Cholinergic signaling influences the expression of immune checkpoint inhibitors, PD-L1 and PD-L2, and tumor hallmarks in human colorectal cancer tissues and cell lines.

BACKGROUND: Cancer cells express immunosuppressive molecules, such as programmed death ligands (PD-L)1 and PD-L2, enabling evasion from the host's immune system. Cancer cells synthesize and secrete acetylcholine (ACh), acting as an autocrine or paracrine hormone to promote their proliferation, differentiation, and migration. METHODS: We correlated the expression of PD-L1, PD-L2, cholinergic muscarinic receptor 3 (M3R), alpha 7 nicotinic receptor (α7nAChR), and choline acetyltransferase (ChAT) in colorectal cancer (CRC) tissues with the stage of disease, gender, age, risk, and patient survival. The effects of a muscarinic receptor blocker, atropine, and a selective M3R blocker, 4-DAMP, on the expression of immunosuppressive and cholinergic markers were evaluated in human CRC (LIM-2405, HT-29) cells. RESULTS: Increased expression of PD-L1, M3R, and ChAT at stages III-IV was associated with a high risk of CRC and poor survival outcomes independent of patients' gender and age. α7nAChR and PD-L2 were not changed at any CRC stages. Atropine and 4-DAMP suppressed the proliferation and migration of human CRC cells, induced apoptosis, and decreased PD-L1, PD-L2, and M3R expression in CRC cells via inhibition of EGFR and phosphorylation of ERK. CONCLUSIONS: The expression of immunosuppressive and cholinergic markers may increase the risk of recurrence of CRC. These markers might be used in determining prognosis and treatment regimens for CRC patients. Blocking cholinergic signaling may be a potential therapeutic for CRC through anti-proliferation and anti-migration via inhibition of EGFR and phosphorylation of ERK. These effects allow the immune system to recognize and eliminate cancer cells.

Involvement of the prefrontal cortex in motor sequence learning: A functional near-infrared spectroscopy (fNIRS) study.

Our previous functional near-infrared spectroscopy (fNIRS) study on motor sequence learning (Polskaia et al., 2020) did not detect the same decrease in activity in the left dorsolateral prefrontal cortex (DLPFC) associated with movement automaticity, as reported by Wu et al. (2004). This was partly attributed to insufficient practice time to reach neural efficiency. Therefore, we sought to expand on our previous work to better understand the contribution of the prefrontal cortex (PFC) to motor sequence learning by examining learning across a longer period of time. Participants were randomly assigned to one of two groups: control or trained. fNIRS was acquired at three time points: pre-test, post-test, and retention. Participants performed four sequences (S1, S2, S3, and S4) of right-hand finger tapping. The trained group also underwent four days of practice of S1 and S2. No group differences in the left DLPFC and ventrolateral (VLPFC) were found between sessions for S1 and S2. Our findings revealed increased contribution from the right VLPFC in post-test for the trained group, which may reflect the active retrieval of explicit information from long-term memory. Our results suggest that despite additional practice time, explicit motor sequence learning requires the continued involvement of the PFC.

Exploring ambivalence toward pregnancy among young Inuit women.

Ambivalence toward pregnancy is an important predictor of early pregnancy as documented in diverse Western societies. Inuit women from Nunavik, a northern region of Quebec, Canada, experience a high rate of early pregnancy, yet no study has explored their attitudes toward pregnancy. Grounded in a participatory approach, this study aimed to explore ambivalence toward pregnancy, among other pregnancy-related attitudes, and identify themes underlying ambivalence among young Inuit women from Nunavik. We conducted semi-structured interviews with 15 women aged 16 to 20 years, who became pregnant during the year preceding the interview. We used an inductive approach to analyse the data. Eleven participants were identified as ambivalent toward pregnancy while three were characterised as having a favourable attitude, and one as unfavourable. Four themes related to ambivalence were identified: the value of childbearing/motherhood; the use of contraceptives; the likelihood of becoming pregnant; and the ideal age to become pregnant. A better understanding of young women's attitudes toward pregnancy could contribute to the development of culturally relevant programmes to more effectively support adolescents, pregnant adolescents and young mothers, and to lead to better care.

Pomegranate bioactive constituents target multiple oncogenic and oncosuppressive signaling for cancer prevention and intervention.

Cancer remains to be the second highest cause of mortality in our society, falling just short of heart disease. Despite major advancement in cancer therapy over the past decade, momentum has been gaining for an alternative approach of using naturally-occurring and dietary agents for cancer prevention and management. Research on pomegranate (Punica granatum L.), a fruit of the Punicaceae family, has shown enormous potential for cancer prevention and intervention. In addition to a rich source of polyphenols, including flavonoids and ellagitannins, in its juice, pomegranate also houses hundreds of other phytochemicals in its pericarp, seed, flower, bark, flowers and leaves. These phytochemicals provide powerful antiproliferative, anti-inflammatory, antioxidant, anti-invasive, antimigratory, anti-angiogenic and anti-metastatic effects without significant toxicity. This makes the use of its various extracts a very attractive strategy to our current battle against cancer. This review article presents a systematic, comprehensive and critical review of research on pomegranate-derived products in both cancer prevention and intervention. It discusses the chemical constituents of pomegranate, the results of both preclinical (in vitro, ex vivo and in vivo) and clinical studies on the anticancer effect of pomegranate phytochemicals and molecular targets in numerous types of cancers, such as breast, gastrointestinal tract (oral, colon, liver and pancreas), gynecological (uterine and ovarian), hematological (lymphoma, leukemia and myeloma), lung, neurological (glioma), urogenital (bladder and prostate), bioavailability, pharmacokinetics and safety of pomegranate constituents. In order to guide the direction of future research, we have also included current limitations and challenges in the field and our post analysis recommendation.

Exploring cognitive and brain oxygenation changes over a 1-year period in physically active individuals with mild cognitive impairment: a longitudinal fNIRS pilot study.

BACKGROUND: Aging is associated with an increased likelihood of developing dementia, but a growing body of evidence suggests that certain modifiable risk factors may help prevent or delay dementia onset. Among these, physical activity (PA) has been linked to better cognitive performance and brain functions in healthy older adults and may contribute to preventing dementia. The current pilot study investigated changes in behavioral and brain activation patterns over a 1-year period in individuals with mild cognitive impairment (MCI) and healthy controls taking part in regular PA. METHODS: Frontal cortical response during a dual-task walking paradigm was investigated at baseline, at 6 months (T6), and at 12 months (T12) by means of a portable functional Near-Infrared Spectroscopy (fNIRS) system. The dual-task paradigm included a single cognitive task (2-back), a single motor task (walking), and a dual-task condition (2-back whilst walking). RESULTS: Both groups showed progressive improvement in cognitive performance at follow-up visits compared to baseline. Gait speed remained stable throughout the duration of the study in the control group and increased at T6 for those with MCI. A significant decrease in cortical activity was observed in both groups during the cognitive component of the dual-task at follow-up visits compared to baseline, with MCI individuals showing the greatest improvement. CONCLUSIONS: The observations of this pilot study suggest that taking part in regular PA may be especially beneficial for both cognitive performance and brain functions in older adulthood and, especially, in individuals with MCI. Our findings may serve as preliminary evidence for the use of PA as a potential intervention to prevent cognitive decline in individuals at greater risk of dementia.

Patient journey mapping to investigate quality and cultural safety in burn care for Aboriginal and Torres Strait Islander children and families - development, application and implications.

BACKGROUND: Quality and safety in Australian healthcare is inequitably distributed, highlighted by gaps in the provision of quality care for Aboriginal and Torres Strait Islander children. Burns have potential for long-term adverse outcomes, and quality care, including culturally safe care, is critical to recovery. This study aimed to develop and apply an Aboriginal Patient Journey Mapping (APJM) tool to investigate the quality of healthcare systems for burn care with Aboriginal and Torres Strait Islander children. STUDY DESIGN: Interface research methodology, using biomedical and cultural evidence, informed the modification of an existing APJM tool. The tool was then applied to the journey of one family accessing a paediatric tertiary burn care site. Data were collected through yarning with the family, case note review and clinician interviews. Data were analysed using Emden's core story and thematic analysis methods. Reflexivity informed consideration of the implications of the APJM tool, including its effectiveness and efficiency in eliciting information about quality and cultural safety. RESULTS: Through application of a modified APJM tool, gaps in quality care for Aboriginal and Torres Strait Islander children and families were identified at the individual, service and system levels. Engagement in innovative methodology incorporating more than biomedical standards of care, uncovered critical information about the experiences of culturally safe care in complex patient journeys. CONCLUSION: Based on our application of the tool, APJM can identify and evaluate specific aspects of culturally safe care as experienced by Aboriginal and Torres Strait Islander peoples and be used for quality improvement.

Blocking Muscarinic Receptor 3 Attenuates Tumor Growth and Decreases Immunosuppressive and Cholinergic Markers in an Orthotopic Mouse Model of Colorectal Cancer.

Tumor cells have evolved to express immunosuppressive molecules allowing their evasion from the host's immune system. These molecules include programmed death ligands 1 and 2 (PD-L1 and PD-L2). Cancer cells can also produce acetylcholine (ACh), which plays a role in tumor development. Moreover, tumor innervation can stimulate vascularization leading to tumor growth and metastasis. The effects of atropine and muscarinic receptor 3 (M3R) blocker, 1,1-dimethyl-4-diphenylacetoxypiperidinium iodide (4-DAMP), on cancer growth and spread were evaluated in vitro using murine colon cancer cell line, CT-26, and in vivo in an orthotopic mouse model of colorectal cancer. In the in vitro model, atropine and 4-DAMP significantly inhibited CT-26 cell proliferation in a dose dependent manner and induced apoptosis. Atropine attenuated immunosuppressive markers and M3R via inhibition of EGFR/AKT/ERK signaling pathways. However, 4-DAMP showed no effect on the expression of PD-L1, PD-L2, and choline acetyltransferase (ChAT) on CT-26 cells but attenuated M3R by suppressing the phosphorylation of AKT and ERK. Blocking of M3R in vivo decreased tumor growth and expression of immunosuppressive, cholinergic, and angiogenic markers through inhibition of AKT and ERK, leading to an improved immune response against cancer. The expression of immunosuppressive and cholinergic markers may hold potential in determining prognosis and treatment regimens for colorectal cancer patients. This study's results demonstrate that blocking M3R has pronounced antitumor effects via several mechanisms, including inhibition of immunosuppressive molecules, enhancement of antitumor immune response, and suppression of tumor angiogenesis via suppression of the AKT/ERK signaling pathway. These findings suggest a crosstalk between the cholinergic and immune systems during cancer development. In addition, the cholinergic system influences cancer evasion from the host's immunity.

Methamphetamine Induces Systemic Inflammation and Anxiety: The Role of the Gut-Immune-Brain Axis.

Methamphetamine (METH) is a highly addictive drug abused by millions of users worldwide, thus becoming a global health concern with limited management options. The inefficiency of existing treatment methods has driven research into understanding the mechanisms underlying METH-induced disorders and finding effective treatments. This study aims to understand the complex interactions of the gastrointestinal-immune-nervous systems following an acute METH dose administration as one of the potential underlying molecular mechanisms concentrating on the impact of METH abuse on gut permeability. Findings showed a decreased expression of tight junction proteins ZO-1 and EpCAm in intestinal tissue and the presence of FABP-1 in sera of METH treated mice suggests intestinal wall disruption. The increased presence of CD45+ immune cells in the intestinal wall further confirms gut wall inflammation/disruption. In the brain, the expression of inflammatory markers Ccl2, Cxcl1, IL-1ß, TMEM119, and the presence of albumin were higher in METH mice compared to shams, suggesting METH-induced blood-brain barrier disruption. In the spleen, cellular and gene changes are also noted. In addition, mice treated with an acute dose of METH showed anxious behavior in dark and light, open field, and elevated maze tests compared to sham controls. The findings on METH-induced inflammation and anxiety may provide opportunities to develop effective treatments for METH addiction in the future.

Coronary artery disease and its impact on the pulsatile brain: A functional NIRS study.

Recent studies have reported that optical indices of cerebral pulsatility are associated with cerebrovascular health in older adults. Such indices, including cerebral pulse amplitude and the pulse relaxation function (PRF), have been previously applied to quantify global and regional cerebral pulsatility. The aim of the present study was to determine whether these indices are modulated by cardiovascular status and whether they differ between individuals with low or high cardiovascular risk factors (LCVRF and HCVRF) and coronary artery disease (CAD). A total of 60 older adults aged 57-79 were enrolled in the study. Participants were grouped as LCVRF, HCVRF, and CAD. Participants were asked to walk freely on a gym track while a near-infrared spectroscopy (NIRS) device recorded hemodynamics data. Low-intensity, short-duration walking was used to test whether a brief cardiovascular challenge could increase the difference of pulsatility indices with respect to cardiovascular status. Results indicated that CAD individuals have higher global cerebral pulse amplitude compared with the other groups. Walking reduced global cerebral pulse amplitude and PRF in all groups but did not increase the difference across the groups. Instead, walking extended the spatial distribution of cerebral pulse amplitude to the anterior prefrontal cortex when CAD was compared to the CVRF groups. Further research is needed to determine whether cerebral pulse amplitude extracted from data acquired with NIRS, which is a noninvasive, inexpensive method, can provide an index to characterize the cerebrovascular status associated with CAD.

Dissecting systemic racism: policies, practices and epistemologies creating racialized systems of care for Indigenous peoples.

In this paper we explore some of the ways systemic racism operates and is maintained within our health and social services. We look at a very specific context, that of Nunavik Quebec, land and home to 13,000 Nunavimmiut, citizens of Quebec and Canada, signatories of the James Bay and Northern Quebec Agreement. We operationalize some of the ways in which policies and practices create and support social hierarchies of knowledges, also called epistemic racism, and how it impacts our ability to offer quality care that Indigenous peoples can trust and use.

On the move: exploring Inuit and non-Inuit health service providers' perspectives about youth, family and community participation in care in Nunavik.

BACKGROUND: Literature about participation in health and social services suggests that youth, and more specifically Indigenous youth, are difficult to engage within health and social services. Youth are less likely to access services or to actively participate in decision-making regarding their personal care. Service providers play a crucial role in engaging youth based on the ways in which they seek, establish, and maintain relationships with youth and their families. The way in which providers engage with youth will depend on various factors including their own perceptions of the roles and relationships of the various people involved in youth's lives. In this article, we analyze health and social service providers' perspectives, experiences and expectations regarding the roles of Indigenous youth, families and community in care settings in Nunavik, Quebec. METHODS: Using a snowball sampling approach, we recruited 58 interview participants (39 non-Inuit and 19 Inuit), including psychiatrists, general practitioners, nurses, social workers, school principals, teachers, student counsellors, representatives of local committees, and police officers. The interviews focused on three broad areas: 1) participants' current and past positions and roles; 2) participants' perceptions of the clientele they work with (youth and their families); and 3) participants' understandings of how collaboration takes place within and between services and the community. We conducted inductive applied thematic analyses and then analyzed the interview transcripts of Inuit and non-Inuit participants separately to explore the similarities and differences in perceptions based on positionality. RESULTS: We organized the findings around three themes: I) the most commonly described interventions, II) different types of challenges to and within participation; and III) what successful participation can look like according to service providers. Participants identified the challenges that families face in moving towards services as well as the challenges that services providers face in moving towards youth and families, including personal, organizational and historical factors. CONCLUSION: We adopt a critical lens to reflect on the key findings in order to tease out points of tension and paradoxes that might hinder the participation of youth and families, specifically in a social context of decolonization and self-governance of services.

Anti-Cancer Effects of Carnosine-A Dipeptide Molecule.

BACKGROUND: Carnosine is a dipeptide molecule (ß-alanyl-l-histidine) with anti-inflammatory, antioxidant, anti-glycation, and chelating properties. It is used in exercise physiology as a food supplement to increase performance; however, in vitro evidence suggests that carnosine may exhibit anti-cancer properties. METHODS: In this study, we investigated the effect of carnosine on breast, ovarian, colon, and leukemic cancer cell proliferation. We further examined U937 promonocytic, human myeloid leukemia cell phenotype, gene expression, and cytokine secretion to determine if these are linked to carnosine's anti-proliferative properties. RESULTS: Carnosine (1) inhibits breast, ovarian, colon, and leukemic cancer cell proliferation; (2) upregulates expression of pro-inflammatory molecules; (3) modulates cytokine secretion; and (4) alters U937 differentiation and phenotype. CONCLUSION: These effects may have implications for a role for carnosine in anti-cancer therapy.

A functional near-infrared spectroscopy (fNIRS) examination of how self-initiated sequential movements become automatic.

The neural mechanisms underlying movement automaticity have been investigated using PET and fMRI and more recently functional near-infrared spectroscopy (fNIRS). As fNIRS is an emerging technique, the objective of the present study was to replicate the functional magnetic resonance imaging-related motor sequence findings as reported by Wu et al. (J Neurophysiol 91:1690-1698, https://doi.org/10.1152/jn.01052.2003, 2004) using fNIRS. Seventeen right-handed participants practiced self-initiated sequential finger movements of two lengths (4 and 12) until a level of automaticity was achieved. Automaticity was evaluated by performing a visual-letter-counting task concurrently with the sequential finger movements. Our data were unable to replicate the pre-to-post-practice decrease in cortical activity in the left dorsolateral prefrontal cortex for both motor sequence tasks. The findings did reveal increased contribution from the right hemisphere following learning. The observed lateralization is suggestive of explicit learning and the involvement of working memory in motor sequence production.

Ageism and COVID-19: what does our society's response say about us?

The goal of this commentary is to highlight the ageism that has emerged during the COVID-19 pandemic. Over 20 international researchers in the field of ageing have contributed to this document. This commentary discusses how older people are misrepresented and undervalued in the current public discourse surrounding the pandemic. It points to issues in documenting the deaths of older adults, the lack of preparation for such a crisis in long-term care homes, how some 'protective' policies can be considered patronising and how the initial perception of the public was that the virus was really an older adult problem. This commentary also calls attention to important intergenerational solidarity that has occurred during this crisis to ensure support and social-inclusion of older adults, even at a distance. Our hope is that with this commentary we can contribute to the discourse on older adults during this pandemic and diminish the ageist attitudes that have circulated.

Leucocyte-Rich Platelet-Rich Plasma Enhances Fibroblast and Extracellular Matrix Activity: Implications in Wound Healing.

BACKGROUND: Platelet-rich plasma (PRP) is an autologous blood product that contains a high concentration of platelets and leucocytes, which are fundamental fibroblast proliferation agents. Literature has emerged that offers contradictory findings about leucocytes within PRP. Herein, we elucidated the effects of highly concentrated leucocytes and platelets on human fibroblasts. METHODS: Leucocyte-rich, PRP (LR-PRP) and leucocyte-poor, platelet-poor plasma (LP-PPP) were compared to identify their effects on human fibroblasts, including cell proliferation, wound healing and extracellular matrix and adhesion molecule gene expressions. RESULTS: The LR-PRP exhibited 1422.00 ± 317.21 × 103 platelets/µL and 16.36 ± 2.08 × 103 white blood cells/µL whilst the LP-PPP demonstrated lower concentrations of 55.33 ± 10.13 × 103 platelets/µL and 0.8 ± 0.02 × 103 white blood cells/µL. LR-PRP enhanced fibroblast cell proliferation and cell migration, and demonstrated either upregulation or down-regulation gene expression profile of the extracellular matrix and adhesion molecules. CONCLUSION: LR-PRP has a continuous stimulatory anabolic and ergogenic effect on human fibroblast cells.

Cross-sectional comparison of spiral versus block integrated curriculums in preparing medical students to diagnose and manage concussions.

BACKGROUND: An integrated curriculum is designed to be repetitive yet progressive and the concept has rapidly established itself within medical education. National organizations have recommended a shift to a spiral curriculum design, which uses both vertical and horizontal integration. This study examined differences between the recently implemented integrated spiral (class of 2019) and conventional block (classes of 2016-2018) MD curricula at the University of British Columbia (UBC) with respect to knowledge of concussion. METHODS: Cross-sectional online survey (FluidSurveys: Fluidware, Ottawa, ON), distributed via email to UBC medical students during the 2015-2016 academic year. Questions focused on demographic data, knowledge of concussion definition, and management considerations. Differences in responses across the two groups were assessed using chi-square tests. Ordinal Likert-scale data were analyzed using Mann-Whitney U-Tests. Statistical significance was determined a priori at p < 0.05. RESULTS: One hundred forty eight medical students (57% female) responded with 78 students in the spiral curriculum and 70 students the block curriculum. Important differences between responses from spiral versus block curricula students included: formal exposure to concussion-related educational material (10.8 h spiral vs. 3.95 h block), understanding concussions can occur without direct head impacts (90% spiral vs. 70% block, X21,148 = 9.41, p = 0.002) and identifying long-term consequences (dementia: 90% spiral vs. 66% block, X21,148 = 12.57, p < 0.0001; second impact syndrome: 80% spiral vs. 57% block, X21,148 = 8.60, p = 0.003; Parkinsonism: 47% spiral vs. 17% block, X21,148 = 14.87, p < 0.001). Block students identified the need for a full neurological exam (X21,148 = 17.63, p < 0.001) and had greater clinical exposure to acute concussion (47% block vs. 14% spiral, X21,148 = 19.27, p < 0.001) and post-concussion syndrome (37% block vs. 19% spiral, X21,148 = 5.91, p = 0.015). CONCLUSIONS: The findings from this preliminary study suggest the spiral curriculum design, which emphasizes and revisits clinical competencies, promotes a strong understanding and retention of knowledge in highly prevalent clinical conditions such as concussion.