Network-Based Transcriptome Analysis Reveals FAM3C as a Novel Potential Biomarker for Glioblastoma.

Glioblastoma (GBM) is the most common form of malignant primary brain tumor with a high mortality rate. The aim of the present study was to investigate the clinical significance of Family with Sequence Similarity 3, Member C, FAM3C, in GBM using bioinformatic-integrated analysis. First, we performed the transcriptomic integration analysis to assess the expression profile of FAM3C in GBM using several data sets (RNA-sequencing and scRNA-sequencing), which were obtained from TCGA and GEO databases. By using the STRING platform, we investigated FAM3C-coregulated genes to construct the protein-protein interaction network. Next, Metascape, Enrichr, and CIBERSORT databases were used. We found FAM3C high expression in GBM with poor survival rates. Further, we observed, via FAM3C coexpression network analysis, that FAM3C plays key roles in several hallmarks of cancer. Surprisingly, we also highlighted five FAM3C­coregulated genes overexpressed in GBM. Specifically, we demonstrated the association between the high expression of FAM3C and the abundance of the different immune cells, which may markedly worsen GBM prognosis. For the first time, our findings suggest that FAM3C not only can be a new emerging biomarker with promising therapeutic values to GBM patients but also gave a new insight into a potential resource for future GBM studies.

Sexual Dimorphism in the Polarization of Cardiac ILCs through Elabela.

Elabela is a component of the apelinergic system and may exert a cardioprotective role by regulating the innate immune responses. Innate lymphoid cells (ILCs) have a significant role in initiating and progressing immune-inflammatory responses. While ILCs have been intensively investigated during the last decade, little is known about their relationship with the apelinergic system and their cardiac diversity in a gender-based paradigm. In this study, we investigated the polarization of cardiac ILCs by Elabela in males versus females in a mouse model. Using flow cytometry and immunohistochemistry analyses, we showed a potential interplay between Elabela and cardiac ILCs and whether such interactions depend on sexual dimorphism. Our findings showed, for the first time, that Elabela is expressed by cardiac ILCs, and its expression is higher in females' ILC class 3 (ILC3s) compared to males. Females had higher frequencies of ILC1s, and Elabela was able to suppress T-cell activation and the expression of co-stimulatory CD28 in a mixed lymphocyte reaction assay (MLR). In conclusion, our results suggest, for the first time, a protective role for Elabela through its interplay with ILCs and that it can be used as an immunotherapeutic target in the treatment of cardiovascular disorders in a gender-based fashion.

White-Eyed Orbital Blowout Fracture With Oculocardiac Reflex Secondary to Extraocular Entrapment in a Pediatric Patient.

White-eyed orbital blowout fractures in the pediatric population can present with acute onset diplopia, ophthalmalgia, and abnormal duction. These findings are attributed to the tendency of younger bone to break and reapproximate owing to greater elasticity. This phenomenon, commonly referred to as the greenstick fracture, increases the risk of entrapment of surrounding soft tissue structures in orbital floor fractures. Further concern arises in the presence of an oculocardiac reflex, which requires urgent intervention to prevent serious bradycardia. Prolonged entrapment can go unnoticed and result in irreversible ischemic damage to entrapped tissues. This case discusses the presentation 16-year-old female who sustained a left sided, white-eyed blowout fracture from a face-first ground level fall. On admission, she displayed restrictive strabismus and mild periorbital edema around the left eye. Vertical gaze was restricted when looking inferiorly on the affected side. With sustained upward gaze, her heart rate decreased from 99 to 81 beats per minute. High-resolution non-contrast computed tomography scans of the head showed entrapment of the inferior rectus muscle and periorbital fat. Liberation of entrapped tissues with reduction of bony segments was performed urgently, utilizing a MEDPOR® Titan 3D orbital floor plate and secured with two screws. The patient had an uneventful postoperative period and showed considerable improvements in periorbital edema, duction, and ophthalmalgia on the affected side. In addition, the oculocardiac reflex could no longer be elicited on prolonged upward gaze. Mild and improving paresthesia was noted in the maxillary distribution of the left trigeminal nerve. Sensory deficits like this are the result of fracture communication with the infraorbital canal, which may cause irritation of the infraorbital nerve responsible for sensation by the maxillary division. By postoperative week 7, she had complete resolution of periorbital edema, indiscernible duction abnormalities, and complete healing of surgical incision sites, and an oculocardiac reflex could not be elicited.

Cannabidiol (CBD) modulation of apelin in acute respiratory distress syndrome.

Considering lack of target-specific antiviral treatment and vaccination for COVID-19, it is absolutely exigent to have an effective therapeutic modality to reduce hospitalization and mortality rate as well as to improve COVID-19-infected patient outcomes. In a follow-up study to our recent findings indicating the potential of Cannabidiol (CBD) in the treatment of acute respiratory distress syndrome (ARDS), here we show for the first time that CBD may ameliorate the symptoms of ARDS through up-regulation of apelin, a peptide with significant role in the central and peripheral regulation of immunity, CNS, metabolic and cardiovascular system. By administering intranasal Poly (I:C), a synthetic viral dsRNA, while we were able to mimic the symptoms of ARDS in a murine model, interestingly, there was a significant decrease in the expression of apelin in both blood and lung tissues. CBD treatment was able to reverse the symptoms of ARDS towards a normal level. Importantly, CBD treatment increased the apelin expression significantly, suggesting a potential crosstalk between apelinergic system and CBD may be the therapeutic target in the treatment of inflammatory diseases such as COVID-19 and many other pathologic conditions.

Cannabinoids as a Potential New and Novel Treatment for Melanoma: A Pilot Study in a Murine Model.

BACKGROUND: Malignant melanoma is a complex malignancy with significant morbidity and mortality. The incidence continues to rise, and despite advances in treatment, the prognosis is poor. Thus, it is necessary to develop novel strategies to treat this aggressive cancer. Synthetic cannabinoids have been implicated in inhibiting cancer cell proliferation, reducing tumor growth, and reducing metastasis. We developed a unique study focusing on the effects of treatment with a cannabinoid derivative on malignant melanoma tumors in a murine model. METHODS: Murine B16F10 melanoma tumors were established subcutaneously in C57BL/6 mice. Mice were then treated with intraperitoneal injections of vehicle twice per week (control-group 1, n = 6), Cisplatin 5 mg/kg/wk (group 2; n = 6), and Cannabidiol (CBD) 5 mg/kg twice per week (group 3; n = 6). Tumors were measured and volume calculated as (4π/3) × (width/2)2 × (length/2). Tumor size and survival curves were measured. Results were compared using a one-way ANOVA with multiple comparison test. RESULTS: A significant decrease in tumor size was detected in mice treated with CBD when compared with the control group (P = 0.01). The survival curve of melanoma tumors treated with CBD increased when compared with the control group and was statistically significant (P = 0.04). The growth curve and survival curve of melanoma tumors treated with Cisplatin were significantly decreased and increased, respectively, when compared with the control and CBD-treated groups. Mice treated with Cisplatin demonstrated the longest survival time, but the quality of life and movement of CBD-treated mice were observed to be better. CONCLUSIONS: We demonstrate a potential beneficial therapeutic effect of cannabinoids, which could influence the course of melanoma in a murine model. Increased survival and less tumorgenicity are novel findings that should guide research to better understand the mechanisms by which cannabinoids could be utilized as adjunctive treatment of cancer, specifically melanoma. Further studies are necessary to evaluate this potentially new and novel treatment of malignant melanoma.

Whole Body Vibration-Induced Omental Macrophage Polarization and Fecal Microbiome Modification in a Murine Model.

Human nutrient metabolism, developed millions of years ago, is anachronistic. Adaptive features that offered survival advantages are now great liabilities. The current dietary pattern, coupled with massively reduced physical activities, causes an epidemic of obesity and chronic metabolic diseases, such as type 2 diabetes mellitus. Chronic inflammation is a major contributing factor to the initiation and progression of most metabolic and cardiovascular diseases. Among all components of an innate immune system, due to their dual roles as phagocytic as well as antigen-presenting cells, macrophages play an important role in the regulation of inflammatory responses, affecting the body's microenvironment and homeostasis. Earlier studies have established the beneficial, anti-inflammatory effects of whole body vibration (WBV) as a partial exercise mimetic, including reversing the effects of glucose intolerance and hepatic steatosis. Here for the first time, we describe potential mechanisms by which WBV may improve metabolic status and ameliorate the adverse consequences through macrophage polarization and altering the fecal microbiome.

Venous Thromboembolism Incidence After Craniofacial Surgery.

INTRODUCTION: Current protocols for venous thromboembolism (VTE) prophylaxis after craniofacial surgery (CFS) vary widely with substantial disagreements in both indications and managements. An evidence-based approach to this issue requires the following: the incidence of postoperative VTE, comorbidities associated with coagulopathy, risk reduction after VTE prophylaxis, and complications attributable to prophylaxis. This study addresses the first two. DESIGN: Retrospective cross-sectional study. METHODS: Discharge data from 64,170 patients undergoing CFS between 2008 and 2013 extracted from the Healthcare Cost and Utilization Project Nationwide Inpatient Sample were analyzed. The outcome measures extracted were: deep venous thrombosis, pulmonary embolism, demographic data, common comorbidities, length of stay, total cost, and discharge outcome. RESULTS: Diagnoses of deep venous thrombosis or pulmonary embolism, collectively classified as VTE, were observed in 355 (0.55%) of 64,170 patients discharged after CFS. Other surgeries exhibited a VTE rate of 1.17%. Men exhibited nearly double the incidence of VTE relative to women (0.69% compared with 0.37% respectively, P < 0.001), and the risk factors of adulthood, advanced age, cardiovascular disease, obesity, and malignancy were associated with increased VTE incidence with odds ratios of 9.93, 3.66, 1.80, 2.02, and 2.02, respectively (P < 0.005). Tobacco use did not exhibit any significant association (odds ratio, 0.94; P = 0.679). Afflicted patients experienced 4.60 times longer hospital stays averaging 23.8 days (95% confidence interval, 21.4-26.2; P < 0.001) compared the average of 5.2 days experienced by CFS patients without VTE. They incurred an average cost of US $298,228 (95% confidence interval, 262,726 to 333,731; P < 0.001) which was 4.17 times the US $72,376 expense of treating other CFS patients. The likelihood for a CFS patient to experience a poor outcome at the time of discharge was 54.6% higher after VTE. CONCLUSIONS: The risk of postoperative VTE after CFS is significantly increased in adults, patients with advanced age, cardiovascular disease, obesity, and malignancy. However even in those high-risk cases, postoperative VTE incidence remains relatively low after CFS. These findings in conjunction with further study regarding the risk associated with the addition of VTE chemoprophylaxis compared against mechanical VTE prophylaxis, such as sequential pneumatic compression stockings, may determine whether routine use of VTE chemoprophylaxis is appropriate.

Aesthetic Unit Boundary Approach to Large Fibroadenoma Resection.

BACKGROUND: Fibroadenomas are the most common benign breast tumors in adolescents. Surgical excision is indicated when the tumor becomes large or symptomatic. Multiple approaches have been described. However, unsightly scars, excess skin, and breast asymmetry are common challenges after tumor resection. The aims of our study were to describe a concentric circumareolar approach combining the round-block technique and geometric principles in the management of large benign breast tumors. METHODS: This was a retrospective review of pediatric patients who have undergone excision of large fibroadenoma with concentric circumareolar approach from June 2007 to May 2017. Preoperatively, the excess skin that needed to be resected was marked based on geometric principles. Under general anesthesia, circumareolar deepithelialization of the excess skin and tumor resection were performed. Purse-string suture technique was used to achieve the proper nipple-areola complex size. RESULTS: Satisfactory breast symmetry and minimal scarring were achieved in all 6 patients. One patient developed a small seroma, which resolved spontaneously without intervention. CONCLUSIONS: Concentric circumareolar approach can be used to resect large benign breast tumors while concealing the scar along the aesthetic unit boundary of the breast. The cosmetic outcome and recovery were promising. The approach is simple to execute, highly reproducible, and less dependent on intuition.

Thyroxine Exposure Effects on the Cranial Base.

Thyroid hormone is important for skull bone growth, which primarily occurs at the cranial sutures and synchondroses. Thyroid hormones regulate metabolism and act in all stages of cartilage and bone development and maintenance by interacting with growth hormone and regulating insulin-like growth factor. Aberrant thyroid hormone levels and exposure during development are exogenous factors that may exacerbate susceptibility to craniofacial abnormalities potentially through changes in growth at the synchondroses of the cranial base. To elucidate the direct effect of in utero therapeutic thyroxine exposure on the synchondroses in developing mice, we provided scaled doses of the thyroid replacement drug, levothyroxine, in drinking water to pregnant C57BL6 wild-type dams. The skulls of resulting pups were subjected to micro-computed tomography analysis revealing less bone volume relative to tissue volume in the synchondroses of mouse pups exposed in utero to levothyroxine. Histological assessment of the cranial base area indicated more active synchondroses as measured by metabolic factors including Igf1. The cranial base of the pups exposed to high levels of levothyroxine also contained more collagen fiber matrix and an increase in markers of bone formation. Such changes due to exposure to exogenous thyroid hormone may drive overall morphological changes. Thus, excess thyroid hormone exposure to the fetus during pregnancy may lead to altered craniofacial growth and increased risk of anomalies in offspring.

Effects of thyroxine exposure on the Twist 1 +/- phenotype: A test of gene-environment interaction modeling for craniosynostosis.

BACKGROUND: Craniosynostosis, the premature fusion of one or more of the cranial sutures, is estimated to occur in 1:1800 to 2500 births. Genetic murine models of craniosynostosis exist, but often imperfectly model human patients. Case, cohort, and surveillance studies have identified excess thyroid hormone as an agent that can either cause or exacerbate human cases of craniosynostosis. METHODS: Here we investigate the influence of in utero and in vitro exogenous thyroid hormone exposure on a murine model of craniosynostosis, Twist 1 +/-. RESULTS: By 15 days post-natal, there was evidence of coronal suture fusion in the Twist 1 +/- model, regardless of exposure. With the exception of craniofacial width, there were no significant effects of exposure; however, the Twist 1 +/- phenotype was significantly different from the wild-type control. Twist 1 +/- cranial suture cells did not respond to thyroxine treatment as measured by proliferation, osteogenic differentiation, and gene expression of osteogenic markers. However, treatment of these cells did result in modulation of thyroid associated gene expression. CONCLUSION: Our findings suggest the phenotypic effects of the genetic mutation largely outweighed the effects of thyroxine exposure in the Twist 1 +/- model. These results highlight difficultly in experimentally modeling gene-environment interactions for craniosynostotic phenotypes. Birth Defects Research (Part A) 106:803-813, 2016. © 2016 Wiley Periodicals, Inc.

Tissue Dynamics: Lessons Learned From Sutural Morphogenesis and Cancer Growth.

UNLABELLED: Why are cranial sutures the way they are? How do cancers grow? Merging physics and mathematics with biology, we develop equations describing these complex adaptive systems, to which all biological entities belong, calling them laws of tissue dynamics:Where t is time, E is energy, M is body mass, X is the biological characteristic of interest, C is a constant, a is an exponent.(1) is based on conservation of matter: for any given tissue, materials in must equal to materials out +/- assimilated or degraded. (2) is based on energy conservation. All living systems require energy, without which life becomes impossible. Equation (2) is a power spectrum. OBJECTIVES: This study aimed to introduce the laws of tissue dynamics and to illustrate them using observations from craniofacial and cancer growth. METHODS: We use cranial sutures as a model system to test Equation (1), we also measure the in vitro growth rate of normal murine liver and spleen cells, comparing them to B16F10 melanoma cells. We show the increase in compound growth rate and energetic requirement of malignant versus normal cells as partial proof of Equation (2). RESULTS: The constant width and wavy form of cranial sutures are the inevitable results of repeated iteration from coupling of growth and stress. The compound growth rate of B10F16 melanoma cells exceeds that of normal cells by 1.0 to 1.5%, whereas their glucose uptake is equal to 3.6 billion glucose molecules/cell per minute. SUMMARY: Living things are complex adaptive systems, thus a different way of thinking and investigating, going beyond the current reductive approach, is required.

Selective serotonin reuptake inhibitor exposure alters osteoblast gene expression and craniofacial development in mice.

BACKGROUND: Selective serotonin reuptake inhibitor (SSRI) use in pregnancy has been linked to craniofacial birth defects. Little is known about the effects of serotonin or SSRIs on craniofacial development. Here, we provide evidence that citalopram (SSRI) alters the osteogenic profile of murine calvarial cells and leads to craniofacial dysmorphology. METHODS: We used mouse calvarial pre-osteoblast cells (MC3T3-E1) to study the biochemical profile (microarray and quantitative reverse transcription polymerase chain reactions) after treatment with a titrated dose of citalopram. We used C57BL-6 wild-type breeders to produce litters treated with a clinical dose of citalopram during the third trimester of pregnancy. We used micro-computed tomography and morphometric measures to determine effects on craniofacial development. RESULTS: Controls included untreated cells and age matched untreated litters. We observed decreases in proliferation and increases in alkaline phosphatase activity after citalopram exposure. We confirmed altered expression of genes linked to osteogenesis including Ocn and significant increase in expression of Alp after 7 days of treatment. Our data suggest altered expression of several genes related to craniofacial development (Fgf2, Fgfr2, Tgfßr2 Irs1, Igf1) and statistically significant changes in expression for (Col2a1, Gdf6, Hmox1, and Notch1). We also observed changes in regulation of the serotonin pathway (Sert, Tph1, Tph2, Htr2a, Lrp5) after treatment with citalopram. After in utero exposure to citalopram, mice displayed shorter narrow snouts, more globular skulls and several craniofacial anomalies. CONCLUSION: Our results provide confirmatory evidence that citalopram exposure is associated with cellular and morphological alterations of the craniofacial complex, which may have important implications for use during pregnancy.

The impact of electronic medical record implementation on the outpatient volumes of a midsize academic center.

BACKGROUND: Despite the proposed clinical advantages of electronic medical records (EMRs), many questions remain regarding how EMRs may limit the number of patients a provider can see on a day-to-day basis. In this study, we measured the impact of EMR implementation on outpatient volumes in the setting of a midsize academic medical center (AMC) in the southeast. METHODS: The AMC outpatient visit volumes of two 12-month periods, one before and one after the EMR implementation, were collected. The mean monthly outpatient visits before and after EMR implementation were compared using the 2-tailed Student t test without assumption for equal variance. We also normalized the total annual visits to the number of full-time equivalent physicians. Power calculation was performed to measure type II error whenever P value was greater than 0.05. RESULTS: There was an 8.37% increase in total outpatient visits after EMR implementation, with the monthly number of patients seen increasing from a mean (SD) of 25,763.75 (1673.96) to 27,919.92 (2229.07) (P = 0.018). However, this increase disappears when normalized to full-time equivalent. After conducting multiple subunit analyses of a multiphysician primary care clinic (Family Medicine), specialty clinic (Plastic Surgery), and single-physician specialty clinic (Pediatric Plastic Surgery), we also did not find a statistically significant difference in outpatient clinic volumes after EMR implementation. CONCLUSIONS: Despite the burdensome time requirements many physicians subjectively attribute to EMRs, this study shows that the EMR has not really caused a statistically significant decrease in outpatient volumes in the setting of a midsize AMC.

Reprofiling synthetic glucocorticoid-induced leucine zipper fusion peptide as a novel and effective hair growth promoter.

Hair is a biofilament with unique multi-dimensional values. In human, in addition to physiologic impacts, hair loss and hair related disorders can affect characteristic features, emotions, and social behaviors. Despite significant advancement, there is a dire need to explore alternative novel therapies with higher efficacy, less side effects and lower cost to promote hair growth to treat hair deficiency. Glucocorticoid-induced leucine zipper (GILZ) is a protein rapidly induced by glucocorticoids. Studies from our group and many others have suggested that a synthetic form of GILZ, TAT-GILZ, a fusion peptide of trans-activator of transcription and GILZ, can function as a potent regulator of inflammatory responses, re-establishing and maintaining the homeostasis. In this study, we investigate whether TAT-GILZ could promote and contribute to hair growth. For our pre-clinical model, we used 9-12 week-old male BALB/c and nude (athymic, nu/J) mice. We applied TAT-GILZ and/or TAT (vehicle) intradermally to depilated/hairless mice. Direct observation, histological examination, and Immunofluorescence imaging were used to assess the effects and compare different treatments. In addition, we tested two current treatment for hair loss/growth, finasteride and minoxidil, for optimal evaluation of TAT-GILZ in a comparative fashion. Our results showed, for the first time, that synthetic TAT-GILZ peptide accelerated hair growth on depilated dorsal skin of BALB/c and induced hair on the skin of athymic mice where hair growth was not expected. In addition, TAT-GILZ was able to enhance hair follicle stem cells and re-established the homeostasis by increasing counter inflammatory signals including higher regulatory T cells and glucocorticoid receptors. In conclusion, our novel findings suggest that reprofiling synthetic TAT-GILZ peptide could promote hair growth by increasing hair follicle stem cells and re-establishing homeostasis.

Altering biomolecular condensates as a potential mechanism that mediates cannabidiol effect on glioblastoma.

Glioblastoma (GBM) is an extremely aggressive primary brain tumor with poor prognosis, short survival time post-diagnosis and high recurrence. Currently, no cure for GBM exists. The identification of an effective therapeutic modality for GBM remains a high priority amongst medical professionals and researches. In recent studies, inhalant cannabidiol (CBD) has demonstrated promise in effectively inhibiting GBM tumor growth. However, exactly how CBD treatment affects the physiology of these tumor cells remains unclear. Stress granules (SG) (a sub-class of biomolecular condensates (BMC)) are dynamic, membrane-less intracellular microstructures which contain proteins and nucleic acids. The formation and signaling of SGs and BMCs plays a significant role in regulating malignancies. This study investigates whether inhaled CBD may play an intervening role towards SGs in GBM tumor cells. Integrated bioinformatics approaches were preformed to gain further insights. This includes use of Immunohistochemistry and flow cytometry to measure SGs, as well as expression and phosphorylation of eukaryotic initiation factor-2α (eIF2α). The findings of this study reveal that CBD receptors (and co-regulated genes) have the potential to play an important biological role in the formation of BMCs within GBM. In this experiment, CBD treatment significantly increased the volume of TIAR-1. This increase directly correlated with elevation in both eIF2α expression and p-eIF2α in CBD treated tissues in comparison to the placebo group (p < 0.05). These results suggest that inhalant CBD significantly up-regulated SGs in GBM, and thus support a theory of targeting BMCs as a potential therapeutic substrate for treating GBM.

Inhalant Cannabidiol Inhibits Glioblastoma Progression Through Regulation of Tumor Microenvironment.

Introduction: Glioblastoma (GBM) is the most common invasive brain tumor composed of diverse cell types with poor prognosis. The highly complex tumor microenvironment (TME) and its interaction with tumor cells play important roles in the development, progression, and durability of GBM. Angiogenic and immune factors are two major components of TME of GBM; their interplay is a major determinant of tumor vascularization, immune profile, as well as immune unresponsiveness of GBM. Given the ineffectiveness of current standard therapies (surgery, radiotherapy, and concomitant chemotherapy) in managing patients with GBM, it is necessary to develop new ways of treating these lethal brain tumors. Targeting TME, altering tumor ecosystem may be a viable therapeutic strategy with beneficial effects for patients in their fight against GBM. Materials and Methods: Given the potential therapeutic effects of cannabidiol (CBD) in a wide spectrum of diseases, including malignancies, we tested, for the first time, whether inhalant CBD can inhibit GBM tumor growth using a well-established orthotopic murine model. Optical imaging, histology, immunohistochemistry, and flow cytometry were employed to describe the outcomes such as tumor progression, cancer cell signaling pathways, and the TME. Results: Our findings showed that inhalation of CBD was able to not only limit the tumor growth but also to alter the dynamics of TME by repressing P-selectin, apelin, and interleukin (IL)-8, as well as blocking a key immune checkpoint-indoleamine 2,3-dioxygenase (IDO). In addition, CBD enhanced the cluster of differentiation (CD) 103 expression, indicating improved antigen presentation, promoted CD8 immune responses, and reduced innate Lymphoid Cells within the tumor. Conclusion: Overall, our novel findings support the possible therapeutic role of inhaled CBD as an effective, relatively safe, and easy to administer treatment adjunct for GBM with significant impacts on the cellular and molecular signaling of TME, warranting further research.

Inhalant cannabidiol impedes tumor growth through decreased tumor stemness and impaired angiogenic switch in NCI-H1437-induced human lung cancer model.

Lung cancer remains the most chronic form of cancer and the leading cause of cancer mortality in the world. Despite significant improvements in the treatment of lung cancer, the current therapeutic interventions are only partially effective, necessitating the continued search for better, novel alternative treatments. Angiogenesis and cancer stem cells play a central role in the initiation and propagation of cancers. Tumor angiogenesis is triggered by an angiogenic switch when pro-angiogenic factors exceed anti-angiogenic components. Although many anti-angiogenic agents are used in cancer treatment, there are therapeutic limitations with significant side effects. In recent years, cannabinoids have been investigated extensively for their potential anti-neoplastic effects. Our previous findings showed that cannabidiol (CBD) could impede tumor growth in mouse models of melanoma and glioblastoma. Importantly, CBD has been suggested to possess anti-angiogenic activity. In this study, we tested, for the first time, inhalant CBD in the treatment of heterotopic lung cancer and whether such potential effects could reduce cancer stem cell numbers and inhibit tumor angiogenesis. We implanted NCI H1437 human lung cancer cells in nude mice and treated the mice with inhalant CBD or placebo. The outcomes were measured by tumor size and imaging, as well as by immunohistochemistry and flow cytometric analysis for CD44, VEGF, and P-selectin. Our findings showed that CBD decreased tumor growth rate and suppressed expression of CD44 and the angiogenic factors VEGF and P-selectin. These results suggest, for the first time, that inhalant CBD can impede lung cancer growth by suppressing CD44 and angiogenesis.

Analysis of the jugular foramen in pediatric patients with craniosynostosis.

INTRODUCTION: Intracranial hypertension due to craniosynostosis is a dreaded potential complication that affects the developing brain. We hypothesized that craniosynostotic patients have significantly reduced jugular foramen (JF) when compared with age-matched controls. This may partially account for the observed increase in intracranial pressure (ICP) seen in some of these patients. We also estimated the potential effects on ICP using the Hagen-Poiseuille equation. MATERIALS AND METHODS: Two institutional review board-approved groups were included in this study. Group 1 consists of 14 randomly selected craniosynostotic patients (7 boys and 7 girls; mean age, 9.33 mo; range, 0.6-21 mo). Group 2, the control group, consists of 27 children without craniosynostosis (13 boys and 14 girls; mean age, 8.71 mo; range, 0.23-45 mo). The same neuroradiologist used axial computed tomographic scans to measure the greatest anterior-posterior (AP) and lateral diameters of the jugular bulb. RESULTS: The right JF AP diameter is 23.02% smaller in group 1 than in group 2 (P = 0.0066, 2-tailed t-test). The left JF AP diameter was also smaller for group 1 but was not statistically significant (P = 0.257, 2-tailed t-test). Group 1 also had a nonsignificant increase in both lateral diameters (P > 0.05). DISCUSSION: The study showed a significant decrease (23.02%) in the right JF AP dimension in children with craniosynostosis. On the basis of the Hagen-Poiseuille equation, a 23.02% AP diameter reduction in 1 JF may theoretically increase the ICP 63.5% or 6.35 mm Hg, keeping all other variables, such as blood flow, constant. Although not supported by aspect ratio analysis, the slight increase in the lateral diameters of the patients' JFs may lessen this effect.

High Levels of Interferon-Alpha Expressing Macrophages in Human Breast Milk During SARS-CoV-2 Infection: A Case Report.

Introduction: In addition to hand washing and wearing masks, social distancing and reducing exposure time to <15 minutes are the most effective measures against the spread of COVID-19. Unfortunately, three of these guidelines are very difficult, if not impossible, for nursing babies: they cannot wear masks, stay six feet away from the lactating breasts, nor consistently finish within 15 minutes while nursing. We report a case of a nursing mother with SARS-CoV-2 infection, documenting changes of immune cells and cytokines in breast milk with and without the infection. Case Description: With Institutional Review Board (IRB) approval, we obtained expressed breast milk samples from a lactating mother before and during SARS-CoV-2 infection as documented by reverse transcription-PCR. Using flow cytometry analysis, we measured the immune cell profiles and expression of cytokines such as interferon alpha (IFNα) in milk leukocytes before and during infection. Results: There was an eightfold increase in IFNα+ milk leukocytes, from 1% before SARS-CoV-2 infection to 8% when actively infected. The milk macrophages showed the highest increase in IFNα expression. Both T and B lymphocytes showed mild increase. Innate lymphoid cells, neutrophils, and natural killer cells showed no increase in IFNα expression and the dendritic cells actually showed a reduction. Conclusion: We document the presence and high expression of IFNα in the breast milk macrophages of a lactating mother with confirmed COVID-19, compared with her milk before the infection.

Inflammaging and Cannabinoids.

Aging is a complex phenomenon associated with a wide spectrum of physical and physiological changes affecting every part of all metazoans, if they escape death prior to reaching maturity. Critical to survival, the immune system evolved as the principal component of response to injury and defense against pathogen invasions. Because how significantly immune system affects and is affected by aging, several neologisms now appear to encapsulate these reciprocal relationships, such as Immunosenescence. The central part of Immunosenescence is Inflammaging -a sustained, low-grade, sterile inflammation occurring after reaching reproductive prime. Once initiated, the impact of Inflammaging and its adverse effects determine the direction and magnitudes of further Inflammaging. In this article, we review the nature of this vicious cycle, we will propose that phytocannabinoids as immune regulators may possess the potential as effective adjunctive therapies to slow and, in certain cases, reverse the pathologic senescence to permit a more healthy aging.