammation with highly increased pro‐inflammatory cytokines including IL‐6, IL‐17 and TNF‐alpha as well as C‐reactive protein, which are accompanied by decreased lymphocyte counts. Clinical evidence supports that gut microbiota dysregulation is common in Covid‐19 and plays a key role in the pathogenesis of Covid‐19. In this narrative review, we summarize the roles of intestinal dysbiosis in Covid‐19 pathogenesis and posit that the associated mechanisms are being mediated by gut bacterial metabolites. Based on this premise, we propose possible clinical implications. Various risk factors could be causal for severe Covid‐19, and these include advanced age, concomitant chronic disease, SARS‐CoV‐2 infection of enterocytes, use of antibiotics and psychological distress. Gut dysbiosis is associated with risk factors and severe Covid‐19 due to decreased commensal microbial metabolites, which cause reduced anti‐inflammatory mechanisms and chronic low‐grade inflammation. The preconditioned immune dysregulation enables SARS‐CoV‐2 infection to progress to an uncontrolled hyperinflammatory response. Thus, a pre‐existing gut microbiota that is diverse and abundant could be beneficial for the prevention of severe Covid‐19, and supplementation with commensal microbial metabolites may facilitate and augment the treatment of severe Covid‐19.

Although the starting event in COVID-19 is a viral infection some patients present with an over-exuberant inflammatory response, leading to acute lung injury (ALI) and adult respiratory distress syndrome (ARDS). Since IL-6 plays a critical role in the inflammatory response, we assessed the efficacy and safety of tocilizumab (TCZ) in this single-centre, observational study in all Covid-19 in-patient with a proven SARS-CoV-2 rapidly progressing infection to prevent ALI and ARDS. 104 patients with COVID-19 treated with TCZ had a lower mortality rate (5·8%) compared with the regional mortality rate (11%), hospitalized patient's mortality (10%), and slightly lower than hospitalized patients treated with our standard of care alone (6%). We found that TCZ rapidly decreased acute phase reactants, ferritin and liver release of proteins. D-Dimer decreased slowly. We did not observe specific safety concerns. Early administration of IL6-R antagonists in COVID-19 patients with impending hyperinflammatory response, may be safe and effective treatment to prevent, ICU admission and further complications., Graphical abstract Unlabelled Image, Highlights • The lack of RCT forced the use of potential treatments in an emergency context, and results are of particular relevance. • Early administration of IL6-R antagonist tocilizumab, may be an effective and safe treatment for moderate to severe SARS-CoV2 positive patients. • Tocilizumab may prevent irreversible cytokine release syndrome CRS. • Tocilizumab reduced intubation, ICU admission, and decreased the risk of mortality. • Future prospective RCT will give answer about which are the first line drugs to treat COVID-19.

Background The aim of the study was to retrospectively evaluate the incidence and outcomes of inferior vena cava (IVC) filter thrombus during catheter-directed thrombolysis (CDT) for acute proximal deep venous thrombosis (DVT). Methods From October 2006 to June 2015, patients diagnosed with acute proximal DVT and received CDT after a retrievable IVC filter was placed were included. The incidence, treatment, and outcomes of IVC filter thrombus during CDT were recorded and analyzed. Results A total of 189 patients (91 women, 98 men; mean age, 57.6 ± 9.8 years; range, 24-85 years) were included in this study. Among the 189 cases, the DVTs involved popliteal iliofemoral veins in 54 patients, iliofemoral veins in 113 patients, and iliac veins in 22 patients, of which 18 patients had thrombus extended into the IVC. Of the 189 patients, a total of 8 (4.2%, 8 of 189) patients were identified with IVC filter thrombus during CDT. The IVC filter thrombus was detected on a median of 2 days (range, 2-4 days) of CDT therapy, including small-size (n = 6) and large-size (n = 2) filter thrombus. Of the 8 patients, CDTs were performed with a mean 7.6 ± 1.1 days (range, 6-11 days) after the presence of symptoms for the treatment of proximal DVT, and all the IVC filter thrombi were lysed during CDT for the proximal DVT. All the IVC filters were removed successfully with a mean of 12.8 ± 0.93 days from placement. There were no procedure- or thrombolysis-related major complications, and no symptomatic pulmonary embolism breakthrough was seen in any of the patients after the filter placement. Conclusions IVC filter thrombus during CDT for the acute proximal DVT is uncommon, and all of them did not need any additional treatment.

The gut microbiota is well known to exert multiple benefits on human health including protection from disease causing pathobiont microbes. It has been recognized that healthy intestinal microbiota is of great importance in the pathogenesis of COVID-19. Gut dysbiosis caused by various reasons is associated with severe COVID-19. Therefore, the modulation of gut microbiota and supplementation of commensal bacterial metabolites could reduce the severity of COVID-19. Many approaches have been studied to improve gut microbiota in COVID-19 including probiotics, bacterial metabolites, and prebiotics, as well as nutraceuticals and trace elements. So far, 19 clinical trials for testing the efficacy of probiotics and synbiotics in COVID-19 prevention and treatment are ongoing. In this narrative review, we summarize the effects of various approaches on the prevention and treatment of COVID-19 and discuss associated mechanisms.

Gut microbiota dysregulation plays a key role in the pathogenesis of nonalcoholic fatty liver disease (NAFLD) through its metabolites. Therefore, the restoration of the gut microbiota and supplementation with commensal bacterial metabolites can be of therapeutic benefit against the disease. In this review, we summarize the roles of various bacterial metabolites in the pathogenesis of NAFLD and their therapeutic implications. The gut microbiota dysregulation is a feature of NAFLD, and the signatures of gut microbiota are associated with the severity of the disease through altered bacterial metabolites. Disturbance of bile acid metabolism leads to underactivation of bile acid receptors FXR and TGR5, causal for decreased energy expenditure, increased lipogenesis, increased bile acid synthesis and increased macrophage activity. Decreased production of butyrate results in increased intestinal inflammation, increased gut permeability, endotoxemia and systemic inflammation. Dysregulation of amino acids and choline also contributes to lipid accumulation and to a chronic inflammatory status. In some NAFLD patients, overproduction of ethanol produced by bacteria is responsible for hepatic inflammation. Many approaches including probiotics, prebiotics, synbiotics, faecal microbiome transplantation and a fasting-mimicking diet have been applied to restore the gut microbiota for the improvement of NAFLD.

The intestinal microbiota plays key roles in human health, and adverse dysbiosis shifts of the microbiota have been associated with chronic diseases, including large bowel cancer. High-fiber diets may reduce the risk for large bowel cancer in association with gut microbiota modulation and butyrate production. Butyrate can inhibit histone deacetylases and associated signaling pathways in cultured cancer cells, promoting cancer cell apoptosis. However, butyrate has prevented colon cancer through the regulation of immune homeostasis rather than histone deacetylases inhibition. It could be important to further examine the pathways of how butyrate encourages immune system changes. We posited that butyrate-activated T-regulatory cells block proinflammatory T cells and thus reduce proinflammatory cytokine production; these cytokines increase cell proliferation and cell survival, the 2 most important cancer cell characteristics. Butyrate can exert anticancer effects through inhibition of multiple signaling pathways. It is possible that a low concentration of butyrate could modulate the immune system before other pathways to exert an anticancer effect. Increasing the concentration of butyrate in the intestines may produce a synergistic inhibitory signaling pathway response and an anti-inflammatory effect.

Purpose Diarrhea-predominant irritable bowel syndrome (IBS-D) is a common functional gastrointestinal disorder. Probiotics and synbiotics have been shown to improve symptoms of IBS, although mechanisms of action are currently not understood. Methods We investigated the effects of a 4-week oral synbiotic treatment (OMNi-BiOTiC® Stress Repair) in ten IBS-D patients on gastrointestinal mucosal and fecal microbiota, mucosa-associated immune cells, and fecal short-chain fatty acids. The upper and lower gastrointestinal tracts were compared before and after a 4-week synbiotic treatment using endoscopic evaluation to collect mucosal specimens for FACS analysis and mucosal 16S rRNA gene analysis. In stool samples, analysis for fecal SCFAs using GC–MS, fecal zonulin using ELISA, and fecal 16S rRNA gene analysis was performed. Results Synbiotics led to an increased microbial diversity in gastric (p = 0.008) and duodenal (p = 0.025) mucosal specimens. FACS analysis of mucosal immune cells showed a treatment-induced reduction of CD4+ T cells (60 vs. 55%, p = 0.042) in the ascending colon. Short-chain fatty acids (acetate 101 vs. 202 µmol/g; p = 0.007) and butyrate (27 vs. 40 µmol/g; p = 0.037) were elevated in fecal samples after treatment. Furthermore, treatment was accompanied by a reduction of fecal zonulin concentration (67 vs. 36 ng/ml; p = 0.035) and disease severity measured by IBS-SSS (237 vs. 54; p = 0.002). Conclusions Our findings indicate that a short-course oral synbiotic trial may influence the human gastrointestinal tract in IBS-D patients on different levels which are region specific. Electronic supplementary material The online version of this article (10.1007/s00394-018-1826-7) contains supplementary material, which is available to authorized users.

Background: The objective of this study was to report a case series on the efficacy and safety of capecitabine 7/7 schedule combined with erlotinib (CAP-ERL) in patients with advanced pancreatic cancer (APC) who have failed prior therapies. Methods: We retrospectively evaluated 13 patients with locally advanced or metastatic pancreatic cancer previously treated with gemcitabine or oxaliplatin–irinotecan-based first-line regimens. Treatment consisted of capecitabine (Xeloda) at a flat dose of 1000 mg orally twice daily on days 1–7 out of 14 days (7/7 schedule) and erlotinib (Tarceva) 100 mg orally once daily until unacceptable toxicity or disease progression. Tumor assessments were repeated every two cycles (8 weeks) and serum tumor markers were measured every 4 weeks. Results: All patients (median age: 63 years; 7 female/3 male) had various previous lines of treatments of chemotherapies. Median number of cycles with CAP-ERL was 4 (range 2–12). The overall response rate was 20%. CA19-9 was reduced more than 25% in 40% patients. The median overall survival and progression-free survival from the start of CAP-ERL were 4.5 months (range 3–7.5) and 2 months (range 1.5–4), respectively. The most common grade 3 toxicities included hand–foot syndrome, nausea, vomiting, diarrhea, rash, and fatigue. Conclusions: Our result suggests that the combination of a fixed low dose of CAP-ERL 7/7 schedule was tolerated with manageable toxicity and showed encouraging activity as salvage treatment in patients with refractory APC with ECOG performance status 0–2. Further prospective studies are warranted to evaluate this combination.

Colon cancer is one of the most common cancers worldwide with high mortality. A major issue in colon cancer treatment is drug-resistance and metastasis that have been ascribed to the cancer stem cells. In this study, colon cancer stem cells were isolated through sphere culture and verified with the cancer stem cell markers CD133, CD44, and CD24. It was demonstrated that the PI3K/Akt/mTOR signalling pathway was highly activated in the colon cancer stem cells and that inhibition of the PI3K/Akt/mTOR pathway by the inhibitor BEZ235 suppressed the colon cancer stem cell proliferation with reduced stemness indicated by CD133 and Lgr5 expressions. Treatment with insulin as a known activator of the PI3K/Akt pathway increased CD133 expression and decreased the effects of BEZ235 on colon cancer proliferation and survival. The data presented here collectively suggest that the PI3K/Akt/mTOR pathway underpins the stemness of colon cancer stem cells and BEZ235 is potentially a good drug candidate for treatment of colon cancer drug resistance and metastasis.

Cervical cancer is a major disease with high mortality. All cervical cancers are caused by infection with human papillomaviruses (HPV). Although preventive vaccines for cervical cancer are successful, treatment of cervical cancer is far less satisfactory because of multidrug resistance and side effects. In this review, we summarize the recent application of nanotechnology to the diagnosis and treatment of cervical cancer as well as the development of HPV vaccines. Early detection of cervical cancer enables tumours to be efficiently removed by surgical procedures, leading to increased survival rate. The current method of detecting cervical cancer by Pap smear can only achieve 50% sensitivity, whereas nanotechnology has been used to detect HPVs with greatly improved sensitivity. In cervical cancer treatment, nanotechnology has been used for the delivery of anticancer drugs to increase treatment efficacy and decrease side effects. Nanodelivery of HPV preventive and therapeutic vaccines has also been investigated to increase vaccine efficacy. Overall, these developments suggest that nanoparticle-based vaccine may become the most effective way to prevent and treat cervical cancer, assisted or combined with some other nanotechnology-based therapy.

Prostate cancer is common in men with very high mortality which is one of leading causes of cancer-related deaths in men. The main treatment approaches for metastasized prostate cancer are androgen deprivation and chemotherapeutic agents. Although there are initial responses to castration, the resistance to the treatment will eventually occur, leading to castration-resistant prostate cancer. The common chemotherapeutic agents for the treatment of prostate cancer are docetaxel and taxane but outcomes of using these drugs have not been satisfactory. Therefore, it is necessary to find better treatment approaches for prostate cancer and to search for compounds that are effective in prostate cancer prevention. Lycopene extracted from tomato and other fruits or plants such as Gac, watermelon, pink grapefruit, pink guava, red carrot and papaya has been shown to be effective on prostate cancer prevention and treatment. The advantage of the application of lycopene for its anti-prostate cancer activity is that lycopene can reach much higher concentration in prostate tissue than other tissues. In this review, the effect of lycopene on PI3K/Akt pathway is summarised, which could be one of major mechanisms for anti-cancer activity of lycopene.

Endometrial cancer is the third most common cancer in women. Endometrial carcinomas (EC) are clinic histologically classified into two types. Type I tumours, which account for 80% of ECs, are estrogen-dependent and are low grade. Type II tumours are more aggressive with invasion into myometrium. Recently a new classification for endometrial cancer has been proposed based on molecular markers. Whether this classification is helpful for clinical management of endometrial cancer remains to be tested. At present, treatment outcomes of endometrial cancer are not satisfactory. Therefore, more effective approaches are sought. This review summarizes the recent studies about activation of PI3K/Akt pathway in EC and therapeutic implications of the inhibitors of the pathways with emphasis on dual inhibitors of PI3K and mTOR. Both genetic defects and environmental factors are involved in carcinogenesis and progression of EC via activation of multiple signal pathways including the PI3K/Akt pathway. Mutations of major components of the PI3K/Akt pathway are common in EC. Type I tumours usually have mutations in Ras, PTEN, PIK3CA, AKT1, beta-catenin and type II tumours have mutations in TP53. Environmental factor like obesity can also activate the PI3K/Akt pathway to increase the incidence of EC and to cause poorer prognosis. Therefore, inhibition of the PI3K/Akt pathway can be used for therapy of the disease. At present, mTOR inhibitors have been extensively studied and tested in clinical trials. A newly synthesised dual inhibitor of PI3K and mTOR BEZ235 has been shown to be more effective than mTOR inhibitor rapamycin. BEZ235 can inhibit feedback activation of PI3K/Akt pathway by rapamycin. It is promising to include effective PI3K/Akt inhibitors in current treatment regime of endometrial cancer to improve the therapeutic efficacy.

Obesity is now a major health problem due to its rapidly increasing incidence worldwide and severe consequences. Among many conditions associated with obesity are some cancers including melanoma. Both genetic defects and environmental risk factors are involved in the carcinogenesis of melanoma. Activation of multiple signal pathways such as the PI3K/Akt and MAPK pathways are necessary for the initiation of melanoma. Activation of the MAPK pathway as a result of activating mutations in BRAF is commonly seen in melanoma though it alone is not sufficient to cause malignant transformation of melanocytes. Obesity can result in the activation of many signal pathways including PI3K/Akt, MAPK, and STAT3. The activation of these pathways may have a synergistic effect with the genetic defects thereby increasing the incidence of melanoma.

Mushrooms have been consumed for their health benefits for thousands of years in China, and the main active component was recently identified as beta-glucan. The immune-stimulating effect of beta-glucans has been well studied, and several beta-glucan receptors have been identified on the surface of immune cells. In addition, mushroom extracts with high levels of beta-glucans have also been shown to have direct cytotoxic effects on cancer cells, and beta-glucans are used for the treatment of cancer. This review summarizes the use of beta-glucans in colon cancer. Evidence has supported the idea that beta-glucans can decrease the size of xenografted colon cancer tumors via the stimulation of the immune system and direct cytotoxicity. Beta-glucans can also have synergistic effects with chemotherapeutic agents and other immune stimulators, and an innovative strategy is to use beta-glucans to deliver nanoparticles containing chemotherapeutic agents to the site of the colon cancer and, thus, improve the therapeutic efficacy.

Chest X-ray and CT examinations often find pulmonary nodules that could be malignant or benign. A case is presented and discussed here in order to improve diagnosis and management of pulmonary nodules. A 62-year-old lady was found to have multiple pulmonary nodules by X-ray when she complained of a cough and fever. This was confirmed by a CT scan. Fine needle aspiration (FNA) of one of the lung lesions reported scant atypical epithelial cells that stained positive for TTF-1 and cytokeratin 7, but negative for cytokeratin 20. Thus, it was suspicious for large cell carcinoma. A videothoracoscopic lung biopsy and histopathology were applied and showed a necrotic nodule with surrounding chronic inflammation and macrophage response, with no evidence of malignant cells. Atypical reactive pneumocytes at the periphery of the lesion (an old infarct) were probably equivalent to the atypical cells seen on cytology. This result changed the diagnosis of our patient from a malignant condition to a benign process. Thus, CT and FNA may give a false positive. A second pathological opinion is very useful for the right diagnosis and management, as shown in our case.

Colorectal cancer is the third most common cancer with a 5-year survival rate of less than 10%. It is caused by alterations of multiple signal pathways which are affected by both genetic and environmental factors. In some cases, EGFR is important in the carcinogenesis of colorectal cancer suggesting anti-EGFR therapy may be a potential treatment option. However, in other cases it is not effective, which may be related to its down-stream targeted gene mutations. KRAS is highly emphasized in the literature but other mutations like Src, PIK3CA, and BRAF may also be important. Furthermore, obesity may decrease the effectiveness of anti-EGFR treatment as it increases the risk factors for colorectal cancer. Using next-generation sequencing technology, it may be possible to identify all gene mutations in an individual with colorectal cancer. Therefore, gene mutations affecting anti-EGFR therapy in colorectal cancer patients can be identified.

Jiezhong Chen1,3, Kenneth Raymond21John Curtin School of Medical Research, Australian National University, Acton, ACT, Australia; 2School of Pharmacy and Applied Science, Faculty of Science, Technology and Engineering, LaTrobe University, Bendigo, Vic, Australia; 3Adjunct Senior Research Fellow, University of Canberra, ACT, AustraliaAbstract: Diabetes mellitus is characterized by high blood glucose level with typical manifestations of thirst, polyuria, polydipsia, and weight loss. It is caused by defects in insulin-mediated signal pathways, resulting in decreased glucose transportation from blood into muscle and fat cells. The major risk is vascular injury leading to heart disease, which is accelerated by increased lipid levels and hypertension. Management of diabetes includes: control of blood glucose level and lipids; and reduction of hypertension. Dietary intake of beta-glucans has been shown to reduce all these risk factors to benefit the treatment of diabetes and associated complications. In addition, beta-glucans also promote wound healing and alleviate ischemic heart injury. However, the mechanisms behind the effect of beta-glucans on diabetes and associated complications need to be further studied using pure beta-glucan.Keywords: diabetes mellitus, hyperglycemia, prevalence, pathogenesis

Endometrial cancer (EC) is a common reproductive system cancer in females and one of the leading causes for cancer-related deaths in women, ranked only after ovarian and cervical cancers. It is classified into two types with type I having better prognosis. At present, surgical removal is the major approach for the treatment of the disease. For those with metastasized cancer, chemotherapy, hormone therapy and radiotherapy are applied. However, the therapeutic efficacy is unsatisfactory and toxicity is severe. Recently, immune system has been recognized as an important factor in both cancer development and treatment. Immunotherapy against PD-1 has been shown to be effective with low side-effects in many cancers. This opens a novel approach for EC treatment as EC has been shown to have increased PD-L1/PD-1 axis. In this review, we summarize the most recent progress in PD-L1/PD-1 axis and prospect that anti PD-L1/PD-1 may be an effective approach for EC treatment.

Background Prostate cancer (PCa) frequently relapses after hormone ablation therapy. Unfortunately, once progressed to the castration resistant stage, the disease is regarded as incurable as prostate cancer cells are highly resistant to conventional chemotherapy. Method We recently reported that the two natural compounds polysaccharopeptide (PSP) and Gamma-tocotrienols (γ-T3) possessed potent anti-cancer activities through targeting of CSCs. In the present study, using both prostate cancer cell line and xenograft models, we seek to investigate the therapeutic potential of combining γ-T3 and PSP in the treatment of prostate cancer. Result We showed that in the presence of PSP, γ-T3 treatment induce a drastic activation of AMP-activated protein kinase (AMPK). This was accompanied with inactivation of acetyl-CoA carboxylase (ACC), as evidenced by the increased phosphorylation levels at Ser 79. In addition, PSP treatment also sensitized cancer cells toward γ-T3-induced cytotoxicity. Furthermore, we demonstrated for the first time that combination of PSP and γ-T3 treaments significantly reduced the growth of prostate tumor in vivo. Conclusion Our results indicate that PSP and γ-T3 treaments may have synergistic anti-cancer effect in vitro and in vivo, which warrants further investigation as a potential combination therapy for the treatment of cancer.

Mengna Chi,1 Yan Ye,1 Xu Dong Zhang,1 Jiezhong Chen2,3 1School of Medicine and Public Health, The University of Newcastle, Newcastle, NSW, Australia; 2School of Biomedical Sciences, The University of Queensland, Brisbane, QLD, Australia; 3Faculty of Science, Medicine and Health, The University of Wollongong, Wollongong, NSW, Australia Introduction: There is currently no curative treatment for melanoma once the disease spreads beyond the original site. Although activation of the PI3K/Akt pathway resulting from genetic mutations and epigenetic deregulation of its major regulators is known to cause resistance of melanoma to therapeutic agents, including the conventional chemotherapeutic drug dacarbazine and the Food and Drug Administration-approved mutant BRAF inhibitors vemurafenib and dabrafenib, the role of extracellular stimuli of the pathway, such as insulin, in drug resistance of melanoma remains less understood. Objective: To investigate the effect of insulin on the response of melanoma cells to dacarbazine, and in particular, the effect of insulin on the response of melanoma cells carrying the BRAFV600E mutation to mutant BRAF inhibitors. An additional aim was to define the role of the PI3K/Akt pathway in the insulin-triggered drug resistance. Methods: The effect of insulin on cytotoxicity induced by dacarbazine or the mutant BRAF inhibitor PLX4720 was tested by pre-incubation of melanoma cells with insulin. Cytotoxicity was determined by the MTS assay. The role of the PI3K/Akt pathway in the insulin-triggered drug resistance was examined using the PI3K inhibitor LY294002 and the PI3K and mammalian target of rapamycin dual inhibitor BEZ-235. Activation of the PI3K/Akt pathway was monitored by Western blot analysis of phosphorylated levels of Akt. Results: Recombinant insulin attenuated dacarbazine-induced cytotoxicity in both wild-type BRAF and BRAFV600E melanoma cells, whereas it also reduced killing of BRAFV600E melanoma cells by PLX4720. Nevertheless, the protective effect of insulin was abolished by the PI3K and mTOR dual inhibitor BEZ-235 or the PI3K inhibitor LY294002. Conclusion: Insulin attenuates the therapeutic efficacy of dacarbazine and PLX4720 in melanoma cells, which is mediated by activation of the PI3K/Akt pathway and can be overcome by PI3K inhibitors. Keywords: insulin, PI3K/Akt, melanoma, drug resistance, DTIC, BRAF inhibitors

Src is a member of a superfamily of membrane-associated nonreceptor protein tyrosine kinases. It is stimulated by receptors of growth hormone, cytokines, and adipokines, and it regulates multiple signaling pathways, including phosphatidylinositide 3 kinase-Akt, mitogen-activated protein kinase, signal transducer and activator of transcription 3, interleukin 8, and vascular endothelial growth factor pathways, and cytoskeletal pathways to cause a cascade of cellular responses. Eighty percent of patients with colon cancer overexpress Src in tumor tissue. Evidence has shown that the overexpression of Src in colon cancer accelerates metastasis and causes chemotherapeutic drug resistance via multiple downstream signaling pathways. Therefore, the inhibition of Src may be useful for the treatment of colon cancer. However, the inhibition of Src may also weaken immune responses that are essential for the eradication of cancer cells. Overcoming the problem of inhibiting Src in cancer cells while retaining immune system efficacy is the key to the successful application of Src-inhibition therapy. Different Src family members are used by the immune system and colon cancer. This differential use may provide a good opportunity to develop Src family member-specific inhibitors to avoid immune inhibition.

Nanotechnology is a vigorous research area and one of its important applications is in biomedical sciences. Among biomedical applications, targeted drug delivery is one of the most extensively studied subjects. Nanostructured particles and scaffolds have been widely studied for increasing treatment efficacy and specificity of present treatment approaches. Similarly, this technique has been used for treating bone diseases including bone regeneration. In this review, we have summarized and highlighted the recent advancement of nanostructured particles and scaffolds for the treatment of cancer bone metastasis, osteosarcoma, bone infections and inflammatory diseases, osteoarthritis, as well as for bone regeneration. Nanoparticles used to deliver deoxyribonucleic acid and ribonucleic acid molecules to specific bone sites for gene therapies are also included. The investigation of the implications of nanoparticles in bone diseases have just begun, and has already shown some promising potential. Further studies have to be conducted, aimed specifically at assessing targeted delivery and bioactive scaffolds to further improve their efficacy before they can be used clinically.

Objectives: HPV is known to play a key role in the growth and maintenance of cervical cancer. Its early genes E6 and E7 can activate several intracellular signal pathways for carcinogenesis. Studies have shown that in vitro knockdown of E6 and E7 can reduce the survival ability of cervical cancer cell lines. In this study, we tested the effect of a lentiviral shRNA against E6/E7 on the tumor growth of xenografted cervical cancer HeLa cells. Methods: In vitro , the growth of HeLa cells transduced with lentiviral shRNA against E6/E7 was compared to controls. In vivo , the RAG -/- mice, which are deficient in T and B lymphocytes were used to establish the HeLa xenografted model. In the treatment group, shRNA against E6/E7 was injected into the tumor directly 30 days after HeLa cell injection when tumors have formed and the injection was repeated at day 60. A lentiviral vector without shRNA was injected in the control group . Results: HeLa cells transduced with lentiviral shRNA against E6/E7 grew slower than those with transduced with the control vector. The difference in growth rate was significant at day 4. We also observed that lentiviral shRNA significantly reduced the size of xenografted tumors compared with controls. The average tumor weight is 60% of the controls. Conclusions: Our results provide evidence that RNAi may be used for the treatment of cervical cancer by intra-tumor injection.

Obesity is associated with the increased incidence of colon cancer. Many cancer risk factors have been identified including increased blood levels of insulin, leptin, interleukin-6, interleukin-17, tumor necrosis factor-alpha, and decreased blood levels of adiponectin. However, the role of blood levels of estrogen in obesity-associated colon cancer is controversial. Evidence showed that obesity affected men more strongly than women in the carcinogenesis of colon cancer, indicating protective effect of estrogen which is increased in obesity. However, an epidemiological study has also shown that endogenous estradiol level is an independent risk factor for colon cancer, positively associated with colon cancer after normalizing insulin, IGF-1. The controversial opinions may be caused by different effects of ER-alpha and ER-beta. ER-alpha can increase colon cancer cell proliferation and increase cancer incidence. ER-beta has the opposite effect to ER-alpha, and it causes apoptosis of colon cancer cells. The normal colonocytes mainly express ER-beta. Therefore, increased estrogen in obesity may have protective effect via ER-beta in obesity-associated colon cancer. However, with the development of colon cancer, ER-alpha is increased and ER-beta is decreased. In the late stage of colon cancer, estrogen may promote cancer development via ER-alpha. The different effects and expression of ER-alpha and ER-beta may explain the different results observed in several epidemiological studies as well as several animal experiments. Therefore, manipulation of estrogen-caused signal pathways to inhibit ER-alpha and stimulate ER-beta may have preventive and therapeutic effect for obesity-associated colon cancer.

Cancer is a common disease responsible for a significant proportion of human mortality. There are totally more than 200 types of cancers. The most common ones are lung, prostate, breast and colorectal cancers. The severity of cancer as a health problem is evidenced by a statistical analysis for the cancer incidence and mortality. It has been estimated that total cancer incidences worldwide are 12.7 million and total cancer mortalities are 7.6 million in 2008 [1]. The global cancer burden rises to 14.1 million new cases with 8.2 million cancer-related deaths in 2012 (www.iarc.fr/en/media-centre/pr/2013). Although the incidence rate is similar in developing and developed countries, the death rate in developing countries is double the number in developed countries. The major reasons for the high death rate are the delayed diagnosis and the lack of standard and effective treatment. Clinically, surgery is often effectively used for removal of the un-metastatic cancers, but less effective in metastatic cancer, that has a significantly reduced survival rate. Therefore, chemotherapeutic drugs are used as a standard therapy for treating the metastasised cancer. Drug resistance to chemotherapy is however a major hurdle to reach satisfactory results and responsible for treatment failure in many cases [2-4]. There are two types of drug resistances; inherent and acquired. In inherent drug resistance, patients do not respond to even initial chemotherapy [2]. In acquired drug resistance, the initial treatment is effective but patients develop drug resistance subsequently. The mechanisms for drug resistance are multifactory such as drug target mutations, increased drug detoxification system to reduce intracellular drug concentrations, increased cell tolerance to apoptosis, and increased ability to repair DNA damage [5-8]. Intracellular signalling pathways play key roles in cellular physiology. They are activated by growth factors, hormones and cytokines, and regulate cell proliferation and survival [9-12]. The signalling pathways are important in carcinogenesis and cancer maintenance [13, 14]. The role of abnormal activation of signalling pathways has also been extensively studied in drug resistance to chemotherapy [15-18]. Targeting these signalling pathways has been an effective strategy to overcome drug resistance in cancer treatment [14, 19]. We have collected several review articles from different research groups to form this special edition of Current Medicinal Chemistry. It discusses specifically the roles of several important signalling pathways in drug resistance to anti-cancer agents. Professor Tamm and his colleagues have reviewed the Hsp90 (heat shock protein 90) inhibitors used for overcoming drug resistance to anti-cancer agents. Hsp90 is a molecular chaperone for maintaining the integrity, folding and function of many proteins. Effects of Hsp90 on the signalling molecules account for its role in activating different signalling pathways such as the JAK/STAT and the PI3K pathways [20-22]. Increased expression of Hsp90 in cancer cells has been shown by many studies. Therefore, it has been proposed to inhibit Hsp90 for the cancer treatment. So far, 17 Hsp90 inhibitors have been developed [20]. In this issue, Professor Tamm and his colleagues summarized the application of Hsp90 inhibitors in multiple myeloma (MM), one of the tumour types with elevated Hsp90 levels. It is pointed out that large variability in response to Hsp90 inhibitors may prevent their use as single drug in the treatment of MM although Hsp90 inhibitors have been demonstrated to have marked anti-cancer activity in MM in both laboratory studies and clinical trials. The biomarker for the sensitivity of Hsp90 inhibitors in MM is the activation of IL-6-activated JAK/STAT3 pathway, rather than a simple over-expression of Hsp90. All these issues have been discussed extensively in this review. Professor Wafik S. El-Deiry and colleagues from Hematology/Oncology, Penn State Hershey Medical Center, provide a review of hypoxia-inducible factor 1 (HIF-1) in drug resistance and the implications of HIF-1 inhibitors for overcoming drug resistance. It is well known that HIF-1 is activated in many cancers due to tumour hypoxia environment [23]. HIF-1 activation results in the inhibition of apoptosis, and increased drug efflux and cellular metabolism, leading to drug resistance [24]. Therefore, targeting HIF-1 can reduce drug resistance to chemotherapy in cancer therapy [24]. Professor El-Deiry introduced the current approaches to inhibit HIF-1 signalling including reducing HIF-1α protein levels, inducing its degradation, inhibiting HIF-1 transcription and its mediated protein transcription, and disrupting the formation of the HIF-1 transcription factor complex. They have also discussed the preclinical and clinical studies using HIF-1 inhibitors. Professor Hui reviewed non-coding RNAs in anti-cancer drug resistance, including microRNAs (miRNAs) and long noncoding RNAs (lncRNAs). Non-coding RNAs have recently been identified as important regulators of gene expression [25, 26]. Professor Hui summarized the effect of mutations and dysregulation of ncRNAs on cancer drug resistance through their regulatory roles in multiple molecules in different signalling pathways. Dr. Ling reviewed phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway in prostate cancer. The PI3K/Akt/mTOR pathway is frequently activated in prostate cancer cells mainly caused by the inactivating mutation of PTEN or constituent activating mutation of PIK3CA [27, 28]. The abnormal activation of PI3K/Akt/mTOR is associated with the development of drug resistance. Therefore, it may be effective for overcoming drug resistance in prostate cancer through inhibiting the PI3K/Akt pathway. It has been noted that a class of dual PI3K/mTOR inhibitors, which bind to and inactivate both PI3K and mTOR, has been developed for treating prostate cancer. They summarized the mechanisms of action of these inhibitors, their effectiveness when used alone or in combination with other chemotherapeutic compounds. The potential of these inhibitors to serve as the new generation therapies for prostate cancer patients, particularly those who are resistant to the frontline chemotherapeutic drugs, has also been discussed. The issue has also included two review articles that discuss the roles of the PI3K/Akt pathway in cervical cancer by Dr. Wu and colleagues and endometrialcancer by Dr. Chen and colleagues. They summarize the published studies indicating that the PI3K/AKT/mTOR pathway is unique, in that all of the major elements of this pathway have been found to be frequently amplified in human cervical and endometrial cancers. Thus, this pathway clearly represents both a great therapeutic target and a practical challenge for both cancer types. One of the important research directions is to identify the therapeutic strategies targeting on the PI3K/AKT/mTOR pathway. Overall, the provocative topics in this special review edition represent some of the most promising observations and strategies in drug resistance in cancer therapy. Current and future cancer patients who desperately await the new and effective treatments may benefit from the studies and efforts reviewed here on discovering signalling inhibitors to overcome drug resistance to chemotherapeutic agents.

Obesity and overweight have become major medical and social problems. Both are increasing worldwide; two-thirds of the population in developed countries is obese or overweight. Obesity has been associated with many comorbidities, including diabetes and heart disease. Studies have also found that obesity is one of the risk factors involved in increased cancer incidence. Many obesity-related factors are responsible, including increased blood levels of insulin/IGF, IL-6, TNF-alpha, and leptin, and decreased blood levels of adiponectin. Recently, it has been shown that IL-17 levels increase in obese patients. IL-17 is well known to increase carcinogenesis; thus, increased IL-17 levels in obesity may contribute to increased cancer incidence in obesity. IL-17 could activate Src/PI3K, MAPK, Stat3, and PKC, resulting in carcinogenesis. It may also change the microenvironment of tumors. Thus, inhibition of IL-17 may have preventive and therapeutic implications in obese patients.

Obesity has been associated with both the carcinogenesis and poor prognosis of colon cancer, one of the leading causes of cancer-related death. Increased blood levels of insulin in obese subjects have been demonstrated to play a key role in carcinogenesis. It is also possible that insulin affects treatment efficacy, leading to poor prognosis. In this study, we demonstrated that insulin can increase HT29 colon cancer cell line resistance to cycloheximide and 5-fluorouracil induced cytotoxicity. This effect can be inhibited by the PI3K/Akt inhibitor Ly294002, indicating the important role of this pathway in the insulin-induced inefficacy of chemotherapy. The insulin-induced resistance to cycloheximide and 5-fluorouracil can be used in drug screening to overcome the inefficacy of chemotherapy in obesity-associated colon cancer.

Colon cancer is the third most common cancer and third most common cause of cancer-related death in the USA according to 2008 American Cancer Society statistics. The carcinogenesis of colon cancer has been associated with both genetics and environmental factors. It has been found that several signal pathways, including K-ras, Src/PI3K/Akt, beta-catenin, TGFbeta and p53 play critical roles in its pathogenesis. The 5 y survival rate of metastatic colon cancer is below 10%. Thus, it is necessary to further understand its biology and search for effective therapy. Azoxymethane (AOM) is a common model for colon cancer. It can specifically induce colon cancer similar to the pathogenesis of human sporadic colon cancer. Thus, it has been extensively used in the study of the molecular biology, prevention and treatment of colon cancer. After administration, AOM is metabolised into methylazoxymethanol by CYP2E1, which causes DNA mutations. Mutation of K-ras activates this pathway and its downstream PI3K/Akt pathway and MAPK pathway. Mutation of beta-catenin also prevents it from being degraded by GSK-3 and accumulation of beta-catenin leads to cell proliferation. TGFbeta, a pro-apoptotic protein, is inhibited. All of these changes form the basis of AOM carcinogenesis. This model has been used in the study of the genetic deficiencies of colon cancer and in the prevention and treatment of the disease. For example, TGF-betaR2 and adiponectin knockout mice are more susceptible to AOM, while high amylose cornstarch, green tea and artemisia have protective effects.

B-cell chronic lymphocytic leukemia (CLL) is caused by the abnormal accumulation of non-functional B-cells in peripheral blood and bone marrow. However, the precise aetiology and mechanism of the disease are unclear. Recently, progress has been made in the identification of both the genetic deficiencies and environmental factors that may underlie CLL. This has provided some clues to the nature of the disease, but no definitive cures. Although treatment has increased remission time, at present the disease is not curable by conventional therapy. Further studies of the pathogenesis of CLL are needed, as are the development of suitable cell lines and animal models in which to study it. This review summarises the most recent progress in CLL with emphasis on molecular events and possible implications in therapy.

Mushroom has been used for thousand years in China and other Asian countries for health improvement and treatment of disease. A few decades ago, its main component beta-gluean was identified. Beta-glueans are now known to have beneficial effects for the prevention and treatment of many diseases including eanccr, infectious disease, hyperlipidemia, diabetes, atherosclerosis and obesity. The effects are mediated by the different properties of beta-glucans such as immune stimulation and bile acid trapping.

Olanzapine treatment has been associated with clinically meaningful weight increases, hypertriglyceridemia, insulin resistance and diabetes mellitus. There are few options for olanzapine-responders who fail other antipsychotic agents. Aripiprazole is a potent (high-affinity) partial agonist at D2 and 5-HT1A receptors and a potent antagonist at 5-HT2A receptor and is associated with less weight gain than olanzapine. We report the results of a 10-week placebo controlled, double-blind crossover study that examined 15 mg/day aripiprazole's effects upon weight, lipids, glucose metabolism, and psychopathology in overweight and obese schizophrenia and schizoaffective disorder subjects treated with a stable dose of olanzapine. During the 4 weeks of aripiprazole treatment there were significant decreases in weight (p = .003) and BMI (p = .004) compared to placebo. Total serum cholesterol (p = .208), HDL-cholesterol (p = .99), HDL-2 (p=.08), HDL-3 (p=.495) and LDL- cholesterol (p=.665) did not change significantly comparing aripiprazole treatment to placebo treatment. However, total serum triglycerides (p = .001), total VLDL-cholesterol (p=.01), VLDL 1- &2-cholesterol (p=.012) decreased significantly during the aripiprazole treatment phase. VLDL-3-cholesterol tended lower during aripiprazole, but the decrease was not significant (p=.062). There was a decrease in c-reactive protein comparing aripiprazole treatment to placebo though it did not reach significance (p=.087). The addition of aripiprazole to a stable dose of olanzapine was well tolerated and resulted in significant improvements on several outcome measures that predict risk for medical morbidity.

The IL-23/IL-17 axis may be important in obesity-associated cancer by way of the activation of multiple signal pathways

Colon cancer is the fourth most common cancer worldwide causing half a million deaths each year. The author of this Viewpoint article discusses the role of Src, a protein tyrosine kinase, in the metastasis of this disease, and potentially its treatment.

Increasing epidemiological evidence has linked the development and progression of several cancers including melanoma with obesity. However, whether obesity impinges on responses of cancer cells to treatment remains less understood. Here we report that human adipocytes contribute to resistance of melanoma cells to various therapeutic agents. Exposure to media from adipocyte cultures (adipocyte media) increased cell proliferation and reduced sensitivity of melanoma cells to apoptosis induced by diverse chemotherapeutic drugs, including the DNA-damaging drug cisplatin, the microtubule-targeting agent docetaxel, and the histone deacetylase inhibitor SAHA. This was associated with increased activation of PI3K/Akt and MEK/ERK signaling, and was attenuated by a PI3K or MEK inhibitor. The effect of adipocyte media on melanoma cells was, at least in part, due to the interaction between the adipokine leptin and its long form receptor OB-Ob, in that immunodepletion of leptin in adipocyte media or siRNA knockdown of OB-Rb in melanoma cells reversed the increase in Akt and ERK activation, enhancement in cell proliferation, and importantly, protection of melanoma cells against the drugs. In support, recombinant leptin partially recapitulated the effect of adipocyte media on melanoma cells. Of note, OB-Rb was increased on the surface of melanoma cells compared to melanocytes, whereas leptin short form receptors appeared to be suppressed post-transcriptionally, suggesting that OB-Rb was selectively upregulated in melanoma cells. Collectively, these results indicate that adipocytes contribute to resistance of melanoma cells to chemotherapeutic drugs and agents targeting the PI3K/Akt and MEK/ERK pathways, and suggest that inhibition of the leptin/ OB-Rb system may be useful to improve the efficacy of multiple therapeutic approaches in the treatment of melanoma. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B242. Citation Format: Mengna Chi, Jiezhong Chen, Yan Ye, Hsin-Yi Tseng, Fritz Lai, Kwang Hong Tay, Lei Jin, Chen Chen Jiang, Xu Dong Zhang. Adipocytes contribute to resistance of human melanoma cells to chemotherapy and targeted therapy. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B242.

Viruses have been shown to be responsible for 10%-15% of cancer cases. Epstein-Barr virus (EBV) is the first virus to be associated with human malignancies. EBV can cause many cancers, including Burkett’s lymphoma, Hodgkin’s lymphoma, post-transplant lymphoproliferative disorders, nasopharyngeal carcinoma and gastric cancer. Evidence shows that phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) plays a key role in EBV-induced malignancies. The main EBV oncoproteins latent membrane proteins (LMP) 1 and LMP2A can activate the PI3K/Akt pathway, which, in turn, affects cell survival, apoptosis, proliferation and genomic instability via its downstream target proteins to cause cancer. It has also been demonstrated that the activation of the PI3K/Akt pathway can result in drug resistance to chemotherapy. Thus, the inhibition of this pathway can increase the therapeutic efficacy of EBV-associated cancers. For example, PI3K inhibitor Ly294002 has been shown to increase the effect of 5-fluorouracil in an EBV-associated gastric cancer cell line. At present, dual inhibitors of PI3K and its downstream target mammalian target of rapamycin have been used in clinical trials and may be included in treatment regimens for EBV-associated cancers.