Role of midkine in cancer drug resistance: Regulators of its expression and its molecular targeting

Molecules involved in drug resistance can be targeted for better therapeutic efficacies. Research on midkine (MDK) has escalated in the last few decades, which affirms a positive correlation between disease progression and MDK expression in most cancers and indicates its association with multi-drug resistance in cancer. MDK, a secretory cytokine found in blood, can be exploited as a potent biomarker for the non-invasive detection of drug resistance expressed in various cancers and, thereby, can be targeted. We summarize the current information on the involvement of MDK in drug resistance, and transcriptional regulators of its expression and highlight its potential as a cancer therapeutic target

Exploiting radiation induction of antigens in cancer: Targeted drug delivery

Therapeutic antibodies used to treat cancer are effective in patients with advanced-stage disease. For example, antibodies that activate T-lymphocytes improve survival in many cancer subtypes. In addition, antibody-drug conjugates effectively target cytotoxic agents that are specific to cancer. This review discusses radiation-inducible antigens, which are stress-regulated proteins that are over-expressed in cancer. These inducible cell surface proteins become accessible to antibody binding during the cellular response to genotoxic stress. The lead antigens are induced in all histologic subtypes and nearly all advanced-stage cancers, but show little to no expression in normal tissues. Inducible antigens are exploited by using therapeutic antibodies that bind specifically to these stress-regulated proteins. Antibodies that bind to the inducible antigens GRP78 and TIP1 enhance the efficacy of radiotherapy in preclinical cancer models. The conjugation of cytotoxic drugs to the antibodies further improves cancer response. This review focuses on the use of radiotherapy to control the cancer-specific binding of therapeutic antibodies and antibody-drug conjugates

Radiation induces iatrogenic immunosuppression by indirectly affecting hematopoiesis in bone marrow

The immune system plays a vital role in cancer therapy, especially with the advent of immunotherapy. Radiation therapy induces iatrogenic immunosuppression referred to as radiation-induced lymphopenia (RIL). RIL correlates with significant decreases in the overall survival of cancer patients. Although the etiology and severity of lymphopenia are known, the mechanism(s) of RIL are largely unknown. We found that irradiation not only had direct effects on circulating lymphocytes but also had indirect effects on the spleen, thymus, and bone marrow. We found that irradiated cells traffic to the bone marrow and bring about the reduction of hematopoietic stem cells (HSC) and progenitor cells. Using mass cytometry analysis (CyTOF) of the bone marrow, we found reduced expression of CD11a, which is required for T cell proliferation and maturation. RNA Sequencing and gene set enrichment analysis of the bone marrow cells following irradiation showed down-regulation of genes involved in hematopoiesis. Identification of CD11a and hematopoietic genes involved in iatrogenic immune suppression can help identify mechanisms of RIL

The ATF6 pathway of the ER stress response contributes to enhanced viability in glioblastoma

Therapeutic resistance is a major barrier to improvement of outcomes for patients with glioblastoma. The endoplasmic reticulum stress response (ERSR) has been identified as a contributor to chemoresistance in glioblastoma; however the contributions of the ERSR to radioresistance have not been characterized. In this study we found that radiation can induce ER stress and downstream signaling associated with the ERSR. Induction of ER stress appears to be linked to changes in ROS balance secondary to irradiation. Furthermore, we observed global induction of genes downstream of the ERSR in irradiated glioblastoma. Knockdown of ATF6, a regulator of the ERSR, was sufficient to enhance radiation induced cell death. Also, we found that activation of ATF6 contributes to the radiation-induced upregulation of glucose regulated protein 78 (GRP78) and NOTCH1. Our results reveal ATF6 as a potential therapeutic target to enhance the efficacy of radiation therapy

Structure Based Design and Synthesis of Peptide Inhibitor of Human LOX-12: In Vitro and In Vivo Analysis of a Novel Therapeutic Agent for Breast Cancer

Human breast cancer cell proliferation involves a complex interaction between growth factors, steroid hormones and peptide hormones. The interaction of growth factors, such as epidermal growth factor (EGF), with their receptors on breast cancer cells can lead to the hydrolysis of phospholipids and release of fatty acid such as arachidonic acid, which can be further metabolized by cyclooxygenase (COX) and lipoxygenase (LOX) pathways to produce prostaglandins. The high concentration of prostaglandins has been associated with chronic inflammatory diseases and several types of human cancers. This is due to the over expression COX, LOX and other inflammatory enzymes. Ten peptides were designed and synthesized by solid phase peptide synthesis and analyzed in vitro for enzyme inhibition. Out of these peptides, YWCS had shown significant inhibitory effects. The dissociation constant (KD) was determined by surface plasmon resonance (SPR) analysis and was found to be 3.39×10−8 M and 8.6×10−8 M for YWCS and baicalein (positive control), respectively. The kinetic constant Ki was 72.45×10−7 M as determined by kinetic assay. The peptide significantly reduced the cell viability of estrogen positive MCF-7 and estrogen negative MDA-MB-231 cell line with the half maximal concentration (IC50) of 75 µM and 400 µM, respectively. The peptide also induced 49.8% and 20.8% apoptosis in breast cancer cells MCF-7 and MDA-MB-231, respectively. The YWCS was also found to be least hemolytic at a concentration of 358 µM. In vivo studies had shown that the peptide significantly inhibits tumor growth in mice (p<0.017). This peptide can be used as a lead compound and complement for ongoing efforts to develop differentiation therapies for breast cancer

Global burden of 288 causes of death and life expectancy decomposition in 204 countries and territories and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BACKGROUND Regular, detailed reporting on population health by underlying cause of death is fundamental for public health decision making. Cause-specific estimates of mortality and the subsequent effects on life expectancy worldwide are valuable metrics to gauge progress in reducing mortality rates. These estimates are particularly important following large-scale mortality spikes, such as the COVID-19 pandemic. When systematically analysed, mortality rates and life expectancy allow comparisons of the consequences of causes of death globally and over time, providing a nuanced understanding of the effect of these causes on global populations. METHODS The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 cause-of-death analysis estimated mortality and years of life lost (YLLs) from 288 causes of death by age-sex-location-year in 204 countries and territories and 811 subnational locations for each year from 1990 until 2021. The analysis used 56 604 data sources, including data from vital registration and verbal autopsy as well as surveys, censuses, surveillance systems, and cancer registries, among others. As with previous GBD rounds, cause-specific death rates for most causes were estimated using the Cause of Death Ensemble model-a modelling tool developed for GBD to assess the out-of-sample predictive validity of different statistical models and covariate permutations and combine those results to produce cause-specific mortality estimates-with alternative strategies adapted to model causes with insufficient data, substantial changes in reporting over the study period, or unusual epidemiology. YLLs were computed as the product of the number of deaths for each cause-age-sex-location-year and the standard life expectancy at each age. As part of the modelling process, uncertainty intervals (UIs) were generated using the 2·5th and 97·5th percentiles from a 1000-draw distribution for each metric. We decomposed life expectancy by cause of death, location, and year to show cause-specific effects on life expectancy from 1990 to 2021. We also used the coefficient of variation and the fraction of population affected by 90% of deaths to highlight concentrations of mortality. Findings are reported in counts and age-standardised rates. Methodological improvements for cause-of-death estimates in GBD 2021 include the expansion of under-5-years age group to include four new age groups, enhanced methods to account for stochastic variation of sparse data, and the inclusion of COVID-19 and other pandemic-related mortality-which includes excess mortality associated with the pandemic, excluding COVID-19, lower respiratory infections, measles, malaria, and pertussis. For this analysis, 199 new country-years of vital registration cause-of-death data, 5 country-years of surveillance data, 21 country-years of verbal autopsy data, and 94 country-years of other data types were added to those used in previous GBD rounds. FINDINGS The leading causes of age-standardised deaths globally were the same in 2019 as they were in 1990; in descending order, these were, ischaemic heart disease, stroke, chronic obstructive pulmonary disease, and lower respiratory infections. In 2021, however, COVID-19 replaced stroke as the second-leading age-standardised cause of death, with 94·0 deaths (95% UI 89·2-100·0) per 100 000 population. The COVID-19 pandemic shifted the rankings of the leading five causes, lowering stroke to the third-leading and chronic obstructive pulmonary disease to the fourth-leading position. In 2021, the highest age-standardised death rates from COVID-19 occurred in sub-Saharan Africa (271·0 deaths [250·1-290·7] per 100 000 population) and Latin America and the Caribbean (195·4 deaths [182·1-211·4] per 100 000 population). The lowest age-standardised death rates from COVID-19 were in the high-income super-region (48·1 deaths [47·4-48·8] per 100 000 population) and southeast Asia, east Asia, and Oceania (23·2 deaths [16·3-37·2] per 100 000 population). Globally, life expectancy steadily improved between 1990 and 2019 for 18 of the 22 investigated causes. Decomposition of global and regional life expectancy showed the positive effect that reductions in deaths from enteric infections, lower respiratory infections, stroke, and neonatal deaths, among others have contributed to improved survival over the study period. However, a net reduction of 1·6 years occurred in global life expectancy between 2019 and 2021, primarily due to increased death rates from COVID-19 and other pandemic-related mortality. Life expectancy was highly variable between super-regions over the study period, with southeast Asia, east Asia, and Oceania gaining 8·3 years (6·7-9·9) overall, while having the smallest reduction in life expectancy due to COVID-19 (0·4 years). The largest reduction in life expectancy due to COVID-19 occurred in Latin America and the Caribbean (3·6 years). Additionally, 53 of the 288 causes of death were highly concentrated in locations with less than 50% of the global population as of 2021, and these causes of death became progressively more concentrated since 1990, when only 44 causes showed this pattern. The concentration phenomenon is discussed heuristically with respect to enteric and lower respiratory infections, malaria, HIV/AIDS, neonatal disorders, tuberculosis, and measles. INTERPRETATION Long-standing gains in life expectancy and reductions in many of the leading causes of death have been disrupted by the COVID-19 pandemic, the adverse effects of which were spread unevenly among populations. Despite the pandemic, there has been continued progress in combatting several notable causes of death, leading to improved global life expectancy over the study period. Each of the seven GBD super-regions showed an overall improvement from 1990 and 2021, obscuring the negative effect in the years of the pandemic. Additionally, our findings regarding regional variation in causes of death driving increases in life expectancy hold clear policy utility. Analyses of shifting mortality trends reveal that several causes, once widespread globally, are now increasingly concentrated geographically. These changes in mortality concentration, alongside further investigation of changing risks, interventions, and relevant policy, present an important opportunity to deepen our understanding of mortality-reduction strategies. Examining patterns in mortality concentration might reveal areas where successful public health interventions have been implemented. Translating these successes to locations where certain causes of death remain entrenched can inform policies that work to improve life expectancy for people everywhere. FUNDING Bill & Melinda Gates Foundation

TAF15 contributes to the radiation-inducible stress response in cancer

Resistance to radiation therapy is a significant problem in the treatment of non-small cell lung cancer (NSCLC). There is an unmet need to discover new molecular targets for drug development in combination with standard of care cancer therapy. We found that TAF15 was radiation-inducible using phage-displayed peptide libraries. In this study, we report that overexpression of TAF15 is correlated with worsened survival in NSCLC patients. Radiation treatment led to surface induction of TAF1

A study on salivary hemagglutinins in a Central Indian population

Purpose: To study the presence of salivary hemagglutinins in a Central Indian Population. Method: A drop of supernatant of centrifuged saliva samples was placed in cavity tiles. A drop of 0.2% cell suspensions of twice washed cells of known A and B blood groups was added into the respectively marked cavities. After mixing, the tiles were kept in a moist chamber for 30 min and examined microscopically. Clumps formed of at least 3–4 cells were taken as positive. Result: A sensitive method for the detection of anti-A and anti-B hemagglutinins in fresh saliva has been developed. Presence of salivary hemagglutinins in Maharashtrians was quite high, i.e., 69.41% as compared with Gonds 17% (Chatterjee and Badiye, 2012) and the Punjabis 35.98% (Chattopadhyay and Ganeson, 1983). Conclusion: Saliva in the form of stains is encountered as physical evidence in many cases, such as anonymous letters, secret writing, sexual assault, rape, murder, disputed paternity, cigarette butt ends, etc. If analyzed properly saliva can not only help in the elimination of the innocents, but also in the actual identification of a specific individual. Like blood grouping, this can also be used for forensic purposes