Neurotoxicity is a common side effect of chemotherapy treatment, with unclear molecular mechanisms. Clinical studies suggest that the most frequent neurotoxic adverse events affect memory and learning, attention, concentration, processing speeds and executive function. Emerging preclinical research points toward direct cellular toxicity and induction of neuroinflammation as key drivers of neurotoxicity and subsequent cognitive impairment. Emerging data now show detectable levels of some chemotherapeutic agents within the CNS, indicating potential disruption of blood brain barrier integrity or transport mechanisms. Blood brain barrier disruption is a key aspect of many neurocognitive disorders, particularly those characterized by a proinflammatory state. Importantly, many proinflammatory mediators able to modulate the blood brain barrier are generated by tissues and organs that are targets for chemotherapy‐associated toxicities. This review therefore aims to explore the hypothesis that peripherally derived inflammatory cytokines disrupt blood brain barrier permeability, thereby increasing direct access of chemotherapeutic agents into the CNS to facilitate neuroinflammation and central neurotoxicity.

Strong epidemiological data indicate that chemotherapy-induced gut toxicity and pain occur in parallel, indicating common underlying mechanisms. We have recently outlined evidence suggesting that TLR4 signaling may contribute to both side effects. We therefore aimed to determine if genetic deletion of TLR4 improves chemotherapy-induced gut toxicity and pain. Forty-two female wild-type (WT) and 42 Tlr4 null (−/−) BALB/c mice weighing between 18 and 25 g (10–13 weeks) received a single 270 mg/kg (i.p.) dose of irinotecan hydrochloride or vehicle control and were killed at 6, 24, 48, 72, and 96 hours. Bacterial sequencing was conducted on cecal samples of control animals to determine the gut microbiome profile. Gut toxicity was assessed using validated clinical and histopathologic markers, permeability assays, and inflammatory markers. Chemotherapy-induced pain was assessed using the validated rodent facial grimace criteria, as well as immunologic markers of glial activation in the lumbar spinal cord. TLR4 deletion attenuated irinotecan-induced gut toxicity, with improvements in weight loss (P = 0.0003) and diarrhea (P < 0.0001). Crypt apoptosis was significantly decreased in BALB/c-Tlr4^−/−billy mice (P < 0.0001), correlating with lower mucosal injury scores (P < 0.005). Intestinal permeability to FITC-dextran (4 kDa) and LPS translocation was greater in WT mice than in BALB/c-Tlr4^−/−billy (P = 0.01 and P < 0.0001, respectively). GFAP staining in the lumbar spinal cord, indicative of astrocytic activation, was increased at 6 and 72 hours in WT mice compared with BALB/c-Tlr4^−/−billy mice (P = 0.008, P = 0.01). These data indicate that TLR4 is uniquely positioned to mediate irinotecan-induced gut toxicity and pain, highlighting the possibility of a targetable gut/CNS axis for improved toxicity outcomes. Mol Cancer Ther; 15(6); 1376–86. ©2016 AACR.

Technology is omnipresent in our rapidly changing digital world. Capitalising on these technologies is paramount for education systems to support a modern workforce. This study presents a review of 10 countries, highlighting how different public education systems have integrated digital technologies for teaching and learning. These education systems were selected based on their high performance and continuous improvement in international assessments. Four main themes emerged as key areas of focus from our analysis: improved and enhanced teaching and learning; digital maturation, including tackling the first and second digital divide; data-driven decision making and evidence-based education; and AI in education. Our findings will help benchmark current approaches and uses of digital teaching and learning, including perceived challenges and opportunities that can be used to inform the development and implementation of digital education policies.

Introduction: Radiotherapy is a mainstay of solid tumor management but can be associated with unacceptable levels of off-target tissue toxicity which impact treatment outcomes and patients’ quality of life. Tumour response to radiotherapy and the frequency and severity of radiotherapy-induced toxicities, especially mucositis, varies among patients. Gut microbiota has been found to modulate both the efficacy and toxicity of some types of cancer chemotherapies and immunotherapies but has yet to be investigated thoroughly in the setting of radiotherapy. Area covered: In this review, we discuss the potential role of gut microbiota on modulating radiotherapy-induced oral and gastrointestinal mucositis and the anti-tumor response to radiotherapy through modulation of immune responses. Expert opinion: The gut microbiota plays a major role in the modulation of systemic immune responses, which influence both radiotherapy response and gastrointestinal toxicities such as mucositis. Hence, investigating the gut microbiota link to the variation in radiotherapy responses and toxicities among patients is warranted. Future targeting of these responses with a patient-tailored restoration of optimal microbial composition could lead to a new era of mucositis prevention and enhanced tumor responses.