HER2 is an established therapeutic target in a large subset of women with breast cancer; a variety of agents including trastuzumab, pertuzumab, lapatinib, neratinib and trastuzumab emtansine (T-DM1) have been approved for the treatment of HER2-positive breast cancer. HER2 is also overexpressed in subsets of patients with other solid tumours. Notably, the addition of trastuzumab to first-line chemotherapy has improved the overall survival of patients with HER2-positive gastric cancer, and has become the standard-of-care treatment for this group of patients. However, trials involving pertuzumab, lapatinib and T-DM1 have failed to provide significant improvements in the outcomes of patients with HER2-positive gastric cancer. HER2-targeted therapies are also being tested in patients with other solid tumours harbouring HER2 overexpression, and/or amplifications or other mutations of the gene encoding HER2 (ERBB2), including biliary tract, colorectal, non-small-cell lung and bladder cancers. The experience with gastric cancer suggests that the successes observed in HER2-positive breast cancer might not be replicated in these other tumour types, owing to differences in the level of HER2 overexpression and other aspects of disease biology. In this Review, we describe the current role of HER2-targeted therapies beyond breast cancer and also highlight the potential of novel HER2-targeted agents that are currently in clinical development.

HER2-targeted therapies — a role beyond breast cancer

The signal transducer and activator of transcription (STAT) proteins have important roles in biological processes. The abnormal activation of STAT signalling pathways is also implicated in many human diseases, including cancer, autoimmune diseases, rheumatoid arthritis, asthma and diabetes. Over a decade has passed since the first inhibitor of a STAT protein was reported and efforts to discover modulators of STAT signalling as therapeutics continue. This Review discusses the outcomes of the ongoing drug discovery research endeavours against STAT proteins, provides perspectives on new directions for accelerating the discovery of drug candidates, and highlights the noteworthy candidate therapeutics that have progressed to clinical trials.

Therapeutic modulators of STAT signalling for human diseases

Background: Patients with gastric cancer (GC) have a poor survival and biologicals such as Trastuzumab have not been used routinely in these patients. Existing data on HER2 expression and its clinical relevance in GC are still limited and controversial. Methods: HER2 expression was investigated by immunohistochemistry in 418 GC from Germany and 506 GC from England. Results were compared to clinicopathological parameters and patient survival. Results: Less than 10% of all GC showed HER2 expression in more than 5% of tumour cells and 91% of these were in- testinal type GC. In both series, no relationship was found between HER2 expression, patient survival or TNM stage. Marked intratumoural heterogeneity was noted. Conclusions: This is the largest study to date demonstrating in two independent series that HER2 expression is not related to gastric cancer patient prognosis and that only a very small subgroup of intestinal type GC may potentially respond to HER2 targeting therapy. Due to prominent intratumoural heterogeneity of HER2 expression in GC, HER2 testing in endoscopic biopsies before treatment will be prone to false negative results.

/pdf/her2-expression-in-gastric-cancer-rare-heterogeneous-and-of-3c0uhe4o9h.pdf

HER2 expression in gastric cancer: Rare, heterogeneous and of no prognostic value - conclusions from 924 cases of two independent series.

Despite the global decline in the incidence and mortality of gastric cancer, it remains one of the most common malignant tumors of the digestive system. Although surgical resection is the preferred treatment for gastric cancer, chemotherapy is the preferred treatment for recurrent and advanced gastric cancer patients who are not candidates for reoperation. The short overall survival and lack of a standard chemotherapy regimen make it important to identify novel treatment modalities for gastric cancer. Within the field of tumor biology, molecular targeted therapy has attracted substantial attention to improve the specificity of anti-cancer efficacy and significantly reduce non-selective resistance and toxicity. Multiple clinical studies have confirmed that molecular targeted therapy acts on various mechanisms of gastric cancer, such as the regulation of epidermal growth factor, angiogenesis, immuno-checkpoint blockade, the cell cycle, cell apoptosis, key enzymes, c-Met, mTOR signaling and insulin-like growth factor receptors, to exert a stronger anti-tumor effect. An in-depth understanding of the mechanisms that underlie molecular targeted therapies will provide new insights into gastric cancer treatment.

/pdf/molecular-targeted-therapy-for-the-treatment-of-gastric-ukqxzh1azz.pdf

Molecular targeted therapy for the treatment of gastric cancer

Natural compounds containing fungal β-glucans have been used to improve general health for thousands of years in China and Japan. Lentinan, the backbone of β-(1, 3)-glucan with β-(1, 6) branches, is one of the active ingredients purified from Shiitake mushrooms and has been approved as a biological response modifier for the treatment of gastric cancer in Japan. Despite recent advances in chemotherapeutic agents, unresectable or recurrent gastric cancer remains an incurable disease, with survival rates being far from satisfactory. Recent clinical studies have shown that chemo-immunotherapy using lentinan prolongs the survival of patients with advanced gastric cancer, as compared to chemotherapy alone. In addition, trastuzumab, an antibody against HER2/neu growth factor receptor, has been used for the treatment of gastric cancer in combination with cytotoxic chemotherapeutic agents. Lentinan may exert a synergistic action with anti-cancer monoclonal antibodies to activate complement systems through the mechanism of antibody-dependent cellular cytotoxicity and complement dependent cytotoxicity. Because a better understanding of its biological activities should enable us to use lentinan more efficiently in the treatment of gastric cancer, immunological effects provided by β-glucans, a possible mode of action of lentinan, and its clinical application including future potential uses are discussed in the present review.

/pdf/the-use-of-lentinan-for-treating-gastric-cancer-1oq8eq7hyj.pdf

The use of lentinan for treating gastric cancer.

Enterococcus faecalis, a Gram-positive opportunistic pathogen having lipoteichoic acid (LTA) as a major virulence factor, is closely associated with refractory apical periodontitis. Short-chain fatty acids (SCFAs) are found in the apical lesion and may affect inflammatory responses induced by E. faecalis. In the current study, we investigated inflammasome activation by E. faecalis LTA (Ef.LTA) and SCFAs in THP-1 cells. Among SCFAs, butyrate in combination with Ef.LTA markedly enhanced caspase-1 activation and IL-1β secretion whereas these were not induced by Ef.LTA or butyrate alone. Notably, LTAs from Streptococcus gordonii, Staphylococcus aureus, and Bacillus subtilis also showed these effects. Activation of TLR2/GPCR, K+ efflux, and NF-κB were necessary for the IL-1β secretion induced by Ef.LTA/butyrate. The inflammasome complex comprising NLRP3, ASC, and caspase-1 was activated by Ef.LTA/butyrate. In addition, caspase-4 inhibitor diminished IL-1β cleavage and release, indicating that non-canonical activation of the inflammasome is also involved. Ef.LTA/butyrate induced Gasdermin D cleavage, but not the release of the pyroptosis marker, lactate dehydrogenase. This indicated that Ef.LTA/butyrate induces IL-1β production without cell death. Trichostatin A, a histone deacetylase (HDAC) inhibitor, enhanced Ef.LTA/butyrate-induced IL-1β production, indicating that HDAC is engaged in the inflammasome activation. Furthermore, Ef.LTA and butyrate synergistically induced the pulp necrosis that accompanies IL-1β expression in the rat apical periodontitis model. Taken all these results together, Ef.LTA in the presence of butyrate is suggested to facilitate both canonical- and non-canonical inflammasome activation in macrophages via HDAC inhibition. This potentially contributes to dental inflammatory diseases such as apical periodontitis, particularly associated with Gram-positive bacterial infection. 

/pdf/butyrate-potentiates-enterococcus-faecalis-lipoteichoic-acid-4tjyen8r.pdf

Butyrate potentiates Enterococcus faecalis lipoteichoic acid-induced inflammasome activation via histone deacetylase inhibition

Abstract Background The aim of this study was to evaluate the influence of increased irradiation distance on the flexural strength (FS), dentin micro-shear bond strength (μSBS), and the degree of conversion (DC) of bulk-fill flowable, conventional flowable, and packable resin composites. Methods The resin composites tested were Surefil® SDR™ (SDR), Filtek Z350 XT Flowable Restorative A2 shade (Z3F), and Filtek Z350 XT Universal Restorative A2 shade (Z3P). Specimens were cured at four irradiation distances (0, 2, 4, and 8 mm) with an Elipar DeepCure-S LED curing light for 20 s. FS tests were performed ( n = 15) using bar-shaped specimens (8 mm × 2 mm × 2 mm) of the resin composites. μSBS tests were performed on the occlusal surfaces of extracted third molars from humans that were ground to expose dentin ( n = 15). DC was measured by using Raman spectroscopy on the top and bottom surfaces of disk specimens (2-mm thick) ( n = 3). To further investigate whether extended irradiation times could compensate for reduced irradiance, additional Z3P specimens were prepared, which were light-cured at 8-mm distances for 40 and 60 s and subjected to FS tests, μSBS tests, and Raman spectroscopy. Both two-way and one-way ANOVA were used for statistical analyses. Results Both FS and DC of Z3P specimens cured at an 8-mm distance were significantly lower than those cured at shorter distances ( p &lt; 0.05), whereas the FS and DC of the Z3F and SDR specimens were not significantly influenced by increasing distances. The μSBSs of the three types of resin composites reduced with increasing irradiation distances. The FS, μSBS, and DC of the Z3P specimen light-cured at 8 mm for 40 s were comparable to those of the Z3P specimen cured at 0 mm for 20 s. Conclusions Increasing the irradiation distance to 8 mm can have a deleterious influence on mechanical performances, including the FS, DC, and dentin μSBS, of the resin composites polymerized with high-irradiance light curing units. 

/pdf/influence-of-irradiation-distance-on-the-mechanical-gjn0jgcn.pdf

Influence of irradiation distance on the mechanical performances of resin composites polymerized with high-irradiance light curing units

Enhancing dental sealant performance: Effects of mesoporous bioactive glass and 10-MDP on adhesion and remineralization.

HER2 has been found to be amplified in 10-20% of gastric cancers, and is correlated with poor outcome. The aims of this study were to recognize HER2 amplification in gastric cancer cell lines via fluorescence in situ hybridization and to evaluate the growth inhibitory effect of trastuzumab in HER2-amplified cell lines. To elucidate the mechanism of the growth inhibition, we performed cell cycle analysis and immunoblotting of downstream molecules. We also conducted drug interaction studies of trastuzumab with other chemotherapeutic agents. HER2 amplification was newly identified only in SNU-216 cells, and trastuzumab moderately inhibited the growth of SNU-216 cells and positive controls. Trastuzumab-mediated G1 arrest occurred with increased expression of p27(KIP1) and decreased cyclins. Phosphorylation of HER2 and downstream molecules, STAT3, AKT, and ERK, was also inhibited by trastuzumab. Treatment of SNU-216 cells with trastuzumab plus cisplatin resulted in a synergistic inhibitory effect, whereas treatment of SNU-216 cells with trastuzumab plus 5-FU, or trastuzumab plus oxaliplatin produced an additive effect. These results suggest that trastuzumab combined with chemotherapeutic agents can be active against gastric cancer with HER2 amplification.

/pdf/trastuzumab-inhibits-the-growth-of-human-gastric-cancer-cell-eq0x2yrtla.pdf

Trastuzumab inhibits the growth of human gastric cancer cell lines with HER2 amplification synergistically with cisplatin.

This study was to investigate the new analysis manner of dental hard tissue change using in vivo micro-computed tomography (CT) in rat. Scanning, registration, analyzing, and presenting method to track longitudinal in vivo micro-CT data on dental hard tissues were validated in murine models: formative, dentin thickness after direct pulp capping with mineral trioxide aggregate; resorptive, development of apical bone rarefaction in apical periodontitis model. Serial in vivo micro-CT scans were analyzed through rigid-registration, active-contouring, deformable-registration, and motion vector-based quantitative analyses. The rate and direction of hard tissue formation after direct pulp capping was datafied by tracing coordinate shift of fiducial points on pulp chamber outline in formative model. The development of apical periodontitis could be monitored with voxel counts, and quantitatively analyzed in terms of lesion size, bone loss, and mineral density in resorptive model. This study supports the application of longitudinal in vivo micro-CT for resorptive- and formative-phase specific monitoring of dental hard tissues. 

A novel analysis of the formation and resorption changes in dental hard tissue using longitudinal in vivo micro computed tomography.

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