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Rubia plants are one of the most important plant resources possessing significant commercial and medicinal values. Plant endophytes could benefit their host plants in different ways. Rubiaceae-type cyclopeptides (RAs), mainly isolated from Rubia plants, have attracted considerable attentions for their distinctive bicyclic structures and significant antitumor activities, but their contents in plants are low. The aim of this study is to investigate the diversity of endophytic fungi in Rubia plants and their potential for production of RAs. In this work, 143 endophytic fungi isolates were obtained from two Rubia plants. Phylogenetic analysis was performed based on the ITS rDNA sequences, and the isolates were classified into 29 genera. Among them, four endophytic fungal strains were found to produce anti-tumour RAs by LC-MS/MS analysis. This work successfully provides valuable knowledges of endophytic fungi microbiome in Rubia plants for agricultural and industrial applications, and exploits a new environmental-friendly resource of RAs.

Objectives Gastrointestinal cancer, one of the major causes of cancer-related deaths in the world, refers to malignant conditions of the gastrointestinal (GI) tract and other organs. Although conventional therapy has been successful to some extent in cancer treatment, drug resistance and cancer recurrence still limit the therapeutic efficacy. There is increasing evidence indicating that ginsenoside, as a kind of high nutritional value and widely used traditional Chinese medicine, could contribute to the promotion of treatment in GI cancer, which deserves further investigation. Key findings Based on previous studies, the possible mechanisms mainly include regulation of autophagy, apoptosis, proliferation, migration and angiogenesis. However, no studies recently have conducted a more in-depth review of the anti-cancer effects of ginsenoside in GI cancer. Summary Therefore, this review will summarise and analyse the latest developments in the anti-tumour effects of ginsenosides in GI cancer, thus may promote further research of the anti-tumour efficacy of ginsenoside.

Uveal melanoma is the most common primary intraocular tumour in adults. There is no standard adjuvant treatment to prevent metastasis and no effective therapy in the metastatic setting. (−)-4-O-(4-...

Cancer is a condition in which cells grow uncontrollably and may metastasis to other parts of the body. Despite the recent advances in synthesising new anticancer agents, plant-derived compounds ar...

Abstract:: Cancer is a leading cause of mortality, and its individual and collective impact is substantial. Conventional chemotherapy utilizes drugs that effectively destroy tumour cells. However, these agents destroy healthy cells along with the tumour cells, leading to many adverse effects, which include hypersensitivity reactions, nephrotoxicity, and neurotoxicity. To minimize these adverse effects, various drug delivery systems (DDSs) have been developed. Among them, nano drug delivery systems are particularly attractive platform. Thus, this review paper explores recent work on targeted delivery; tumour accumulation enhancement and sustained blood circulation using more effective biomaterials to enhance the properties of nanoparticles. Moreover, various target-specific drug delivery mechanisms, such as antibody-mediated delivery as well as the targeting of angiogenesis, mitochondria, and the CD44 receptor, are also explained.

21 p.-4 fig.-3 tab., Searching for improved indolesulfonamides with higher polarities, 45 new analogues with modifications on the sulfonamide nitrogen, the methoxyaniline, and/or the indole 3-position were synthesised. They show submicromolar to nanomolar antiproliferative IC50 values against four human tumour cell lines and they are not P-glycoprotein substrates as their potencies against HeLa cells did not improve upon cotreatment with multidrug resistance (MDR) inhibitors. The compounds inhibit tubulin polymerisation in vitro and in cells, thus causing a mitotic arrest followed by apoptosis as shown by cell cycle distribution studies. Molecular modelling studies indicate binding at the colchicine site. Methylated sulfonamides were more potent than those with large and polar substitutions. Amide, formyl, or nitrile groups at the indole 3-position provided drug-like properties for reduced toxicity, with Polar Surface Areas (PSA) above a desirable 75 Å2. Nitriles 15 and 16 are potent polar analogues and represent an interesting class of new antimitotics., This work was financially supported by the Consejería de Educacion de la Junta de Castilla y León [SA262P18 and SA116P20], co-funded by the EU’s European Regional Development Fund-FEDER, and the Spanish Ministry of Science,Innovation, and Universities [RTI2018-099474-B-I00 and SAF2017-89672-R].

Injectable hydrogels have become the material of choice for the treatment of solid tumours based on their advantages in loading anti-tumour materials. This study reviews the main scientific research achievements on anti-tumour injectable hydrogels in recent years. The gel-forming mechanism of anti-tumour injectable hydrogels was listed, and the advantages and difficulties of each gel-forming mechanism were summarised. In addition, several current anti-tumour methods based on injectable hydrogels were discussed, including chemotherapy, hyperthermia-based therapy, catalytic therapy and immune therapy, as well as the integration of diagnosis and treatment to monitor the progress of cancer treatment. The anti-tumour mechanism and the advantages and disadvantages of various tumour treatments were analysed. Finally, the future development trend of injectable hydrogels for anti-tumour therapy was discussed.

Introduction Alkaloids are a large group of organic compounds of natural origin. One of the most popular alkaloids is magnoflorine. This compound is synthesized by plants from the Ranunculaceae, Menispermaceae and Magnoliaceae families. Magnoflorine has unique biological properties and a broad spectrum of physiotherapeutic activity. It has antibacterial, antifungal, antidiabetic, immunomodulating and anticancer properties. Objective The aim of the study is to present magnoflorine as a compound with anti-cancer potential. Brief description of the state of knowledge Magnoflorine is a compound belonging to the isoquinolone alkaloids. Metabolized by secondary metabolism it is most commonly collected in the roots, rhizomes, tubers and bark of plants. It can be isolated from all plant elements by chromatographic methods. Magnoflorine has a number of therapeutic properties, including anti-cancer. Magnoflorine has been shown to inhibit cell proliferation, migration and cause apoptosis. The possibility of using this compound in the treatment of breast and stomach cancer has been confirmed. Results The combination of DOX with magnoflorine reduces the expression of Bcl-2 and enhances the cleavage of caspase-9 and -3, causing apoptosis in breast cancer cells. Moreover, they block the activation of PI3K / AKT / mTOR signaling, which play an important role in regulating tumour growth. Magnoflorine inhibits the activity of caspases in liver cancer cells, resulting in inhibition of proliferation Conclusions Magnoflorine is an interesting research target due to its unique anticancer properties. Detailed knowledge of the pharmacological possibilities of magnoflorine will enable its effective use in the prevention and treatment of many civilization diseases.

Background/Aims: Colorectal cancer (CRC) is the third most common malignant tumour worldwide and the second leading cause of cancer-related deaths. Commonly, 5'-aminolevulinic acid synthase1 (ALAS1) is the rate-limiting enzyme for haem biosynthesis. Recent studies have shown that ALAS1 is involved in a number of cellular functions and has significant effects on non-small cell lung cancer (NSCLC). However, current concepts of disease pathogenesis fail to fully explain the role of ALAS1 expression and biological functions in CRC. Materials and Methods: A total of 67 paired tumour tissues and adjacent colorectal tissues were used to detect ALAS1 levels and further analyse the correlation between ALAS1 expression levels and clinical features. Using HCT116 cell lines, we studied the impact of ALAS1 on biological function by knocking down or inhibiting ALAS1. Results: We found an increase in the levels of ALAS1 in cancer tissues compared to adjacent colorectal tissues. The increase in ALAS1 expression was closely related to the invasion depth, N staging and tumour size of CRC patients. The proliferation and metastasis of CRC cells could be inhibited by suppressing ALAS1. Conclusions: The abnormal expression of ALAS1 is closely related to the proliferation and metastasis of CRC cells, suggesting that ALAS1 may be a novel therapeutic target for the treatment of CRC.

Hanna T Sjoberg, Yiannis Philippou, Anette L Magnussen, Iain DC Tullis, Esther Bridges, Andrea Chatrian, Joel Loefebvre, Ka Ho Tam, Emma A Murphy, Jens Rittscher, Dina Preise, Lilach Agemy, Tamar Yechezkel, Sean C Smart, Paul Kinchesh, Stuart Gilchrist, Danny P Allen, David A Scheiblin, Stephen J Lockett, David A Wink, Alastair D Lamb, Ian G Mills, Adrian Harris, Ruth J Muschel, Boris Vojnovic, Avigdor Scherz, Freddie C Hamdy, Richard J Bryant. Introduction There is an important clinical need to improve the treatment of high risk localised and locally advanced prostate cancer (PCa), and to reduce the side effects of these treatments. We hypothesised that multi-modality therapy combining radiotherapy and vascular-targeted photodynamic therapy (VTP) could PCa tumour control compared against monotherapy with each of these treatments alone. This could provide proof-of-concept to take to the clinic. VTP is a minimally invasive focal surgical therapy for localised PCa, which rapidly destroys targeted tumours through vascular disruption. Tumour vasculature is characterised by vessel immaturity, increased permeability, aberrant branching and inefficient flow. Fractionated radiotherapy (FRT) alters the tumour microenvironment and promotes transient vascular normalisation. Materials and Methods We investigated whether sequential delivery of FRT followed by VTP 7 days later improves PCa tumour control compared to monotherapy with FRT or VTP alone. Results FRT induced vascular normalisation changes in PCa flank tumour allografts, improving vascular function as demonstrated using dynamic contrast enhanced magnetic resonance imaging. FRT followed by VTP significantly delayed tumour growth in flank PCa allograft pre-clinical models, compared with monotherapy with FRT or VTP alone, and improved overall survival. Conclusion Taken together, these results suggest that combining FRT and VTP could become a promising multimodal clinical strategy in PCa therapy. This provides proof-of-concept for this multi-modality therapy approach to take forward to early phase clinical trials.

Barrigenol-like triterpenoids (BATs), which contain an unusual oleanane substituted by many hydroxyl groups as the skeleton, are subdivided into five subtypes: barrigenol A1, barrigenol A2, barrigenol R1, barringtogenol C, and 16-deoxybarringtogenol C. The variations in acyl derivatives, hydroxyl groups, and carbohydrate chains in their structures have enhanced the diversity of BATs. Moreover, the stable polyhydroxy-replaced pentacyclic skeleton provides an ideal platform for structural modifications. To date, more than 500 BAT derivatives have been isolated from plants. Synchronously, BATs possess anti-tumour, anti-Alzheimer's disease, anti-inflammatory, anti-microbial, anti-obesity and anti-allergic activities by regulating numerous cellular molecules. Some BAT derivatives, such as escin obtained from Aesculus hippocastanum L. and xanthoceraside isolated from Xanthoceras sorbifolia Bunge, have been used to treat encephaloedema or inflammatory diseases. This review aims to provide comprehensive information about the chemistry, sources, bioavailability, and anti-tumour effects of BATs, with a particular emphasis on the molecular mechanisms of action. The pharmacokinetics and clinical progress are also concerned. More than 300 structures identified over past 25 years are summarized here (249 compounds) and in the supplementary information (114 compounds). Accordingly, the pharmaceutical activity of barrigenol triterpenoids suggests that some compounds should be developed as promising anti-tumour or anti- Alzheimer's disease agents in future.

Extensive studies have been conducted on natural materials due to their unique and biodegradable properties for oral drug delivery. In the current research, we fabricated sodium caseinate nanomicelles (NaCNs) using casein as a natural polymer to develop a controlled-release oral drug delivery system. NaCNs was explored to improve the therapeutic potential of Doxorubicin (DOX) with reduced toxicity in healthy organs. The synthesized and thoroughly characterized DOX-loaded NaCNs were subjected to in vivo anti-tumour evaluation and bio-distribution analysis in a 4T1-induced breast cancer model. Our findings indicated an almost eight-fold reduction in tumour size in the group orally treated with DOX-NaCNs when compared to free DOX. It is plausible that the enhanced anti-tumour effects of oral DOX-NaCNs is related to the controlled release of DOX from the delivery system as well as the longer circulatory time of the drug in the blood, as confirmed by the bio-distribution study, when compared with free DOX and the intravenous formulation of DOX-NaCNs. Additionally, the tumour drug accumulation for the orally administered DOX-NaCNs was 1.27- and 6.8-fold higher than that of the intravenously administered DOX-NaCNs and free DOX, respectively and overall, was 8.34-times higher than the orally administered free DOX. In comparison, the orally administered DOX-NaCNs showed significant reduction in tumour size (5.66 ± 4.36mm3) after the two doses as compared to intravenously administered DOX-NaCNs (10.29 ± 4.86 mm3) on day 17 of the experimental period. Moreover, NaCNs were well tolerated in the mice at a single dose of 2,000 mg/kg in an acute oral toxicity study. Moreover, no significant change in the body weight was observed after treatment with the single dose of NaCNs when compared to the control group. Thus, NaCNs emerge as a safe and non-toxic delivery system with excellent bio-distribution profile and high anti-tumour effects that present as a potential option for oral chemotherapy.

Katuki or Picrorhiza is a well-known herb for its hepatoprotective action and its wide range of pharmacological activities...

Cervical cancer is the fourth most common carcinoma in women. Cisplatin (DDP) is the first-line drug for the treatment of cervical cancer. Although efficacious, its application is constrained by the intolerance and serious adverse effects associated with cisplatin. Here, we aimed to investigate the in vivo anti-cervical cancer effects of cyanidin-3-o-glucoside (C3G), a type of anthocyanin, and DDP, when used alone or in combination; a BALB/c nude mouse xenograft tumour model was used. The tumour was inhibited in the three treatment groups when compared with untreated controls. The inhibition of tumour was 40.49%, 50.15%, and 58.49% when treated with C3G alone [40 mg/kg body weight (bw)], DDP alone (3 mg/kg bw), or a combination of C3G and DDP, respectively. Immunohistochemistry analysis indicated that treatment with C3G, DDP, or the combination induced apoptosis in xenograft tumours. Furthermore, after treatment, Bcl-2 level was decreased, Bax and cleaved caspase-3 expression was activated, and the PI3K/AKT/mTOR signalling pathway was modulated. These results suggest that the combination of C3G and DDP may have significant synergistic anti-tumour efficacy in patients; therefore, this combination therapy has great potential for the treatment of cervical cancer.

Mycomedicine is a unique class of natural medicine that has been widely used in Asian countries for thousands of years. Modern mycomedicine consists of fruiting bodies, spores, or other tissues of medicinal fungi, as well as bioactive components extracted from them, including polysaccharides and, triterpenoids, etc. Since the discovery of the famous fungal extract, penicillin, by Alexander Fleming in the late 19th century, researchers have realised the significant antibiotic and other medicinal values of fungal extracts. As medicinal fungi and fungal metabolites can induce apoptosis or autophagy, enhance the immune response, and reduce metastatic potential, several types of mushrooms, such as Ganoderma lucidum and Grifola frondosa, have been extensively investigated, and anti-cancer drugs have been developed from their extracts. Although some studies have highlighted the anti-cancer properties of a single, specific mushroom, only limited reviews have summarised diverse medicinal fungi as mycomedicine. In this review, we not only list the structures and functions of pharmaceutically active components isolated from mycomedicine, but also summarise the mechanisms underlying the potent bioactivities of several representative mushrooms in the Kingdom Fungi against various types of tumour.

The development of nucleic acid drugs with unique structures and mechanisms has stimulated great research interest. Herein, we report a general strategy to construct “stapled” structures of single-stranded antisense oligonucleotides (ASONs) with a stimuli-responsive feature. “Stapled” cyclic structures can be synthesized with reactive bifunctional handles that react with thiol groups of phosphorothioate (PS)-modified ASONs, and can be alternatively adjusted depending on the desired PS sites in the ASON strand. The disulphide group in the stapled handle can be cleaved in the reducing microenvironment of tumour cells. Thus, “stapled” ASONs may be transformed back to a linear conformation to facilitate binding to target mRNAs. Stapling conferred protection against degradation, and enhanced anti-tumour activity compared to linear counterparts. This study provides a new, effective, and convenient strategy for designing ASONs with “stapled” structures, and also adds a further contribution to facilitate the stability and biological efficacy of novel nucleic acid-based therapeutics.

The aim of this study was to surface-functionalize PEGylated liposomal doxorubicin (PLD) using anti-p32 CGKRK peptide to evaluate its anti-angiogenic and anti-tumour activities. CGKRK was conjugated to DSPE-mPEG2000-maleimide and post-inserted into PLD at 25, 50, 100, 200 and 400 peptides per each liposome and characterised for their size, zeta potential, drug loading, release properties; and cell binding, cell uptake and cytotoxicity on three C26, 4T1 and human umbilical vein endothelial cell (HUVEC) cell lines. The in vitro results indicated the better efficiency of the PLD-100 (PLD with 100 CGKRK) formulation on 4T1 and HUVEC cell lines. The results of anti-tube formation and spheroid assay indicated the efficiencies of the PLD-100 formulation compared with Caelyx® in vitro. The in vivo studies indicated the higher tumour accumulation of PLD-100 formulation in comparison with Caelyx® which also implied the higher survival rates in mice treated with PLD-100 formulation. Histological evaluations demonstrated that PLD-100 had no side-effects on major organs. In conclusion, the results of this study indicated that PLD-CGKRK- could efficiently target endothelial and tumour parenchymal cells which enhance the therapeutic efficacy of PLD and merits further investigation.

Induction of differentiation is a promising therapeutic strategy against acute myeloid leukemia. However, current differentiation therapies are effective only to specific patient populations. To identify novel differentiation agents with wider efficacy, we developed a phenotypic high-throughput screen with a range of genetically diverse cell lines. From the resulting hits, one chemical scaffold was optimised in terms of activity and physicochemical properties to yield OXS007417, which was also able to decrease tumour volume in a murine in vivo xenograft model.

Highlights • Endogenous retroviruses are expressed in human tumours. • In some animal tumour models passive and active immunization against retroviral antigens expressed in the tumour tissues helped to inhibit tumour development. • Human tumour cells expressing human endogenous retroviruses (HERVs) transplanted into animals were also inhibited by antibodies against HERVs. • Since HERVs are also expressed in the human placenta, on human stem cells and immune cells, immunisation against HERVs may be harmful if applied., Many tumour cells express on their surface proteins of endogenous retroviruses (ERVs) and there are suggestions to use these retroviral antigens as target for anti-tumour vaccines. However, until now there is no convincing data showing that this strategy works, in contrast, there are considerations suggesting that this strategy may be harmful if applied.

Three carbamidocyclophanes, A, F and V, and carbamidocylindrofridin A were isolated from the cultured freshwater cyanobacterium Cylindrospermum stagnale, collected in the Canary Islands. The chemical structures of these compounds were elucidated through NMR, HRMS and ECD spectroscopy. The absolute configuration of carbamidocyclophane A was confirmed using X-ray-diffraction. All compounds showed apoptotic capacity against the SK-MEL-1, SK-MEL-28 and SK-MEL-31 tumour cells. Carbamidocylindrofridin A had the highest anti-tumour potential, with an IC50 of 1 ± 0.3 μM in the SK-MEL-1 cell line, This work was supported by the Fundación de la Universidad Autónoma de Madrid (FUAM)

Human cytomegalovirus (CMV) is a ubiquitous, persistent beta herpesvirus. CMV infection contributes to the accumulation of functional antigen‐specific CD8(+) T‐cell pools with an effector‐memory phenotype and enrichment of these immune cells in peripheral organs. We review here this ‘memory T‐cell inflation’ phenomenon and associated factors including age and sex. ‘Collateral damage’ due to CMV‐directed immune reactivity may occur in later stages of life – arising from CMV‐specific immune responses that were beneficial in earlier life. CMV may be considered an age‐dependent immunomodulator and a double‐edged sword in editing anti‐tumour immune responses. Emerging evidence suggests that CMV is highly prevalent in patients with a variety of cancers, particularly glioblastoma. A better understanding of CMV‐associated immune responses and its implications for immune senescence, especially in patients with cancer, may aid in the design of more clinically relevant and tailored, personalized treatment regimens. ‘Memory T‐cell inflation’ could be applied in vaccine development strategies to enrich for immune reactivity where long‐term immunological memory is needed, e.g. in long‐term immune memory formation directed against transformed cells.

The active constituents present in Persicaria salicifolia and Persicaria senegalensis seeds may possess anti-tumour activity. Therefore, P. salicifolia and P. senegalensis seeds were extracted and analysed to identify their active constituents. Phytochemical compounds exist in 50 % methanol extracts of P. salicifolia and P. senegalensis seeds were identified through High-Performance Liquid Chromatography (HPLC), Liquid Chromatography/ Mass Spectrometry (LC/MS), and Gas Chromatography-Mass Spectrometry (GC/MS). MTT assay was utilized to analyse the anti-tumour activity of P. salicifolia and P. senegalensis seeds compared to their aerial parts against CaCo-2 and PC3 cell lines. The constituents of Persicaria species seeds have phenolic acids, flavonoid, and lipid compounds. The cytotoxicity of aerial parts of P. salicifolia showed half maximal inhibitory concentration (IC50) of 1.1 ± 0.15 µg/ml and 0.5 ± 0.0011 µg/ml and the seeds were 0.6 ± 0.0018 µg/ml and 1.0 ± 0.009 µg/ml against PC3 and CaCO-2 cell lines, respectively. While, the aerial parts of P. senegalensis showed IC50 of 2.3 ± 0.03 µg/ml and 2.0 ± 0.03 µg/ml, and the seeds were 3.5 ± 0.06 µg/ml and 1.5 ± 0.03 µg/ml against PC3 and Caco-2, respectively. The results showed that there was a potential cytotoxicity of two Persicaria species seeds against two human cancer cell lines comparing to their aerial parts that have antitumor activity as it is confirmed by the literature.

Cancer is a disorder which has noted a significant rise in incidence worldwide and continues to be the largest cause of mortality. It has a dramatic impact on human life expectancy and quality of life in spite of the increase in technology and the treatments available for cancer patients. These new therapeutic options being chemotherapy, radiotherapy, photolytic therapy and catalytic therapy are known to have many adverse reactions and also no better positive outcomes than before. Hence, research is now focused more on utilizing the vast repertoire of traditional medicinal knowledge i.e. the use of flora for treatment of cancer rather than the use of chemicals. One such herb is the Crocus sativus L., commonly known as Saffron, rich in carotenoids - crocin, crocetin and safranal. Various studies have been carried out over the past few years to confirm the anti-cancer properties of saffron, both in vivo using animal models and in vitro using human malignant cell lines on various types of cancers with positive results. The proposed mechanism of actions has also been worked upon. This review is aimed to provide a brief overview on the anti-tumor potential of saffron focusing on the molecular mechanism involved.

Radiation damage can occur in nuclear power plant workers when physical protections fail, which results in nuclear leakage through the protective layers. Alternatively, workers may be unable to use physical protection in time (in the case of a sudden nuclear weapons attack). In addition, patients who receive local radiotherapy and are not allowed to adopt local physical protection may experience radiation damage. Thus, protection against chemical radiation has become indispensable. In view of the side effects caused by synthetic radioprotective agents (such as amisfostine), searching for radioprotective agents from plant sources is an alternative strategy. Radiation damage can cause multiple signalling pathway disturbances, leading to multiple organ injuries. Changes in these signalling pathways can lead to apoptosis, necrosis, and autophagy, as well as organ fibrosis, atrophy, and inflammation. Through literature searches, we determined that most targets for treating radiation injury are mechanistically opposite those of anti-tumour agents. This is likely attributable to the idea that anti-tumour agents promote cell necrosis or apoptosis, whereas the goal of anti-radiation agents is to promote cell survival or autophagy. This observation has important theoretical and practical significance when searching and developing new radioprotective agents derived from plant extracts. Further, it has important guiding value for meeting military needs and serving the public.

SummaryDuring treatment, the development of drug-resistant tumours remains an important challenge in cancer treatment. Epigenetic changes have been reported as one of the mechanisms for anti-tumour drug resistance. In clinical practice, a combination of epigenetic-related drugs can be considered as a future selection of cancer therapeutic drugs.

Medicinal plants continue to be of real interest to researchers in interdisciplinary fields such as chemistry, pharmacy, medicine. Due to the metabolites in which it abounds, the plant material can successfully represent both a prophylactic and curative treatment. At present, countless studies, both in vitro and in vivo, are conducted to elucidate the pharmacological effects and establish the mechanisms involved. The actual experiment was purposed to evaluate the activity of raw birch bark, apple pomace and olive leaves extracts rich in triterpenes, formulated as PLGA nanoparticles, on normal/healthy different cell lines immortalized and of primary origin, such as keratinocytes, dermal fibroblasts, and gingival fibroblasts.

Several tumour types are responsive to immunotherapy, as shown by regulatory approvals for immune checkpoint inhibitors. However, many patients either do not respond or do not have durable clinical benefit. Thus, there is great interest in developing predictors of response to immunotherapy and rational combination therapies that can enhance efficacy by overcoming primary and acquired resistance. In this Review, we provide an assessment of immunotherapy response biomarkers that can identify patients who will benefit from monotherapy rather than from combinations. We review the rationale for combination therapy and different strategies, including combinations with chemotherapy, targeted therapy, radiation therapy, intratumoural therapies, other immunomodulators, and adaptive cell therapy, including chimeric antigen T-cell receptors and other novel T-cell receptor-based therapies. There are many combination partners in development; therefore, a programmatic approach is needed to develop a framework for biomarker-driven combination therapy selection.

Vaccine development is an enormous leap in the world of scientific and therapeutic fields. Carbohydrates pose as a promising candidate for vaccine development. With proper identification and isolation of the active carbohydrate antigens, their synthetic protocols and the practical strategy behind their increase in antigenicity, carbohydrate based vaccines have shown widespread development and acceptance in the scientific community. This chapter describes the overall principle behind the development and design of glycoconjugate vaccines. It also covers their synthetic steps, systematic strategy of vaccine development and commercialization as well as the various progress achieved in the domain of carbohydrate based anti bacterial, anti tumour and anti cancer vaccines.

Background: Thymic carcinoma is a rare malignant disease, and standard treatment for advanced/metastatic thymic carcinoma previously treated with platinum-based chemotherapy has not been established. Several multi-targeted inhibitors have demonstrated efficacy as second-line treatment. Lenvatinib is a novel multi-targeted inhibitor of vascular endothelial growth factor receptor, fibroblast growth factor receptor, RET, c-Kit, and other kinases. It has shown anti-tumour activity and manageable toxicity profiles and has been approved for thyroid cancer and hepatocellular cancer in several countries. Methods: The open-label, single-arm, multi-centre phase II trial investigated the efficacy and safety of lenvatinib in patients with advanced/metastatic thymic carcinoma. Patients with pathologically confirmed thymic carcinoma that progressed following at least one platinum-based chemotherapy were enrolled. Lenvatinib was administered orally once daily until disease progression or unacceptable adverse events. The primary endpoint was objective response rate (ORR) by independent central review. Secondary endpoints were disease control rate (DCR), progression free survival (PFS), overall survival (OS), and safety profiles. Findings: Between April 2017 and February 2018, 42 patients were enrolled from eight institutions in Japan. The median follow-up period was 15·5 months (interquartile range: 13·1–17·5 months). The ORR was 38·1% (90% confidence interval [CI]: 25·6–52·0%); 16 of 42 patients had partial response, while 24 of 42 patients had stable disease. The DCR was 95·2% (95% CI: 83·8–99·4%). The median duration of PFS was 9·3 months (95% CI: 7·7–13·9 months), and the median OS was not reached. The most frequent treatment-related adverse events were hypertension, diarrhoea, palmar-plantar erythrodysaesthesia syndrome, proteinuria, hypothyroidism, and reduced platelet count. Interpretation: The efficacy and safety of lenvatinib in patients with advanced/metastatic thymic carcinoma was confirmed. These encouraging results suggested that lenvatinib can become a standard treatment option for patients with previously treated advanced/metastatic thymic carcinoma. Trial Registration: This trial is registered as JMA-IIA00285 and UMIN000026777. Funding Statement: Lenvatinib was provided by Eisai Co., Ltd. (Bunkyō, Tokyo, Japan) and distributed by SAROUTE Co., Ltd (Shinjuku-ku, Tokyo, Japan). The funder of the study was the Center for Clinical Trials, Japan Medical Association, which approved the study protocol and the final version but did not contribute to the clinical data collection. Declaration of Interests: JS reports honoraria from Chugai Pharmaceutical Co.. NY reports research grant from Chugai Pharmaceutical Co., Taiho Pharmaceutical, Eisai, Eli Lilly, Quintiles, Astellas, Bristol-Myers Squibb, Novartis, Daiichi-Sankyo, Pfizer, Boehringer Ingelheim, Kyowa-Hakko Kirin, Bayer, Ono Pharmaceutical, Takeda, Janssen Pharma, MSD, Merck and GSK; and honoraria from Ono Pharmaceutical, Chugai Pharmaceutical Co., AstraZeneca, Pfizer, Eli Lilly, Bristol-Myers Squibb and Sysmex; and personal fees for consulting from Eisai, Otsuka, Takeda, Boehringer Ingelheim and Cimic. YO* reports research grant from AstraZeneca, Chugai Pharmaceutical Co., Ono Pharmaceutical, MSD, Bristol-Myers Squibb, Eli Lilly, Taiho Pharmaceutical, Kyorin, Novartis, Kissei, Ignyta, Janssen and LOXO; and personal fees from AstraZeneca, Chugai Pharmaceutical Co., Ono Pharmaceutical, MSD, Bristol-Myers Squibb, Eli Lilly, Taiho Pharmaceutical, Kyorin, Novartis, Boehringer Ingelheim, Pfizer, Kyowa Hakko Kirin, Celtrion, Amgen and Nippon Kayaku. YO** reports research grant from Chugai Pharmaceutical Co. and Takeda, and received personal fees from MSD, Ono Pharmaceutical, Taiho Pharmaceutical, Chugai Pharmaceutical Co., Takeda, Eli Lilly, AstraZeneca, Boehringer Ingelheim and Pfizer. SN reports research grant from AstraZeneca, Pfizer, Eli Lilly, MSD and Merck, and personal fees from AstraZeneca, Pfizer, Chugai Pharmaceutical Co., Eli Lilly, Taiho Pharmaceutical, Bristol-Myers Squibb, MSD, Boehringer Ingelheim, Novartis, Shionogi and Yakult. HM reports research grant from AstraZeneca, Chugai Pharmaceutical Co., Eli Lilly, Taiho Pharmaceutical, Takeda, Abbvie, Daiichi-Sankyo and IQvia; and personal fees from AstraZeneca, Chugai Pharmaceutical Co., Eli Lilly, Taiho Pharmaceutical, Ono Pharmaceutical, Boehringer Ingelheim, MSD and Takeda. MS reports research grant from AstraZeneca, Chugai Pharmaceutical Co., Eli Lilly, Pfizer, Boehringer Ingelheim, Ono Pharmaceutical, EPS international, Novartis, MSD, Takeda and Ignyta; and personal fees from AstraZeneca, Chugai Pharmaceutical Co., Eli Lilly, Pfizer, Boehringer Ingelheim, Ono Pharmaceutical, Taiho Pharmaceutical, Novartis and MSD. TK reports reserch grant from AstraZeneca, Chugai Pharmaceutical Co., Eli Lilly, Bristol-Myers Squibb and Merck; and personal fees from AstraZeneca, Chugai Pharmaceutical Co., Eli Lilly, Taiho Pharmaceutical, Bristol-Myers Squibb, Ono Pharmaceutical, MSD, Pfizer, Kyowa Hakko Kirin, Boehringer Ingelheim and Nippon Kayaku. KN reports personal fees from Chugai Pharmaceutical Co., Taiho Pharmaceutical and Bayer. RM reports research grant from Ministry of Health, Labour and Welfare, Japan. YK reports personal fees from Chugai Pharmaceutical Co.. All other authors declare no competing interests. YO*; Yuichiro Ohe, YO**; Yusuke Okuma Ethics Approval Statement: The study was approved by the institutional review board at each participating institution and was conducted in accordance with the principles of Declaration of Helsinki and Good Clinical Practice Guidelines. Written informed consent was obtained from all the patients before enrolment in the study.

A new report in Science by Ma and colleagues uncovers the interplay of microbiota-controlled bile acid metabolism and immune responses in the context of primary and metastatic liver tumours in mice. Their findings shed light on the gut–liver axis in hepatic malignancies.

This study reviewed aspects of the biology of two members of the glucosinolate family, namely sinigrin and glucoraphanin and their anti-tumour and anti-microbial properties. Sinigrin and glucoraphanin are converted by the β-sulphoglucosidase myrosinase or the gut microbiota into their bioactive forms, allyl isothiocyanate (AITC) and sulphoraphanin (SFN) which constitute part of a sophisticated defence system plants developed over several hundred million years of evolution to protect them from parasitic attack from aphids, ticks, bacteria or nematodes. Delivery of these components from consumption of cruciferous vegetables rich in the glucosinolates also delivers many other members of the glucosinolate family so the dietary AITCs and SFN do not act in isolation. In-vitro experiments with purified AITC and SFN have demonstrated their therapeutic utility as antimicrobials against a range of clinically important bacteria and fungi. AITC and SFN are as potent as Vancomycin in the treatment of bacteria listed by the World Health Organisation as antibiotic-resistant "priority pathogens" and also act as anti- cancer agents through the induction of phase II antioxidant enzymes which inactivate potential carcinogens. Glucosinolates may be useful in the treatment of biofilms formed on medical implants and catheters by problematic pathogenic bacteria such as Pseudomonas aeruginosa and Staphylococcus aureus and are potent antimicrobials against a range of clinically important bacteria and fungi. The glucosinolates have also been applied in the prevention of bacterial and fungal spoilage of food products in advanced atmospheric packaging technology which improves the shelf-life of these products.