Neoadjuvant radiotherapy (RT) is commonly used as standard treatment for rectal cancer. However, response rates are variable and survival outcomes remain poor, highlighting the need to develop new therapeutic strategies. Research is focused on identifying novel methods for sensitising rectal tumours to RT to enhance responses and improve patient outcomes. This can be achieved through harnessing tumour promoting effects of radiation or preventing development of radio-resistance in cancer cells. Many of the approaches being investigated involve targeting the recently published new dimensions of cancer hallmarks. This review article will discuss key radiation and targeted therapy combination strategies being investigated in the rectal cancer setting, with a focus on exploitation of mechanisms which target the hallmarks of cancer.

Deubiquitinases are a group of proteins that identify and digest monoubiquitin chains or polyubiquitin chains attached to substrate proteins, preventing the substrate protein from being degraded by the ubiquitin-proteasome system. Deubiquitinases regulate cellular autophagy, metabolism and oxidative stress by acting on different substrate proteins. Recent studies have revealed that deubiquitinases act as a critical regulator in various cardiac diseases, and control the onset and progression of cardiac disease through a board range of mechanism. This review summarizes the function of different deubiquitinases in cardiac disease, including cardiac hypertrophy, myocardial infarction and diabetes mellitus-related cardiac disease. Besides, this review briefly recapitulates the role of deubiquitinases modulators in cardiac disease, providing the potential therapeutic targets in the future.

Although immune checkpoint inhibitors (ICIs) have produced remarkable responses in non-small cell lung cancer (NSCLC) patients, receivers still have a relatively low response rate. Initial response assessment by conventional imaging and evaluation criteria is often unable to identify whether patients can achieve durable clinical benefit from ICIs. Overall, there are sparse effective biomarkers identified to screen NSCLC patients responding to this therapy. A lot of studies have reported that patients with specific gene mutations may benefit from or resist to immunotherapy. However, the single gene mutation may be not effective enough to predict the benefit from immunotherapy for patients. With the advancement in sequencing technology, further studies indicate that many mutations often co-occur and suggest a drastic transformation of tumour microenvironment phenotype. Moreover, co-mutation events have been reported to synergise to activate or suppress signalling pathways of anti-tumour immune response, which also indicates a potential target for combining intervention. Thus, the different mutation profile (especially co-mutation) of patients may be an important concern for predicting or promoting the efficacy of ICIs. However, there is a lack of comprehensive knowledge of this field until now. Therefore, in this study, we reviewed and elaborated the value of cancer mutation profile in predicting the efficacy of immunotherapy and analysed the underlying mechanisms, to provide an alternative way for screening dominant groups, and thereby, optimising individualised therapy for NSCLC patients.

Colorectal cancer (CRC) is one of the major causes of death across the world and incidence rate of CRC increasing alarmingly each passing year. Diet, genomic anomalies, inflammation and deregulated signalling pathways are among the major causes of CRC. Because of numerous side effects of CRC therapies available now, researchers all over the world looking for alternative treatment/preventive strategy with lesser/no side effects. Olive oil which is part of Mediterranean diet contains numerous phenolic compounds that fight against free radicals and inflammation and also well-known for protective role against CRC. The current review focused on the recent evidences where olive oil and its phenolic compounds such as hydroxytyrosol, oleuropein and oleocanthal showed activities against CRC as well to analyse the cellular and molecular signalling mechanism through which these compounds act on. These compounds shown to combat CRC by reducing proliferation, migration, invasion and angiogenesis through regulation of numerous signalling pathways including MAPK pathway, PI3K-Akt pathway and Wnt/β-catenin pathway and at the same time, induce apoptosis in different CRC model. However, further research is an absolute necessity to establish these compounds as nutritional supplements and develop therapeutic strategy in CRC.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has recently caused acute respiratory distress syndrome affecting more than 200 countries with varied mortality rate. Successive genetic variants of SARS-CoV-2 become evident across the globe immediately after its complete genome sequencing. Here, we found a decent association of SARS-CoV-2 ORF3a mutation with higher mortality rate. Extensive in silico studies revealed several amino acid changes in ORF3a protein which ultimately leads to diverse structural modifications like B cell epitope loss, gain/loss of phosphorylation site and loss of leucine zipper motif. We could further relate these changes to the enhanced antigenic diversity of SARS-CoV-2. Through protein−protein network analysis and functional annotation studies, we obtained a close federation of ORF3a protein with host immune response via divergent signal transduction pathways including JAK-STAT, chemokine and cytokine-related pathways. Our data not only unveil the fairly appreciable association of ORF3a mutation with higher mortality rate, but also suggest a potential mechanistic insight towards the immunopathogenic manifestation of SARS-CoV-2 infection.

Small intestinal epithelium homeostasis involves four principal cell types: enterocytes, goblet, enteroendocrine and Paneth cells. Epidermal growth factor (EGF) has been shown to affect enterocyte differentiation. This study determined the effect of dietary EGF on goblet, enteroendocrine and Paneth cell differentiation in piglet small intestine and potential mechanisms. Forty-two weaned piglets were used in a 2 × 3 factorial design; the major factors were time post-weaning (days 7 and 14) and dietary treatment (0, 200 or 400 µg/kg EGF supplementation). The numbers of goblet and enteroendocrine cells were generally greater with the increase in time post-weaning. Moreover, the supplementation of 200 µg/kg EGF increased (P < 0.01) the number of goblet and enteroendocrine cells in villus and crypt of the piglet small intestine as compared with the control. Dietary supplementation with 200 µg/kg EGF enhanced (P < 0.05) abundances of differentiation-related genes atonal homologue 1, mucin 2 and intestinal trefoil factor 3 messenger RNA (mRNA) as compared with the control. Piglets fed 200 or 400 µg/kg EGF diet had increased (P < 0.05) abundances of growth factor-independent 1, SAM pointed domain containing ETS transcription factor and pancreatic and duodenal homeobox 1 mRNA, but decreased the abundance (P < 0.01) of E74 like ETS transcription factor 3 mRNA as compared with the control. Animals receiving 400 µg/kg EGF diets had enhanced (P < 0.05) abundances of neurogenin3 and SRY-box containing gene 9 mRNA as compared with the control. The mRNA abundance and protein expression of lysozyme, a marker of Paneth cell, were also increased (P < 0.05) in those animals. As compared with the control, dietary supplementation with 200 µg/kg EGF increased the abundance of EGF receptor mRNA and the ratio of non-phospho(p)-β-catenin/β-catenin (P < 0.05) in villus epithelial cells at days 7 and 14. This ratio in crypt epithelial cells was higher (P < 0.05) on the both 200 and 400 µg/kg EGF groups during the same period. Our results demonstrated that dietary EGF stimulated goblet, enteroendocrine and Paneth cell differentiation in piglets during the post-weaning period, partly through EGFR and Wnt/β-catenin signalling.

Despite the worldwide research efforts to combat cancer, it remains a leading cause of death. Although various specific kinase inhibitors already have been approved for clinical cancer treatment, occurrence of intrinsic or acquired resistance and intermittent response over longer periods limits long-term success of single kinase-targeted therapies. In this respect, there is a renewed interest in polypharmaceutical natural compounds, which simultaneously target various hyperactivated kinases involved in tumour-inflammation, angiogenesis, cell survival, proliferation, metastasis and angiogenesis. The dietary medicinal phytochemical withaferin A (WA), isolated from Withaferin somnifera (popular Indian name Ashwagandha), holds promise as a novel anti-cancer agent, which targets multiple cell survival kinase pathways, including IκB kinase/NF-κB, PI3 kinase/protein kinase B/mammalian target of rapamycin and mitogen-activated protein kinase/extracellular signal-regulated kinase amongst others. In this review, we propose a novel mechanism of WA-dependent kinase inhibition via electrophilic covalent targeting of cysteine residues in conserved kinase activation domains (kinase cysteinome), which could underlie its pleiotropic therapeutic effects in cancer signalling.

The aim of the present study was to assess the effects of dietary supplementation with epidermal growth factor (EGF)-expressing Saccharomyces cerevisiae on duodenal development in weaned piglets. In total, forty piglets weaned at 21–26 d of age were assigned to one of the five groups that were provided basic diet (control group) or diet supplemented with S. cerevisiae expressing either empty-vector (INVSc1(EV) group), tagged EGF (T-EGF) (INVSc1-TE(−) group), extracellular EGF (EE-EGF) (INVSc1-EE(+) group) or intracellular EGF (IE-EGF) (INVSc1-IE(+) group). All treatments were delivered as 60·00 μg/kg body weight EGF/d. On 0, 7, 14 and 21 d, eight piglets per treatment were sacrificed to analyse the morphology, activities and mRNA expressions of digestive enzymes, as well as Ig levels (IgA, IgM, IgG) in duodenal mucosa. The results showed significant improvement on 7, 14 and 21 d, with respect to average daily gain (P<0·05), mucosa morphology (villus height and crypt depth) (P<0·05), Ig levels (P<0·01), activities and mRNA expressions of digestive enzymes (creatine kinase, alkaline phosphatase, lactate dehydrogenase and sucrase) (P<0·05) and the mRNA expression of EGF-receptor (P<0·01) in NVSc1-TE(−), INVSc1-EE(+) and INVSc1-IE(+) groups compared with control and INVSc1(EV) groups. In addition, a trend was observed in which the INVSc1-IE(+) group showed an improvement in Ig levels (0·05<P<0·10), mRNA expressions of digestive enzymes and EGF-receptor (P<0·05) compared with NVSc1-TE(−) and INVSc1-EE(+) groups. These results indicate that supplementing recombinant EGF-expressing S. cerevisiae to the diet of weaned piglets enhanced duodenal development. Moreover, biological activity (Ig levels, mRNA expressions of digestive enzymes and EGF-receptor) of IE-EGF was better than either EE-EGF or T-EGF.

Epidermal growth factor receptor (EGFR) is becoming a perfect target for killing carcinoma cells, especially because of its overexpression on the surface of these cells. Cationic antimicrobial peptides (CAP) have their own special mechanism of membrane-lytic cytotoxicity. In this study, a membrane-lytic immunotoxin (IT), chimeric protein MEGFMEL, was constructed to kill carcinoma cells with EGFR overexpression. This protein is composed of mouse (Mus musculus) epidermal growth factor (MEGF), as the target part, and melittin (MEL), as the cytotoxic part. Using Escherichia coli BL21 and pET30a as expression strain and vector, respectively, 63.45 μg/ml of MEGFMEL (68% purity) was obtained through low-temperature induction of expression and a thawing-freezing purification procedure (without cytolysis). In vitro activity measurement showed that this MEGFMEL significantly induced a lethal effect on A431 carcinoma cells overexpressing EGFR on the surface, with an LD50 value 52.6 μg/ml. The results suggest that the use of CAP as the toxin in the construction of unique membrane-lytic ITs aimed at EGFR is feasible.

The Epidermal Growth Factor (EGF) receptor is a tyrosine kinase that mediates the biological effects of ligands such as EGF and transforming growth factor alpha. An understanding of the molecular basis of its action has been hindered by a lack of structural and mutational data on the receptor. We have constructed comparative models of the four extracellular domains of the EGF receptor that are based on the structure of the first three domains of the insulin-like growth factor-1 (IGF-1) receptor. The first and third domains of the EGF receptor, L1 and L2, are right-handed beta helices. The second and fourth domains of the EGF receptor, S1 and S2, consist of the modules held together by disulfide bonds, which, except for the first module of the S1 domain, form rod-like structures. The arrangement of the L1 and S1 domains of the model are similar to that of the first two domains of the IGF-1 receptor, whereas that of the L2 and S2 domains appear to be significantly different. Using the EGF receptor model and limited information from the literature, we have proposed a number of regions that may be involved in the functioning of the receptor. In particular, the faces containing the large beta sheets in the L1 and L2 domains have been suggested to be involved with ligand binding of EGF to its receptor.