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Objective: The objective of the present study is to examine variations in paramedic care of the agitated patient, including verbal de‐escalation, physical restraint and sedation, provided by ambulance services in Australia and New Zealand. Methods: To examine the care of agitated patients, we first identified and reviewed all clinical practice guidelines for the management of agitated patients in Australian and New Zealand ambulance services between September and November 2018. We then conducted a structured questionnaire to obtain further information on the training, assessment and care of agitated patients by the ambulance services. Two authors extracted the data independently, and all interpretations and results were reviewed and confirmed by relevant ambulance services. Results: There were 10 independent clinical practice guidelines for the care of agitated patients in the 10 ambulance services. All services reported training in the management of agitated patients, and two services used a validated tool to assess the level of agitation. All services used physical restraint, although six services required police presence to restrain the patient. All ambulance services used some form of sedation, typically divided into the management of mild to moderate, and severe agitation. The most common agent for sedation was midazolam, while ketamine was the most common agent for sedating severely agitated patients. The maximum dose was varied, and contraindications for sedating agents varied between services. Conclusions: There were wide variations across the ambulance services in terms of the assessment of agitation, as well as the use of physical restraint and sedation. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors (ICIs), although promising, have variable benefit in head and neck cancer (HNC). We noted that tumor galectin-1 (Gal1) levels were inversely correlated with treatment response and survival in patients with HNC who were treated with ICIs. Using multiple HNC mouse models, we show that tumor-secreted Gal1 mediates immune evasion by preventing T cell migration into the tumor. Mechanistically, Gal1 reprograms the tumor endothelium to upregulate cell-surface programmed death ligand 1 (PD-L1) and galectin-9. Using genetic and pharmacological approaches, we show that Gal1 blockade increases intratumoral T cell infiltration, leading to a better response to anti-PD1 therapy with or without radiotherapy. Our study reveals the function of Gal1 in transforming the tumor endothelium into an immune-suppressive barrier and that its inhibition synergizes with ICIs. [ABSTRACT FROM AUTHOR]

Background: Although people who inject drugs (PWID) have been described as frequent users of emergency services, the majority of research is cross-sectional and involves records from a single emergency department (ED). Objectives: We describe characteristics of state-wide ED presentations in a cohort of PWID, and compare presentation rates to the general population. We also examine characteristics associated with frequent ED use. Methods: We used data from a retrospective linkage of public ED presentations from a cohort of 678 PWID between January 2008 and June 2013. Common principal diagnoses were described using the International Classification of Diseases, Tenth Revision, Australian Modification (ICD-10-AM) chapter headings. The ED presentation trend was estimated using negative-binomial regression. Characteristics associated with frequent use of EDs were identified using generalized estimating equations (GEEs). Results: There were 3437 presentations over 4163.5 person-years (PY) and the most common principal diagnosis was injury, poisoning and other externalities (19%). ED presentations increased by 4% every six months (95% confidence interval (CI) 0.1%-0.8%) and were three times greater than the general population. A quarter (24%) of the cohort presented frequently, and they were more likely to have noninjury-related diagnoses and be aged below 30 years, and less likely to have nonurgent presentations and be male. Conclusions: PWID use EDs at a higher rate than the general population, and typically present with injuries and mental and behavioral disorders. Referrals to drug treatment, mental health, and social support services can improve patient care and reduce the burden on EDs. [ABSTRACT FROM AUTHOR]

Background: People who inject drugs (PWID) have been described as frequent users of health services such as emergency departments (EDs), however few studies have described demographic factors, patterns of substance use and previous health service use associated with frequent use of EDs in this population.Methods: Using a combination of self-reported data from a cohort of PWID and administrative ED data obtained through record linkage, we identified longitudinal factors associated with the use of ED services. Bivariate and multivariate analyses were conducted using negative binomial regression to identify exposures associated with both cumulative ED presentations, and logistic regression to identify exposures of frequent ED presentations (defined as three or more annual presentations).Results: Among 612 PWID, over half (58%) presented to EDs at least once and over a third (36%) presented frequently between January 2008 and June 2013. Frequent and cumulative ED presentations were associated with reporting the main drug of choice as cannabis (AOR:1.42, 95%CI:1.07-1.89 and AIRR:2.96, 95%CI:1.44-6.07 respectively) or methamphetamine (AOR:1.62, 95%CI:1.17-2.2 and AIRR:2.42, 95%CI:1.08-5.46 respectively) compared to heroin, and past month use of mental health (AOR:1.42, 95%CI:1.08-1.85 and AIRR:3.32, 95%CI:1.69-6.53 respectively) and outpatient services (AOR:1.47, 95%CI: 1.00-2.16 and AIRR:0.95, 95%CI 1.52-10.28 respectively).Conclusion: PWID who are frequent users of EDs are likely to have complex health and substance use-related needs. EDs should actively refer people who present with cannabis and methamphetamine dependence to harm reduction services. Harm reduction services should ensure people referred from EDs are screened for co-occurring mental health conditions and receive adequate support. [ABSTRACT FROM AUTHOR]

Background: There are few studies of mortality amongst people who inject drugs (PWID) in Australia. In this study, we estimate mortality in a cohort of PWID in Melbourne and examine predictors of mortality including health service use, demographic characteristics, drug use and personal wellbeing. Findings: We linked identifiers from the Melbourne injecting drug use cohort study (MIX; n = 655) to the National Death Index from 2008 to 2012 to estimate standardised mortality ratios (SMRs). Cox regression was used to examine the bivariate relationship between exposures determined at baseline and subsequent mortality. There were 24 (3.6 %) deaths over the study period. The mortality rate in the cohort was 1.0 per 100 PY (95 % CI 0.71-1.57), with an SMR of 17.3 (95 % CI 11.6-25.8). Baseline reports of four or more lifetime incarcerations (HR 3.65, 95 % CI 1.16-11.52), past month ambulance attendance (HR 4.43, 95 % CI 1.76-11.17), past month emergency department presentation (HR 3.44, 95 % CI 1.47-8.03) and past 6-month self-reported heroin overdose (HR 3.14, 95 % CI 1.24-7.96) were associated with increased mortality risk. Conclusions: Contact with emergency services, particularly for drug overdose, remains a lost opportunity to provide referrals for harm reduction and naloxone training programmes to PWID at greater risk of mortality. [ABSTRACT FROM AUTHOR]

Background Injecting drug use is associated with a range of harms, however cessation of injecting is rare. There is a lack of evidence on factors associated with cessation, notably those related to health services other than drug treatment. We examined the incidence and identified longitudinal correlates of first episode of cessation in a cohort of people who inject drugs (PWID). Methods Using discrete-time survival analysis, we examined correlates of the first episode of cessation (no self-reported injecting drug use in the past 12 months), including the use of health services, socio-demographics and drug-related behaviour in a cohort of PWID recruited between 2008 and 2010. Results The cohort of 467 participants contributed 1527 person-years from recruitment to 2014. Under a fifth (17.8%) of people reported cessation of 12 months or more, yielding a cessation rate of 5.4 events per 100 person-years. Younger age (25–29 compared to 30 and above) (adjusted hazard ratio (AHR) 1.79, 95% confidence interval (CI) 1.07–3.00) and male gender (AHR 1.67, 95% CI 2.01–2.76) were positively associated with cessation, while past year use of benzodiazepines (AHR 0.45, 95% CI 0.28–0.72), arrest in the past year (AHR 0.50, 95% CI 0.30–0.83) and low SF-8 physical dimension score (AHR 0.42, 95% CI 0.20–1.88) were negatively associated with cessation. Outpatient service use had the largest effect on cessation (AHR 2.28, 95% CI 0.94–5.48, p = 0.067). Conclusions Low rates of cessation emphasise the need for sustained and comprehensive harm reduction services. The relationship between outpatient services and cessation suggests that further research into the use in health services among PWID is warranted. [ABSTRACT FROM AUTHOR]

Background To describe all-cause and cause-specific mortality in a cohort of people who had ever injected drugs (PWID) with a low prevalence of HIV over 20–30 years. Methods Using a retrospective study design, identifying data from a cohort of PWID recruited between 1982 and 1993 through in-patient drug treatment services were linked to National Records for Scotland deaths data using probabilistic record linkage. We report all-cause and cause-specific mortality rates; standardized mortality ratios (SMR) across time, gender and age were estimated. Results Among 456 PWID, 139 (30.5%) died over 9024 person-years (PY) of follow-up. Mortality within the cohort was almost nine times higher than the general population, and remained elevated across all age groups. The greatest excess mortality rate was in the youngest age group, who were 15–24 years of age (SMR 31.6, 95% CI 21.2–47.1). Drug-related deaths declined over time and mortality was significantly higher among HIV positive participants. Although SMRs declined with follow-up, the SMR of the oldest age group (45–60) was 4.5 (95% CI 3.0–6.9). There were no significant differences in all-cause mortality rates between participants who were 25 years and older at cohort entry compared to younger participants. Conclusion Mortality rates remained higher than the general population across all age groups. Screening services that identify a history of injecting drug use may be an opportunity to address risk factors faced by an ageing population of PWID and potentially have implications for future health care planning. [ABSTRACT FROM AUTHOR]

Radiotherapy of is well established and frequently utilized in prostate cancer (PCa) patients. However, recurrence following therapy and distant metastases are commonly encountered problems. Previous studies underline that, in addition to its therapeutic effects, ionizing radiation (IR) increases the vascularity and invasiveness of surviving radioresistant cancer cells. This invasive phenotype of radioresistant cells is an upshot of IR-induced pro-survival and mitogenic signaling in cancer as well as endothelial cells. Here, we demonstrate that a plant flavonoid, silibinin can radiosensitize endothelial cells by inhibiting expression of pro-angiogenic factors. Combining silibinin with IR not only strongly down-regulated endothelial cell proliferation, clonogenicity and tube formation ability rather it strongly ( p < 0.001) reduced migratory and invasive properties of PCa cells which were otherwise marginally affected by IR treatment alone. Most of the pro-angiogenic (VEGF, iNOS), migratory (MMP-2) and EMT promoting proteins (uPA, vimentin, N-cadherin) were up-regulated by IR in PCa cells. Interestingly, all of these invasive and EMT promoting actions of IR were markedly decreased by silibinin. Further, we found that potentiated effect was an end result of attenuation of IR-activated mitogenic and pro-survival signaling, including Akt, Erk1/2 and STAT-3, by silibinin. [ABSTRACT FROM AUTHOR]

Background: People who inject drugs (PWID) use healthcare services, including primary care, at a disproportionately high rate. We investigated key correlates of general practitioner (GP) related service utilisation within a cohort of PWID. Methods: Using baseline data from a cohort of 645 community-recruited PWID based in Melbourne, Victoria, we conducted a secondary analysis of associations between past month use of GP services unrelated to opioid substitution therapy (OST) and socio-demographic and drug use characteristics and self-reported health using multivariate logistic regression. Results: Just under one-third (29%) of PWID had accessed GP services in the month prior to being surveyed. Participants who reported living with children (adjusted odds ratio, AOR 1.97, 95% CI 1.04 - 3.73) or having had contact with a social worker in the past month (AOR 1.92, 95% CI 1.24 - 2.98) were more likely to have seen a GP in the past month. Participants who were injecting daily or more frequently (AOR 0.50, 95% CI 0.30 - 0.83) or had a weekly income of less than $400 (AOR 0.59, 95% CI 0.38 - 0.91) were less likely to report having seen a GP in the past month. Conclusions: Our sample frequently attended GP services for health needs unrelated to OST. Findings highlight both the characteristics of PWID accessing GP services and also those potentially missing out on primary care and preventive services. [ABSTRACT FROM AUTHOR]

Background Needle and syringe programmes (NSP) aim to reduce the risk of HIV by providing people who inject drugs (PWID) with sterile injecting equipment. A recent review of reviews (ROR) concluded that there was only tentative evidence to support the effectiveness of NSP in reducing HIV. We carried out a systematic review and meta-analysis to assess the association between NSP and HIV transmission.Methods Relevant primary articles presenting data on the risk of HIV transmission associated with NSP were identified in two stages: (i) from reviews identified in two published RORs (covering the period 1980–2008); and (ii) a literature search of CINAHL, Cochrane Library, EMBASE, MEDLINE and PsychINFO for primary articles published since the most recent high quality review (covering the period 2008–12). Study results were synthesized using random-effects meta-analysis.Results There were 12 studies comprising at least 12 000 person-years of follow-up. Exposure to NSP was associated with a reduction in HIV transmission: pooled effect size 0·66 [95% confidence interval (CI) 0·43, 1·01] across all studies, and 0·42 (95% CI 0·22, 0·81) across six higher quality studies (according to the Newcastle-Ottawa tool).Conclusions There is evidence to support the effectiveness of NSP in reducing the transmission of HIV among PWID, although it is likely that other harm reduction interventions have also contributed to the observed reduction in HIV risk. NSP should be considered as just one component of a programme of interventions to reduce both injecting risk and other types of HIV risk behaviour. [ABSTRACT FROM PUBLISHER]

Chemopreventive interventions are steadily emerging as an important aspect of cancer management and control. Herein, we have discussed the major epidemiological and clinical studies advocating the role of androgen inhibitors, flavonoids and antioxidants in preventing prostate cancer (PCa). Androgen inhibitors have lately been discussed not only in treatment of PCa, but also as preventive agents especially after trials with Finasteride and Dutasteride. Flavonoids such as silibinin, green tea polyphenols, genistein, curcumin have shown great promise, but avenues to improve their bioavailability are requisite. Agents with antioxidant potentials like lycopene, selenium, and vitamin E have also been explored. Antioxidant trials have yielded mixed results or benefitted only a subgroup of population, although further studies are needed to establish them as preventive agent. Although a majority of the trials resulted in positive outcomes supporting their role as preventive agents; one should be cautious of neutral or negative results as well. For clinical applicability of these agents, we need to identify the ideal target population, time of intervention, appropriate dosage, and extent of intervention required. Incoherency of data with these agents urges for a stringent study design and thorough interpretation to accurately judge the necessity and feasibility of the preventive measures. [ABSTRACT FROM PUBLISHER]

Usnic acid (UA) is a secondary metabolite abundantly found in lichens. Some studies have shown the anticancer potential of UA; however, its efficacy and associated mechanisms are yet to be fully explored. Herein, we assessed the anticancer potency and associated molecular alterations by UA in human lung carcinoma A549 cells. UA treatment (25–100 μM) for 24 and 48 h decreased total cell number by 39–67% (P< 0.01) and 68–89% (P< 0.001), respectively, and enhanced cell death by up to twofold and eightfold (P< 0.001), respectively. UA (1–10 μM) also significantly (P< 0.001) suppressed colony formation of A549 cells. The cell growth inhibition was associated with cell cycle arrest at G0/ G1 phase. UA decreased the expression of cyclin-dependent kinase (CDK)4, CDK6, and cyclin D1 and increased the expression of CDK inhibitor (CDKI) p21/cip1 protein. While examining the cell death associated molecular changes, we observed that UA induces mitochondrial membrane depolarization and led to more than twofold increase (P< 0.01) in apoptotic cells. The apoptotic effect of UA was accompanied by enhanced poly(ADP-ribose) polymerase cleavage. This study shows that UA inhibits cell growth involving G0/G1 phase cell cycle arrest and induces cell death via mitochondrial membrane depolarization and induction of apoptosis in human lung carcinoma cells. [ABSTRACT FROM PUBLISHER]

Studies have shown that fisetin, a small phytochemical molecule, has antitumor activity; however, its antiangiogenic activity has not yet been examined. Accordingly, herein, we investigated the antiangiogenic efficacy and associated mechanisms of fisetin in human umbilical vein endothelial cells (HUVECs). Fisetin (10–50 μM) strongly inhibited the regular serum plus growth supplement- and vascular endothelial growth factor (VEGF)-induced growth (up to 92%, P < 0.001) and survival (up to 16%, P < 0.001) of HUVEC in a dose- and time-dependent manner. Fisetin also caused cell cycle arrest at G1 (strong) and G2/M (moderate) phases together with a decrease in cyclin D1 and an increase in p53 levels. Fisetin-caused cell death was accompanied by decreased expression of survivin and an increase in cleaved levels of caspases-3 and -7 and poly-(ADP-ribose) polymerase along with an increased ratio of Bax to Bcl-2. Furthermore, fisetin inhibited capillary-like tube formation on Matrigel (up to 85%, P < 0.001) as well as migration (up to 66%, P < 0.001), which were associated with decreased expression of endothelial nitric oxide synthase (eNOS) and VEGF in HUVEC. It also decreased the expression of eNOS, VEGF, inducible nitric oxide synthase, matrix metalloproteinase-2 and -9 in A549 and DU145 human cancer cells. In vivo matrigel plug assay in mice showed significant decrease in size (up to 43%, P < 0.001), vascularization and hemoglobin content (up to 94%, P < 0.001) in the plugs from fisetin-treated, compared with control mice. Overall, these results suggest that fisetin inhibits various attributes of angiogenesis, which might contribute to its reported antitumor effects, and therefore, fisetin warrants further investigation for its angiopreventive potential toward cancer control. [ABSTRACT FROM PUBLISHER]

Abstract: Ionizing radiation (IR)-induced cellular damage is implicated in carcinogenesis as well as therapy of cancer. Advances in radiation therapy have led to the decrease in dosage and localizing the effects to the tumor; however, the development of radioresistance in cancer cells and radiation toxicity to normal tissues are still the major concerns. The development of radioresistance involves several mechanisms, including the activation of mitogenic and survival signaling, induction of DNA repair, and changes in redox signaling and epigenetic regulation. The current strategy of combining radiation with standard cytotoxic chemotherapeutic agents can potentially lead to unwanted side effects due to both agents. Thus agents are needed that could improve the efficacy of radiation killing of cancer cells and prevent the damage to normal cells and tissues caused by the direct and bystander effects of radiation, without have its own systemic toxicity. Chemopreventive phytochemicals, usually non-toxic agents with both cancer preventive and therapeutic activities, could rightly fit in this approach. In this regard, naturally occurring compounds, including curcumin, parthenolide, genistein, gossypol, ellagic acid, withaferin, plumbagin and resveratrol, have shown considerable potential. These agents suppress the radiation-induced activation of receptor tyrosine kinases and nuclear factor-κB signaling, can modify cell survival and DNA repair efficacy, and may potentiate ceramide signaling. These radiosensitizing and counter radioresistance mechanisms of phytochemicals in cancer cells are also associated with changes in epigenetic gene regulation. Because radioresistance involves multiple mechanisms, more studies are needed to discover novel phytochemicals having multiple mechanisms of radiosensitization and to overcome radioresistance of cancer cells. Pre-clinical studies are needed to address the appropriate dosage, timing, and duration of the application of phytochemicals with radiation to justify clinical trials. Nonetheless, some phytochemicals in combination with IR may play a significant role in enhancing the therapeutic index of cancer treatment. [Copyright &y& Elsevier]

Background: People who inject drugs (PWID) have been identified as frequent users of emergency department (ED) and hospital inpatient services. The specific challenges of record linkage in cohorts with numerous administrative health records occurring in close proximity are not well understood. Here, we present a method for patient-specific record linkage of ED and hospital admission data for a cohort of PWID.Methods: Data from 688 PWID were linked to two state-wide administrative health databases identifying all ED visits and hospital admissions for the cohort between January 2008 and June 2013. We linked patient-specific ED and hospital admissions data, using administrative date-time timestamps and pre-specified linkage criteria, to identify hospital admissions stemming from ED presentations for a given individual. The ability of standalone databases to identify linked ED visits or hospital admissions was examined.Results: There were 3459 ED visits and 1877 hospital admissions identified during the study period. Thirty-four percent of ED visits were linked to hospital admissions. Most links had hospital admission timestamps in-between or identical to their ED visit timestamps (n = 1035, 87%). Allowing 24-h between ED visits and hospital admissions captured more linked records, but increased manual inspection requirements. In linked records (n = 1190), the ED 'departure status' variable correctly reflected subsequent hospital admission in only 68% of cases. The hospital 'admission type' variable was non-specific in identifying if a preceding ED visit had occurred.Conclusions: Linking ED visits with subsequent hospital admissions in PWID requires access to date and time variables for accurate temporal sorting, especially for same-day presentations. Selecting time-windows to capture linked records requires discretion. Researchers risk under-ascertainment of hospital admissions if using ED data alone. [ABSTRACT FROM AUTHOR]

Background: Drug overdose is a leading cause of mortality and morbidity amongst people who inject drugs (PWID). Drug overdose surveillance typically relies on the International Classification of Diseases (ICD-10) coding system, however its real world utilisation and the implications for surveillance have not been well characterised. This study examines the patterns of ICD-10 coding pertaining to drug overdoses within emergency departments for a cohort of known PWID.Methods: Cohort data from 688 PWID was linked to statewide emergency department administrative data between January 2008 and June 2013. ICD-10 diagnostic codes pertaining to poisonings by drugs, medicaments and biological substances (T-codes T36-T50) as well as mental and behavioural disorders due to psychoactive substance use (F-codes F10-F19) were examined.Results: There were 449 unique ED presentations with T or F code mentions contributed by 168 individuals. Nearly half of the T and F codes used were non-specific and did not identify either a drug class (n = 160, 36%) or clinical reaction (n = 46, 10%) and 8% represented withdrawal states. T and F codes could therefore be used to reasonably infer an illicit drug overdose in only 42% (n = 188) of cases. Majority of presentations with T or F overdose codes recorded only one diagnostic code per encounter (83%) and representing multiple-drug overdose (F19.- = 18%) or unidentified substances (T50.9 = 17%) using a single, broad diagnostic code was common.Conclusions: Reliance on diagnoses alone when examining ED data will likely significantly underestimate incidence of specific drug overdose due to frequent use of non-specific ICD-10 codes and the use of single diagnostic codes to represent polysubstance overdose. Measures to improve coding specificity should be considered and further work is needed to determine the best way to use ED data in overdose surveillance. [ABSTRACT FROM AUTHOR]

An immunosuppressive microenvironment causes poor tumor T cell infiltration and is associated with reduced patient overall survival in colorectal cancer. How to improve treatment responses in these tumors is still a challenge. Using an integrated screening approach to identify cancer-specific vulnerabilities, we identified complement receptor C5aR1 as a druggable target, which when inhibited improved radiotherapy, even in tumors displaying immunosuppressive features and poor CD8+ T cell infiltration. While C5aR1 is well-known for its role in the immune compartment, we found that C5aR1 is also robustly expressed on malignant epithelial cells, highlighting potential tumor cell–specific functions. C5aR1 targeting resulted in increased NF-κB–dependent apoptosis specifically in tumors and not normal tissues, indicating that, in malignant cells, C5aR1 primarily regulated cell fate. Collectively, these data revealed that increased complement gene expression is part of the stress response mounted by irradiated tumors and that targeting C5aR1 could improve radiotherapy, even in tumors displaying immunosuppressive features. [ABSTRACT FROM AUTHOR]

Background: People who inject drugs (PWID) use healthcare services, including primary care, at a disproportionately high rate. We investigated key correlates of general practitioner (GP) related service utilisation within a cohort of PWID.Methods: Using baseline data from a cohort of 645 community-recruited PWID based in Melbourne, Victoria, we conducted a secondary analysis of associations between past month use of GP services unrelated to opioid substitution therapy (OST) and socio-demographic and drug use characteristics and self-reported health using multivariate logistic regression.Results: Just under one-third (29%) of PWID had accessed GP services in the month prior to being surveyed. Participants who reported living with children (adjusted odds ratio, AOR 1.97, 95% CI 1.04 - 3.73) or having had contact with a social worker in the past month (AOR 1.92, 95% CI 1.24 - 2.98) were more likely to have seen a GP in the past month. Participants who were injecting daily or more frequently (AOR 0.50, 95% CI 0.30 - 0.83) or had a weekly income of less than $400 (AOR 0.59, 95% CI 0.38 - 0.91) were less likely to report having seen a GP in the past month.Conclusions: Our sample frequently attended GP services for health needs unrelated to OST. Findings highlight both the characteristics of PWID accessing GP services and also those potentially missing out on primary care and preventive services. [ABSTRACT FROM AUTHOR]

Background: To circumvent Warburg effect, several clinical trials for different cancers are utilising a combinatorial approach using metabolic reprogramming and chemotherapeutic agents including metformin. The majority of these metabolic interventions work via indirectly activating AMP-activated protein kinase (AMPK) to alter cellular metabolism in favour of oxidative phosphorylation over aerobic glycolysis. The effect of these drugs is dependent on glycaemic and insulin conditions.  Therefore, development of small molecules, which can activate AMPK, irrespective of the energy state, may be a better approach for triple-negative breast cancer (TNBC) treatment.Methods: Therapeutic effect of SU212 on TNBC cells was examined using in vitro and in vivo models.Results: We developed and characterised the efficacy of novel AMPK activator (SU212) that selectively induces oxidative phosphorylation and decreases glycolysis in TNBC cells, while not affecting these pathways in normal cells.   SU212 accomplished this metabolic reprogramming by activating AMPK independent of energy stress and irrespective of the glycaemic/insulin state. This leads to mitotic phase arrest and apoptosis in TNBC cells. In vivo, SU212 inhibits tumour growth, cancer progression and metastasis.Conclusions: SU212 directly activates AMPK in TNBC cells, but does not hamper glucose metabolism in normal cells. Our study provides compelling preclinical data for further development of SU212 for the treatment of TNBC. [ABSTRACT FROM AUTHOR]

Glial cell-derived neurotrophic factor (GDNF) is reported to promote the survival of neurons and salivary gland regeneration after radiation damage. This study investigated the effect of GDNF on cell migration, growth, and response to radiation in preclinical models of head and neck squamous cell carcinoma (HNSCC) and correlated GDNF expression to treatment outcomes in HNSCC patients. Our ultimate goal is to determine whether systemic administration of GDNF at high dose is safe for the management of hyposalivation or xerostomia in HNSCC patients. Three HPV-positive and three HPV-negative cell lines were examined for cell migration, growth, and clonogenic survival in vitro and tumor growth assay in vivo. Immunohistochemical staining of GDNF, its receptors GFRα1 and its co-receptor RET was performed on two independent HNSCC tissue microarrays (TMA) and correlated to treatment outcomes. Results showed that GDNF only enhanced cell migration in two HPV-positive cells at supra-physiologic doses, but not in HPV-negative cells. GDNF did not increase cell survival in the tested cell lines post-irradiation. Likewise, GDNF treatment affected neither tumor growth in vitro nor response to radiation in xenografts in two HPV-positive and two HPV-negative HNSCC models. High stromal expression of GDNF protein was associated with worse overall survival in HPV-negative HNSCC on multivariate analysis in a combined cohort of patients from Stanford University (n = 82) and Washington University (n = 189); however, the association between GDNF gene expression and worse survival was not confirmed in a separate group of HPV-negative HNSCC patients identified from the Cancer Genome Atlas (TCGA) database. Based on these data, we do not believe that GNDF is a safe systemic treatment to prevent or treat xerostomia in HNSCC and a local delivery approach such as intraglandular injection needs to be explored. [ABSTRACT FROM AUTHOR]

Xerostomia (dry mouth) is the most common side effect of radiation therapy in patients with head and neck cancer and causes difficulty speaking and swallowing. Since aldehyde dehydrogenase 3A1 (ALDH3A1) is highly expressed in mouse salivary stem/progenitor cells (SSPCs), we sought to determine the role of ALDH3A1 in SSPCs using genetic loss-of-function and pharmacologic gain-of-function studies. Using DarkZone dye to measure intracellular aldehydes, we observed higher aldehyde accumulation in irradiated Aldh3a1−/− adult murine salisphere cells and in situ in whole murine embryonic salivary glands enriched in SSPCs compared with wild-type glands. To identify a safe ALDH3A1 activator for potential clinical testing, we screened a traditional Chinese medicine library and isolated d-limonene, commonly used as a food-flavoring agent, as a single constituent activator. ALDH3A1 activation by d-limonene significantly reduced aldehyde accumulation in SSPCs and whole embryonic glands, increased sphere-forming ability, decreased apoptosis, and improved submandibular gland structure and function in vivo after radiation. A phase 0 study in patients with salivary gland tumors showed effective delivery of d-limonene into human salivary glands following daily oral dosing. Given its safety and bioavailability, d-limonene may be a good clinical candidate for mitigating xerostomia in patients with head and neck cancer receiving radiation therapy. [ABSTRACT FROM AUTHOR]

Introduction and Aims: Take-home naloxone (THN) programs targeting people who inject drugs (PWID) have been running in some Australian states and territories since 2012. In this study, we aimed to determine the extent to which PWID in the capital cities of all Australian states and territories are aware of naloxone and THN programs, whether awareness of these programs has changed over time.Design and Methods: Data were obtained from cross-sectional surveys of a total of 2088 PWID conducted annually as part of the Illicit Drug Reporting System from 2013 to 2015. Specific questions about THN added to the survey in 2013 allowed assessment of the extent to which sampled PWID were aware of naloxone and its function and THN programs in Australia and whether they had participated in a THN program. These main outcomes were examined over time and across states and territories using a mix of descriptive statistics and logistic regression.Results: Over 80% of the sample reported having heard of naloxone across survey years. Less than half of the participants reported having heard of THN programs in 2013 (35%), but this increased to just over (52%) half in 2015 (P < 0.01). Changes over time differed across cities with increases in reports of having heard of THN occurring over time most clearly in those cities with operational THN programs.Discussion and Conclusions: Around half of the PWID sampled for this study are aware of THN programs. Further work is needed to ensure widespread awareness of THN programs which should include implementing THN in all Australian states and territories. [ABSTRACT FROM AUTHOR]

Y box binding protein 1 (YB-1) is a multifunctional protein associated with tumor progression and the emergence of treatment resistance (TR). Here, we report an azopodophyllotoxin small molecule, SU056, that potently inhibits tumor growth and progression via YB-1 inhibition. This YB-1 inhibitor inhibits cell proliferation, resistance to apoptosis in ovarian cancer (OC) cells, and arrests in the G1 phase. Inhibitor treatment leads to enrichment of proteins associated with apoptosis and RNA degradation pathways while downregulating spliceosome pathway. In vivo , SU056 independently restrains OC progression and exerts a synergistic effect with paclitaxel to further reduce disease progression with no observable liver toxicity. Moreover, in vitro mechanistic studies showed delayed disease progression via inhibition of drug efflux and multidrug resistance 1, and significantly lower neurotoxicity as compared with etoposide. These data suggest that YB-1 inhibition may be an effective strategy to reduce OC progression, antagonize TR, and decrease patient mortality. [Display omitted] • Azopodophyllotoxin small molecule, SU056, inhibits YB-1 • YB-1 inhibition decreases OC cell proliferation and resistance to apoptosis • YB-1 inhibition sensitizes OC cells for paclitaxel treatment Tailor et al. reported azopodophyllotoxin derivative SU056 as a Y box binding protein 1 (YB-1) inhibitor. YB-1 inhibitor co-treatment sensitizes ovarian cancer cells for paclitaxel treatment. [ABSTRACT FROM AUTHOR]

• A review of road trauma fatalities from Victoria, Australia from 2006 to 2016, was undertaken. • There were 2287 road traffic fatalities of which 51.9% were positive for alcohol or other drugs. • Alcohol was most commonly detected in 21.1% of cases, but declined by 9% per year. • Methylamphetamine was detected in 6.6% of cases and increased 7% per year. • There was no change in the incidence of THC over time, observed in 13.1% of cases. Driving under the influence of drugs, including alcohol, is a globally recognised risk factor for road traffic crashes. While the prevalence of alcohol and other drugs in fatal road crashes has been examined in other countries, recent data investigating drug driving in fatal Australian crashes are limited. This study aimed to examine how the presence of alcohol and other drugs in fatal road trauma in Victoria has changed over time in different road users. A population-based review of road trauma deaths was performed over the period of 01 July 2006 to 30 June 2016 in Victoria, Australia, using data from the National Coronial Information System (NCIS) and the Victorian State Trauma Registry (VSTR). Drugs were grouped according to type and analysed accordingly. Poisson regression models were used to determine change in incidence rates over the study period. There were 2287 road traffic fatalities with complete toxicology data (97% of all road traffic fatalities). Alcohol (blood alcohol concentration, BAC) was the most commonly detected drug (>0.001 g/100 mL: 21.1%; >0.05 g/100 mL: 18.4%), followed by opioids (17.3%), THC (13.1%), antidepressants (9.7%), benzodiazepines (8.8%), amphetamine-type stimulants (7.1%), ketamine (3.4%), antipsychotics (0.9%) and cocaine (0.2%). Trends demonstrated changing use over time with specific drugs. Alcohol positive road fatalities declined 9% per year in passenger car/4WD drivers (IRR = 0.91, 95% CI: 0.88−0.95). The incidence of strong opioids (oxycodone, fentanyl, morphine, and methadone) increased 6% per year (IRR = 1.06; 95% CI: 1.02–1.10). Methylamphetamine was detected in 6.6% of cases and showed a yearly increase of 7% (IRR = 1.07; 95% CI: 1.01–1.13). The incidence of THC remained unchanged over the period, observed in 13.1% of cases. Stronger opioids were more commonly detected among pedal cyclists (19.0%) and pedestrians (20.9%) while THC was more commonly detected among motorcyclists (19.8%) and other light vehicle drivers (17.6%). A decline in the prevalence of alcohol in fatalities suggests that law enforcement and public health strategies in Australia to address road fatalities and drink-driving may have had a positive effect. However, increases were observed in the incidence of other potentially impairing drugs including opioids and amphetamines, specifically methylamphetamine, indicating a concerning trend in road safety in Victoria that warrants further monitoring. [ABSTRACT FROM AUTHOR]