Evaluation of Glutathione in Spike Protein of SARS-CoV-2 Induced Immunothrombosis and Cytokine Dysregulation.

Thrombotic microangiopathy has been identified as a dominant mechanism for increased mortality and morbidity in coronavirus disease 2019 (COVID-19). In the context of severe COVID-19, patients may develop immunothrombosis within the microvasculature of the lungs, which contributes to the development of acute respiratory distress syndrome (ARDS), a leading cause of death in the disease. Immunothrombosis is thought to be mediated in part by increased levels of cytokines, fibrin clot formation, and oxidative stress. Glutathione (GSH), a well-known antioxidant molecule, may have therapeutic effects in countering this pathway of immunothrombosis as decreased levels of (GSH) have been associated with increased viral replication, cytokine levels, and thrombosis, suggesting that glutathione supplementation may be therapeutic for COVID-19. GSH supplementation has never been explored as a means of treating COVID-19. This study investigated the effectiveness of liposomal glutathione (GSH) as an adjunctive therapy for peripheral blood mononuclear cells (PBMC) treated with SARS CoV-2 spike protein. Upon the addition of GSH to cell cultures, cytokine levels, fibrin clot formation, oxidative stress, and intracellular GSH levels were measured. The addition of liposomal-GSH to PBMCs caused a statistically significant decrease in cytokine levels, fibrin clot formation, and oxidative stress. The addition of L-GSH to spike protein and untreated PBMCs increased total intracellular GSH, decreased IL-6, TGF-beta, and TNF-alpha levels, decreased oxidative stress, as demonstrated through MDA, and decreased fibrin clot formation, as detected by fluorescence microscopy. These findings demonstrate that L-GSH supplementation within a spike protein-treated PBMC cell culture model reduces these factors, suggesting that GSH supplementation should be explored as a means of reducing mediators of immunothrombosis in COVID-19.

Topical Absorption of Glutathione-Cyclodextrin Nanoparticle Complex in Healthy Human Subjects Improves Immune Response against Mycobacterium avium Infection.

Glutathione (GSH) is an important intracellular antioxidant responsible for neutralizing reactive oxygen species (ROS). Our laboratory previously demonstrated that the oral administration of liposomal GSH improves immune function against mycobacterium infections in healthy patients along with patients with HIV and Type 2 diabetes. We aim to determine if the topical application of a glutathione-cyclodextrin nanoparticle complex (GSH-CD) confers a therapeutic effect against mycobacterium infections. In our study, healthy participants received either topical GSH-CD (n = 15) or placebo (n = 15) treatment. Subjects were sprayed four times twice a day for three days topically on the abdomen. Blood draws were collected prior to application, and at 1, 4, and 72 h post-initial topical application. GSH, malondialdehyde (MDA), and cytokine levels were assessed in the processed blood samples of study participants. Additionally, whole blood cultures from study participants were challenged with Mycobacterium avium (M. avium) infection in vitro to assess mycobacterium survival post-treatment. Topical GSH-CD treatment was observed to elevate GSH levels in peripheral blood mononuclear cells (PBMCs) and red blood cells and decrease MDA levels in PBMCs 72 h post-treatment. An increase in plasma IL-2, IFN-γ, IL-12p70, and TNF-α was observed at 72 h post-topical GSH-CD treatment. Enhanced mycobacterium clearance was observed at 4 h and 72 h post-topical GSH-CD treatment. Overall, topical GSH-CD treatment was associated with improved immune function against M. avium infection. The findings of this pilot study suggest GSH-cyclodextrin complex formulation can be used topically as a safe alternative mode of GSH delivery in the peripheral blood.

Implementation of 3D conformal radiotherapy technology at the National Cancer Centre Mongolia: A successful Asia-Pacific collaborative initiative.

INTRODUCTION: Mongolia has a population of 3.3 million and is classified by the WHO as a lower middle-income country. Cancer is now a major public health issue and one of the leading causes of mortality. Within the framework of an existing national cancer control plan, the National Cancer Centre of Mongolia (NCCM) aimed to implement 3D conformal radiation planning and linac-based treatment delivery. METHODS: In 2018, an opportunity arose for collaboration between the Mongolia Society for Radiation Oncology (MOSTRO), the National Cancer Centre Mongolia (NCCM), the Asia-Pacific Radiation Oncology Special Interest Group (APROSIG) of the Royal Australian and New Zealand College of Radiologists (RANZCR) and the Asia-Pacific Special Interest Group (APSIG) of the Australasian College of Physical Scientists and Engineers in Medicine (ACPSEM) and radiation therapists (RTTs) from a range of Australian centres. We describe here the results to date of this collaboration. RESULTS: Despite a number of significant technical and practical barriers, successful linac commissioning was achieved in 2019. Key factors for success included a leadership receptive to change management, stable bureaucracy and health systems, as well as a synchronised effort, regional cooperation and mentorship. CONCLUSION: Future directions for ongoing collaborative efforts include a continued focus on education, practical training in radiotherapy planning and delivery and postgraduate education initiatives. Radiotherapy safety and quality assurance remain an ongoing priority, particularly as technological advances are sequentially implemented.

Cautiously optimistic: A survey of radiation oncology professionals' perceptions of automation in radiotherapy planning.

INTRODUCTION: While there is evidence to show the positive effects of automation, the impact on radiation oncology professionals has been poorly considered. This study examined radiation oncology professionals' perceptions of automation in radiotherapy planning. METHOD: An online survey link was sent to the chief radiation therapists (RT) of all Australian radiotherapy centres to be forwarded to RTs, medical physicists (MP) and radiation oncologists (RO) within their institution. The survey was open from May-July 2019. RESULTS: Participants were 204 RTs, 84 MPs and 37 ROs (response rates ∼10% of the overall radiation oncology workforce). Respondents felt automation resulted in improvement in consistency in planning (90%), productivity (88%), quality of planning (57%), and staff focus on patient care (49%). When asked about perceived impact of automation, the responses were; will change the primary tasks of certain jobs (66%), will allow staff to do the remaining components of their job more effectively (51%), will eliminate jobs (20%), and will not have an impact on jobs (6%). 27% of respondents believe automation will reduce job satisfaction. 71% of respondents strongly agree/agree that automation will cause a loss of skills, while only 25% strongly agree/agree that the training and education tools in their department are sufficient. CONCLUSION: Although the effect of automation is perceived positively, there are some concerns on loss of skillsets and the lack of training to maintain this. These results highlight the need for continued education to ensure that skills and knowledge are not lost with automation.

Impact of dosimetric differences between CT and MRI derived target volumes for external beam cervical cancer radiotherapy.

OBJECTIVES: The use of MRI is becoming more prevalent in cervical cancer external beam radiotherapy (RT). The aim of this study was to investigate the impact of dosimetric differences between CT and MRI-derived target volumes for cervical cancer external beam RT. METHODS: An automated planning technique for volumetric modulated arc therapy was developed. Two automated planning plans were generated for 18 cervical cancer patients where planning target volumes (PTVs) were generated based on CT or MRI data alone. Dose metrics for planning target volumes and organs at risk (OARs) were compared to analyse any differences based on imaging modality. RESULTS: All treatment plans were clinically acceptable. Bladder doses (V40) were lower in MRI-based plans (p = 0.04, 53.6 ± 17.2 % vs 60.3 ± 13.1 % for MRI vs CT, respectively). The maximum dose for left iliac crest showed lower doses in CT-based plans (p = 0.02, 47.8 ± 0.7 Gy vs 47.4 ± 0.4 Gy MRI vs CT, respectively). No significant differences were seen for other OARs. CONCLUSIONS: The dosimetric differences of CT- and MRI-based contouring variability for this study was small. CT remains the standard imaging modality for volume delineation for these patients. ADVANCES IN KNOWLEDGE: This is the first study to evaluate the dosimetric implications of imaging modality on target and OAR doses in cervical cancer external beam RT.

Evaluation of the introduction of a 'traffic light protocol' for dose-volume histogram constraints of organs at risk in definitive radiotherapy at Liverpool and Macarthur Cancer Therapy Centres.

INTRODUCTION: Protocols have been developed in our department with recommended dose constraints for organs at risk (OAR) for each tumour site receiving definitive radiotherapy. We have developed a colour coding system to indicate when constraints are meeting objectives (green), have minor variation from planning objectives (yellow) and have major variation from planning objectives (red). We performed a quality audit to assess adherence to the protocol and to determine the rate of acute and subacute toxicities. METHODS: All definitive radiotherapy dose-volume histogram (DVH) reports generated in the first 6 months of 2017 at Liverpool and Macarthur cancer therapy centres were collected. For each radiotherapy group, the overridden dose constraints were evaluated and categorized to red and yellow. For all patients in our data set, follow-up documents/assessments were searched for grade 3 or higher acute or subacute radiotherapy toxicity and compared with those who had overridden dose constraints. RESULTS: There were 210 (34%) plans accepted with at least one major variation and 161 (26%) plans with minor variation. Head and neck group had the most rate of major variations (77%). The best groups in adherence to protocol were lymphoma and breast groups. In general, grade 3 toxicity was observed in 1%, 4% and 9% of patients who were in green, yellow and red categories. Overall, we noted a correlation with grade 3 toxicities between acceptable plans (green) and ones with a minor or major variation (yellow or red) (1% vs. 7% P = 0.0001). CONCLUSION: In conclusion this study showed an increased risk of higher grade toxicities when DVHs were beyond our departmental constraints using a 'Traffic Light System'. With this new colour coding system, we can facilitate auditing of the dose constraints in order to improve the quality of radiotherapy plans and potentially provide benchmarking for reducing toxicities in radiotherapy treatments.

Comparing the influence of 2009 versus 2016 ASE/EACVI diastolic function guidelines on the prevalence and echocardiographic characteristics of preclinical diastolic dysfunction (stage B heart failure) in a Hispanic population with type 2 diabetes mellitus.

AIMS: To identify prevalence and predictors of undetected pre-clinical diastolic dysfunction (PDD) in a cohort of adult Hispanic patients with type 2 diabetes (T2D), and compare variations in epidemiology and echocardiographic characteristics between categorization based on the 2009 versus 2016 guidelines. METHODS: From 2013 to 2016, a cross-sectional cohort study of adults with T2D was performed. Patients without signs/symptoms of heart failure (HF) underwent 2D/Doppler echocardiographic screening, and were grouped into two subcohorts: 1) normal diastolic function, and 2) PDD, defined by the 2009 or 2016 ASE/EACVI criteria. RESULTS: Among 307 Hispanic subjects, by 2009 criteria, 193 (62.9%) had normal diastolic function, 113 (36.8%) diastolic dysfunction and 1 (0.3%) indeterminate. Those that had diastolic dysfunction (DD) were older (mean age 59.1 ±â€¯12.7 vs 52.2 ±â€¯12.2 years, p< 0.0001), with higher proportion female (69.0 vs 53.9%, p = 0.0092), and higher systolic blood pressure (136.5 ±â€¯18.6 vs 131.7 ±â€¯19.9, p = 0.0372). By 2016 criteria, 261 (85%) had normal diastolic function, 22 (7.2%) diastolic dysfunction and 24 (7.8%) indeterminate. Among those that had normal diastolic function (n = 261) by 2016 criteria, 29% (n = 76) had DD by 2009 criteria, and they were more likely to have higher E/e' and left atrial volume index (LAVI). CONCLUSIONS: By applying the 2016 versus the 2009 diastolic function criteria to a Hispanic population with T2D, the prevalence of PDD decreased significantly from 37% to 7%. These findings are consistent with recent studies demonstrating that the 2016 ASE/EACVI guidelines are more specific for diagnosing DD and hence less sensitive leading to lower prevalence of diastolic dysfunction.

Adapting automated treatment planning configurations across international centres for prostate radiotherapy.

BACKGROUND AND PURPOSE: Automated configurations are increasingly utilised for radiotherapy treatment planning. This study investigates whether automated treatment planning configurations are adaptable across clinics with different treatment planning protocols for prostate radiotherapy. MATERIAL AND METHODS: The study comprised three participating centres, each with pre-existing locally developed prostate AutoPlanning configurations using the Pinnacle3® treatment planning system. Using a three-patient training dataset circulated from each centre, centres modified local prostate configurations to generate protocol compliant treatment plans for the other two centres. Each centre applied modified configurations on validation datasets distributed from each centre (10 patients from 3 centres). Plan quality was assessed through DVH analysis and protocol compliance. RESULTS: All treatment plans were clinically acceptable, based off relevant treatment protocol. Automated planning configurations from Centre's A and B recorded 2 and 18 constraint and high priority deviations respectively. Centre C configurations recorded no high priority deviations. Centre A configurations produced treatment plans with superior dose conformity across all patient PTVs (mean = 1.14) compared with Centre's B and C (mean = 1.24 and 1.22). Dose homogeneity was consistent between all centre's configurations (mean = 0.083, 0.077, and 0.083 respectively). CONCLUSIONS: This study demonstrates that automated treatment planning configurations can be shared and implemented across multiple centres with simple adaptations to local protocols.

Metabolic Syndrome and Cardiovascular Disease: A Health Challenge.

Metabolic Syndrome (MetS) is a cluster of risk factors that, taken alone or synergically, are independent predictors of type 2 diabetes and cardiovascular disease (CVD), which are both major public health problems that requires urgent containment actions. Current controversies regarding MetS are focused on ascertain the unifying explanation of molecular and pathophysiological mechanisms originating the syndrome, involving insulin resistance and low-grade chronic inflammation. This review aims to present the clinical relevance of MetS and its complications, as well as the hypotheses addressing its etiopathogenic relation with CVD. We conclude that health policies should emphasize basic research promotion, timely detection and early treatment of MetS, which will help to reduce the risk of CVD and their impact on public health and health-care related costs.

Nivolumab in Renal Cell Carcinoma: Current Trends and Future Perspectives.

Targeted agents form the backbone of most therapeutic strategies in advanced renal cell carcinoma (aRCC) but ultimately resistance develops and toxicity often leads to discontinuation of treatment, limiting the clinical benefits of these treatments. Nivolumab, a fully human IgG4 anti-PD-1 antibody, selectively blocks the interaction between PD-1 and its ligands PD-L1 and PD-L2 and provides a novel therapy option for patients with aRCC. In 2015, the pivotal phase III study CheckMate 025 led to the Food and Drug Administration approval of nivolumab in patients with aRCC who had received prior anti-angiogenic therapy, and in 2017, the phase III study CheckMate 214 showed that combined immunotherapy with nivolumab plus ipilimumab resulted in greater objective response rate and prolonged progression-free survival when compared with sunitinib in intermediate- and poor-risk patients with previously untreated aRCC. Early studies of nivolumab in association with anti-angiogenic therapy have generated enthusiasm and multiple combination trials are ongoing.

Investigating the impact of treatment delivery uncertainties on treatment effectiveness for lung SABR.

To quantify the impact of treatment delivery uncertainties on lung stereotactic ablative body radiotherapy (SABR) plans for step-and-shoot intensity-modulated radiotherapy (ssIMRT) and volumetric modulated arc therapy (VMAT). Baseline ssIMRT and VMAT treatment plans were generated for a cohort of 18 lung SABR patients. Modified plans were generated for each baseline plan by systematically varying gantry and collimator angles between - 5 and + 5 degrees, as well as multi-leaf collimator (MLC) leaf position errors of magnitude between 1 and 5 mm in both directions (i.e. leaf banks shifted either in the same (Type 1) or opposite (Type 2) directions). Planning target volume (PTV), spinal cord and healthy lung dose-volume histogram (DVH) metrics were compared between the modified and baseline plans. Collimator and gantry angle uncertainties did not significantly impact any of the PTV DVH metrics considered. MLC shifts of 5 mm resulted in average V95% changes of [Formula: see text] (Type 1) and [Formula: see text] (Type 2) and average [Formula: see text] changes of [Formula: see text] (Type 1) and [Formula: see text] (Type 2) for ssIMRT and VMAT plans. Comparatively, MLC shifts of - 2 mm resulted in average [Formula: see text] changes of [Formula: see text] (Type 1) and [Formula: see text] (Type 2) and average [Formula: see text] changes of [Formula: see text] (Type 1) and [Formula: see text] (Type 2) for ssIMRT and VMAT plans. ssIMRT gantry angle uncertainties impacted spinal cord DVH metrics the most, with increases in [Formula: see text] of [Formula: see text] occurring for a 1 degree shift. Type 2 MLC modifications impacted all OAR DVH metrics substantially with differences in spinal cord [Formula: see text] (ssIMRT) and healthy lung [Formula: see text] (VMAT) exceeding [Formula: see text] for 5 mm shifts. Uncertainties in MLC leaf positions affected target and OAR DVH metrics more than collimator or gantry angle uncertainties for lung SABR plans. Less patient-to-patient variation occurred from delivery uncertainties in VMAT than ssIMRT.

Multi-institutional comparison of simulated treatment delivery errors in ssIMRT, manually planned VMAT and autoplan-VMAT plans for nasopharyngeal radiotherapy.

PURPOSE: To quantify the impact of simulated errors for nasopharynx radiotherapy across multiple institutions and planning techniques (auto-plan generated Volumetric Modulated Arc Therapy (ap-VMAT), manually planned VMAT (mp-VMAT) and manually planned step and shoot Intensity Modulated Radiation Therapy (mp-ssIMRT)). METHODS: Ten patients were retrospectively planned with VMAT according to three institution's protocols. Within one institution two further treatment plans were generated using differing treatment planning techniques. This resulted in mp-ssIMRT, mp-VMAT, and ap-VMAT plans. Introduced treatment errors included Multi Leaf Collimator (MLC) shifts, MLC field size (MLCfs), gantry and collimator errors. A change of more than 5% in most selected dose metrics was considered to have potential clinical impact. The original patient plan total Monitor Units (MUs) were correlated to the total number of dose metrics exceeded. RESULTS: The impact of different errors was consistent, with ap-VMAT plans (two institutions) showing larger dose deviations than mp-VMAT created plans (one institution). Across all institutions' VMAT plans the significant errors included; ±5° for the collimator angle, ±5mm for the MLC shift and +1, ±2 and ±5mm for the MLC field size. The total number of dose metrics exceeding tolerance was positively correlated to the VMAT total plan MUs (r=0.51, p<0.001), across all institutions and techniques. CONCLUSIONS: Differences in VMAT robustness to simulated errors across institutions occurred due to planning method differences. Whilst ap-VMAT was most sensitive to MLC errors, it also produced the best quality treatment plans. Mp-ssIMRT was most robust to errors. Higher VMAT treatment plan complexity led to less robust plans.

Standardized screening for periodontitis as an integral part of multidisciplinary management of adults with type 2 diabetes: an observational cross-sectional study of cohorts in the USA and UK.

OBJECTIVE: To determine prevalence and factors predictive of periodontitis by using a standardized assessment model in adults with type 2 diabetes. RESEARCH DESIGN AND METHODS: We performed an observational cross-sectional study to determine the burden of periodontitis in adults with type 2 diabetes attending urban, ambulatory referral centers in the USA and UK. Full-mouth probing was performed and periodontitis was diagnosed based on either a low (≥5 mm at ≥1 site) or high pocket probing-depth threshold (≥6 mm at ≥1 site). Results were stratified into a five-stage schema and integrated with other clinical variables into the novel Diabetes Cross-Disciplinary Index to function as a balanced health scorecard. Corresponding demographic and routinely collected health data were obtained and comparisons were made between patients with and without periodontitis. Multivariable logistic regression was performed to identify factors predictive of the presence or absence of periodontitis. RESULTS: Between our two cohorts, 253 patients were screened. Caucasians comprised >90% and Hispanic Americans >75% of the UK and US cohorts, respectively. Males and females were equally distributed; mean age was 53.6±11 years; and 17 (6.7%) were edentulous. Of the 236 dentate patients, 128 (54.2%) had periodontitis by low threshold and 57 (24.2%) by high threshold. Just 17 (7.2%) were periodontally healthy. No significant differences in age, HbA1c, blood pressure, body mass index, low-density lipoprotein cholesterol, or smoking status (all p>0.05) were identified between those with or without periodontitis (regardless of threshold) and none was found to be a significant predictor of disease. CONCLUSIONS: Periodontitis is frequent in adults with type 2 diabetes and all should be screened. Periodontal health status can be visualized with other comorbidities and complications using a novel balanced scorecard that could facilitate patient-clinician communication, shared decision-making, and prioritization of individual healthcare needs.

Dose discrepancy between planning system estimation and measurement in spine stereotactic body radiation therapy: A case report.

Stereotactic body radiation therapy (SBRT) to treat spinal metastases has shown excellent clinical outcomes for local control. High dose gradients wrapping around spinal cord make this treatment technically challenging. In this work, we present a spine SBRT case where a dosimetric error was identified during pre-treatment dosimetric quality assurance (QA). A patient with metastasis in T7 vertebral body consented to undergo SBRT. A dual arc volumetric modulated arc therapy plan was generated on the Pinnacle treatment planning system (TPS) with a 6 MV Elekta machine using gantry control point spacing of 4°. Standard pre-treatment QA measurements were performed, including ArcCHECK, ion chamber in CTV and spinal cord (SC) region and film measurements in multiple planes. While the dose measured at CTV region showed good agreement with TPS, the dose measured to the SC was significantly higher than reported by TPS in the original and repeat plans. Acceptable agreement was only achieved when the gantry control point spacing was reduced to 3°. A potentially harmful dose error was identified by pre-treatment QA. TPS parameter settings used safely in conventional treatments should be re-assessed for complex treatments.

Restoring Cytokine Balance in HIV-Positive Individuals with Low CD4 T Cell Counts.

HIV infects and destroys CD4+ T cells leading to a compromised immune system. In a double-blinded study, a group of HIV-infected individuals with CD4+ T cell counts below 350 cells/mm3 were given either an empty liposomal supplement or a liposomal glutathione (L-GSH) supplement to take over a 3-month period. Baseline measurements in HIV-positive subjects show a significant decrease in levels of interleukin (IL)-12, IL-2, and interferon (IFN)-γ, along with a substantial increase in the levels of IL-6, IL-10, transforming growth factor (TGF)-ß, and free radicals, compared to healthy individuals. Supplementation of HIV-positive subjects with L-GSH for 3 months resulted in a notable increase in the levels of IL-12, IL-2, and IFN-γ, with a concomitant decrease in the levels of IL-6, IL-10, and free radicals, and stabilization in the levels of TGF-ß, IL-1, and IL-17, compared to their placebo counterparts. Levels of free radicals in CD4+ T cells stabilized, while GSH levels increased in the treatment group. Those in the placebo group showed no significant difference throughout the study. In summary, supplementation with L-GSH in HIV-infected individuals with CD4+ T cell counts below 350 cells/mm3 can help restore redox homeostasis and cytokine balance, therefore aiding the immune system to control opportunistic infections.

Tumor necrosis factor links chronic obstructive pulmonary disease and K-ras mutant lung cancer through induction of an immunosuppressive pro-tumor microenvironment.

Tumor necrosis factor (TNF) is known as an important regulator of tumor microenvironment and inflammation. TNF levels are markedly elevated in the bronchoalveolar lavage fluid (BALF) of patients with chronic obstructive pulmonary disease (COPD), which is an independent risk factor for lung cancer. We have previously shown that COPD-like airway inflammation promotes lung cancer in a K-ras mutant mouse model (CC-LR mouse). This was associated with a significant increase of neutrophils in BALF, accompanied by a marked increase in TNF level, suggesting a link between COPD, TNF, and lung cancer promotion. Therefore, we first overexpressed TNF in the airway epithelium of CC-LR mice, which promoted lung cancer by ∼2-fold. This was associated with increased numbers of Ki67 and CD31 positive cells in lung tumors of CC-LR/TNF-Tg mice. We also found a robust increase in NF-κB activation, and numbers of neutrophils and myeloid-derived suppressor cells (MDSCs) in lung. Accordingly, we depleted MDSCs in CC-LR/TNF-Tg mice, which lead to significant tumor suppression emphasizing on the role of TNF-induced MDSCs in K-ras induced lung tumorigenesis. Finally, we targeted TNF expression by crossing CC-LR mice with TNF knock-out mice (CC-LR/TNF-KO), which resulted in a significant decrease in lung tumor burden in the absence or presence of COPD-like airway inflammation. Interestingly, there were less MDSCs and lower Ki67 and CD31 expression in the lung of the CC-LR/TNF-KO mice. We conclude that TNF links COPD to lung cancer promotion by induction of an immunosuppressive MDSC response, and subsequent amplification of proliferation and angiogenesis in tumors.

Complement 3 Receptor Expression in Individuals with Type 2 Diabetes.

BACKGROUND: According to the World Health Organization, as of 2014 9% of the world's adult population is affected by diabetes. Uncontrolled diabetes is a pro-inflammatory process that increases generation of reactive oxygen species (ROS). METHODS: The production of ROS leads to a chronic increase in oxidative stress which results in an increased susceptibility to infections. Individuals with type 2 diabetes mellitus (T2DM) are highly susceptible to Mycobacterium tuberculosis (M. tb) infection. Previous research has demonstrated that glutathione (GSH) plays an important role in the control of M. tb infection. Recent studies have demonstrated that phagocytosis of M.tb is diminished in patients with T2DM. Phagocytosis in macrophages is thought to be mediated in part by complement protein 3b (C3b)-complement protein receptor 3b (C3R) interactions. Since C3b production is not diminished in patients with T2DM we propose that C3R production is reduced and is the cause for impaired macrophage phagocytosis as well as IL-12 and IFN-γ signaling. CONCLUSION: This study utilizes a quantitative PCR (qPCR), demonstrating decreased transcription of C3R mRNA in patients with T2DM as compared to non-diabetics.

IL6 Blockade Reprograms the Lung Tumor Microenvironment to Limit the Development and Progression of K-ras-Mutant Lung Cancer.

Activating mutations of K-ras are the most common oncogenic alterations found in lung cancer. Unfortunately, attempts to target K-ras-mutant lung tumors have thus far failed, clearly indicating the need for new approaches in patients with this molecular profile. We have previously shown NF-κB activation, release of IL6, and activation of its responsive transcription factor STAT3 in K-ras-mutant lung tumors, which was further amplified by the tumor-enhancing effect of chronic obstructive pulmonary disease (COPD)-type airway inflammation. These findings suggest an essential role for this inflammatory pathway in K-ras-mutant lung tumorigenesis and its enhancement by COPD. Therefore, here we blocked IL6 using a monoclonal anti-IL6 antibody in a K-ras-mutant mouse model of lung cancer in the absence or presence of COPD-type airway inflammation. IL6 blockade significantly inhibited lung cancer promotion, tumor cell-intrinsic STAT3 activation, tumor cell proliferation, and angiogenesis markers. Moreover, IL6 inhibition reduced expression of protumor type 2 molecules (arginase 1, Fizz 1, Mgl, and IDO), number of M2-type macrophages and granulocytic myeloid-derived suppressor cells, and protumor T-regulatory/Th17 cell responses. This was accompanied by increased expression of antitumor type 1 molecule (Nos2), and antitumor Th1/CD8 T-cell responses. Our study demonstrates that IL6 blockade not only has direct intrinsic inhibitory effect on tumor cells, but also reeducates the lung microenvironment toward an antitumor phenotype by altering the relative proportion between protumor and antitumor immune cells. This information introduces IL6 as a potential druggable target for prevention and treatment of K-ras-mutant lung tumors. Cancer Res; 76(11); 3189-99. ©2016 AACR.