Simple and objective prediction of survival in patients with lung cancer: staging the host systemic inflammatory response

Background. Prediction of survival in patients diagnosed with lung cancer remains problematical. The aim of the present study was to examine the clinical utility of an established objective marker of the systemic inflammatory response, the Glasgow Prognostic Score, as the basis of risk stratification in patients with lung cancer. Methods. Between 2005 and 2008 all newly diagnosed lung cancer patients coming through the multidisciplinary meetings (MDTs) of four Scottish centres were included in the study. The details of 882 patients with a confirmed new diagnosis of any subtype or stage of lung cancer were collected prospectively. Results. The median survival was 5.6 months (IQR 4.8–6.5). Survival analysis was undertaken in three separate groups based on mGPS score. In the mGPS 0 group the most highly predictive factors were performance status, weight loss, stage of NSCLC, and palliative treatment offered. In the mGPS 1 group performance status, stage of NSCLC, and radical treatment offered were significant. In the mGPS 2 group only performance status and weight loss were statistically significant. Discussion. This present study confirms previous work supporting the use of mGPS in predicting cancer survival; however, it goes further by showing how it might be used to provide more objective risk stratification in patients diagnosed with lung cancer

Characterization of ocular clinical isolates of Pseudomonas aeruginosa from non-contact lens related keratitis patients from south India

P. aeruginosa is the most common Gram-negative organism causing bacterial keratitis. Pseudomonas utilizes various virulence mechanisms to adhere and colonize in the host tissue. In the present study, we examined virulence factors associated with thirty-four clinical P. aeruginosa isolates collected from keratitis patients seeking care at L V Prasad Eye Institute, Hyderabad. The virulence-associated genes in all the isolates were genotyped and characteristics such as antibiotic susceptibility, biofilm formation, swarming motility, pyoverdine production and cell cytotoxicity were analyzed. All the isolates showed the presence of genes related to biofilm formation, alkaline proteases and elastases; however, there was a difference in the presence of genes related to the type III secretion system (T3SS). A higher prevalence of exoU+ genotype was noted in the drug-resistant isolates. All the isolates were capable of forming biofilms and more than 70% of the isolates showed good swarming motility. Pyoverdine production was not associated with the T3SS genotype. In the cytotoxicity assay, the presence of exoS, exoU or both resulted in higher cytotoxicity compared to the absence of both the genes. Overall, our results suggest that the T3SS profile is a good indicator of P. aeruginosa virulence characteristics and the isolates lacking the effector genes may have evolved alternate mechanisms of colonization in the host

Identification and management of atherosclerotic cardiovascular disease risk in south Asian populations in the U.S.

South Asians (SAs, individuals with ancestry from Bangladesh, Bhutan, India, Maldives, Nepal, Pakistan, and Sri Lanka) are among the fastest growing ethnic subgroups in the United States. SAs typically experience a high prevalence of diabetes, abdominal obesity, and hypertension, among other cardiovascular disease risk factors, which are often under recognized and undermanaged. The excess coronary heart disease risk in this growing population must be critically assessed and managed with culturally appropriate preventive services. Accordingly, this scientific document prepared by a multidisciplinary group of clinicians and investigators in cardiology, internal medicine, pharmacy, and SA-centric researchers describes key characteristics of traditional and nontraditional cardiovascular disease risk factors, compares and contrasts available risk assessment tools, discusses the role of blood-based biomarkers and coronary artery calcium to enhance risk assessment and prevention strategies, and provides evidenced-based approaches and interventions that may reduce coronary heart disease disparities in this higher-risk population

The antifibrotic and the anticarcinogenic activity of capsaicin in hot chili pepper in relation to oral submucous fibrosis

A burning sensation on eating spicy foods purportedly supports the role of capsaicin, an active component of chili peppers, in the etiology of oral submucous fibrosis (OSF). Although the mast cell mediators and activated P2X receptors induce a constant burning sensation through an ATP-dependent mechanism, it is the activation of the transient receptor potential vanilloid 1 (TRPV-1) receptor by capsaicin that aggravates it. The molecular basis for the burning pain in OSF is thus attributable to the activation of TRPV1. There is overwhelming evidence that confirms capsaicin has more of a protective role in attenuating fibrosis and is potentially therapeutic in reversing conditions linked to collagen accumulation. The activation of TRPV-1 by capsaicin increases intracellular calcium ([Ca2+]i), upregulates AMP-activated protein kinase (AMPK) and Sirtuin-1 (SIRT-1), to enrich endothelium-dependent vasodilation via endothelial nitric oxide synthase (eNOS). The induction of vasodilation induces antifibrotic effects by alleviating hypoxia. The antifibrotic effects of capsaicin are mediated through the upregulation of antioxidant enzymes, downregulation of inflammatory genes and suppression of new collagen fibril formation. Capsaicin also demonstrates an anticarcinogenic effect by upregulating the cytotoxic T cells and downregulating regulatory T cells through the inhibition of angiogenesis and promotion of apoptosis. Judicious administration of capsaicin with an appropriate delivery mechanism may have therapeutic benefits in reducing pain sensation, rendering antifibrotic effects, and preventing the malignant transformation of OSF. This paper provides an overview of the molecular basis of capsaicin and its therapeutic application as an antifibrotic and anticarcinogenic agent for the treatment of OSF

The NeST (Neoadjuvant systemic therapy in breast cancer) study: National Practice Questionnaire of United Kingdom multi-disciplinary decision making.

BACKGROUND: Neoadjuvant systemic therapy (NST) is increasingly used in the treatment of breast cancer, yet it is clear that there is significant geographical variation in its use in the UK. This study aimed to examine stated practice across UK breast units, in terms of indications for use, radiological monitoring, pathological reporting of treatment response, and post-treatment surgical management. METHODS: Multidisciplinary teams (MDTs) from all UK breast units were invited to participate in the NeST study. A detailed questionnaire assessing current stated practice was distributed to all participating units in December 2017 and data collated securely usingREDCap. Descriptive statistics were calculated for each questionnaire item. RESULTS: Thirty-nine MDTs from a diverse range of hospitals responded. All MDTs routinely offered neoadjuvant chemotherapy (NACT) to a median of 10% (range 5-60%) of patients. Neoadjuvant endocrine therapy (NET) was offered to a median of 4% (range 0-25%) of patients by 66% of MDTs. The principal indication given for use of neoadjuvant therapy was for surgical downstaging. There was no consensus on methods of radiological monitoring of response, and a wide variety of pathological reporting systems were used to assess tumour response. Twenty-five percent of centres reported resecting the original tumour footprint, irrespective of clinical/radiological response. Radiologically negative axillae at diagnosis routinely had post-NACT or post-NET sentinel lymph node biopsy (SLNB) in 73.0 and 84% of centres respectively, whereas 16% performed SLNB pre-NACT. Positive axillae at diagnosis would receive axillary node clearance at 60% of centres, regardless of response to NACT. DISCUSSION: There is wide variation in the stated use of neoadjuvant systemic therapy across the UK, with general low usage of NET. Surgical downstaging remains the most common indication of the use of NAC, although not all centres leverage the benefits of NAC for de-escalating surgery to the breast and/or axilla. There is a need for agreed multidisciplinary guidance for optimising selection and management of patients for NST. These findings will be corroborated in phase II of the NeST study which is a national collaborative prospective audit of NST utilisation and clinical outcomes

Genotype, age, genetic background, and sex influence Epha2-related cataract development in mice

Purpose: Age-related cataract is the leading cause of blindness worldwide. Variants in the EPHA2 gene increase the disease risk, and its knockout in mice causes cataract. We investigated whether age, sex, and genetic background, risk factors for age-related cataract, and Epha2 genotype influence Epha2-related cataract development in mice. Methods: Cataract development was monitored in Epha2+/+, Epha2+/−, and Epha2−/− mice (Epha2Gt(KST085)Byg) on C57BL/6J and FVB:C57BL/6J (50:50) backgrounds. Cellular architecture of lenses, endoplasmic reticulum (ER) stress, and redox state were determined using histological, molecular, and analytical techniques. Results: Epha2−/− and Epha2+/− mice on C57BL/6J background developed severe cortical cataracts by 18 and 38 weeks of age, respectively, compared to development of similar cataract significantly later in Epha2−/− mice and no cataract in Epha2+/− mice in this strain on FVB background, which was previously reported. On FVB:C57BL/6J background, Epha2−/− mice developed severe cortical cataract by 38 weeks and Epha2+/− mice exhibited mild cortical cataract up to 64 weeks of age. Progression of cataract in Epha2−/− and Epha2+/− female mice on C57BL/6J and mixed background, respectively, was slower than in matched male mice. N-cadherin and β-catenin immunolabeling showed disorganized lens fiber cells and disruption of lens architecture in Epha2−/− and Epha2+/− lenses, coinciding with development of severe cataracts. EPHA2 immunolabeling showed intracellular accumulation of the mutant EPHA2-β-galactosidase fusion protein that induced a cytoprotective ER stress response and in Epha2+/− lenses was also accompanied by glutathione redox imbalance. Conclusions: Both, Epha2−/− and Epha2+/− mice develop age-related cortical cataract; age as a function of Epha2 genotype, sex, and genetic background influence Epha2-related cataractogenesis in mice

Breast cancer management pathways during the COVID-19 pandemic: outcomes from the UK 'Alert Level 4' phase of the B-MaP-C study

BACKGROUND: The B-MaP-C study aimed to determine alterations to breast cancer (BC) management during the peak transmission period of the UK COVID-19 pandemic and the potential impact of these treatment decisions. METHODS: This was a national cohort study of patients with early BC undergoing multidisciplinary team (MDT)-guided treatment recommendations during the pandemic, designated 'standard' or 'COVID-altered', in the preoperative, operative and post-operative setting. FINDINGS: Of 3776 patients (from 64 UK units) in the study, 2246 (59%) had 'COVID-altered' management. 'Bridging' endocrine therapy was used (n = 951) where theatre capacity was reduced. There was increasing access to COVID-19 low-risk theatres during the study period (59%). In line with national guidance, immediate breast reconstruction was avoided (n = 299). Where adjuvant chemotherapy was omitted (n = 81), the median benefit was only 3% (IQR 2-9%) using 'NHS Predict'. There was the rapid adoption of new evidence-based hypofractionated radiotherapy (n = 781, from 46 units). Only 14 patients (1%) tested positive for SARS-CoV-2 during their treatment journey. CONCLUSIONS: The majority of 'COVID-altered' management decisions were largely in line with pre-COVID evidence-based guidelines, implying that breast cancer survival outcomes are unlikely to be negatively impacted by the pandemic. However, in this study, the potential impact of delays to BC presentation or diagnosis remains unknown

Transposing tirtha: Understanding religious reforms and locative piety in early modern Hinduism

The paper deals with a historical and hitherto obscure case of de-commercialisation of sacred geography of India. Sahajanand Swami, an eighteenth century religious leader from Gujarat who became popular as Bhagwan Swaminarayan took an initiative to eliminate corruption in Dwarka, one of the most sacred destination in Hindu imagination. He also attempted to transpose the piety of Dwarka and recreate a parallel religious experience at Vadtal, an important site in Swaminarayan Hinduism. This process of making sacred sites more egalitarian is classified here as a 'religious reform'. The paper assesses this bivalent pursuit as an institutional reform within religion as well as a religious process in the context of piety, authority and orthodoxy. Through the example of Sahajanand Swami, it is argued to calibrate the colonial paradigm of reform that was largely contextual to social issues and western thought and failed to appreciate the religious reforms of that era. By constructing a nuanced typology of 'religious reform' distinct from 'social reforms', the paper eventually calls for a reassessment of religious figures who have significantly contributed in reforming the Hindu tradition in the medieval and modern era

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment