Redesigning crop varieties to win the race between climate change and food security.

Climate change poses daunting challenges to agricultural production and food security. Rising temperatures, shifting weather patterns, and more frequent extreme events have already demonstrated their effects on local, regional, and global agricultural systems. Crop varieties that withstand climate-related stresses and are suitable for cultivation in innovative cropping systems will be crucial to maximize risk avoidance, productivity, and profitability under climate-changed environments. We surveyed 588 expert stakeholders to predict current and novel traits that may be essential for future pearl millet, sorghum, maize, groundnut, cowpea, and common bean varieties, particularly in sub-Saharan Africa. We then review the current progress and prospects for breeding three prioritized future-essential traits for each of these crops. Experts predict that most current breeding priorities will remain important, but that rates of genetic gain must increase to keep pace with climate challenges and consumer demands. Importantly, the predicted future-essential traits include innovative breeding targets that must also be prioritized; for example, (1) optimized rhizosphere microbiome, with benefits for P, N, and water use efficiency, (2) optimized performance across or in specific cropping systems, (3) lower nighttime respiration, (4) improved stover quality, and (5) increased early vigor. We further discuss cutting-edge tools and approaches to discover, validate, and incorporate novel genetic diversity from exotic germplasm into breeding populations with unprecedented precision, accuracy, and speed. We conclude that the greatest challenge to developing crop varieties to win the race between climate change and food security might be our innovativeness in defining and boldness to breed for the traits of tomorrow.

Plasma endocannabinoids and cannabimimetic fatty acid derivatives are altered in cyclic vomiting syndrome: The effects of sham feeding.

Cyclic vomiting syndrome (CVS) is an underdiagnosed disorder of the gut-brain interaction. Our understanding of the pathophysiology of CVS is evolving. Here, we tested the hypotheses that: (1) the levels of endocannabinoids and related lipids are altered in CVS, and (2) cephalic-vagal stimulation drive changes in endolipid levels. Ten adult patients with CVS and eight healthy controls were included. Indirect measurements of parasympathetic (RFa) functions were performed with spectral analysis of heart rate variability and respiratory activity. Plasma levels of endocannabinoids and related lipids were measured at baseline and during a sham feeding. Values are reported as mean ± standard error of the mean and compared using t-test or ANOVA. CVS patients had a lower parasympathetic tone and response to the Valsalva maneuver and deep breathing than the controls. The baseline 2-Arachidonoylglycerol (2-AG) had a significantly higher concentration in CVS (5.9e-008 ± 3.7e-008 mol/L) than control (3.7e-008 ± 1.3e-008 mol/; p < 0.05). Sham feeding did not change the concentration of 2-AG. 2-oleoylglycerol (2-OG) was significantly higher in CVS than control and did not change with sham feeding. Levels of N-acylethanolamines, including anandamide (AEA), were not different in CVS vs control. After sham feeding, AEA showed a trend toward increasing (p = 0.08) in CVS, but not in control. With sham feeding, palmitoyl ethanolamine significantly increased in both CVS and control groups; oleoyl ethanolamine in CVS only, and stearoyl ethanolamine in the control group. Levels of endocannabinoids and related lipids are altered in CVS patients. Sham feeding affects endogenous signaling lipids in a disease and time-dependent manner.

Cannabinoid mechanisms contribute to the therapeutic efficacy of the kratom alkaloid mitragynine against neuropathic, but not inflammatory pain.

AIMS: Mitragynine (MG) is an alkaloid found in Mitragyna speciosa (kratom), a plant used to self-treat symptoms of opioid withdrawal and pain. Kratom products are commonly used in combination with cannabis, with the self-treatment of pain being a primary motivator of use. Both cannabinoids and kratom alkaloids have been characterized to alleviate symptoms in preclinical models of neuropathic pain such as chemotherapy-induced peripheral neuropathy (CIPN). However, the potential involvement of cannabinoid mechanisms in MG's efficacy in a rodent model of CIPN have yet to be explored. MAIN METHODS: Prevention of oxaliplatin-induced mechanical hypersensitivity and formalin-induced nociception were assessed following intraperitoneal administration of MG and CB1, CB2, or TRPV1 antagonists in wildtype and cannabinoid receptor knockout mice. The effects of oxaliplatin and MG exposure on the spinal cord endocannabinoid lipidome was assessed by HPLC-MS/MS. KEY FINDINGS: The efficacy of MG on oxaliplatin-induced mechanical hypersensitivity was partially attenuated upon genetic deletion of cannabinoid receptors, and completely blocked upon pharmacological inhibition of CB1, CB2, and TRPV1 channels. This cannabinoid involvement was found to be selective to a model of neuropathic pain, with minimal effects on MG-induced antinociception in a model of formalin-induced pain. Oxaliplatin was found to selectively disrupt the endocannabinoid lipidome in the spinal cord, which was prevented by repeated MG exposure. SIGNIFICANCE: Our findings suggest that cannabinoid mechanisms contribute to the therapeutic efficacy of the kratom alkaloid MG in a model of CIPN, which may result in increased therapeutic efficacy when co-administered with cannabinoids.

Effects of combined use of alcohol and delta-9-tetrahydrocannibinol on working memory in Long Evans rats.

The increase in social acceptance and legalization of cannabis over the last several years is likely to increase the prevalence of its co-use with alcohol. In spite of this, the potential for effects unique to co-use of these drugs, especially in moderate doses, has been studied relatively infrequently. We addressed this in the current study using a laboratory rat model of voluntary drug intake. Periadolescent male and female Long-Evans rats were allowed to orally self-administer ethanol, Δ9-tetrahydrocannibinol (THC), both drugs, or their vehicle controls from postnatal day (P) 30 to P47. They were subsequently trained and tested on an instrumental behavior task that assesses attention, working memory and behavioral flexibility. Similar to previous work, consumption of THC reduced both ethanol and saccharin intake in both sexes. Blood samples taken 14 h following the final self-administration session revealed that females had higher levels of the THC metabolite THC-COOH. There were modest effects of THC on our delayed matching to position (DMTP) task, with females exhibiting reduced performance compared to their control group or male, drug using counterparts. However, there were no significant effects of co-use of ethanol or THC on DMTP performance, and drug effects were also not apparent in the reversal learning phase of the task when non-matching to position was required as the correct response. These findings are consistent with other published studies in rodent models showing that use of these drugs in low to moderate doses does not significantly impact memory or behavioral flexibility following a protracted abstinence period.

Effects of combined use of alcohol and delta-9-tetrahydrocannibinol on working memory in Long Evans rats.

The increase in social acceptance and legalization of cannabis over the last several years is likely to increase the prevalence of its co-use with alcohol. In spite of this, the potential for effects unique to co-use of these drugs, especially in moderate doses, has been studied relatively infrequently. We addressed this in the current study using a laboratory rat model of voluntary drug intake. Periadolescent male and female Long-Evans rats were allowed to orally self-administer ethanol, Î" 9 -tetrahydrocannibinol (THC), both drugs, or their vehicle controls from postnatal day (P) 30 to P47. They were subsequently trained and tested on an instrumental behavior task that assesses attention, working memory and behavioral flexibility. Similar to previous work, consumption of THC reduced both ethanol and saccharin intake in both sexes. Blood samples taken 14h following the final self-administration session revealed that females had higher levels of the THC metabolite THC-COOH. There were modest effects of THC on our delayed matching to position (DMTP) task, with females exhibiting reduced performance compared to their control group or male, drug using counterparts. However, there were no significant effects of co-use of ethanol or THC on DMTP performance, and drug effects were also not apparent in the reversal learning phase of the task when non-matching to position was required as the correct response. These findings are consistent with other published studies in rodent models showing that use of these drugs in low to moderate doses does not significantly impact memory or behavioral flexibility following a protracted abstinence period.

Effects of inhaled cannabis high in Δ9-THC or CBD on the aging brain: A translational MRI and behavioral study.

With the recent legalization of inhaled cannabis for medicinal and recreational use, the elderly represents one of the newest, rapidly growing cohorts of cannabis users. To understand the neurobiological effects of cannabis on the aging brain, 19-20 months old mice were divided into three groups exposed to vaporized cannabis containing ~10% Δ9-THC, ~10% CBD, or placebo for 30 min each day. Voxel based morphometry, diffusion weighted imaging, and resting state functional connectivity data were gathered after 28 days of exposure and following a two-week washout period. Tail-flick, open field, and novel object preference tests were conducted to explore analgesic, anxiolytic, and cognitive effects of cannabis, respectively. Vaporized cannabis high in Δ9-THC and CBD achieved blood levels reported in human users. Mice showed antinociceptive effects to chronic Δ9-THC without tolerance while the anxiolytic and cognitive effects of Δ9-THC waned with treatment. CBD had no effect on any of the behavioral measures. Voxel based morphometry showed a decrease in midbrain dopaminergic volume to chronic Δ9-THC followed but an increase after a two-week washout. Fractional anisotropy values were reduced in the same area by chronic Δ9-THC, suggesting a reduction in gray matter volume. Cannabis high in CBD but not THC increased network strength and efficiency, an effect that persisted after washout. These data would indicate chronic use of inhaled cannabis high in Δ9-THC can be an effective analgesic but not for treatment of anxiety or cognitive decline. The dopaminergic midbrain system was sensitive to chronic Δ9-THC but not CBD showing robust plasticity in volume and water diffusivity prior to and following drug cessation an effect possibly related to the abuse liability of Δ9-THC. Chronic inhaled CBD resulted in enhanced global network connectivity that persisted after drug cessation. The behavioral consequences of this sustained change in brain connectivity remain to be determined.

Measuring the Content of Endocannabinoid-Like Compounds in Biological Fluids: A Critical Overview of Sample Preparation Methodologies.

Different mass spectrometric techniques have been used over the past decade to quantify endocannabinoids (eCBs) and related lipids. Even with the level of molecular fingerprinting accuracy of an instrument like the most advanced triple quadrupole mass spectrometer, if one is not getting the most optimized sample to the detector in a way that this improved technology can be of use, then advancements can be stymied. Here, our focus is on review and discussion of sample preparation methodologies used to isolate the eCB anandamide and its close congeners N-acyl ethanolamines and structural congeners (i.e., lipo amino acids, lipoamines, N-acyl amides) in biological fluids. Most of our focus will be on the analysis of these lipids in plasma/serum, but we will also discuss how the same techniques can be used for the analysis of saliva and breast milk.

Impact of current Australian paid parental leave on families of preterm and sick infants.

AIM: Parents of preterm or sick infants are at increased risk of mental health problems. The financial stress associated with an infant's prolonged hospital stay can have an additional negative effect on families' wellbeing and child development. This study explores parent use of Australian paid parental leave (PPL) and the financial impact of having an infant requiring neonatal care. METHODS: Retrospective, cross-sectional, online survey study conducted from November 2020 to February 2021. Participants were parents of babies born from 1 January 2013, admitted to a neonatal intensive care unit or special care nursery in Australia. The survey explored use of Australian Government and private sector PPL, and financial stress. Parent-reported anxiety and depression were measured using the EuroQol Group 5D-5L Anxiety and Stress Subscale. RESULTS: Two hundred and thirty-one parents responded of which 93% had a preterm infant. Seventy-three percent of infants were hospitalised for more than 1 month, and 34% were readmitted to hospital within the first year following discharge home. Eighty-three percent of parents reported moderate, severe or extreme levels of anxiety or depression. Seventy-six percent reported that having a child in hospital had a moderate-very large financial impact on their family. Parents identified main costs to be travel, food, inability to work and direct medical costs. CONCLUSIONS: Having an infant born preterm or sick has significant emotional and financial implications for families. The current Australian Government PPL scheme does not adequately support parents of preterm or sick infants, and a change is urgently needed to improve outcomes for this vulnerable population.

Interactive effects of multiple stressors on the physiological performance of the invasive mussel Mytilus galloprovincialis.

The invasive mussel Mytilus galloprovincialis is a heat-tolerant species relative to its competative congener M. trossulus, that dominates warm seawater environments but it is unknown how multiple stressors (MS) may affect its physiology. Our study determined the effects of MS on the metabolic rate (MR), superoxide dismutase (SOD) antioxidant enzyme activity, and clearance rate (CR) of M. galloprovincialis. Mussels were exposed for 7 d to hyposalinity (20, 28, 34 ppt) then to heat shock (17, 20, 25 °C) after which MR and SOD activity were determined. CR was quantified following a 30 min MS exposure. We found a significant influence of MS on MR, SOD, and CR. We identified synergistic effects on MR under the most extreme treatment. SOD activity was the greatest under 20 °C exposure while CR declined under heat shock. Thus, our study suggests that mussels experiencing MS may become energy limited as MR increases and feeding rates decrease.

Individualism versus collective movement during travel.

Collective movement may emerge if coordinating one's movement with others produces a greater benefit to oneself than can be achieved alone. Experimentally, the capacity to manoeuvre simulated groups in the wild could enable powerful tests of the impact of collective movement on individual decisions. Yet such experiments are currently lacking due to the inherent difficulty of controlling whole collectives. Here we used a novel technique of experimentally simulating the movement of collectives of social hermit crabs (Coenobita compressus) in the wild. Using large architectural arrays of shells dragged across the beach, we generated synchronous collective movement and systematically varied the simulated collective's travel direction as well as the context (i.e., danger level). With drone video from above, we then tested whether focal individuals were biased in their movement by the collective. We found that, despite considerable engagement with the collective, individuals' direction was not significantly biased. Instead, individuals expressed substantial variability across all stimulus directions and contexts. Notably, individuals typically achieved shorter displacements in the presence of the collective versus in the presence of the control stimulus, suggesting an impact of traffic. The absence of a directional bias in individual movement due to the collective suggests that social hermit crabs are individualists, which move with a high level of opportunistic independence, likely thanks to the personal architecture and armour they carry in the form of a protective shell. Future studies can manipulate this level of armour to test its role in autonomy of movement, including the consequences of shell architecture for social decisions. Our novel experimental approach can be used to ask many further questions about how and why collective and individual movement interact.

Establishing consensus for the assessment of chronic pain in children and young people with cerebral palsy: a Delphi study.

PURPOSE: Inconsistent and inadequate pain assessment practices in cerebral palsy (CP) have resulted from a lack of standardisation of pain assessment, limited use of appropriate tools and failure to integrate disability and biopsychosocial models. To assist with improving consistency, this study aimed to establish consensus from key stakeholders regarding domains considered essential for measuring chronic pain in children and young people with CP. METHOD: A modified electronic Delphi study was conducted on 83 stakeholders, including clinicians, researchers, people with CP and parents of children with CP. Participants rated 18 domains sourced from existing literature as either "core", "recommended", "exploratory" or "not required". RESULTS: After two rounds of surveys, 12 domains were considered core: pain location, pain frequency, pain intensity, changeable factors, impact on emotional wellbeing, impact on participation, pain communication, influence on quality of life, physical impacts, sleep, pain duration and pain expression. CONCLUSION: These domains reflect the complexity of pain in a heterogeneous population where medical comorbidities are common and communication and intellectual limitations impact significantly on the ability of many to self-report. The domains will be utilised to build a framework of pain assessment specific to children and young people with CP guided by the biopsychosocial model.Implications for rehabilitationChronic pain is under-identified and poorly assessed in the cerebral palsy (CP) population.The perspectives of clinicians, researchers and consumers are vital for developing a framework for chronic pain assessment in CP.Consensus of key stakeholders found 12 domains considered essential to incorporate into a chronic pain assessment model in CP.

Cannabinoids accumulate in mouse breast milk and differentially regulate lipid composition and lipid signaling molecules involved in infant development.

Maternal cannabis use during lactation may expose developing infants to cannabinoids (CBs) such as Δ-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). CBs modulate lipid signaling molecules in the central nervous system in age- and cell-dependent ways, but their influence on the lipid composition of breast milk has yet to be established. This study investigates the effects of THC, CBD, or their combination on milk lipids by analyzing the stomach contents of CD1 mouse pups that have been nursed by dams injected with CBs on postnatal days (PND) 1 -10. Stomach contents were collected 2 hours after the last injection on PND10 and HPLC/MS/MS was used to identify and quantify over 80 endogenous lipid species and cannabinoids in the samples. We show that CBs differentially accumulate in milk, lead to widespread decreases in free fatty acids, decreases in N-acyl methionine species, increases N-linoleoyl species, as well as modulate levels of endogenous CBs (eCBs) AEA, 2-AG, and their structural congeners. Our data indicate the passage of CBs to pups through breast milk and that maternal CB exposure alters breast milk lipid compositions.

Monoacylglycerol Lipase Inhibitor MJN110 Reduces Neuronal Hyperexcitability, Restores Dendritic Arborization Complexity, and Regulates Reward-Related Behavior in Presence of HIV-1 Tat.

While current therapeutic strategies for people living with human immunodeficiency virus type 1 (HIV-1) suppress virus replication peripherally, viral proteins such as transactivator of transcription (Tat) enter the central nervous system early upon infection and contribute to chronic inflammatory conditions even alongside antiretroviral treatment. As demand grows for supplemental strategies to combat virus-associated pathology presenting frequently as HIV-associated neurocognitive disorders (HAND), the present study aimed to characterize the potential utility of inhibiting monoacylglycerol lipase (MAGL) activity to increase inhibitory activity at cannabinoid receptor-type 1 receptors through upregulation of 2-arachidonoylglycerol (2-AG) and downregulation of its degradation into proinflammatory metabolite arachidonic acid (AA). The MAGL inhibitor MJN110 significantly reduced intracellular calcium and increased dendritic branching complexity in Tat-treated primary frontal cortex neuron cultures. Chronic MJN110 administration in vivo increased 2-AG levels in the prefrontal cortex (PFC) and striatum across Tat(+) and Tat(-) groups and restored PFC N-arachidonoylethanolamine (AEA) levels in Tat(+) subjects. While Tat expression significantly increased rate of reward-related behavioral task acquisition in a novel discriminative stimulus learning and cognitive flexibility assay, MJN110 altered reversal acquisition specifically in Tat(+) mice to rates indistinguishable from Tat(-) controls. Collectively, our results suggest a neuroprotective role of MAGL inhibition in reducing neuronal hyperexcitability, restoring dendritic arborization complexity, and mitigating neurocognitive alterations driven by viral proteins associated with latent HIV-1 infection.

Modulatory Potential of Cannabidiol on the Opioid-Induced Inflammatory Response.

Opioids are effective analgesics; however, there are many negative consequences of chronic use. One important side effect of chronic opioid use is the continuous engagement of the immune response that can exacerbate chronic pain. The opioid, morphine, initiates a Toll-like receptor 4 (TLR4) signaling cascade that drives the activation of NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome proteins, resulting in cytokine production and effectively creating a positive feedback loop for continuous TLR4 activation. In addition to driving cytokine production, morphine drives changes in proinflammatory lipid signaling. The alteration of both cytokine and lipid signaling systems by morphine suggests that its chronic use leads to a pathological immune response that would benefit from targeted therapy. Engaging the endogenous cannabinoid system has shown therapeutic benefit, particularly regarding its anti-inflammatory and immunosuppressive effects. Promising preclinical and clinical investigations suggest that cannabidiol (CBD) is an effective adjuvant for treatment of symptoms of opioid use disorders; however, the mechanism through which CBD drives this outcome is unclear. One potential source of insight into this mechanism is in how CBD regulates immune regulators such as cytokines and lipid signaling systems, including endocannabinoids and related immune-responsive lipids. In this review, we outline the immune response to chronic opioid use as well as CBD in the context of a lipopolysaccharide-induced immune response and speculate on the mechanism of CBD as a modulator of chronic opioid-induced immune system dysregulation.

The Rey 15-Item Memory Test in US veterans.

INTRODUCTION: The Rey 15-item Test is a public-domain, memory-based performance validity test, frequently used in clinical settings. Various efforts have been made to modify the test to make it more sensitive and more robust to effects of lower education and intelligence. The most promising of these is the addition of a recognition trial to the existing free recall paradigm. METHOD: The present study explored the use of the Rey-15 + Recognition Trial in a sample of 155 younger U.S. military veterans seen for evaluation of mild traumatic brain injury or attention deficit hyperactivity disorder (50 cases classified as invalid, 105 classified as valid). RESULTS: Optimal classification accuracy was obtained on the Combination index (cutoff ≤23, sensitivity = 50%, specificity = 95%) and the Recognition Hits score (cutoff ≤11, sensitivity = 52%, specificity = 93%). The Free Recall score had somewhat lower sensitivity when a similar 95% specificity threshold was set (cutoff ≤11, 38% sensitivity). A qualitative error score used in previous studies did not improve classification accuracy. CONCLUSIONS: The Rey-15 + Recognition Trial proved to be effective, with particular advantage bestowed by the recognition trial. Implications of these findings in the context of the study's clinical sample of military veterans and in the broader literature are discussed.

Timeliness and completeness of laboratory-based surveillance of COVID-19 cases in England.

OBJECTIVES: The aim of the study was to evaluate completeness and timeliness of the rapidly developed surveillance of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in England using patient-level data. STUDY DESIGN: This is an observational study wherein public health surveillance systems are evaluated. METHODS: Data were collected in the Public Health England's Second-Generation Surveillance System through routine laboratory reporting processes, as well as via enhanced testing in collaboration with commercial partners. Three periods were chosen to present developments in disease surveillance around the first pandemic wave in England. Completeness of valid entries for key demographic and epidemiological fields was summarised. Timeliness was assessed using recorded date intervals: from sample collection to the laboratory reporting a positive result, the positive result being received by the national surveillance system and the data being available for epidemiological analysis. RESULTS: In each period, demographic variables were more than 95% complete and enhanced ethnicity more than 85%, allowing a rich understanding of the general characteristics of COVID-19 cases in England. The proportion of cases completing all reporting stages of the national system within 3 days of when the specimen was taken increased from 69.1% in period 1 to 76.6% in period 3. In period 3, the median number of days to complete all reporting stages decreased to 2, from 3 in previous periods. Analysis of each reporting stage offers suggestive evidence that timeliness of the system has improved as reporting has become established over time. CONCLUSIONS: Timely processing of data for epidemiological use was consistent and rapid once received by the national system. Delays in timeliness were most likely to occur in the first stage of the reporting process, before laboratory input to the surveillance platform. Existing national surveillance mechanisms enhanced during the response have succeeded in providing rapid collection and reporting of case data to facilitate epidemiological monitoring and analysis and guide public health policy and strategy.

Cannabidiol has a unique effect on global brain activity: a pharmacological, functional MRI study in awake mice.

BACKGROUND: The phytocannabinoid cannabidiol (CBD) exhibits anxiolytic activity and has been promoted as a potential treatment for post-traumatic stress disorders. How does CBD interact with the brain to alter behavior? We hypothesized that CBD would produce a dose-dependent reduction in brain activity and functional coupling in neural circuitry associated with fear and defense. METHODS: During the scanning session awake mice were given vehicle or CBD (3, 10, or 30 mg/kg I.P.) and imaged for 10 min post treatment. Mice were also treated with the 10 mg/kg dose of CBD and imaged 1 h later for resting state BOLD functional connectivity (rsFC). Imaging data were registered to a 3D MRI mouse atlas providing site-specific information on 138 different brain areas. Blood samples were collected for CBD measurements. RESULTS: CBD produced a dose-dependent polarization of activation along the rostral-caudal axis of the brain. The olfactory bulb and prefrontal cortex showed an increase in positive BOLD whereas the brainstem and cerebellum showed a decrease in BOLD signal. This negative BOLD affected many areas connected to the ascending reticular activating system (ARAS). The ARAS was decoupled to much of the brain but was hyperconnected to the olfactory system and prefrontal cortex. CONCLUSION: The CBD-induced decrease in ARAS activity is consistent with an emerging literature suggesting that CBD reduces autonomic arousal under conditions of emotional and physical stress.

The development of sex differences in the nervous system and behavior of flies, worms, and rodents.

Understanding how sex differences in innate animal behaviors arise has long fascinated biologists. As a general rule, the potential for sex differences in behavior is built by the developmental actions of sex-specific hormones or regulatory proteins that direct the sexual differentiation of the nervous system. In the last decade, studies in several animal systems have uncovered neural circuit mechanisms underlying discrete sexually dimorphic behaviors. Moreover, how certain hormones and regulatory proteins implement the sexual differentiation of these neural circuits has been illuminated in tremendous detail. Here, we discuss some of these mechanisms with three case-studies-mate recognition in flies, maturation of mating behavior in worms, and play-fighting behavior in young rodents. These studies illustrate general and unique developmental mechanisms to establish sex differences in neuroanatomy and behavior and highlight future challenges for the field.

Combining 1,4-dihydroxy quininib with Bevacizumab/FOLFOX alters angiogenic and inflammatory secretions in ex vivo colorectal tumors.

BACKGROUND: Colorectal cancer (CRC) is the second most common cause of cancer-related mortality worldwide with one in every five patients diagnosed with metastatic CRC (mCRC). In mCRC cases, the 5-year survival rate remains at approximately 14%, reflecting the lack of effectiveness of currently available treatments such as the anti-VEGF targeting antibody Bevacizumab combined with the chemotherapy folinic acid, fluorouracil and oxaliplatin (FOLFOX). Approximately 60% of patients do not respond to this combined treatment. Furthermore, Bevacizumab inhibits dendritic cell (DC) maturation in poor responders, a key process for tumor eradication. METHOD: Following drug treatment, secreted expression levels of angiogenic and inflammatory markers in tumor conditioned media generated from human ex vivo colorectal tumors were measured by ELISA. Dendritic cell phenotypic and maturation markers were assessed by flow cytometry. RESULTS: Our novel compound, 1,4-dihydroxy quininib, acts in an alternative pathway compared to the approved therapy Bevacizumab. 1,4-dihydroxy quininib alone, and in combination with Bevacizumab or FOLFOX significantly reduced TIE-2 expression which is involved in the promotion of tumor vascularization. Combination treatment with 1,4-dihydroxy quininib significantly increased the expression level of DC phenotypic and maturation markers. CONCLUSION: Our results indicate the anti-angiogenic small molecule 1,4-dihydroxy quininib could be an alternative novel treatment in combination therapy for CRC patients.

Pain in children with dyskinetic and mixed dyskinetic/spastic cerebral palsy.

AIM: To evaluate pain prevalence and characteristics in children and adolescents with predominant dyskinetic and mixed (dyskinetic/spastic) cerebral palsy (CP) motor types. METHOD: Seventy-five participants with a diagnosis of CP and confirmed dyskinetic or mixed (dyskinetic/spastic) motor type took part in a multisite cross-sectional study. The primary outcome was carer-reported pain prevalence (preceding 2wks) measured using the Health Utilities Index-3. Secondary outcomes were chronicity, intensity, body locations, quality of life, and activity impact. RESULTS: Mean participant age was 10 years 11 months (SD 4y 2mo, range 5-18y). There were 44 males and 31 females and 37 (49%) had predominant dyskinetic CP. Pain was prevalent in 85% and it was chronic in 77% of participants. Fifty-two per cent experienced moderate-to-high carer-reported pain intensity, which was significantly associated with predominant dyskinetic motor types (p=0.008). Pain occurred at multiple body locations (5 out of 21), with significantly increased numbers of locations at higher Gross Motor Function Classification System levels (p=0.02). Face, jaw, and temple pain was significantly associated with predominant dyskinetic motor types (p=0.005). Poorer carer proxy-reported quality of life was detected in those with chronic pain compared to those without (p=0.03); however, chronic pain did not affect quality of life for self-reporting participants. INTERPRETATION: Pain was highly prevalent in children and adolescents with predominant dyskinetic and mixed (dyskinetic/spastic) motor types, highlighting a population in need of lifespan pain management. WHAT THIS PAPER ADDS: Chronic pain prevalence in children and adolescents with predominant dyskinetic and mixed (dyskinetic/spastic) motor types is high. Pain occurs across multiple body locations in predominant dyskinetic and mixed (dyskinetic/spastic) motor types. Less recognized locations of pain include the face, jaw, and temple for predominant dyskinetic motor types.