A comprehensive overview of radiation therapy impacts of various cancer treatments and pivotal role in the immune system.

The cancer treatment landscape is significantly evolving, focusing on advanced radiation therapy methods to maximize effectiveness and minimize the adverse effects. Recognized as a pivotal component in cancer and disease treatment, radiation therapy (RT) has drawn attention in recent research that delves into its intricate interplay with inflammation and the immune response. This exploration unveils the underlying processes that significantly influence treatment outcomes. In this context, the potential advantages of combining bronchoscopy with RT across diverse clinical scenarios, alongside the targeted impact of brachytherapy, are explored. Concurrently, radiation treatments serve multifaceted roles such as DNA repair, cell elimination, and generating immune stress signaling molecules known as damage-associated molecular patterns, elucidating their effectiveness in treating various diseases. External beam RT introduces versatility by utilizing particles such as photons, electrons, protons, or carbon ions, each offering distinct advantages. Advanced RT techniques contribute to the evolving landscape, with emerging technologies like FLASH, spatially fractionated RT, and others poised to revolutionize the field. The comprehension of RT, striving for improved treatment outcomes, reduced side effects, and facilitating personalized and innovative treatments for cancer and noncancer patients. After navigating these advancements, the goal is fixed to usher in a new era in which RT is a cornerstone of precision and effectiveness in medical interventions. In summarizing the myriad findings, the review underscores the significance of understanding the differential impacts of radiation approaches on inflammation and immune modulation, offering valuable insights for developing innovative therapeutic interventions that harness the immune system in conjunction with RT.

Influence of Intravascular Laser Irradiation of Blood (ILIB) on inflammatory cytokines and nitric oxide in vivo: a systematic review.

The use of Intravascular Laser Irradiation of Blood (ILIB) as a treatment or adjunct tool has been used around the world since the 1980s. So that more professionals can deliver benefits to their patients in different areas of health, it is necessary to understand in depth the mechanisms of laser action at the molecular level, for correct indication and success in the treatment. To analyze works that evaluated the influence of ILIB on inflammatory cytokines and nitric oxide (NO) in animals and humans. The literature search was carried out between February and April 2023 in Pubmed, Medline, Web of Science, SciELO, Lilacs database. The risk of bias was assessed using the bias table where the authors performed the analyzes of all articles with the risk of bias domains. The methodology was defined following the PRISMA guidelines (Preferred Systematic Reviews and MetaAnalysis Report). The search retrieved 135 possibly relevant articles. After removing duplicates, according to the eligibility criteria, evaluation of titles and review of abstracts, in the end, 6 articles were included. An increase in anti-inflammatory cytokines, a decrease in pro-inflammatory cytokines and an increase in NO can be observed. The wavelengths used ranged from 660 to 808 nm when using a low intensity laser and when using a VIP light source 480-3400 nm, they also differed in terms of the light emission pattern. ILIB may be a complementary treatment option for patients who have comorbidities that lead to systemic inflammation.

Low-level laser therapy alleviates periodontal age-related inflammation in diabetic mice via the GLUT1/mTOR pathway.

Diabetes mellitus (DM) is a chronic age-related disease that was recently found as a secondary aging pattern regulated by the senescence associated secretory phenotype (SASP). The purpose of this study is to detect the potential efficacy and the specific mechanisms of low-level laser therapy (LLLT) healing of age-related inflammation (known as inflammaging) in diabetic periodontitis. Diabetic periodontitis (DP) mice were established by intraperitoneal streptozotocin (STZ) injection and oral P. gingivalis inoculation. Low-level laser irradiation (810 nm, 0.1 W, 398 mW/cm2, 4 J/cm2, 10 s) was applied locally around the periodontal lesions every 3 days for 2 consecutive weeks. Micro-CT and hematoxylin-eosin (HE) stain was analyzed for periodontal soft tissue and alveolar bone. Western blots, immunohistochemistry, and immunofluorescence staining were used to evaluate the protein expression changes on SASP and GLUT1/mTOR pathway. The expression of aging-related factors and SASP including tumor necrosis factor-α, interleukin (IL)-1ß, and IL-6 were reduced in periodontal tissue of diabetic mice. The inhibitory effect of LLLT on GLUT1/mTOR pathway was observed by detecting the related factors mTOR, p-mTOR, GLUT1, and PKM2. COX, an intracytoplasmic photoreceptor, is a key component of the anti-inflammatory effects of LLLT. After LLLT treatment a significant increase in COX was observed in macrophages in the periodontal lesion. Our findings suggest that LLLT may regulate chronic low-grade inflammation by modulating the GLUT1/mTOR senescence-related pathway, thereby offering a potential treatment for diabetic periodontal diseases.

Potential of combined red and near-infrared photobiomodulation to mitigate pro-osteoclastic and inflammatory gene expression in human mandibular osteogenic cells.

Appropriate regeneration of jawbone after dental or surgical procedures relies on the recruitment of osteoprogenitor cells able to differentiate into matrix-producing osteoblasts. In this context, photobiomodulation (PBM) has emerged as promising therapy to improve tissue regeneration and to facilitate wound healing processes. The aim of this study was to determine the effect of PBM on human osteoprogenitor cells isolated from mandibular trabecular bone.Bone marrow stromal cell cultures were established from 4 donors and induced toward osteogenic differentiation for 14 days in a standard osteogenic assay. Cells were irradiated with a combined red/near-infrared (NIR) laser following different schedules and expression of osteogenic, matrix-related, osteoclastogenic and inflammatory genes was analyzed by quantitative PCR.Gene expression analysis revealed no overall effects of PBM on osteogenic differentiation. However, a statistically significant reduction was observed in the transcripts of COL1A1 and MMP13, two important genes involved in the bone matrix homeostasis. Most important, PBM significantly downregulated the expression of RANKL, IL6 and IL1B, three genes that are involved in both osteoclastogenesis and inflammation.In conclusion, PBM with a red/NIR laser did not modulate the osteogenic phenotype of mandibular osteoprogenitors but markedly reduced their expression of matrix-related genes and their pro-osteoclastogenic and pro-inflammatory profile.

Unraveling the RAGE-NF-κB pathway: implications for modulating inflammation in diabetic neuropathy through photobiomodulation therapy.

Diabetic peripheral neuropathy (DPN) is a primary complication observed in diabetes that severely affects quality of life. Recent evidence suggests that photobiomodulation (PBM) is a promising therapy against painful conditions and nerve damage. However, the effects of PBM on DPN remains mostly unknown. In the present study, we investigated the efficacy of PBM therapy in modulating proinflammatory cytokine expression in both central and peripheral nervous systems of rats with Streptozotocin (STZ)-induced type 1 diabetes. Male Wistar rats were allocated into control (naïve), diabetic (STZ), and treatment (STZ + PBM) groups. A single intraperitoneal (i.p.) injection of STZ (85 mg/kg) was administered for the induction of diabetes. Animals were subjected to 10 treatment sessions, every other day. The results herein presented indicate that PBM treatment diminishes Receptor for Advanced Glycation End-products (RAGE) and Nuclear Factor Kappa B (NF-Ï°B) expression in peripheral nervous system and suppresses TNF-α expression in central nervous system tissues. Furthermore, PBM-therapy in diabetic rats also induces increased levels of the anti-inflammatory protein IL-10 in both peripheral and central nervous system. Collectively, our findings demonstrate compelling evidence that PBM-therapy modulates cytokine dynamics and influences RAGE/NF-Ï°B axis in a STZ-induced model of type 1 diabetes.

Photobiomodulation, alone or combined with adipose-derived stem cells, reduces inflammation by modulation of microRNA-146a and interleukin-1ß in a delayed-healing infected wound in diabetic rats.

Diabetic wounds are categorized by chronic inflammation, leading to the development of diabetic foot ulcers, which cause amputation and death. Herewith, we examined the effect of photobiomodulation (PBM) plus allogeneic diabetic adipose tissue-derived stem cells (ad-ADS) on stereological parameters and expression levels of interleukin (IL)-1ß and microRNA (miRNA)-146a in the inflammatory (day 4) and proliferation (day 8) stages of wound healing in an ischemic infected (with 2×107 colony-forming units of methicillin-resistant Staphylococcus aureus) delayed healing wound model (IIDHWM) in type I diabetic (TIDM) rats. There were five groups of rats: group 1 control (C); group 2 (CELL) in which rat wounds received 1×106 ad-ADS; group 3 (CL) in which rat wounds received the ad-ADS and were subsequently exposed to PBM(890 nm, 80 Hz, 3.5 J/cm2, in vivo); group 4 (CP) in which the ad-ADS preconditioned by the PBM(630 nm + 810 nm, 0.05 W, 1.2 J/cm2, 3 times) were implanted into rat wounds; group 5 (CLP) in which the PBM preconditioned ad-ADS were implanted into rat wounds, which were then exposed to PBM. On both days, significantly better histological results were seen in all experimental groups except control. Significantly better histological results were observed in the ad-ADS plus PBM treatment correlated to the ad-ADS alone group (p<0.05). Overall, PBM preconditioned ad-ADS followed by PBM of the wound showed the most significant improvement in histological measures correlated to the other experimental groups (p<0.05). On days 4 and 8, IL-1 ß levels of all experimental groups were lower than the control group; however, on day 8, only the CLP group was different (p<0.01). On day 4, miR-146a expression levels were substantially greater in the CLP and CELL groups correlated to the other groups, on day 8 miR-146a in all treatment groups was upper than C (p<0.01). ad-ADS plus PBM, ad-ADS, and PBM all improved the inflammatory phase of wound healing in an IIDHWM in TIDM1 rats by reducing inflammatory cells (neutrophils, macrophages) and IL-1ß, and increasing miRNA-146a. The ad-ADS+PBM combination was better than either ad-ADS or PBM alone, because of the higher proliferative and anti-inflammatory effects of the PBM+ad-ADS regimen.

Q-switched Nd:YAG laser protects human keratinocytes from oxidative stress and inflammation via AhR-Nrf2 pathway.

In recent years, some treatments for esthetic and pathologic skin conditions have increasingly been based on the use of non-ablative neodymium-doped yttrium aluminum garnet (Nd:YAG) laser due to its greater penetration ability than other types of lasers, few contraindications, minimal side effects, no damage for epidermidis and the rapid recovery of the treated patients. The skin is frequently exposed to many stressors such as radiation, toxic substances, metabolites, foods, mechanical insults, and allergen exposition that cause oxidative damage and have a decisive influence on the aging process. The imbalance between reactive oxygen species, reactive nitrogen species, and the malfunctioning of the antioxidant defense system promotes the establishment of an excessive inflammatory process, which can induce various diseases including cancer and neurodegenerative disorders. The present study investigated the cytoprotective function of Q-switched Nd:YAG laser against stress aging and cell injury in HaCaT cells. We evaluated the effect of the laser on antioxidant defenses, inflammation, metalloproteinases' expression, and the AhR-Nrf2 pathway. Q-switched Nd:YAG is able to upregulate the AhR pathway and the expression of IL-6 and TGF-ß, which are involved in wound repair process, and to downregulate the expression of MMP-2 and 9, so preventing the collagen degradation. Q-switched Nd:YAG can stimulate the cellular antioxidant defenses by activating the AhR-Nrf2 system.

Photobiomodulation exerts anti-inflammatory effects on the vascular and cellular phases of experimental inflammatory models.

Photobiomodulation therapy (PBMT) is a non-thermal therapeutic procedure widely used in clinical practice. It is considered an effective modality of treatment for the control of various inflammatory conditions with fewer adverse effects as compared to conventional therapy. However, despite the clinical effects, the mechanisms of action and dosimetric parameters of PBMT are not fully understood. This study was performed to describe the effects of two different doses of PBMT on experimental models of inflammation. Male Swiss mice were administered with 0.9% of saline or phlogistic agents (carrageenan, dextran, serotonin, histamine, or bradykinin) by intra-plantar injection and were treated with PBMT at a dose of 1 or 5 J/cm2; right after, the variation of the paw volume was made, and histopathological analysis and myeloperoxidase assay of the carrageenan-induced edematous paw tissues were performed. The action of PBMT on carrageenan-induced vascular permeability was further evaluated. Our results showed that PBMT (1 J/cm2) led to an improvement in paw edema induced by the phlogistic agents and further reduced the histological scores. Inhibition of neutrophil migration was observed following the administration of 1 and 5 J/cm2 of PBMT. However, only 1 J/cm2 of PBMT showed beneficial effects on carrageenan-induced edema. Laser at a dose of 1 J/cm2 showed cellular and vascular effects since it was able to reverse all the inflammatory parameters, and laser at a dose of 5 J/cm2 probably has only cellular effects in the presence of acute inflammation.

The effect of low-level laser irradiation on the proliferation, osteogenesis, inflammatory reaction, and oxidative stress of human periodontal ligament stem cells under inflammatory conditions.

Periodontitis often causes damage to the periodontal tissue and affects the function of human periodontal ligament stem cells (hPDLSCs). Low-level laser therapy (LLLT) has been used for periodontal treatment and can upregulate the proliferation and osteogenesis of hPDLSCs. The purpose of this study was to investigate the effects of LLLT on the proliferation, osteogenic differentiation, inflammatory reaction, and oxidative stress of hPDLSCs in an inflammatory environment (pPDLSCs). We designed one control group and three testing groups (treated with Nd:YAG laser at 4, 8, and 16 J/cm2) of hPDLSCs from periodontitis patients who were diagnosed with stable phase periodontitis. Cell proliferation was measured by colony-forming unit fibroblast (CFU-F) assays and 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyltetrazolium bromide (MTT) assays. The osteogenic capacity of the cells was determined by alkaline phosphatase (ALP) staining, ALP activity assays, Alizarin Red S staining and the mRNA transcript levels of runt-related transcription factor 2 (Runx2), ALP, and osteocalcin (OCN). The effects of LLLT on the secretion of tumor necrosis factor-α (TNF-α) and interleukin (IL)-1ß by PDLSCs were measured by enzyme-linked immunosorbent assay (ELISA). We also evaluated the oxidative stress of hPDLSCs and pPDLSCs by measuring the reactive oxygen species (ROS) level, malondialdehyde (MDA) level, and superoxide dismutase (SOD) activity after treatment with LLLT at 4, 8, and 16 J/cm2. Our results demonstrated that LLLT could modulate the osteogenic potential of pPDLSCs at 8 J/cm2. Inflammatory stimuli induced excess ROS release, and LLLT at 4-8 J/cm2 promoted oxidative stress levels in hPDLSCs but decreased the expression of inflammatory cytokines and ROS levels in pPDLSCs. Moreover, LLLT at 16 J/cm2 could significantly suppress proliferation and osteogenic differentiation and promote inflammatory cytokines and ROS levels in pPDLSCs. In conclusion, LLLT could regulate proliferation, osteogenesis, inflammatory reaction, and oxidative stress of human periodontal ligament stem cells under inflammatory conditions.

Serum fatty acid binding protein 5 (FABP5) as a potential biomarker of inflammation in psoriasis.

Fatty acid binding protein 5 (FABP5) is elevated in psoriatic keratinocytes and could be involved in systemic metabolic disturbances in psoriasis. The aim of the study was to evaluate serum FABP5 in obese and non-obese psoriatic patients, to assess the relationship between FABP5 and the duration, severity of the disease, inflammatory and metabolic markers and influence of treatment with narrowband-ultraviolet B (NB-UVB). Seventy-four patients (30 treated with NB-UVB) with psoriasis were enrolled in the study. The serum concentrations of FABP5 were measured using Human FABP5 Enzyme-Linked Immunosorbent Assay kit. Serum fatty acids were measured by gas-liquid chromatography. Serum FABP5 levels in psoriatic patients were higher versus control group (P < 0.001). FABP5 in patients with PASI > 20 was higher compared to the mild group (PASI < 10) (P < 0.001) and serum FABP5 correlated positively with PASI score (r = 0.41, P < 0.001). There was also positive correlation between FABP5 and basic inflammation indices. Decrease of PASI after NB-UVB treatment (P < 0.001) was observed and accompanied by decrease of the serum FABP5 (P = 0.007). FABP5 is a potential marker of psoriasis, its severity and clinical outcome after therapy with NB-UVB. FABP5 may reflect metabolic disturbances in psoriatic patients.

Anandamide Concentration-Dependently Modulates Toll-Like Receptor 3 Agonism or UVB-Induced Inflammatory Response of Human Corneal Epithelial Cells.

Photodamage-induced and viral keratitis could benefit from treatment with novel nonsteroid anti-inflammatory agents. Therefore, we determined whether human corneal epithelial cells (HCECs) express members of the endocannabinoid system (ECS), and examined how the endocannabinoid anandamide (AEA, N-arachidonoyl ethanolamine) influences the Toll-like receptor 3 (TLR3) agonism- or UVB irradiation-induced inflammatory response of these cells. Other than confirming the presence of cannabinoid receptors, we show that endocannabinoid synthesizing and catabolizing enzymes are also expressed in HCECs in vitro, as well as in the epithelial layer of the human cornea in situ, proving that they are one possible source of endocannabinoids. p(I:C) and UVB irradiation was effective in promoting the transcription and secretion of inflammatory cytokines. Surprisingly, when applied alone in 100 nM and 10 µM, AEA also resulted in increased pro-inflammatory cytokine production. Importantly, AEA further increased levels of these cytokines in the UVB model, whereas its lower concentration partially prevented the transcriptional effect of p(I:C), while not decreasing the p(I:C)-induced cytokine release. HCECs express the enzymatic machinery required to produce endocannabinoids both in vitro and in situ. Moreover, our data show that, despite earlier reports about the anti-inflammatory potential of AEA in murine cornea, its effects on the immune phenotype of human corneal epithelium may be more complex and context dependent.

Systemic immune-inflammation index predicted overall survival and radiosensitivity in advanced non-small-cell lung cancer.

Aim: To evaluate the predictive significance of systemic immune-inflammation index (SII) on overall survival (OS) and radiosensitivity in advanced non-small-cell lung cancer. Materials & methods: Kaplan-Meier analysis and Cox proportional hazard models were used to assess the prognostic value of SII. Results: The optimal cutoff for SII was 555.59, with an area under the curve of 0.782 (sensitivity: 76.6%, specificity: 71.9%, 95% CI: 0.730-0.833), respectively. Median OS (p < 0.001) in the low SII group (32.8 months) was better than the OS in the high SII group (8.5 months). SII-low group statistically exhibited a better radiosensitivity. Conclusion: SII was an independent prognostic factor for OS and predictive factor for radiosensitivity. Higher level of SII associated with poorer OS and poorer radiosensitivity.

Attenuation of the inflammatory response and polarization of macrophages by photobiomodulation.

In spinal cord injury (SCI), inflammation is a major mediator of damage and loss of function and is regulated primarily by the bone marrow-derived macrophages (BMDMs). Photobiomodulation (PBM) or low-level light stimulation is known to have anti-inflammatory effects and has previously been used in the treatment of SCI, although its precise cellular mechanisms remain unclear. In the present study, the effect of PBM at 810 nm on classically activated BMDMs was evaluated to investigate the mechanisms underlying its anti-inflammatory effects. BMDMs were cultured and irradiated (810 nm, 2 mW/cm2) following stimulation with lipopolysaccharide and interferon-γ. CCK-8 assay, 2',7'-dichlorofluorescein diacetate assay, and ELISA and western blot analysis were performed to measure cell viability, reactive oxygen species production, and inflammatory marker production, respectively. PBM irradiation of classically activated macrophages significantly increased the cell viability and inhibited reactive oxygen species generation. PBM suppressed the expression of a marker of classically activated macrophages, inducible nitric oxide synthase; decreased the mRNA expression and secretion of pro-inflammatory cytokines, tumor necrosis factor alpha, and interleukin-1 beta; and increased the secretion of monocyte chemotactic protein 1. Exposure to PBM likewise significantly reduced the expression and phosphorylation of NF-κB p65 in classically activated BMDMs. Taken together, these results suggest that PBM can successfully modulate inflammation and polarization in classically activated BMDMs. The present study provides a theoretical basis to support wider clinical application of PBM in the treatment of SCI.

Targeted Delivery of Iron Oxide Nanoparticle-Loaded Human Embryonic Stem Cell-Derived Spherical Neural Masses for Treating Intracerebral Hemorrhage.

This study evaluated the potential of iron oxide nanoparticle-loaded human embryonic stem cell (ESC)-derived spherical neural masses (SNMs) to improve the transportation of stem cells to the brain, ameliorate brain damage from intracerebral hemorrhage (ICH), and recover the functional status after ICH under an external magnetic field of a magnet attached to a helmet. At 24 h after induction of ICH, rats were randomly separated into three experimental groups: ICH with injection of phosphate-buffered saline (PBS group), ICH with intravenous injection of magnetosome-like ferrimagnetic iron oxide nanocubes (FION)-labeled SNMs (SNMs* group), and ICH with intravenous injection of FION-labeled SNMs followed by three days of external magnetic field exposure for targeted delivery by a magnet-embedded helmet (SNMs*+Helmet group). On day 3 after ICH induction, an increased Prussian blue-stained area and decreased swelling volume were observed in the SNMs*+Helmet group compared with that of the other groups. A significantly decreased recruitment of macrophages and neutrophils and a downregulation of pro-inflammatory cytokines followed by improved neurological function three days after ICH were observed in the SNMs*+Helmet group. Hemispheric atrophy at six weeks after ICH was significantly decreased in the SNMs*+Helmet group compared with that of the PBS group. In conclusion, we have developed a targeted delivery system using FION tagged to stem cells and a magnet-embedded helmet. The targeted delivery of SNMs might have the potential for developing novel therapeutic strategies for ICH.

Photobiomodulation of the microbiome: implications for metabolic and inflammatory diseases.

The human microbiome is intimately associated with human health, with a role in obesity, metabolic diseases such as type 2 diabetes, and divergent diseases such as cardiovascular and neurodegenerative diseases. The microbiome can be changed by diet, probiotics, and faecal transplants, which has flow-on effects to health outcomes. Photobiomodulation has a therapeutic effect on inflammation and neurological disorders (amongst others) and has been reported to influence metabolic disorders and obesity. The aim of this study was to examine the possibility that PBM could influence the microbiome of mice. Mice had their abdomen irradiated with red (660 nm) or infrared (808 nm) low-level laser, either as single or multiple doses, over a 2-week period. Genomic DNA extracted from faecal pellets was pyrosequenced for the 16S rRNA gene. There was a significant (p < 0.05) difference in microbial diversity between PBM- and sham-treated mice. One genus of bacterium (Allobaculum) significantly increased (p < 0.001) after infrared (but not red light) PBM by day 14. Despite being a preliminary trial with small experimental numbers, we have demonstrated for the first time that PBM can alter microbiome diversity in healthy mice and increase numbers of Allobaculum, a bacterium associated with a healthy microbiome. This change is most probably a result of PBMt affecting the host, which in turn influenced the microbiome. If this is confirmed in humans, the possibility exists for PBMt to be used as an adjunct therapy in treatment of obesity and other lifestyle-related disorders, as well as cardiovascular and neurodegenerative diseases. The clinical implications of altering the microbiome using PBM warrants further investigation.

Photobiomodulation modulates the resolution of inflammation during acute lung injury induced by sepsis.

Sepsis is a big health problem and one of the most common causes of acute lung injury (ALI) leading to high mortality. Pro-resolving mediators play an important role in abrogating the inflammation and promoting tissue homeostasis restoration. ALI treatment is still a clinical health problem, so new therapies are needed. Here, we evaluated the effect of photobiomodulation treatment on the resolution process of ALI induced by lipopolysaccharide (LPS). Male Balb/c mice were submitted to LPS (ip) or vehicle and irradiated or not with light emitting diode (LED) 2 and 6 h after LPS or vehicle injection, and the parameters were investigated 3 and 7 days after the injections. Our results showed that after 3 days of LED treatment the blood and bronchoalveolar lavage (BAL) cells as well as interleukins (IL) including IL-6 and IL-17 were reduced. No differences were observed in the bone marrow cells, tracheal reactivity, and lipoxin A4 and resolvin E2. Indeed, after 7 days of LED treatment the bone marrow cells, lymphocytes, and lipoxin A4 were increased, while IL-6, IL-17, and IL-10 were decreased. No differences were observed in the blood cells and tracheal reactivity. Thus, our results showed that LED treatment attenuated ALI induced by sepsis by modulating the cell mobilization from their reserve compartments. In addition, we also showed later effects of the LED up to 7 days after the treatment. This study proposes photobiomodulation as therapeutic adjuvant to treat ALI.

The effect of low-level laser irradiation on hyperglycemia-induced inflammation in human gingival fibroblasts.

Hyperglycemia-induced inflammation can greatly increase the risk of periodontal disease in people with diabetes. Low-level laser irradiation (LLLI) has been used for wound healing and anti-inflammation in many cases, and LLLI is known to inhibit the lipopolysaccharide (LPS)-stimulated inflammatory response. However, the therapeutic effect of LLLI in diabetes patients with periodontitis remains unknown. In this study, we cultured human gingival fibroblasts (HGFs) in high-glucose medium (35 mM) to mimic a hyperglycemic environment, and then measured the anti-inflammatory effect of LLLI by assessing the expression of pro-inflammatory genes including tumor necrosis factor-α (TNF-α), interleukin (IL)-1ß, IL-6, and IL-8 by quantitative real-time polymerase chain reaction. The results demonstrated no significant inflammatory response in HGFs cultured in mannitol medium and in those treated only with LLLI. However, HGFs cultured only in high-glucose medium showed significantly higher expression of pro-inflammatory cytokine than in those treated together with LLLI. We then observed that LLLI reduced the expression of pro-inflammatory cytokines in HGFs cultured in high-glucose medium by modulating cAMP signaling. We also investigated whether antioxidant (vitamin C) treatment reduced the inflammatory effect of oxidative stress in HGFs cultured in high-glucose medium but found no additive effect upon co-treatment with LLLI, suggesting that LLLI may activate cAMP signaling, but not reactive oxygen species (ROS) signaling, to reduce the high glucose-induced inflammation. In conclusion, LLLI may have an anti-inflammatory effect on HGFs in a high glucose environment and may benefit the treatment of periodontal disease in diabetes patients.

Radiation, inflammation and the immune response in cancer.

Radiation is an important component of cancer treatment with more than half of all patients receive radiotherapy during their cancer experience. While the impact of radiation on tumour morphology is routinely examined in the pre-clinical and clinical setting, the impact of radiation on the tumour microenvironment and more specifically the inflammatory/immune response is less well characterised. Inflammation is a key contributor to short- and long-term cancer eradication, with significant tumour and normal tissue consequences. Therefore, the role of radiation in modulating the inflammatory response is highly topical given the current wave of targeted and immuno-therapeutic treatments for cancer. This review provides a general overview of how radiation modulates the inflammatory and immune response-(i) how radiation induces the inflammatory/immune system, (ii) the cellular changes that take place, (iii) how radiation dose delivery affects the immune response, and (iv) a discussion on research directions to improve patient survival, reduce side effects, improve quality of life, and reduce financial costs in the immediate future. Harnessing the benefits of radiation on the immune response will enhance its maximal therapeutic benefit and reduce radiation-induced toxicity.

Lack of beneficial effects of low-dose radiation therapy on hand osteoarthritis symptoms and inflammation: a randomised, blinded, sham-controlled trial.

OBJECTIVES: Low-dose radiation therapy (LDRT) is widely used as treatment for osteoarthritis (OA) in some countries, while relatively unknown in others. Systematic literature review displayed a lack of high-level evidence for beneficial effects in clinical practice. The aim was to assess the efficacy of LDRT on symptoms and inflammation in hand OA patients in a randomised, blinded, sham-controlled trial, using validated outcome measures. DESIGN: Hand OA patients, ≥50 years, with pain ≥5 (scale 0-10) and non-responding to conservative therapy were included and randomised 1:1 to receive LDRT (6 × 1 Gy in 2 weeks) or sham (6 × 0 Gy in 2 weeks). Primary outcome was the proportion of OMERACT-OARSI responders, 3 months post-intervention. Secondary outcomes were pain and functioning (Australian/Canadian Hand Osteoarthritis Index; AUSCAN), quality of life (Short Form Health Survey; SF36) and inflammatory outcomes: erythrocyte sedimentation rate and C-reactive protein serum levels, effusion, synovial thickening and power Doppler signal on ultrasound (range 0-3). RESULTS: Fifty-six patients were included. After 3 months, no significant difference in responders was observed between groups (LDRT: 8 (29%); sham: 10 (36%); difference -7% (95%CI -31-17%)). Also, differences in clinical and inflammatory outcomes between groups were small and not significant. CONCLUSIONS: We were unable to demonstrate a substantial beneficial effect of LDRT on symptoms and inflammation in patients with hand OA, compared to sham treatment. Although a small effect can not be excluded, a treatment effect exceeding 20% is very unlikely, given the confidence interval. Therefore, in the absence of other high-level evidence, we advise against the use LDRT as treatment for patients with hand OA. CLINICAL TRIAL REGISTRATION NUMBER: NTR4574 (Dutch Trial Register).

Immune modulatory effects of radiotherapy as basis for well-reasoned radioimmunotherapies.

BACKGROUND: Radiotherapy (RT) has been known for decades as a local treatment modality for malign and benign disease. In order to efficiently exploit the therapeutic potential of RT, an understanding of the immune modulatory properties of ionizing radiation is mandatory. These should be used for improvement of radioimmunotherapies for cancer in particular. METHODS: We here summarize the latest research and review articles about immune modulatory properties of RT, with focus on radiation dose and on combination of RT with selected immunotherapies. Based on the knowledge of the manifold immune mechanisms that are triggered by RT, thought-provoking impulse for multimodal radioimmunotherapies is provided. RESULTS: It has become obvious that ionizing radiation induces various forms of cell death and associated processes via DNA damage initiation and triggering of cellular stress responses. Immunogenic cell death (ICD) is of special interest since it activates the immune system via release of danger signals and via direct activation of immune cells. While RT with higher single doses in particular induces ICD, RT with a lower dose is mainly responsible for immune cell recruitment and for attenuation of an existing inflammation. The counteracting immunosuppression emanating from tumor cells can be overcome by combining RT with selected immunotherapies such as immune checkpoint inhibition, TGF-ß inhibitors, and boosting of immunity with vaccination. CONCLUSION: In order to exploit the full power of RT and thereby develop efficient radioimmunotherapies, the dose per fraction used in RT protocols, the fractionation, the quality, and the quantity of certain immunotherapies need to be qualitatively and chronologically well-matched to the individual immune status of the patient.