Photophysical Mechanisms of Photobiomodulation Therapy as Precision Medicine.

Despite a significant focus on the photochemical and photoelectrical mechanisms underlying photobiomodulation (PBM), its complex functions are yet to be fully elucidated. To date, there has been limited attention to the photophysical aspects of PBM. One effect of photobiomodulation relates to the non-visual phototransduction pathway, which involves mechanotransduction and modulation to cytoskeletal structures, biophotonic signaling, and micro-oscillatory cellular interactions. Herein, we propose a number of mechanisms of PBM that do not depend on cytochrome c oxidase. These include the photophysical aspects of PBM and the interactions with biophotons and mechanotransductive processes. These hypotheses are contingent on the effect of light on ion channels and the cytoskeleton, the production of biophotons, and the properties of light and biological molecules. Specifically, the processes we review are supported by the resonant recognition model (RRM). This previous research demonstrated that protein micro-oscillations act as a signature of their function that can be activated by resonant wavelengths of light. We extend this work by exploring the local oscillatory interactions of proteins and light because they may affect global body circuits and could explain the observed effect of PBM on neuro-cortical electroencephalogram (EEG) oscillations. In particular, since dysrhythmic gamma oscillations are associated with neurodegenerative diseases and pain syndromes, including migraine with aura and fibromyalgia, we suggest that transcranial PBM should target diseases where patients are affected by impaired neural oscillations and aberrant brain wave patterns. This review also highlights examples of disorders potentially treatable with precise wavelengths of light by mimicking protein activity in other tissues, such as the liver, with, for example, Crigler-Najjar syndrome and conditions involving the dysregulation of the cytoskeleton. PBM as a novel therapeutic modality may thus behave as "precision medicine" for the treatment of various neurological diseases and other morbidities. The perspectives presented herein offer a new understanding of the photophysical effects of PBM, which is important when considering the relevance of PBM therapy (PBMt) in clinical applications, including the treatment of diseases and the optimization of health outcomes and performance.

Evaluation of Gender Differences in Response to Photobiomodulation Therapy, Including Laser Acupuncture: A Narrative Review and Implication to Precision Medicine.

Background: The influence of gender is significant in the manifestation and response to many diseases and in the treatment strategy. Photobiomodulation (PBM) therapy, including laser acupuncture, is an evidence-based treatment and disease prevention modality that has shown promising efficacy for a myriad of chronic and acute diseases. Anecdotal experience and limited clinical trials suggest gender differences exist in treatment outcomes to PBM therapy. There is preliminary evidence that gender may be as important as skin color in the individual response to PBM therapy. Purpose: To conduct a literature search of publications addressing the effects of gender differences in PBM therapy, including laser acupuncture, to provide a narrative review of the findings, and to explore potential mechanisms for the influence of gender. Methods: A narrative review of the literature on gender differences in PBM applications was conducted using key words relating to PBM therapy and gender. Results: A total of 13 articles were identified. Of these articles, 11 have direct experimental investigations into the response difference in gender for PBM, including laser acupuncture. A variety of cadaver, human, and experimental studies demonstrated results that gender effects were significant in PBM outcome responses, including differences in tendon structural and mechanical outcomes, and mitochondrial gene expression. One cadaver experiment showed that gender was more important than skin tone. The physiologic mechanisms directing gender differences are explored and postulated. Conclusions: The review suggests that to address the requirements of a proficient precision medicine-based strategy, it is important for PBM therapy to consider gender in its treatment plan and dosing prescription. Further research is warranted to determine the correct dose for optimal gender treatment, including gender-specific treatment plans to improve outcomes, taking into account wavelength, energy exposure, intensity, and parameters related to the deliverance of treatment to each anatomical location.

Narrative Review of Russian, Ukrainian and English-Language Publications Investigating the Effects of Photobiomodulation on Red Blood Cell Physiology.

Objective: The beneficial effects of photobiomodulation (PBM) on cellular function are well characterized, principally deriving from the absorption of red to near-infrared radiation by chromophores such as cytochrome-c-oxidase. However, the effects and underlying mechanisms of PBM on non-mitochondria containing cells, such as red blood cells (RBCs), are relatively unknown. In this review, we evaluate studies that investigated the effects of PBM on RBCs in the peripheral circulation, with particular attention on changes in the structural and functional features of RBC membrane dynamics, as well as the potential implications of PBM as an intervention for pathologies related to RBC dysfunction. Methods: A literature review was performed in concordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses protocol, using the following databases: PubMed; Ovid (OvidMedline); Scopus; Web of Science; Google Scholar; Scholar.ru; eLIBRARY.ru; Digital Library: Dissertation; and Russian State Library. Search results included publications in Russian, Ukrainian, and English languages after 1995. Eligible articles included the effects of PBM on RBC membrane morphology and function in the peripheral circulation, used either in isolation or alongside other interventions. Results: The majority of articles indicated beneficial changes in RBC structure and function following exposure to PBM, including increased osmotic resistance, normalization of membrane permeability, decreased free radical oxidation and concentration of intermediate products of lipid peroxidation, reduced phospholipase A2 membrane activity, and normalization of the viscoelastic properties of RBCs and erythrocyte deformability index. Most trials had small patient numbers with no long-term follow-up. Conclusions: The importance of RBC membrane dysfunction as a potential marker and mechanism for RBC pathologies was highlighted. PBM has shown to have membrane protective effects. Further clinical trials are recommended to provide more evidence PBM therapy to treat RBC-related diseases, which may, at the correct dose, improve RBC stability and deformability in RBC-related pathologies.

A Perspective on the Potential of Opsins as an Integral Mechanism of Photobiomodulation: It's Not Just the Eyes.

Objective: To investigate the potential relationship between opsins and photobiomodulation. Background: Opsins and other photoreceptors occur in all phyla and are important in light-activated signaling and organism homeostasis. In addition to the visual opsin systems of the retina (OPN1 and OPN2), there are several non-visual opsins found throughout the body tissues, including encephalopsin/panopsin (OPN3), melanopsin (OPN4), and neuropsin (OPN5), as well as other structures that have light-sensitive properties, such as enzymes, ion channels, particularly those located in cell membranes, lysosomes, and neuronal structures such as the nodes of Ranvier. The influence of these structures on exposure to light, including self-generated light within the body (autofluorescence), on circadian oscillators, and circadian and ultradian rhythms have become increasingly reported. The visual and non-visual phototransduction cascade originating from opsins and other structures has potential significant mechanistic effects on tissues and health. Methods: A PubMed and Google Scholar search was made using the search terms "photobiomodulation", "light", "neuron", "opsins", "neuropsin", "melanopsin", "encephalopsin", "rhodopsin", and "chromophore". Results: This review was examined the influence of neuropsin (also known as kallikrein 8), encephalopsin, and melanopsin specifically on ion channel function, and more broadly on the central and peripheral nervous systems. The relationship between opsins 3, 4, and 5 and photobiomodulation mechanisms was evaluated, along with a proposed role of photobiomodulation through opsins and light-sensitive organelles as potential alleviators of symptoms and accelerators of beneficial regenerative processes. The potential clinical implications of this in musculoskeletal conditions, wounds, and in the symptomatic management of neurodegenerative disease was also examined. Conclusions: Systematic research into the pleotropic therapeutic role of photobiomodulation, mediated through its action on opsins and other light-sensitive organelles may assist in the future execution of safe, low-risk precision medicine for a variety of chronic and complex disease conditions, and for health maintenance in aging.

Anatomical and Clinical Comparison of Small Free Flaps for Repairing Finger Skin Defects.

The reconstruction of finger defects requires improved functional outcomes and acceptable esthetic outcomes, and small free flaps present a good alternative technique for repairing finger skin defects. From January 2006 to December 2018, we investigated the number and diameter of proximal digital artery perforators, medial plantar artery perforators, and peroneal proper plantar digital arteries of the hallux by dissection and then transplanted free digital arterial perforator flaps, free medial plantar flaps, and free peroneal flaps from the hallux to repair small finger skin defects. The number (SD) of perforators from the medial plantar artery was approximately 2.2 (0.5), and these perforators measured 0.53 (0.20) mm in diameter. The diameter (SD) of the first metatarsal dorsal artery was approximately 1.16 (0.30) mm. A total of 25 patients were included in this study. The transplantation times (SD) for free digital arterial perforator flaps, free medial plantar flaps, and free peroneal flaps from the hallux were 3.5 (0.5) hours, 3.2 (0.7) hours, and 2.0 (0.4) hours, respectively. The follow-up period ranged from 8 to 15 months. All flaps survived and were appropriately shaped. The donor site was either covered with a free flap or directly sutured. Among these 3 types of small flaps, the free peroneal flap from the hallux can be recommended for clinical use because of the large diameter of the contributing vessels, the short operative time, the ease of access, and the improved appearance of the donor site.

Activation of Notch signaling by soluble Dll4 decreases vascular permeability via a cAMP/PKA-dependent pathway.

The Notch ligand delta-like ligand 4 (Dll4), upregulated by VEGF, is a key regulator of vessel morphogenesis and function, controlling tip and stalk cell selection during sprouting angiogenesis. Inhibition of Dll4 results in hypersprouting, nonfunctional, poorly perfused vessels, suggesting a role for Dll4 in the formation of mature, reactive, functional vessels, with low permeability and able to restrict fluid and solute exchange. We tested the hypothesis that Dll4 controls transvascular fluid exchange. A recombinant protein expressing only the extracellular portion of Dll4 [soluble Dll4 (sDll4)] induced Notch signaling in endothelial cells (ECs), resulting in increased expression of vascular-endothelial cadherin, but not the tight junctional protein zonula occludens 1, at intercellular junctions. sDll4 decreased the permeability of FITC-labeled albumin across EC monolayers, and this effect was abrogated by coculture with the γ-secretase inhibitor N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester. One of the known molecular effectors responsible for strengthening EC-EC contacts is PKA, so we tested the effect of modulation of PKA on the sDll4-mediated reduction of permeability. Inhibition of PKA reversed the sDll4-mediated reduction in permeability and reduced expression of the Notch target gene Hey1. Knockdown of PKA reduced sDLL4-mediated vascular-endothelial cadherin junctional expression. sDll4 also caused a significant decrease in the hydraulic conductivity of rat mesenteric microvessels in vivo. This reduction was abolished upon coperfusion with the PKA inhibitor H89 dihydrochloride. These results indicate that Dll4 signaling through Notch activation acts through a cAMP/PKA pathway upon intercellular adherens junctions, but not tight junctions, to regulate endothelial barrier function. NEW & NOTEWORTHY Notch signaling reduces vascular permeability through stimulation of cAMP-dependent protein kinase A.

Regulation of human feto-placental endothelial barrier integrity by vascular endothelial growth factors: competitive interplay between VEGF-A165a, VEGF-A165b, PIGF and VE-cadherin.

The human placenta nourishes and protects the developing foetus whilst influencing maternal physiology for fetal advantage. It expresses several members of the vascular endothelial growth factor (VEGF) family including the pro-angiogenic/pro-permeability VEGF-A165a isoform, the anti-angiogenic VEGF-A165b, placental growth factor (PIGF) and their receptors, VEGFR1 and VEGFR2. Alterations in the ratio of these factors during gestation and in complicated pregnancies have been reported; however, the impact of this on feto-placental endothelial barrier integrity is unknown. The present study investigated the interplay of these factors on junctional occupancy of VE-cadherin and macromolecular leakage in human endothelial monolayers and the perfused placental microvascular bed. Whilst VEGF-A165a (50 ng/ml) increased endothelial monolayer albumin permeability (P<0.0001), equimolar concentrations of VEGF-A165b (P>0.05) or PlGF (P>0.05) did not. Moreover, VEGF-A165b (100 ng/ml; P<0.001) but not PlGF (100 ng/ml; P>0.05) inhibited VEGF-A165a-induced permeability when added singly. PlGF abolished the VEGF-A165b-induced reduction in VEGF-A165a-mediated permeability (P>0.05); PlGF was found to compete with VEGF-A165b for binding to Flt-1 at equimolar affinity. Junctional occupancy of VE-cadherin matched alterations in permeability. In the perfused microvascular bed, VEGF-A165b did not induce microvascular leakage but inhibited and reversed VEGF-A165a-induced loss of junctional VE-cadherin and tracer leakage. These results indicate that the anti-angiogenic VEGF-A165b isoform does not increase permeability in human placental microvessels or HUVEC primary cells and can interrupt VEGF-A165a-induced permeability. Moreover, the interplay of these isoforms with PIGF (and s-flt1) suggests that the ratio of these three factors may be important in determining the placental and endothelial barrier in normal and complicated pregnancies.

The role of adjuvant platinum-based chemotherapy in esophagogastric cancer patients who received neoadjuvant chemotherapy prior to definitive surgery.

BACKGROUND AND OBJECTIVES: For patients with operable esophagogastric cancer, peri-operative chemotherapy confers a significant overall survival benefit compared to surgery alone, however only 30-40% of patients demonstrate histopathological response. It is unclear whether those with no neoadjuvant chemotherapy response should go onto receive adjuvant chemotherapy, as no further benefit may be conferred. METHODS: Esophagogastric cancers were prospectively captured with associated histopathological tumor regression grades following neoadjuvant chemotherapy. This cohort was then interrogated for clinico-pathological and survival outcomes. RESULTS: Following neoadjuvant chemotherapy and surgery, patients with chemotherapy responsive cancers, who were administered adjuvant chemotherapy gained a significant overall survival benefit. Multivariate Cox analysis, demonstrated a final adjusted hazard ratio for adjuvant therapy of 0.509; (95%CI 0.28-0.93); P = 0.028. In contrast, patients with non-responsive tumors, who underwent adjuvant chemotherapy, did not show any survival benefit. Chemotherapy toxicity was prevalent and contributed to only half of patients receiving adjuvant chemotherapy. CONCLUSIONS: These results suggest the benefit of the adjuvant portion of chemotherapy is limited to those who demonstrate a histopathological response to neoadjuvant chemotherapy. The administration of the adjuvant portion of chemotherapy to patients without a response to neoadjuvant chemotherapy may not provide any survival benefit, while potentially causing increased morbidity.

Human papillomavirus and host genetic polymorphisms in carcinogenesis: a systematic review and meta-analysis.

BACKGROUND: As the role of human papillomavirus (HPV) in carcinogenesis continues to rise, the role of genetic factors that modify this risk have become increasingly important. In this study, we reviewed the literature for associations between polymorphisms and HPV in carcinogenesis. OBJECTIVE: To identify any associations of genetic polymorphisms with oncogenic HPV in carcinogenesis and to evaluate the methodology used. STUDY DESIGN: Systematic literature review of HPV, genetic polymorphisms, and cancer risk. Odds ratios (OR), interaction terms, and p-values were tabulated. Meta-analyses and measures of heterogeneity were estimated using RevMan 5.1. RESULTS: The cervix was the most frequently studied cancer site followed by the head and neck. Overall risk of cancer (cancer vs. control) was the most common comparison, whereas reports of initiation (pre-cancer vs. control) and progression (cancer vs. pre-cancer) were rare. Case-series and joint-effect of HPV and genotype on risk was evaluated frequently, but the independent effect of either risk factor alone was rarely provided. P53-Arg72Pro was the most commonly studied polymorphism studied. No consistent interaction was detected by meta-analysis in the HPV(+) [OR 0.98 (0.55-1.76)] or the HPV(-) [OR 1.10 (0.76-1.60)] subsets in head and neck cancer risk. Polymorphisms in genes known to encode proteins that physically interact with HPV were infrequently studied. CONCLUSION: No consistent polymorphism-HPV interactions were observed. Study design, choice of candidate polymorphisms/genes, and a focus on overall risk rather than any specific portions of the carcinogenic pathway may have contributed to lack of significant findings.

p53 Arg72Pro polymorphism, HPV status and initiation, progression, and development of cervical cancer: a systematic review and meta-analysis.

Cervical cancer develops through progression from normal cervical epithelium through squamous intraepithelial lesions (SIL) to invasive cancer. Cervical cancer is associated with oncogenic human papillomavirus (HPV). The HPV E6 oncoprotein binds to the tumor suppressor gene product p53, promoting its degradation; the Arg allele of p53 Arg72Pro polymorphism binds more ardently with HPV E6 than the Pro variant. Here we evaluate the role of p53 Arg72Pro polymorphism and HPV status on the initiation, progression, and development of cervical cancer. A systematic review and meta-analysis were conducted. Events of interest were the initiation of neoplasia (SIL vs. normal), progression to invasive cancer (cervical cancer vs. SIL), and risk of invasive cancer (cervical cancer vs. normal) by HPV status. OR were extracted from individual studies and pooled using generic inverse variance and random effects modeling. Forty-nine studies were included. In individuals showing HPV positivity, there was a significantly higher odds of progression from SIL to cervical cancer with the p53 Arg allele [OR 1.37; 95% confidence intervals (CI), 1.15-1.62; P < 0.001]. This association was not seen in HPV-negative individuals. p53 Arg72Pro was not associated with the risk of cervical cancer or initiation of SIL in either HPV-positive or HPV-negative patient subsets. The Arg variant of p53 Arg72Pro is associated with progression of SIL to cervical cancer only in the presence of HPV positivity. There were no associations of this variant with overall risk or initiation of cancer in either HPV-positive or HPV-negative patients. Clin Cancer Res; 18(23); 6407-15.

Vascular endothelial growth factor pathway polymorphisms as prognostic and pharmacogenetic factors in cancer: a systematic review and meta-analysis.

Angiogenesis is an important host process that interacts with cancer cells to promote growth, invasion, and metastasis. Numerous therapeutic agents targeting the VEGF pathway have been developed. Host variability in VEGF pathway can influence angiogenesis-dependent signaling, altering sensitivity to antiangiogenic drugs and prognosis. A systematic review and meta-analysis was conducted (May 1990-July 2011). Eligible studies involved cancer patients and compared polymorphisms in the VEGF pathway [VEGF and molecules directly interacting with VEGF: KDR, FLT1, FGF, FGF2, FGFR, NRP1, endostatin (encoded by COL18A1)], and reported one of the following outcomes: overall survival, progression-free survival, time to recurrence, disease-free survival, response rate, or drug toxicity. We identified 48 cancer studies assessing prognosis and 12 cancer studies exploring pharmacogenetics of anti-VEGF therapy across various VEGF pathway polymorphisms. There was marked inter- and intradisease site heterogeneity in the effect of polymorphisms on both outcome and response to therapy. Meta-analyses of 5 VEGF polymorphisms (+936C>T, -460T>C, +405G>C, -1154G>A, and -2578C>A) identified a significant prognostic relationship: VEGF +405G>C variants showed a highly statistically significant improvement in overall survival [HR, 0.74; 95% confidence interval, 0.60-0.91; P = 0.004]. Variants (heterozygotes and/or homozygotes) of VEGF +405G>C were significantly associated with improved survival in a meta-analysis of multiple cancer sites.