CCR2 and CCR5 co-inhibition modulates immunosuppressive myeloid milieu in glioma and synergizes with anti-PD-1 therapy.

Immunotherapy has revolutionized the treatment of cancers. Reinvigorating lymphocytes with checkpoint blockade has become a cornerstone of immunotherapy for multiple tumor types, but the treatment of glioblastoma has not yet shown clinical efficacy. A major hurdle to treat GBM with checkpoint blockade is the high degree of myeloid-mediated immunosuppression in brain tumors that limits CD8 T-cell activity. A potential strategy to improve anti-tumor efficacy against glioma is to use myeloid-modulating agents to target immunosuppressive cells, such as myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment. We found that the co-inhibition of the chemokine receptors CCR2 and CCR5 in murine model of glioma improves the survival and synergizes robustly with anti-PD-1 therapy. Moreover, the treatment specifically reduced the infiltration of monocytic-MDSCs (M-MDSCs) into brain tumors and increased lymphocyte abundance and cytokine secretion by tumor-infiltrating CD8 T cells. The depletion of T-cell subsets and myeloid cells abrogated the effects of CCR2 and CCR5 blockade, indicating that while broad depletion of myeloid cells does not improve survival, specific reduction in the infiltration of immunosuppressive myeloid cells, such as M-MDSCs, can boost the anti-tumor immune response of lymphocytes. Our study highlights the potential of CCR2/CCR5 co-inhibition in reducing myeloid-mediated immunosuppression in GBM patients.

Widespread nuclear lamina injuries defeat proteostatic purposes of α-synuclein amyloid inclusions.

Biogenesis of inclusion bodies (IBs) facilitates protein quality control (PQC). Canonical aggresomes execute degradation of misfolded proteins while non-degradable amyloids sequester into insoluble protein deposits. Lewy bodies (LBs) are filamentous amyloid inclusions of α-synuclein, but PQC benefits and drawbacks associated with LB-like IBs remain underexplored. Here, we report that crosstalk between filamentous LB-like IBs and aggresome-like IBs of α-synuclein (Syn-aggresomes) buffer the load, aggregation state, and turnover of the amyloidogenic protein in mouse primary neurons and HEK293T cells. Filamentous LB-like IBs possess unorthodox PQC capacities of self-quarantining α-synuclein amyloids and being degradable upon receding fresh amyloidogenesis. Syn-aggresomes equilibrate biogenesis of filamentous LB-like IBs by facilitating spontaneous degradation of α-synuclein and conditional turnover of disintegrated α-synuclein amyloids. Thus, both types of IB primarily contribute to PQC. Incidentally, the overgrown perinuclear LB-like IBs become degenerative once these are misidentified by BICD2, a cargo-adapter for the cytosolic motor-protein dynein. Microscopy indicates that microtubules surrounding the perinuclear filamentous inclusions are also distorted, misbalancing the cytoskeleton-nucleoskeleton tension leading to widespread lamina injuries. Together, nucleocytoplasmic mixing, DNA damage, and deregulated transcription of stress chaperones defeat the proteostatic purposes of the filamentous amyloids of α-synuclein.

Soluble PD-L1 reprograms blood monocytes to prevent cerebral edema and facilitate recovery after ischemic stroke.

Acute cerebral ischemia triggers a profound inflammatory response. While macrophages polarized to an M2-like phenotype clear debris and facilitate tissue repair, aberrant or prolonged macrophage activation is counterproductive to recovery. The inhibitory immune checkpoint Programmed Cell Death Protein 1 (PD-1) is upregulated on macrophage precursors (monocytes) in the blood after acute cerebrovascular injury. To investigate the therapeutic potential of PD-1 activation, we immunophenotyped circulating monocytes from patients and found that PD-1 expression was upregulated in the acute period after stroke. Murine studies using a temporary middle cerebral artery (MCA) occlusion (MCAO) model showed that intraperitoneal administration of soluble Programmed Death Ligand-1 (sPD-L1) significantly decreased brain edema and improved overall survival. Mice receiving sPD-L1 also had higher performance scores short-term, and more closely resembled sham animals on assessments of long-term functional recovery. These clinical and radiographic benefits were abrogated in global and myeloid-specific PD-1 knockout animals, confirming PD-1+ monocytes as the therapeutic target of sPD-L1. Single-cell RNA sequencing revealed that treatment skewed monocyte maturation to a non-classical Ly6Clo, CD43hi, PD-L1+ phenotype. These data support peripheral activation of PD-1 on inflammatory monocytes as a therapeutic strategy to treat neuroinflammation after acute ischemic stroke.

The Cynosure of CtBP: Evolution of a Bilaterian Transcriptional Corepressor.

Evolution of sequence-specific transcription factors clearly drives lineage-specific innovations, but less is known about how changes in the central transcriptional machinery may contribute to evolutionary transformations. In particular, transcriptional regulators are rich in intrinsically disordered regions that appear to be magnets for evolutionary innovation. The C-terminal Binding Protein (CtBP) is a transcriptional corepressor derived from an ancestral lineage of alpha hydroxyacid dehydrogenases; it is found in mammals and invertebrates, and features a core NAD-binding domain as well as an unstructured C-terminus (CTD) of unknown function. CtBP can act on promoters and enhancers to repress transcription through chromatin-linked mechanisms. Our comparative phylogenetic study shows that CtBP is a bilaterian innovation whose CTD of about 100 residues is present in almost all orthologs. CtBP CTDs contain conserved blocks of residues and retain a predicted disordered property, despite having variations in the primary sequence. Interestingly, the structure of the C-terminus has undergone radical transformation independently in certain lineages including flatworms and nematodes. Also contributing to CTD diversity is the production of myriad alternative RNA splicing products, including the production of "short" tailless forms of CtBP in Drosophila. Additional diversity stems from multiple gene duplications in vertebrates, where up to five CtBP orthologs have been observed. Vertebrate lineages show fewer major modifications in the unstructured CTD, possibly because gene regulatory constraints of the vertebrate body plan place specific constraints on this domain. Our study highlights the rich regulatory potential of this previously unstudied domain of a central transcriptional regulator.

Do journals raise their impact factor or SCImago ranking by self-citing in editorials? A bibliometric analysis of trauma and orthopaedic journals.

BACKGROUND: Impact factor (IF) is widely accepted as a measure of a journal's quality but it can be influenced by self-citation. However, the SCImago Journal Rank (SJR) is based on journal prestige, excludes self-citation and considers quality of citations of a journal. This study aimed to investigate journal editors' use of self-citation and whether this correlated with IFs or SJR in trauma and orthopaedic (T&O) journals. METHODS: T&O journals on the SJR database were identified. From each journal, data including country of publication, number of annual issues, IF, SJR indicator and citable articles were extracted. The editorial(s) of each issue in 2018 were reviewed. The total number of times the editors cited their own previous work or their journal (in the preceding 2 years, 2016-2017) were identified. Regression analyses were performed to investigate the association of editorial self-citation with journal IF or SJR indicator. RESULTS: Of the 270 journals identified, 43 T&O journals with 151 editorials were included in the final analysis. A positive correlation between journal self-citation in the editorial and IF (P = 0.02) and SJR indicator (P = 0.02) was found. Citation by editors of their own publications within editorials also positively correlated with IF (P = 0.04) but not for SJR indicator (P = 0.19). There was a positive linear relationship between journal IF and SJR indicators (P < 0.01). CONCLUSION: Editor self-citation influences the IF and SJR indicators in T&O journals. Therefore, these metrics should be considered in conjunction with other factors such as audience, topics included and international presence when evaluating journals.

Parametric survival analysis using R: Illustration with lung cancer data.

BACKGROUND: Cox regression is the most widely used survival model in oncology. Parametric survival models are an alternative of Cox regression model. In this study, we have illustrated the application of semiparametric model and various parametric (Weibull, exponential, log-normal, and log-logistic) models in lung cancer data by using R software. AIMS: The aim of the study is to illustrate responsible factors in lung cancer and compared with Cox regression and parametric models. METHODS: A total of 66 lung cancer patients of African Americans (AAs) (data available online at http://clincancerres.aacrjournals.org) was used. To identify predictors of overall survival, stage of patient, sex, age, smoking, and tumor grade were taken into account. Both parametric and semiparametric models were fitted. Performance of parametric models was compared by Akaike information criterion (AIC). "Survival" package in R software was used to perform the analysis. Posterior density was obtained for different parameters through Bayesian approach using WinBUGS. RESULTS: The illustration about model fitting problem was documented. Parametric models were fitted only for stage after controlling for age. AIC value was minimum (462.4087) for log-logistic model as compared with other parametric models. Log-logistic model was the best fit for AAs lung cancer data under study. CONCLUSION: Exploring parametric survival models in daily practice of cancer research is challenging. It may be due to many reasons including popularity of Cox regression and lack of knowledge about how to perform it. This paper provides the application of parametric survival models by using freely available R software with illustration. It is expected that this present work can be useful to apply parametric survival models.

Widening is a predictive factor of bucket handle tear in tibial plateau fractures.

BACKGROUND: It is well known that tibial plateau fractures have an association with soft tissue injuries. However, as far as the authors are aware, there has been no literature specifically on the incidence of bucket handle meniscal tears in patients with tibial plateau fractures. Bucket handle tears are often symptomatic and amenable to repair if detected early. Our objective was therefore to determine the incidence of bucket handle tears specifically in tibial plateau fractures and identify radiographic features which are suggestive of bucket handle tears. METHOD: Data for 88 consecutive patients with tibial plateau fractures in a major trauma centre over a two-year period were analysed. Clinical records were reviewed to identify injuries with an associated bucket handle tear. Pre-operative computerised tomography was reviewed. Monovariant and multivariant analyses were conducted to identify radiographic predictive features. RESULTS: The results showed a 20% incidence of soft tissue injuries in concurrence with the existing literature. In addition, there was found to be a 10% incidence of meniscal bucket handle tears. Articular widening of > 8 mm was found to be a unique significant predictor of bucket handle tears. CONCLUSION: It is essential to bear in mind the association with soft tissue injuries in tibial plateau fractures and the incidence of bucket handle tears in particular. The radiographic feature of articular widening should alert the clinician to the possibility of this injury. This will enable appropriate investigations and surgical planning to be carried out in order to improve patient management and outcomes.

Squamous cell carcinoma of buccal mucosa: An analysis of prognostic factors.

INTRODUCTION: Carcinoma of the buccal mucosa is the most common oral cavity cancer in the Indian subcontinent. The aim of this study was to analyze the outcome and evaluate prognostic factors in surgically treated buccal mucosa squamous cell carcinoma (BMSCC) patients. MATERIALS AND METHODS: A retrospective study was performed by reviewing the medical records of 409 pathologically proven buccal mucosa cancer patients, who were diagnosed and surgically treated in Tata Memorial Hospital between January 1, 2006, and December 31, 2008. RESULTS: The overall 5-year survival of the cohort was found to be 54.1%. The stage-wise survival rate for tumor, node, metastasis (TNM) Stage I, II, III, and IV patients was found to be 85.2%, 82.9%, 56.3%, and 42.6% (P < 0.00), respectively. On multivariate Cox proportional hazard analysis, the presence of comorbidity, histological tumor size, pathological lymph node status, tumor differentiation, perineural invasion, and extracapsular spread were found to be independently associated with overall survival. CONCLUSION: BMSCC is an aggressive malignant tumor. In addition to TNM classification, other clinical and pathological factors also have a significant role in BMSCC prognostication. Hence, there is a need to move beyond TNM and develop a more inclusive, flexible, and easy to use prognostic system.

Sociodemographic Factors and Late-stage Diagnosis of Breast Cancer in India: A Hospital-based Study.

CONTEXT: Breast cancer (BC) is one of the major causes of cancer mortality in India. Late-stage diagnosis of BC is associated with poor survival. Identification of factors affecting late presentation of the disease could be an effective step to reduce BC mortality. AIMS: To study the association of sociodemographic factors with BC stage at diagnosis. SETTINGS AND DESIGN: The study is a retrospective analysis from the case records from a single institution. SUBJECTS AND METHODS: Data for the year 2008 was collected from the hospital records. A total of 1210 cases were included for the analysis. Sociodemographic factors included were age, place of residence, religion, marital status, level of education, and occupation. Other study variables were family history, presence of comorbidity, and stage at diagnosis. STATISTICAL ANALYSIS: Association between sociodemographic factors by stage at diagnosis was tested using Chi-square statistics, with odds ratios (ORs) estimated through logistic regression modeling. RESULTS: In the study cohort, 46% patients had reported at early stages and 54% at advanced stages. All factors were evaluated for being predictors of disease stage at presentation using univariate and multivariate logistic regression model. Women from urban background were less likely to present with advanced stage disease (OR = 0.64; 95% confidence interval [CI]: 0.49-0.84) as compared to rural women. Similarly, illiterate women were also more likely to present with advanced-stage disease (OR = 1.55; 95% CI: 1.16-2.09). CONCLUSIONS: This data clearly indicate that the patients of rural background and of low education status are more likely than their respective counterparts to have an advanced stage of BC diagnosis. Our results may be considered the keys to determining how stage variation may be related to patients and community characteristics and where limited resources need to be invested to ensure early diagnosis of BC.

Sociodemographic and Clinical Profile of Cervical Cancer Patients Visiting in a Tertiary Care Hospital in India.

CONTEXT: Cancer of the cervix is the most common genital tract malignancy in the female and is a major public health problem in the developing countries. Study of the sociodemographic and clinical profile of patients is the first step in planning control measures and treatment facilities. AIMS: The aims of the study were to determine the sociodemographic and clinical profile of cervical cancer patients and study their association with other tumor-related factors. SETTINGS AND DESIGN: This is a record-based retrospective study from a single institution. SUBJECTS AND METHODS: The data on sociodemographic and clinical factors of 765 cervical cancer patients visited and treated at tertiary care cancer hospital in Mumbai in 1 year period were analyzed. STATISTICAL ANALYSIS: Data were analyzed using descriptive statistics. Kruskal-Wallis and Chi-square test were used to assess relationship between variables. RESULTS: The median age of the cohort was 54 years and interquartile range was 16 years. Nearly 53.6% of patients were illiterate. About 88.10% of patient's had squamous cell carcinoma. Only 13% of cases had early stage disease and 77% of patient's had not taken any treatment before coming to the hospital. Of the total, about 26% patients also had concomitant comorbidities, of which hypertension was found to be the leading comorbid condition. Stage of disease was found to be significantly (P < 0.05) associated with age and educational status. CONCLUSION: This study highlights certain important baseline characteristics of cervical cancer patients. This basic information on profile of patients can help plan and optimum utilization of hospital services, especially in resource-poor countries like India.

Role of Monocyte Count and Neutrophil-to- Lymphocyte Ratio in Survival of Oral Cancer Patients

Abstract Introduction Inflammation seems to play a critical role in the development and progression of numerous cancers. Peripheral blood leukocyte count is an easily assessable parameter of systemic inflammatory response. Objective The aim of this study was to investigate whether the pretreatment leukocyte counts can predict the prognosis of patients with oral cavity cancer. Methods Medical records of 471 oral cavity cancer patients diagnosed between January 2007 and December 2008 were retrospectively analyzed. Receiver operating characteristic curve analysis and Cox proportional hazards analyses were applied to evaluate the associations of leukocyte counts with overall survival. Results The overall five year's survival of the cohort was found to be 49.4%. On univariate analysis, elevated monocyte count (≥500/mm3) and neutrophil-to-lymphocyte ratio (NLR) (>2.38) were associated with poor overall survival (OS) (p = 0.001 and 0.000, respectively). Multivariate Cox proportional hazard analysis showed that higher monocyte and NLR levels were significant independent predictors of worse OS (HR = 1.385, 95% CI = 1.049 - 1.829; p < 0.05 and HR = 1.392, 95% CI = 1.045 - 1.855; p < 0.05, respectively). The advanced overall stage and lymph nodal involvement were also independent indicators for poor OS. Conclusions Higher pretreatment monocyte and NLR levels are independent predictors of poor prognosis for patients with oral cavity cancer. Thus, these easily accessed variables can serve as a potent marker to predict the outcomes of oral cancer patients.

Role of Monocyte Count and Neutrophil-to-Lymphocyte Ratio in Survival of Oral Cancer Patients.

Introduction Inflammation seems to play a critical role in the development and progression of numerous cancers. Peripheral blood leukocyte count is an easily assessable parameter of systemic inflammatory response. Objective The aim of this study was to investigate whether the pretreatment leukocyte counts can predict the prognosis of patients with oral cavity cancer. Methods Medical records of 471 oral cavity cancer patients diagnosed between January 2007 and December 2008 were retrospectively analyzed. Receiver operating characteristic curve analysis and Cox proportional hazards analyses were applied to evaluate the associations of leukocyte counts with overall survival. Results The overall five year's survival of the cohort was found to be 49.4%. On univariate analysis, elevated monocyte count (≥500/mm3) and neutrophil-to-lymphocyte ratio (NLR) (>2.38) were associated with poor overall survival (OS) (p = 0.001 and 0.000, respectively). Multivariate Cox proportional hazard analysis showed that higher monocyte and NLR levels were significant independent predictors of worse OS (HR = 1.385, 95% CI = 1.049 - 1.829; p < 0.05 and HR = 1.392, 95% CI = 1.045 - 1.855; p < 0.05, respectively). The advanced overall stage and lymph nodal involvement were also independent indicators for poor OS. Conclusions Higher pretreatment monocyte and NLR levels are independent predictors of poor prognosis for patients with oral cavity cancer. Thus, these easily accessed variables can serve as a potent marker to predict the outcomes of oral cancer patients.

Burden of cervical cancer and role of screening in India.

BACKGROUND: Cervical cancer is a major cause of cancer mortality in women and more than a quarter of its global burden is contributed by developing countries. In India, in spite of alarmingly high figures, there is no nationwide government-sponsored screening program. This study was conducted to assess the burden of cervical cancer in India and review the performance characteristics of available cervical cancer screening tools, so as to provide evidence-based recommendations for application of most practically suited screening test to be used in resource-poor field settings. MATERIALS AND METHODS: MEDLINE and Web of Science electronic database were searched from January 1990 to December 2015, using the keywords such as "cervical cancer", "screening", "early detection", "cervical cytology" and "visual inspection", and their corresponding MeSH terms in combination with Boolean operators "OR, AND." Two authors independently selected studies that are published in English and conducted in India. A total of 11 studies were found to be relevant and eligible to be included in the present study. RESULTS: In India, cervical cancer contributes to approximately 6-29% of all cancers in women. The age-adjusted incidence rate of cervical cancer varies widely among registries; highest is 23.07/100,000 in Mizoram state and the lowest is 4.91/100,000 in Dibrugarh district. The pooled estimates of sensitivity and specificity of visual inspection with acetic acid (VIA), magnified VIA, visual inspection with Lugol's iodine (VILI), cytology (Pap smear), and human papillomavirus DNA were found to be 67.65% and 84.32%, 65.36% and 85.76%, 78.27% and 87.10%, 62.11% and 93.51%, and 77.81% and 91.54%, respectively. CONCLUSIONS: In developing countries because of lack of necessary infrastructure and quality control, high-quality cytology screening may not be feasible for wide-scale implementation. Hence, cervical cancer screening program based on visual screening test such as VIA/VILI should be adopted as an integral part of primary health-care setup in resource-poor countries like India.

Cancer Screening: Should Cancer Screening be Essential Component of Primary Health Care in Developing Countries?

BACKGROUND: Cancer is a fatal disease and is on the rise across the globe. In India, breast, cervix and the oral cavity are the leading cancer sites, but, unfortunately, in-spite of availability of screening tools, there is no organized cancer screening program in India. The main objective of this study was to review the performance of various cancer screening modalities in a resource poor setting. METHODS: MEDLINE and web of science electronic database was searched from January 1990 to December 2013, using keywords such as "breast cancer, cervical cancer, oral cancer and their corresponding mesh terms were also used in combination with Boolean operators OR, AND." Two authors independently selected studies published in English and conducted in India. A total of 16 studies was found relevant and eligible for the review. The data on sensitivity and specificity of various screening tool was extracted and analyzed. RESULTS: Most of the reported screening trails in India are on cervical cancer and few on breast and oral cancer screening. The pooled estimates of sensitivity and specificity of cervical cancer screening test such as visual inspection with acetic acid, magnified visual inspection with acetic acid, visual inspection with Lugol's iodine, cytology (Papanicolaou smear) and human papillomavirus deoxyribonucleic acid was found to be 68.76% and 84.02%, 63.27% and 85.43%, 81.86% and 87.03%, 63.25% and 93.17% and 75.04% and 91.66%, respectively. Sensitivity and specificity of clinical breast examination was found to be 94.30% and 94.30%, respectively. Oral cancer screening through visual inspection by trained health care worker was found to have 87.90% sensitivity and 92.05% specificity. CONCLUSIONS: Our study highlights the availability and success of visual screening tools in early detection and mortality reduction of major neoplasia in resource-poor health care settings and recommends implementation of oral and cervical cancer screening as part of assured primary health care package in developing countries.

Epidemiological review of laryngeal cancer: An Indian perspective.

BACKGROUND: Laryngeal cancer is one of the 10 leading causes of cancer in Indian men. The association of laryngeal cancer and tobacco smoking is well-established, but the peculiarities such as wide variation of disease distribution and survival, role of tobacco chewing, indoor air pollution, and dietary factors in laryngeal cancer causation needs to be understood. In this study, we review the descriptive and observational epidemiology of laryngeal cancer in India. MATERIALS AND METHODS: MEDLINE and Web of science electronic database was searched from January 1995 to December 2013, using the using keywords "laryngeal cancer, laryngeal cancer outcome, epidemiology, etiological factor and their corresponding Mesh terms were used in combination like OR, AND." Two authors independently selected studies published in English and conducted in India. A total of 15 studies were found to be relevant and eligible for this review. RESULTS: In India, laryngeal cancer contributes to approximately 3-6% of all cancers in men. The age-adjusted incidence rate of cancer larynx in males varies widely among registries, highest is 8.18 per 100,000 in Kamprup Urban District and the lowest is 1.26 per 100,000 in Nagaland. The 5-year survival for laryngeal cancer in India is approximately 28%. Indian studies show tobacco, alcohol, long-term exposure to indoor air pollution, spicy food, and nonvegetarian diet as risk factors for laryngeal cancer. CONCLUSION: There is wide regional variation in the incidence of laryngeal cancer in India. Survival rates of laryngeal carcinoma are much lower as compared to other Asian countries. Studies conducted in India to identify important risk factors of laryngeal cancer are very limited, especially on diet and indoor air pollution. Hence, more research is required for identifying the etiological factors and development of scientifically sound laryngeal cancer prevention programs.

Probing interaction of gram-positive and gram-negative bacterial cells with ZnO nanorods.

In the present work, the physiological effects of the ZnO nanorods on the Gram positive (Staphylococcus aureus and Bacillus subtilis) and Gram-negative (Escherichia coli and Aerobacter aerogenes) bacterial cells have been studied. The analysis of bacterial growth curves for various concentrations of ZnO nanorods indicates that Gram positive and Gram negative bacterial cells show inhibition at concentrations of ~64 and ~256 µg/mL respectively. The marked difference in susceptibility towards nanorods was also validated by spread plate and disk diffusion methods. In addition, the scanning electron micrographs show a clear damage to the cells via changed morphology of the cells from rod to coccoid etc. The confocal optical microscopy images of these cells also demonstrate the reduction in live cell count in the presence of ZnO nanorods. These, results clearly indicate that the antibacterial activity of ZnO nanorods is higher towards Gram positive bacterium than Gram negative bacterium which indicates that the structure of the cell wall might play a major role in the interaction with nanostructured materials and shows high sensitivity to the particle concentration.