Mechanisms of cancer pain

Personalised and targeted interventions have revolutionised cancer treatment and dramatically improved survival rates in recent decades. Nonetheless, effective pain management remains a problem for patients diagnosed with cancer, who continue to suffer from the painful side effects of cancer itself, as well as treatments for the disease. This problem of cancer pain will continue to grow with an ageing population and the rapid advent of more effective therapeutics to treat the disease. Current pain management guidelines from the World Health Organisation are generalised for different pain severities, but fail to address the heterogeneity of mechanisms in patients with varying cancer types, stages of disease and treatment plans. Pain is the most common complaint leading to emergency unit visits by patients with cancer and over one-third of patients that have been diagnosed with cancer will experience under-treated pain. This review summarises preclinical models of cancer pain states, with a particular focus on cancer-induced bone pain and chemotherapy-associated pain. We provide an overview of how preclinical models can recapitulate aspects of pain and sensory dysfunction that is observed in patients with persistent cancer-induced bone pain or neuropathic pain following chemotherapy. Peripheral and central nervous system mechanisms of cancer pain are discussed, along with key cellular and molecular mediators that have been highlighted in animal models of cancer pain. These include interactions between neuronal cells, cancer cells and non-neuronal cells in the tumour microenvironment. Therapeutic targets beyond opioid-based management are reviewed for the treatment of cancer pain

Physiologic osteoclasts are not sufficient to induce skeletal pain in mice

Background: Increased bone resorption is driven by augmented osteoclast activity in pathological states of the bone, including osteoporosis, fracture and metastatic bone cancer. Pain is a frequent co‐morbidity in bone pathologies and adequate pain management is necessary for symptomatic relief. Bone cancer is associated with severe skeletal pain and dysregulated bone remodelling, while increased osteoclast activity and bone pain are also observed in osteoporosis and during fracture repair. However, the effects of altered osteoclast activity and bone resorption on nociceptive processing of bone afferents remain unclear. / Methods: This study investigates whether physiologic osteoclasts and resulting changes in bone resorption can induce skeletal pain. We first assessed correlation between changes in bone microarchitecture (through µCT) and skeletal pain using standardized behavioural phenotyping assays in a mouse model of metastatic bone cancer. We then investigated whether increased activity of physiologic osteoclasts, and the associated bone resorption, is sufficient to induce skeletal pain using mouse models of localized and widespread bone resorption following administration of exogenous receptor activator of nuclear factor kappa‐B ligand (RANKL). / Results: Our data demonstrates that mice with bone cancer exhibit progressive pain behaviours that correlate with increased bone resorption at the tumour site. Systemic RANKL injections enhance osteoclast activity and associated bone resorption, without producing any changes in motor function or pain behaviours at both early and late timepoints. / Conclusion: These findings suggest that activation of homeostatic osteoclasts alone is not sufficient to induce skeletal pain in mice. / Significance statement: The role of osteoclasts in peripheral sensitization of sensory neurones is not fully understood. This study reports on the direct link between oestrogen‐independent osteoclast activation and skeletal pain. Administration of exogenous receptor activator of nuclear factor kappa‐B ligand (RANKL) increases bone resorption, but does not produce pro‐nociceptive changes in behavioural pain thresholds. Our data demonstrates that physiologic osteoclasts are not essential for skeletal pain behaviours

Cohort-based kernel principal component analysis with Multi-path Service Routing in Federated Learning

Federated Learning (FL) is a machine learning (ML) strategy that is performed in a decentralized environment. The training is performed locally by the client on the global model shared by the server. Federated learning has recently been used as a service (FLaaS) to provide a collaborative training environment to independent third-party applications. However, the widespread adoption in distributed settings of FL has opened venues for a number of security attacks. A number of studies have been performed to prevent multiple FL attacks. However, sophisticated attacks, such as label-flipping attacks, have received little or no attention. From the said perspective, this research is focused on providing a defense mechanism for the aforesaid attack. The proposed approach is based on Type-based Cohorts (TC) with Kernel Principal Component Analysis (KPCA) to detect and defend against label-flipping attacks. Moreover, to improve the performance of the network, we will deploy Multi-path Service Routing (MSR) for edge nodes to work effectively. The KPCA will be used to secure the network from attacks. The proposed mechanism will provide an effective and secure FL system. The proposed approach is evaluated with respect to the following measures: execution time, memory consumption, information loss, accuracy, service request violations, and the request’s waiting time

In vivo characterization of distinct modality-specific subsets of somatosensory neurons using GCaMP

Mechanistic insights into pain pathways are essential for a rational approach to treating this vast and increasing clinical problem. Sensory neurons that respond to tissue damage (nociceptors) may evoke pain sensations and are typically classified on the basis of action potential velocity. Electrophysiological studies have suggested that most of the C-fiber nociceptors are polymodal, responding to a variety of insults. In contrast, gene deletion studies in the sensory neurons of transgenic mice have frequently resulted in modality-specific deficits. We have used an in vivo imaging approach using the genetically encoded fluorescent calcium indicator GCaMP to study the activity of dorsal root ganglion sensory neurons in live animals challenged with painful stimuli. Using this approach, we can visualize spatially distinct neuronal responses and find that >85% of responsive dorsal root ganglion neurons are modality-specific, responding to either noxious mechanical, cold, or heat stimuli. These observations are mirrored in behavioral studies of transgenic mice. For example, deleting sodium channel Nav1.8 silences mechanical- but not heat-sensing sensory neurons, consistent with behavioral deficits. In contrast, primary cultures of axotomized sensory neurons show high levels of polymodality. After intraplantar treatment with prostaglandin E2, neurons in vivo respond more intensely to noxious thermal and mechanical stimuli, and additional neurons (silent nociceptors) are unmasked. Together, these studies define polymodality as an infrequent feature of nociceptive neurons in normal animals

A Context-aware and Intelligent Framework for the Secure Mission Critical Systems

Recent technological advancements in pervasive systems have shown the poten-tial to address challenges in the military domain. Research developments in mili-tary-based mission-critical systems have refined a lot as in autopilot, sensing true target behavior, battle damage conditions, acquiring and manipulating command control information. However, the application of pervasive systems in the military domain is still evolving. In this paper, an intelligent framework has been pro-posed for mission-critical systems to incorporate advanced heterogeneous com-munication protocols; service-oriented layered structure and context-aware infor-mation manipulation. The proposed framework addresses the limitation of “time-space” constraints in Mission-critical systems that have been improved signifi-cantly. This improvement is courtesy to enhancing situation-aware tactical capa-bilities such as localization, decision significance, strategic span, strategic inten-tions, resource coordination and profiling concerning the situation. A comprehen-sive use case model has been presented for a typical battle-field scenario followed by a comparison of the proposed framework with existing techniques. It is evi-dent from experiments and analyses that the proposed framework provides more effective and seamless interaction with contextual resources to improve tactical capabilities. This is the peer reviewed version of the following article: A Context-aware and Intelligent Framework for the Secure Mission Critical Systems, which has been published in final form in Transactions on Emerging Telecommunications Technologies. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Version

Diffusion of the Cu monomer and dimer on Ag(111): Molecular dynamics simulations and density functional theory calculations

We present results of molecular dynamics (MD) simulations and density functional theory (DFT) calculations of the diffusion of Cu adatom and dimer on Ag(111). We have used potentials generated by the embedded-atom method for the MD simulations and pseudopotentials derived from the projected-augmented-wave method for the DFT calculations. The MD simulations (at three different temperatures: 300, 500, and 700 K) show that the diffusivity has an Arrhenius behavior. The effective energy barriers obtained from the Arrhenius plots are in excellent agreement with those extracted from scanning tunneling microscopy experiments. While the diffusion barrier for Cu monomers on Ag(111) is higher than that reported (both in experiment and theory) for Cu(111), the reverse holds for dimers [which, for Cu(111), has so far only been theoretically assessed]. In comparing our MD result with those for Cu islets on Cu(111), we conclude that the higher barriers for Cu monomers on Ag(111) results from the comparatively large Ag-Ag bond length, whereas for Cu dimers on Ag(111) the diffusivity is taken over and boosted by the competition in optimization of the Cu-Cu dimer bond and the five nearest-neighbor Cu-Ag bonds. Our DFT calculations confirm the relatively large barriers for the Cu monomer on Ag(111)-69 and 75 meV-compared to those on Cu(111) and hint a rationale for them. In the case of the Cu dimer, the relatively long Ag-Ag bond length makes available a diffusion route whose highest relevant energy barrier is only 72 meV and which is not favorable on Cu(111). This process, together with another involving an energy barrier of 83 meV, establishes the possibility of low-barrier intercell diffusion by purely zigzag mechanisms

Students' Feedback of Written Examination: A Public Sector Medical University Experience

Objective: To determine the students’ perceptions regarding the examination in a public sector medical university. Methodology: This cross-sectional study was conducted at Shaheed Zulfiqar Ali Bhutto Medical University Islamabad. An examination feedback proforma was developed to collect the feedback from students appearing for the written exam for MD/MS/MTA during 2015. Multiple variables were assessed and descriptive analysis was done. Results: The feedback proforma was distributed to 98 candidates with response rate was 68.36%. Overall feedback from students about the examination was positive. Majority of the students were satisfied with the process and arrangements of the examination. However a large number of students did not comment on some important issues. Conclusion: Collecting students’ feedback about examination was a good effort to identify our deficiencies and indication for areas of improvement. This study revealed a positive response from students regarding overall management of the examination process

Brainstem facilitations and descending serotonergic controls contribute to visceral nociception but not pregabalin analgesia in rats.

Pro-nociceptive ON-cells in the rostral ventromedial medulla (RVM) facilitate nociceptive processing and contribute to descending serotonergic controls. We use RVM injections of neurotoxic dermorphin-saporin (Derm-SAP) in rats to evaluate the role of putative ON-cells, or μ-opioid receptor-expressing (MOR) neurones, in visceral pain processing. Our immunohistochemistry shows that intra-RVM Derm-SAP locally ablates a substantial proportion of MOR and serotonergic cells. Given the co-localization of these neuronal markers, some RVM ON-cells are serotonergic. We measure visceromotor responses in the colorectal distension (CRD) model in control and Derm-SAP rats, and using the 5-HT(3) receptor antagonist ondansetron, we demonstrate pro-nociceptive serotonergic modulation of visceral nociception and a facilitatory drive from RVM MOR cells. The α(2)δ calcium channel ligand pregabalin produces state-dependent analgesia in neuropathy and osteoarthritis models relating to injury-specific interactions with serotonergic facilitations from RVM MOR cells. Although RVM MOR cells mediate noxious mechanical visceral input, we show that their presence is not a permissive factor for pregabalin analgesia in acute visceral pain

Influence of β-galacto-oligosaccharide on growth performance and components of intestinal barrier in broilers during heat stress

This study aimed to investigate the influence of β-galacto-oligosaccharides (β-GOS) on growth performance, organ development and intestinal microarchitecture of broilers during heat stress. Day-old chicks (n = 125) were divided into five groups. The control or thermoneutral zone group (TNZ) was raised under standard management until the 35th day. Four groups were exposed to cyclic heat stress (35 °C 8 h/d) from the 22nd to the 35th day. The TNZ and heat stress control (HSCT) groups were fed a corn-based diet and HS + 0.1% β-GOS; HS + 0.2% β-GOS; and HS + 0.5% β-GOS were fed a corn-based diet supplemented with β-GOS (0.1%, 0.2%, and 0.5%), respectively. Exposure to heat stress reduced feed consumption, feed efficiency and the relative weight of the liver, bursa of Fabricius, and small intestine, compared with the TNZ group. Morphometric evaluation of the small intestine revealed reduced villus surface area, villus height to crypt depth ratio (VH : CD) and intraepithelial lymphocytes (IELs) in all segments, and reduced acidic goblet cells (AGCs) in the ileum of the HSCT group compared with the TNZ group. Compared with the HSCT group, dietary β-GOS (0.2% and 0.5%) improved the feed efficiency and relative weight of the small intestine. Furthermore, dietary β-GOS (0.1%) increased villus surface area in the duodenum and IEL count in the small intestine compared with the HSCT group. Dietary β-GOS 0.5% increased villi surface area (VSA) in the jejunum and ileum, whereas the IEL count in the small intestine and acidic goblet cells (AGCs) in the jejunum and ileum were reduced compared with the HSCT group. In conclusion, dietary supplementation of β-GOS (0.2% and 0.5%) improved the growth performance and intestinal microarchitecture of broilers during heat exposure, along with partial immune stimulation. Keywords: Feed efficiency, goblet cell, intraepithelial lymphocytes, mucosal architecture, prebiotics, poultry, villus morphometr