Immune checkpoint inhibitors efficacy across solid cancers and the utility of PD-L1 as a biomarker of response: a systematic review and meta-analysis.

Background: Immune checkpoint inhibitors (ICPI) are a tumor agnostic treatment. However, trials of their use have been site specific. Here we summarize the trial data and explore the utility of programmed death-ligand 1 (PD-L1) expression as a biomarker to direct their pan-cancer use. Method: A systematic review of literature, following PRISMA guidelines, was performed. Medline, Embase, Cochrane CENTRAL, NHS Health and Technology, and Web of Science were searched from their conception to June 2022 limited to the English language. The search terms and method were devised by a specialist medical librarian. Studies were limited to adults with solid cancers (excluding melanomas) treated with ICPIs. Only phase III randomized control trials (RCT) were included. The primary outcome was overall survival and secondary outcomes were progression free survival, PD-L1 expression, quality of life outcomes and adverse event data. Where present in eligible clinical trials, hazard ratios (HR), risk ratios (RR), standard error (SE) and 95% confidence intervals (CI) were extracted or calculated. Heterogeneity across studies was described with the use of an I2 score (Low: 25, 50%: moderate, 75% low heterogeneity). HR pools inverse variance methods were adopted by Random Effects (RE). Means were standardized across any heterogenous scale limits. Results: In total 46,510 participants were included in the meta-analysis. Overall, meta-analysis favored the use of ICPIs with an overall survival (OS) HR of 0.74 (95% CI 0.71 to 0.78). Lung cancers showed the most benefit in OS [HR 0.72 (95% 0.66-0.78)] followed by head and neck cancers [HR 0.75 (95% CI 0.66-0.84)] and gastroesophageal junction cancers [HR 0.75 (95% CI 0.61-0.92)]. ICPIs seem to be efficacious at both primary presentation and recurrence [OS HR 0.73 (95% CI 0.68-0.77)] vs. [OS HR 0.79 (95% CI 0.72 to 0.87)] respectively. Interestingly, subgroup analysis comparing studies in which most cancers demonstrated PD-L1 expression vs. those studies in which a minority of cancer demonstrated PD-L1 expression reported similar effect of ICPI use on OS; oddly the data favored ICPI use in studies with a minority of PD-L1 expression. Specifically, studies with minority PD-L1 expression had an HR 0.73 (95% CI 0.68-0.78) vs. studies with majority PD-L1 expression HR 0.76 (95% CI 0.70-0.84). This was maintained even when studies exploring the same cancer site were directly compared. Subgroup analysis was performed comparing the impact on OS subdivided by the specific ICPI used. Where meta-analysis was performed, Nivolumab led to the greatest impact [HR 0.70 (95% CI 0.64-0.77)] with Avelumab failing to reach significance [HR 0.93 (95% CI 0.80-1.06)]. However, overall heterogenicity was high (I2 = 95%). Finally, the use of ICPIs led to an improved side effect profile when compared with standard chemotherapy [RR 0.85 (95% CI 0.73-0.98)]. Conclusion: ICPIs improve survival outcomes in all cancer types. These effects are seen in the primary, recurrent, chemotherapy sensitive, chemotherapy resistant disease. These data support their use as a tumor agnostic therapy. Furthermore, they are well tolerated. However, PD-L1 as a biomarker for the targeting of ICPI use seems problematic. Other biomarkers such as mismatch repair or tumor mutational burden should be explored in randomized trials. In addition, there are still limited trials looking at ICPI use outside of lung cancer.

Effectiveness of tea tree oil versus chlorhexidine in the treatment of periodontal diseases: a systematic review.

Background Plaque biofilm that adheres to tooth surfaces and gingiva is the main aetiology of periodontitis. Chlorhexidine (CHX) is considered as a gold standard anti-plaque and anti-gingivitis agent but it has side effects such as permanent staining of teeth and dysgeusia. Tea tree oil (TTO) is an essential oil extracted from the leaves of Melaleuca alternifolia. Many studies have reported that TTO exerts strong antibacterial, antifungal, antiviral and anti-inflammatory activities.Primary study objective The review aims to answer the question of whether TTO (intervention) is a viable alternative to CHX (comparator) for the management of gingival and periodontal disease (outcomes) in adolescents and adults (population).Methods/design The following search terms were used in PubMed, Scopus, Proquest, Web of Science, EBSCO (dentistry and open access), Cochrane database, Clinical.gov.org and ctri.nic.in to search for relevant articles: patients with periodontal disease; OR periodontitis; OR gingivitis; OR gingival inflammation; AND essential oil; OR tea tree oil; OR Melaleuca alternifolia; AND chlorhexidine; AND reduction in gingival index; OR reduction in plaque index; OR reduction in bleeding from gums. The initial check for the title and abstract screening followed by removal of duplicates in Mendeley Reference Manager (version 1.19.4) based on the inclusion and exclusion criteria were performed.Primary outcome measures Parameters such as plaque index (PI), plaque surface score, gingival index (GI), bleeding index or bleeding as measured by % of sites with bleeding on probing (BOP) or bleeding scores, papillary bleeding index (PBI), were the primary outcomes considered.Results TTO is found to be superior to CHX in reducing signs of gingival inflammation; however, CHX is superior to TTO in inhibiting plaque formation, probably due to its increased substantivity.Conclusion TTO may be used as an alternative to CHX for reduction of gingival inflammation in conjunction with efficient plaque control measures.

Analytical methods to determine and sense heavy metal pollutants using MXene and MXene-based composites: Mechanistic prophecy into sensing properties.

The presence of heavy metal ions in the biosphere is of grave concern, as these are toxic and impact living organisms. Lack of pure drinking water can spread waterborne diseases like cholera, dysentery, typhoid, etc. The presence of heavy metals like arsenic and radioactive materials can cause cancer. The detection and removal of these heavy metals are important for sustaining life. Herein, MXene comes to the rescue as a crucial and potential material, which can sense and adsorb heavy metal ions. Developed in 2011, MXenes are an emerging class of 2D nanomaterials that are appropriate substitutes for existing heavy metal ions sensing materials and have shown excellent efficiency due to their better hydrophilicity, capacity of transportation of electrons, functionalization, and a great variety in compositions as compared to the other nanomaterials properties. This work gives an insight into the chemistry and synthesis of MXenes for further utilization as a sensor in heavy metal ions toxicity and underlines the key future challenges to knowing the full prospective of MXenes in environmental systems.

Host SUMOylation Pathway Negatively Regulates Protective Immune Responses and Promotes Leishmania donovani Survival.

SUMOylation is one of the post-translational modifications that have recently been described as a key regulator of various cellular, nuclear, metabolic, and immunological processes. The process of SUMOylation involves the modification of one or more lysine residues of target proteins by conjugation of a ubiquitin-like, small polypeptide known as SUMO for their degradation, stability, transcriptional regulation, cellular localization, and transport. Herein, for the first time, we report the involvement of the host SUMOylation pathway in the process of infection of Leishmania donovani, a causative agent of visceral leishmaniasis. Our data revealed that infection of L. donovani to the host macrophages leads to upregulation of SUMOylation pathway genes and downregulation of a deSUMOylating gene, SENP1. Further, to confirm the effect of the host SUMOylation on the growth of Leishmania, the genes associated with the SUMOylation pathway were silenced and parasite load was analyzed. The knockdown of the SUMOylation pathway led to a reduction in parasitic load, suggesting the role of the host SUMOylation pathway in the disease progression and parasite survival. Owing to the effect of the SUMOylation pathway in autophagy, we further investigated the status of host autophagy to gain mechanistic insights into how SUMOylation mediates the regulation of growth of L. donovani. Knockdown of genes of host SUMOylation pathway led to the reduction of the expression levels of host autophagy markers while promoting autophagosome-lysosome fusion, suggesting SUMOylation-mediated autophagy in terms of autophagy initiation and autophagy maturation during parasite survival. The levels of reactive oxygen species (ROS) generation, nitric oxide (NO) production, and pro-inflammatory cytokines were also elevated upon the knockdown of genes of the host SUMOylation pathway during L. donovani infection. This indicates the involvement of the SUMOylation pathway in the modulation of protective immune responses and thus favoring parasite survival. Taken together, the results of this study indicate the hijacking of the host SUMOylation pathway by L. donovani toward the suppression of host immune responses and facilitation of host autophagy to potentially facilitate its survival. Targeting of SUMOylation pathway can provide a starting point for the design and development of novel therapeutic interventions to combat leishmaniasis.

Outcomes of macular buckling with a T-shaped buckle for myopic tractional maculopathies associated with posterior staphyloma: An Indian experience.

PURPOSE: : To report the anatomic and visual outcomes following macular buckling in patients affected by pathological myopia-associated foveoschisis (FS) and macular detachment with or without macular hole (MH). METHODS: A retrospective interventional consecutive case series wherein 25 highly myopic eyes (mean axial length 28.46 mm; range, 25-33.8 mm) of 24 patients (16 females and 8 males; mean age 54.1 years; range, 35-74 years) presenting with macular detachment associated with a posterior staphyloma (PS), who underwent macular buckling, were evaluated. Patients with absence or reduction in subretinal fluid by more than 90% during the final follow-up along with inversion of contour of staphyloma were considered to have a successful anatomical outcome and those with improvement or maintenance in visual acuity were considered to have a successful functional outcome. The mean duration of follow-up was 11.2 months. RESULTS: At the time of initial presentation, the mean age of the 24 patients was 54.1 ± 10.28 years. Macular detachment along with FS was present in all cases, whereas full-thickness macular hole-related retinal detachment was present in nine cases. Swept-source optical coherence tomography parameters showed reduction of FS with foveal reattachment in all eyes except one at last visit. Mean axial length decreased from 28.5 mm preoperatively (range 26-33.8 mm) to 26.2 mm (range 24-29.3 mm). The mean best-corrected visual acuity changed from 1.16 log MAR to 1.096 Log MAR (P = 0.165). Visual acuity improved in 10 eyes (40%), remained stable in 11 eyes (44%) and decreased in 4 eyes (16%). CONCLUSION: Macular buckling is a good surgical technique with encouraging anatomic and visual outcomes in patients with myopic macular detachment associated with PS. Highly selective cases of myopic traction maculopathy can have a viable option of macular buckle surgery in stabilizing the retinal tractional changes, and thereby, vision loss.

Artificial Intelligence Efficiently Identifies Regional Differences in the Progression of Tomographic Parameters of Keratoconic Corneas.

PURPOSE: To develop an artificial intelligence (AI) model to effectively assess local versus global progression of keratoconus using multiple tomographic parameters. METHODS: This was a retrospective review of medical records of patients diagnosed as having keratoconus. A total of 1,884 Pentacam (Oculus Optikgeräte GmbH) scans of 366 eyes (296 patients) were analyzed. Based on an increase in maximum anterior curvature (Kmax), the eyes were classified as actual "progression" and "no progression." The corresponding changes in other Pentacam parameters were incorporated to train and cross-validate (five-fold) the AI models. Three AI models were trained (an increase in Kmax by A = 0.75 diopters [D], B = 1.00 D, and C = 1.25 D). The area under the curve (AUC), sensitivity, specificity, and classification accuracy, along with other metrics, were evaluated. RESULTS: The AUC, sensitivity, specificity, and classification accuracy were 0.90, 85%, 82%, and 83%, respectively, for Model A; 0.91, 86%, 82%, and 88%, respectively, for Model B; and 0.93, 89%, 81%, and 91%, respectively, for Model C. All models also predicted that 60% to 62% of the actual progression eyes had concomitant progression-associated changes in the other Pentacam parameters (global progression). However, there was discordance between increase in Kmax and concomitant associated changes in the other parameters in 38.8% to 40% of the eyes (local progression). CONCLUSIONS: The AI models identified the eyes where the increase in Kmax and corresponding progression-associated changes in the other parameters were in agreement. These eyes may require corneal cross-linking earlier than the rest. [J Refract Surg. 2021;37(4):240-248.].

Influence of segmental supply of Cilioretinal artery on morphology of diabetic macular edema.

BACKGROUND: The supply of Cilioretinal artery (CRA) to different layers of the retina influences retinal pathologies such as diabetic retinopathy (DR). Since the supply of CRA is segmental, our aim was to analyze the location of CRA with respect to non - center involving diabetic macular edema (DME) differentiated by various segments and center involving DME based on Early Treatment of Diabetic Retinopathy Study (ETDRS) scale using optical coherence tomography (OCT). METHODS: A retrospective study was conducted in which forty-three patients with various stages of DR and the presence of CRA were identified. Presence and location of CRA was recognized using fundus fluorescein angiography. Classification of DME was based on ETDRS subfields on OCT. RESULTS: Evaluation of 26 men and 17 women with varying degrees of severity involving DR revealed the presence of unilateral CRA in 40 subjects and bilateral CRA in 3 subjects. When CRA supplied the central area, maximum retinal thickness was noted at the temporal quadrant (271.67 ± 164.02 µm) along with non - center involving DME (194.87 ± 121.06 µm); when CRA supplied the lower area, maximum retinal thickness was noted at the superior quadrant (293.64 ± 159.36 µm) along with center involving DME (395 ± 285.75 µm) and when it supplied the upper area, maximum retinal thickness was noted at the nasal quadrant (293.49 ± 176.18 µm) along with center involving DME (292 ± 192.79 µm). CONCLUSION: The presence of CRA seems to influence the morphology of the retina amongst patients diagnosed with DR by altering the segments involved in DME based on its supply location. However, further studies with a larger sample size are warranted to strenghten this association.

Outcomes of surgery in eyes with familial exudative vitreoretinopathyassociated retinal detachment.

OBJECTIVE: The aim of this study was to evaluate various techniques of surgical treatment of retinal detachment associated with familial exudative vitreoretinopathy (FEVR) and the factors affecting the anatomical and visual outcome. DESIGN: Retrospective case series. PARTICIPANTS: Patients diagnosed with FEVR associated retinal detachment and operated for the same between January 2004 and September 2017. METHODS: A retrospective chart review was conducted of all patients diagnosed with FEVR between January 2004 and September 2017. Patients with rhegmatogenous retinal detachment (RRD) and tractional retinal detachment (TRD) were included for analysis. Statistical analysis was performed using the t test for mean visual acuities, Fisher's exact test for categorical data, and the one-way analysis of variance for visual outcomes among surgical management options. RESULTS: A total of 44 eyes of 38 patients diagnosed with FEVR-associated retinal detachment and operated for the same were evaluated. At the time of initial presentation, the mean age of the 38 patients was 14.6 ± 10.9 years and 57.8% were males. Out of 44 eyes that underwent surgical intervention, 79.5% cases were of RRD (n = 35), and TRD was seen in 20.5% cases (n = 9). Primary management in the form of scleral buckle was done in 14 (31.8%) eyes, with 11 eyes (78.6%) having an attached retina after a single surgery and 85.7% after multiple surgeries. Primary pars plana vitrectomy (PPV) was done in 30 (68.2%) eyes, of which 73.3% had attached retina after single surgery and 83.8% after multiple surgeries. Poor pre-operative best-corrected visual acuity, presence of TRD, and presence of falciform folds were associated with poor anatomical outcome. CONCLUSIONS: Favourable outcomes can be achieved, though multiple surgical interventions may, however, be necessary for the ultimate success in some cases.

Late onset Descemet's membrane detachment: 15 years after limbal lensectomy with vitrectomy for ROP.

A case of stage 4B retinopathy of prematurity (ROP) after successful retinal reattachment surgery with maintained vision presented with hazy cornea with spontaneous Descemet's membrane detachment (DMD) 15 years after the surgery, requiring Descemet Stripping Endothelial Keratoplasty (DSEK) to restore vision. There are reports of late spontaneous DMD after phacoemulsification or previous corneal surgeries. This report is unique as there is no published literature of spontaneous DMD after limbal surgery for ROP when searched in PubMed. The immature Descemet's membrane (DM), surgical intervention and changes in immature DM with age would have contributed to spontaneous DMD and warrant a long-term follow-up of premature kids.

BILATERAL SIMULTANEOUS RHEGMATOGENOUS RETINAL DETACHMENT: Clinical Characteristics and Surgical Outcome.

PURPOSE: To elucidate the clinical characteristics and surgical outcome of consecutive patients with bilateral simultaneous retinal detachment who reported to a tertiary eye care institution over a period of 10 years. METHODS: Retrospective interventional consecutive study of 168 eyes of 84 patients with bilateral simultaneous retinal detachment, observed by indirect ophthalmoscopy at the initial examination was performed. Demographic and clinical characteristics were collected before and after surgery. Patients with attached retina at final follow-up were considered to have anatomical success and those with two or more lines improvement in visual acuity were considered to have functional success. RESULTS: Most cases (90% in the better eye and 82.1% in the worse eye) were managed by scleral buckling procedure. With scleral buckle, anatomical success was seen in 99% and functional success was seen in 87% of the cases. Pars plana vitrectomy was performed in remaining cases with anatomical success in 83% and functional success in 78% of cases. Eyes with partial retinal detachment, without macular involvement, and eyes in which additional surgeries were not performed had significantly better anatomical and functional results. CONCLUSION: Early sequential surgery gives good anatomical and functional outcomes. Surgical outcomes were better with scleral buckling than pars plana vitrectomy.

Dysregulated Marginal Zone B Cell Compartment in a Mouse Model of Sjögren's Syndrome with Ocular Inflammation.

The risk of developing lymphoma in patients with Sjögren's syndrome (SS) is 44 times higher than in the normal population with the most common lymphomas derived from marginal zone B (MZB) cells. Current understanding of the role of MZB cells in SS is primarily based on salivary gland pathology, while their contextual association with lacrimal glands and ocular manifestations largely remains unknown. We examined this possibility using a SS mouse model (thrombospondin-1 deficient (TSP1-/-)) with well-characterized ocular disease. We determined the frequency, localization, and cytokine profiles of MZB cells and their association with an antibody response in TSP1-/- mice treated with a TSP-derived peptide. A significantly increased frequency of MZB cells was detected in the spleens and lacrimal glands of TSP1-/- mice in comparison to wild-type tissues as detected by immunostaining. An altered cytokine profile of TSP1-/- MZB cells was supportive of T helper 17 (Th17)-related pathogenesis. A significantly reduced antibody response and the splenic MZB compartment against an eye-derived antigen were noted in TSP-derived peptide-treated mice. These changes correspond with the previously reported ability of the peptide to ameliorate SS-related ocular manifestations. Collectively, our results demonstrate dysregulation of MZB cells in TSP1-/- mice and highlight their role in the context of SS-related chronic ocular surface disease.

Risk Factors for Endophthalmitis after Pars Plana Vitrectomies in a Tertiary Eye Institute in India.

PURPOSE: To identify the risk factors associated with endophthalmitis after pars plana vitrectomy (PPV). DESIGN: Retrospective case-control study. PARTICIPANTS: All eyes that presented with endophthalmitis after PPV within 6 weeks in a tertiary eye care center were evaluated. There were 36 cases with endophthalmitis and 93 controls without endophthalmitis. METHODS: Other patients undergoing operation by the same surgeon on the same date and in the same operating room were included as controls. Univariate and multivariate regression analyses were performed to evaluate the risk factors. MAIN OUTCOME MEASURES: Incidence and risk factors for endophthalmitis after PPV. RESULTS: In this study, 36 cases and 93 controls met the inclusion criteria. For endophthalmitis, 3 independent risk factors were identified: systemic immunosuppression (odds ratio [OR], 10.673; 95% confidence interval [CI], 1.114-102.292; P = 0.04), balanced salt solution (BSS) or Ringer's lactate (RL) as vitreous substitute (OR, 5.288; 95% CI, 1.769-15.813; P = 0.003), and surgery performed in the second half of the day (OR, 0.016; 95% CI, 1.266-10.398; P = 0.016). Operating on phakic patients compared with pseudophakic or aphakic patients (OR, 0.962; 95% CI, 5.049-57.644; P < 0.001) and the use of endotamponade (OR, 5.288; 95% CI, 1.769-15.813; P = 0.003) were associated with a reduced risk for endophthalmitis. In culture-positive endophthalmitis, the presence of diabetes (OR, 4.61; 95% CI, 1.15-18.39; P = 0.03), vitreous substitute (BSS or RL) (OR, 6.08, 95% CI, 1.47-25.10, P = 0.012), and pseudophakia (OR, 5.68; 95% CI, 1.37-23.47; P = 0.016) were significant risk factors. CONCLUSIONS: Patients who are immunocompromised, pseudophakic, or aphakic are at a higher risk of endophthalmitis after PPV. Endotamponade significantly mitigates the risk of infection after vitrectomy surgery.

Prevention of Age-Related Macular Degeneration.

Age-related macular degeneration (AMD) compromises quality of life. However, the available therapeutic options are limited. This has led to the identification of modifiable risk factors to prevent the development or alter the natural course and prognosis of AMD. The identification and modification of risk factors has the potential for greater public health impact on reducing morbidity from AMD. Likewise, identifying the imaging clues and genetic clues could serve as a guide to recognizing the propensity for progression to severe and end stages of the disease. Several attempts, both successful and unsuccessful, have been made for interventions that could delay the progression of AMD. Of these, pharmacological interventions have shown promising results. The Age-Related Eye Disease Study 1 and 2 have shown the beneficial role of antioxidants in a selected group of patients.

Malignant Catatonia and Neuroleptic Malignant Syndrome in Relation to Disulfiram Overdose.

Disulfiram is a widely used drug in the management of alcohol dependence syndrome as an aversive agent. Although a drug of high efficacy, it has a large number of side effects. Disulfiram-induced catatonia is a known rare side effect of the drug and herein we report a case of what appeared to be the sequential development of malignant catatonia and neuroleptic malignant syndrome in a patient with a diagnosis of alcohol dependence syndrome and co-morbid paranoid schizophrenia following disulfiram overdose. Clinicians need to be vigilant on the emergence of such rare side effects.

Inhibition of quorum-sensing-mediated biofilm formation in Cronobacter sakazakii strains.

The present study investigated plant extracts for their anti-quorum-sensing (QS) potential to inhibit the biofilm formation in Cronobacter sakazakii strains. The bioassay based on loss of pigment production by Chromobacterium violaceum 026 and Agrobacterium tumefaciens NTL4(pZLR4) was used for initial screening of the extracts. Further, the effect of extracts on the inhibition of QS-mediated biofilm in C. sakazakii isolates was evaluated using standard crystal violet assay. The effect on biofilm texture was studied using SYTO9 staining and light and scanning electron microscopy. Among the tested extracts, Piper nigrum and Cinnamomum verum at 100 ppm resulted in 78 and 68 % reduction in the production of violacein as well as blue-green colour in both biosensor strains. A higher inhibitory activity (>50 %) on biofilm formation in C. sakazakii was observed for Pip. nigrum and Cin. verum, whereas the other extracts possessed moderate (25-50 %) and minimal (<25 %) inhibitory activities. Further, the fluorescent and scanning electron microscopic images indicated a major disruption in the architecture of biofilms of tested strains by Pip. nigrum. This study points to the possibility of using Pip. nigrum and Cin. verum as inhibitor of QS-mediated biofilm formation by C. sakazakii that could be further explored for novel bioactive molecules to limit the emerging infections of C. sakazakii.

Curcuma oil attenuates accelerated atherosclerosis and macrophage foam-cell formation by modulating genes involved in plaque stability, lipid homeostasis and inflammation.

In the present study, the anti-atherosclerotic effect and the underlying mechanism of curcuma oil (C. oil), a lipophilic fraction from turmeric (Curcuma longa L.), was evaluated in a hamster model of accelerated atherosclerosis and in THP-1 macrophages. Male golden Syrian hamsters were subjected to partial carotid ligation (PCL) or FeCl3-induced arterial oxidative injury (Ox-injury) after 1 week of treatment with a high-cholesterol (HC) diet or HC diet plus C. oil (100 and 300 mg/kg, orally). Hamsters fed with the HC diet were analysed at 1, 3 and 5 weeks following carotid injury. The HC diet plus C. oil-fed group was analysed at 5 weeks. In hyperlipidaemic hamsters with PCL or Ox-injury, C. oil (300 mg/kg) reduced elevated plasma and aortic lipid levels, arterial macrophage accumulation, and stenosis when compared with those subjected to arterial injury alone. Similarly, elevated mRNA transcripts of matrix metalloproteinase-2 (MMP-2), MMP-9, cluster of differentiation 45 (CD45), TNF-α, interferon-γ (IFN-γ), IL-1ß and IL-6 were reduced in atherosclerotic arteries, while those of transforming growth factor-ß (TGF-ß) and IL-10 were increased after the C. oil treatment (300 mg/kg). The treatment with C. oil prevented HC diet- and oxidised LDL (OxLDL)-induced lipid accumulation, decreased the mRNA expression of CD68 and CD36, and increased the mRNA expression of PPARα, LXRα, ABCA1 and ABCG1 in both hyperlipidaemic hamster-derived peritoneal and THP-1 macrophages. The administration of C. oil suppressed the mRNA expression of TNF-α, IL-1ß, IL-6 and IFN-γ and increased the expression of TGF-ß in peritoneal macrophages. In THP-1 macrophages, C. oil supplementation prevented OxLDL-induced production of TNF-α and IL-1ß and increased the levels of TGF-ß. The present study shows that C. oil attenuates arterial injury-induced accelerated atherosclerosis, inflammation and macrophage foam-cell formation.

Enhanced antitumor immunity contributes to the radio-sensitization of ehrlich ascites tumor by the glycolytic inhibitor 2-deoxy-D-glucose in mice.

Two-deoxy-D-glucose (2-DG), an inhibitor of glycolysis differentially enhances the radiation and chemotherapeutic drug induced cell death in cancer cells in vitro, while the local tumor control (tumor regression) following systemic administration of 2-DG and focal irradiation of the tumor results in both complete (cure) and partial response in a fraction of the tumor bearing mice. In the present studies, we investigated the effects of systemically administered 2-DG and focal irradiation of the tumor on the immune system in Ehrlich ascites tumor (EAT) bearing Strain "A" mice. Markers of different immune cells were analyzed by immune-flow cytometry and secretary cytokines by ELISA, besides monitoring tumor growth. Increase in the expression of innate (NK and monocytes) and adaptive CD4+cells, and a decrease in B cells (CD19) have been observed after the combined treatment, suggestive of activation of anti-tumor immune response. Interestingly, immature dendritic cells were found to be down regulated, while their functional markers CD86 and MHC II were up regulated in the remaining dendritic cells following the combination treatment. Similarly, decrease in the CD4(+) naïve cells with concomitant increase in activated CD4+ cells corroborated the immune activation. Further, a shift from Th2 and Th17 to Th1 besides a decrease in inflammatory cytokines was also observed in the animals showing complete response (cure; tumor free survival). This shift was also complimented by respective antibody class switching followed by the combined treatment. The immune activation or alteration in the homeostasis favoring antitumor immune response may be due to depletion in T regulatory cells (CD4(+)CD25(+)FoxP3(+)). Altogether, these results suggest that early differential immune activation is responsible for the heterogenous response to the combined treatment. Taken together, these studies for the first time provided insight into the additional mechanisms underlying radio-sensitization by 2-DG in vivo by unraveling its potential as an immune-modulator besides direct effects on the tumor.