Psychosocial/survivorship issues in breast cancer: are we doing better?

Modern breast cancer treatment offers many women greater prospects of cure or lengthier, good quality survival than was possible in the past. Advances include improved diagnostic and staging procedures, sophisticated onco-plastic surgery, enhanced radiotherapy techniques, and targeted systemic therapies. Much more attention has also been paid to cancer care delivery and access to specialist nurses, counsellors, support groups, and services provided by breast cancer charities. However, there are some concerns that these considerable improvements in treatment delivery and clinical outcomes have not led to similar benefits in the psychosocial, functional, and sexual well-being of women. The impact that non-life threatening, long-term iatrogenic harms of otherwise efficacious anticancer treatments has on patients is often overlooked; this is in part because of the emphasis given to physician-reported safety data in trials and the general exclusion of patient-reported outcomes (PROs). A failure to utilise reliable PRO measures has meant that some problems are underreported, which consequently has hampered much-needed research into ameliorative interventions. Systematic monitoring of quality of life-threatening side effects would permit early implementation of effective interventions and enhance long-term survivorship. Some examples of the pervasive difficulties that continue to affect survivors and evidence that certain interventions might help are provided in this commentary

Role of Neurokinin 1 Receptor in Modulating the Immune-Stimulatory Function of Dendritic Cells

There is a growing body of evidence indicating that the nervous and immune systems cross-talk during inflammatory and immune responses. Secretion of pro-inflammatory neuropeptides from the tachykinin family, including substance P (SP) and hemokinin-1 (HK-1), favors cellular immunity by binding the neurokinin 1 receptor (NK1R) to promote immune cell survival and activation. Dendritic cells (DCs) are essential for the stimulation of cellular immunity; however, the ability of pro-inflammatory tachykinins to affect the immune-stimulatory function of DCs remains elusive. Since DCs home strategically to peripheral and lymphoid tissues where tachykinins are secreted, we hypothesized that signaling via the NK1R enhances DC longevity and their T cell-stimulatory function, including the induction of type-1 CD4+ T cell helper (Th1) and CD8+ cytotoxic T cell (CTL/Tc1) responses. Using DCs generated from murine bone marrow precursors (BMDCs), I describe that BMDCs express functional NK1R, and agonistic signaling via the receptor rescues BMDCs from apoptosis. The immunological relevance of these findings were validated in vivo, as I demonstrate that adoptive transfer of NK1R-signaled BMDCs loaded with antigen (Ag) migrate efficiently to tissue-draining lymph nodes (DLNs) where they survive longer and induce superior type-1 DTH responses compared to adoptive transfer of control Ag-loaded BMDCs. Secondly, I investigated the mechanisms by which NK1R-signaled BMDCs favor cellular immunity, including their ability to generate Th1 and CTL/Tc1 responses. I show that agonistic signaling via the NK1R promotes the maturation of BMDCs and inhibits their secretion of IL-10, and adoptive transfer of NK1R-signaled BMDCs elicits enhanced Ag-specific Th1 and CTL/Tc1 responses. The individual roles of adoptively transferred NK1R-signaled BMDCs and endogenous DCs were further addressed by comparing the development of type-1 immunity in wild-type, IL-12 knockout (IL-12p35-/-) and Diphtheria Toxin Recetor (DTR) transgenic (inducible depletion of CD11c+ DCs) mice. With these models, I demonstrate that generation of robust Ag-specific Th1 and CTL/Tc1 responses requires secretion of IL-12p70 by endogenous DCs and inhibition of IL-10 production by transferred BMDCs. Collectively, our data strongly suggest that adoptive transfer of NK1R-signaled BMDCs promotes enhanced type-1 immunity by mechanisms involving both exogenous and endogenous DC populations

Cigarette smoking disparities among sexual minority cancer survivors

AbstractObjectiveSexual minority (i.e., lesbian, gay, and bisexual) adults smoke cigarettes at higher rates than heterosexual adults. Smoking after receiving a cancer diagnosis is a major health concern, yet risk of continued smoking among sexual minority cancer survivors is as yet unknown. The current study examines current smoking among sexual minority vs. heterosexual adult cancer survivors.MethodData drawn from the 2010 Behavioral Risk Factor Surveillance System survey in five states (Alaska, California, Massachusetts, New Mexico, and Wisconsin) included items about sexual orientation, cancer diagnosis, and tobacco use. The analytic sample included 124 sexual minority and 248 propensity score matched heterosexual adult cancer survivors.ResultsBivariate analysis showed that sexual minority cancer survivors had twice the odds of current smoking as their heterosexual counterparts (OR=2.03, 95%CI:1.09–3.80). In exploratory analyses stratified by sex, sexual minority disparities in prevalence of smoking post-cancer showed a trend toward significance among females, not males.ConclusionThe current study offers preliminary evidence that sexual minority status is one variable among many that must be taken into account when assessing health behaviors post-cancer diagnosis. Future research should identify mechanisms leading from sexual minority status to increased rates of smoking and develop tailored smoking cessation interventions

Effect of systemic transplantation of bone marrow-derived mesenchymal stem cells on neuropathology markers in APP/PS1 Alzheimer mice

Mesenchymal stem cells (MSC) have recently attracted interest as a potential basis for a cell based therapy of AD. We investigated the putative immune-modulatory effects in neuroinflammation of systemic transplantation of MSC into APP/PS1 transgenic mice.10(6) MSC were injected into APP/PS1 mice via the tail vein and histological analysis was performed for microglia and amyloid (pE3-A[beta]) plaque numbers, glial distribution and pE3-A[beta] plaque size. In addition, a biochemical analysis by qPCR for pro-inflammatory, chemoattractant and neurotrophic factors was performed.MSC co-localized with pE3-A[beta] plaques. The effects of transplantation on microglia-associated pathology could be observed after 28 hours. Animals showed a reduction in microglial numbers in the cortex and in size. Gene expression was reduced for TNF-[alpha], IL-6, MCP-1, and for NGF, in MSC recipients. Also, we investigated for the first time and found no changes in expression of IL-10, CCR5, BDNF, VEGF and IFN[gamma]. PTGER2 expression levels were increased in the hippocampus but were reduced in the cortex of MSC recipients. While there were no transplant-related changes in pE3-A[beta] plaque numbers, a reduction in the size of pE3-A[beta] plaques was observed in the hippocampus of transplant recipients.This is the first study to show reduction in pE3-A[beta] plaque size. pE3-A[beta] plaques have gained attention as potential key participants in AD due to their increased aggregation propensity, the possibility for the initial seeding event, resistance against degradation and neurotoxicity. These findings support the hypothesis that MSC-transplants may affect AD pathology via an immune modulatory function that includes an effect on microglial cells

Oral delivery of il-27 recombinant bacteria attenuates immune colitis in mice

BACKGROUND & AIMS: Treatment of inflammatory bowel disease (IBD) would benefit from specific targeting of therapeutics to the intestine. We developed a strategy for localized delivery of the immunosuppressive cytokine IL27, which is actively synthesized in situ by the food-grade bacterium Lactococcuslactis (LL-IL-27), and tested its ability to reduce colitis in mice. METHODS: The 2 genes encoding mouse IL27 were synthesized with optimal codon usage for L lactis and joined with a linker; a signal sequence was added to allow for secretion of the product. The construct was introduced into L lactis. Colitis was induced via transfer of CD4(+)CD45RB(hi) T cells into Rag(−/−) mice to induce colitis; 7.5 weeks later, LL-IL-27 was administered to mice via gavage. Intestinal tissues were collected and analyzed. RESULTS: LL-IL-27 administration protected mice from T-cell transfer-induced enterocolitis and death. LL-IL-27 reduced disease activity scores, pathology features of large and small bowel, and levels of inflammatory cytokines in colonic tissue. LL-IL-27 also reduced numbers of CD4(+) and IL17(+) T cells in gut-associated lymphoid tissue. The effects of LL-IL-27 required production of IL10 by the transferred T cells. LL-IL-27 was more effective than either LL-IL-10 or systemic administration of recombinant IL27 in reducing colitis in mice. LL-IL-27 also reduced colitis in mice following administration of dextran sodium sulfate. CONCLUSIONS: L lactis engineered to express IL27 (LL-IL-27) reduces colitis in mice, by increasing production of IL10. Mucosal delivery of LL-IL-27 could be a more effective and safer therapy for IBD

AVNP2 protects against cognitive impairments induced by C6 glioma by suppressing tumour associated inflammation in rats

© 2020 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/).Glioblastoma is a kind of malignant tumour and originates from the central nervous system. In the last century, some researchers and clinician have noticed that the psychosocial and neurocognitive functioning of patients with malignant gliomas can be impaired. Many clinical studies have demonstrated that part of patients, adults or children, diagnosed with glioblastoma will suffer from cognitive deficiency during their clinical course, especially in long-term survivors. Many nanoparticles (NPs) can inhibit the biological functions of tumours by modulating tumour-associated inflammation, which provokes angiogenesis and tumour growth. As one of the best antiviral nanoparticles (AVNPs), AVNP2 is the 2nd generation of AVNP2 that have been conjugated to graphite-graphene for improving physiochemical performance and reducing toxicity. AVNP2 inactivates viruses, such as the H1N1 and H5N1influenza viruses and even the SARS coronavirus, while it inhibits bacteria, such as MRSA and E. coli. As antimicrobials, nanoparticles are considered to be one of the vectors for the administration of therapeutic compounds. Yet, little is known about their potential functionalities and toxicities to the neurotoxic effects of cancer. Herein, we explored the functionality of AVNP2 on inhibiting C6 in glioma-bearing rats. The novel object-recognition test and open-field test showed that AVNP2 significantly improved the neuro-behaviour affected by C6 glioma. AVNP2 also alleviated the decline of long-term potentiation (LTP) and the decreased density of dendritic spines in the CA1 region induced by C6. Western blot assay and immunofluorescence staining showed that the expressions of synaptic-related proteins (PSD-95 and SYP) were increased, and these findings were in accordance with the results mentioned above. It revealed that the sizes of tumours in C6 glioma-bearing rats were smaller after treatment with AVNP2. The decreased expression of inflammatory factors (IL-1β, IL-6 and TNF-α) by Western blotting assay and ELISA, angiogenesis protein (VEGF) by Western blotting assay and other related proteins (BDNF, NF-ĸB, iNOS and COX-2) by Western blotting assay in peri-tumour tissue indicated that AVNP2 could control tumour-associated inflammation, thus efficiently ameliorating the local inflammatory condition and, to some extent, inhibiting angiogenesis in C6-bearing rats. In conclusion, our results suggested that AVNP2 could have an effect on the peri-tumor environment, obviously restraining the growth progress of gliomas, and eventually improving cognitive levels in C6-bearing rats.Peer reviewedProo

Understanding cognition in older patients with cancer

Cancer and neurocognitive disorders, such as dementia and delirium, are common and serious diseases in the elderly that are accompanied by high degree of morbidity and mortality. Furthermore, evidence supports the under-diagnosis of both dementia and delirium in older adults. Complex questions exist regarding the interaction of dementia and delirium with cancer, beginning with guidelines on how best measure disease severity, the optimal screening test for either disorder, the appropriate level of intervention in the setting of abnormal findings, and strategies aimed at preventing the development or progression of either process. Ethical concerns emerge in the research setting, pertaining to the detection of cognitive dysfunction in participants, validity of consent, disclosure of abnormal results if screening is pursued, and recommended level of intervention by investigators. Furthermore, understanding the ways in which comorbid cognitive dysfunction and cancer impact both cancer and non-cancer-related outcomes is essential in guiding treatment decisions. In the following article, we will discuss what is presently known of the interactions of pre-existing cognitive impairment and delirium with cancer. We will also discuss identified deficits in our knowledge base, and propose ways in which innovative research may address these gaps

Review of the Role of the Brain in Chemotherapy-Induced Peripheral Neuropathy

Chemotherapy-induced peripheral neuropathy (CIPN) is a common, debilitating, and dose-limiting side effect of many chemotherapy regimens yet has limited treatments due to incomplete knowledge of its pathophysiology. Research on the pathophysiology of CIPN has focused on peripheral nerves because CIPN symptoms are felt in the hands and feet. However, better understanding the role of the brain in CIPN may accelerate understanding, diagnosing, and treating CIPN. The goals of this review are to (1) investigate the role of the brain in CIPN, and (2) use this knowledge to inform future research and treatment of CIPN. We identified 16 papers using brain interventions in animal models of CIPN and five papers using brain imaging in humans or monkeys with CIPN. These studies suggest that CIPN is partly caused by (1) brain hyperactivity, (2) reduced GABAergic inhibition, (3) neuroinflammation, and (4) overactivation of GPCR/MAPK pathways. These four features were observed in several brain regions including the thalamus, periaqueductal gray, anterior cingulate cortex, somatosensory cortex, and insula. We discuss how to leverage this knowledge for future preclinical research, clinical research, and brain-based treatments for CIPN

Death anxiety in patients with metastatic non-small cell lung cancer with and without brain metastases

Context: Death anxiety is common in patients with metastatic cancer, but its relationship to brain metastases and cognitive decline is unknown. Early identification of death anxiety and its determinants allows proactive interventions to be offered to those in need. Objectives: To identify psychological, physical, and disease-related (including brain metastases and cognitive impairment) factors associated with death anxiety in metastatic non-small cell lung cancer (mNSCLC) patients. Methods: A cross-sectional pilot study with mNSCLC outpatients completing standardized neuropsychological tests and validated questionnaires measuring death anxiety, cognitive concerns, illness intrusiveness, depression, demoralization, self-esteem, and common cancer symptoms. We constructed a composite for objective cognitive function (mean neuropsychological tests z-scores). Results: Study measures were completed by 78 patients (50% females; median age 62 years [range 37–82]). Median time since mNSCLC diagnosis was 11 months (range 0–89); 53% had brain metastases. At least moderate death anxiety was reported by 43% (n = 33). Objective cognitive impairment was present in 41% (n = 32) and perceived cognitive impairment in 27% (n = 21). Death anxiety, objective, and perceived cognitive impairment did not significantly differ between patients with and without brain metastases. In univariate analysis, death anxiety was associated with demoralization, depression, self-esteem, illness intrusiveness, common physical cancer symptoms, and perceived cognitive impairment. In multivariate analysis, demoralization (P < 0.001) and illness intrusiveness (P = 0.001) were associated with death anxiety. Conclusion: Death anxiety and brain metastases are common in patients with mNSCLC but not necessarily linked. The association of death anxiety with both demoralization and illness intrusiveness highlights the importance of integrated psychological and symptom management. Further research is needed on the psychological impact of brain metastases

RIG-I Mediates Innate Immune Response in Mouse Neurons Following Japanese Encephalitis Virus Infection

Neuroinflammation associated with Japanese encephalitis (JE) is mainly due to the activation of glial cells with subsequent release of proinflammatory mediators from them. The recognition of viral RNA, in part, by the pattern recognition receptor retinoic acid-inducible gene I (RIG-I) has been indicated to have a role in such processes. Even though neurons are also known to express this receptor, its role after JE virus (JEV) infections is yet to be elucidated.Upon infecting murine neuroblastoma cells and primary cortical neurons with JEV the expression profile of key proinflammatory cyto/chemokines were analyzed by qRT-PCR and bead array, both before and after ablation of RIG-I. Immunoblotting was performed to evaluate the levels of key molecules downstream to RIG-I leading to production of proinflammatory mediators. Changes in the intracellular viral antigen expression were confirmed by intracellular staining and immunoblotting. JEV infection induced neuronal expression of IL-6, IL-12p70, MCP-1, IP-10 and TNF-α in a time-dependent manner, which showed significant reduction upon RIG-I ablation. Molecules downstream to RIG-I showed significant changes upon JEV-infection, that were modulated following RIG-I ablation. Ablation of RIG-I in neurons also increased their susceptibility to JEV.In this study we propose that neurons are one of the potential sources of proinflammatory cyto/chemokines in JEV-infected brain that are produced via RIG-I dependent pathways. Ablation of RIG-I in neurons leads to increased viral load and reduced release of the cyto/chemokines