Academy of Medical Sciences

BACKGROUND: The Global Burden of Diseases, Injuries, and Risk Factors Study 2015 provides an up-to-date synthesis of the evidence for risk factor exposure and the attributable burden of disease. By providing national and subnational assessments spanning the past 25 years, this study can inform debates on the importance of addressing risks in context. METHODS: We used the comparative risk assessment framework developed for previous iterations of the Global Burden of Disease Study to estimate attributable deaths, disability-adjusted life-years (DALYs), and trends in exposure by age group, sex, year, and geography for 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks from 1990 to 2015. This study included 388 risk-outcome pairs that met World Cancer Research Fund-defined criteria for convincing or probable evidence. We extracted relative risk and exposure estimates from randomised controlled trials, cohorts, pooled cohorts, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. We developed a metric that allows comparisons of exposure across risk factors-the summary exposure value. Using the counterfactual scenario of theoretical minimum risk level, we estimated the portion of deaths and DALYs that could be attributed to a given risk. We decomposed trends in attributable burden into contributions from population growth, population age structure, risk exposure, and risk-deleted cause-specific DALY rates. We characterised risk exposure in relation to a Socio-demographic Index (SDI). FINDINGS: Between 1990 and 2015, global exposure to unsafe sanitation, household air pollution, childhood underweight, childhood stunting, and smoking each decreased by more than 25%. Global exposure for several occupational risks, high body-mass index (BMI), and drug use increased by more than 25% over the same period. All risks jointly evaluated in 2015 accounted for 57·8% (95% CI 56·6-58·8) of global deaths and 41·2% (39·8-42·8) of DALYs. In 2015, the ten largest contributors to global DALYs among Level 3 risks were high systolic blood pressure (211·8 million [192·7 million to 231·1 million] global DALYs), smoking (148·6 million [134·2 million to 163·1 million]), high fasting plasma glucose (143·1 million [125·1 million to 163·5 million]), high BMI (120·1 million [83·8 million to 158·4 million]), childhood undernutrition (113·3 million [103·9 million to 123·4 million]), ambient particulate matter (103·1 million [90·8 million to 115·1 million]), high total cholesterol (88·7 million [74·6 million to 105·7 million]), household air pollution (85·6 million [66·7 million to 106·1 million]), alcohol use (85·0 million [77·2 million to 93·0 million]), and diets high in sodium (83·0 million [49·3 million to 127·5 million]). From 1990 to 2015, attributable DALYs declined for micronutrient deficiencies, childhood undernutrition, unsafe sanitation and water, and household air pollution; reductions in risk-deleted DALY rates rather than reductions in exposure drove these declines. Rising exposure contributed to notable increases in attributable DALYs from high BMI, high fasting plasma glucose, occupational carcinogens, and drug use. Environmental risks and childhood undernutrition declined steadily with SDI; low physical activity, high BMI, and high fasting plasma glucose increased with SDI. In 119 countries, metabolic risks, such as high BMI and fasting plasma glucose, contributed the most attributable DALYs in 2015. Regionally, smoking still ranked among the leading five risk factors for attributable DALYs in 109 countries; childhood underweight and unsafe sex remained primary drivers of early death and disability in much of sub-Saharan Africa. INTERPRETATION: Declines in some key environmental risks have contributed to declines in critical infectious diseases. Some risks appear to be invariant to SDI. Increasing risks, including high BMI, high fasting plasma glucose, drug use, and some occupational exposures, contribute to rising burden from some conditions, but also provide opportunities for intervention. Some highly preventable risks, such as smoking, remain major causes of attributable DALYs, even as exposure is declining. Public policy makers need to pay attention to the risks that are increasingly major contributors to global burden. FUNDING: Bill & Melinda Gates Foundation.

ABSTRACT In monolayer cultures of guinea‐pig bone marrow and spleen the development of discrete fibroblast colonies takes place on days 9–12. The linear increase in the number of colonies with increasing numbers of explanted cells and the distribution of male and female cells in mixed cultures support the view that fibroblast colonies are clones. The concentration of colony‐forming cells in bone marrow and spleen is approximately 10 ‐5 . Bone marrow culture (but not spleen culture) fibroblasts are capable of spontaneous bone formation in diffusion chambers. Fibroblasts from both bone marrow and spleen cultures are inducible to osteogenesis in diffusion chambers in the presence of transitional epithelium.

BACKGROUND: ) mutation-positive advanced non-small-cell lung cancer (NSCLC). The efficacy and safety of osimertinib as adjuvant therapy are unknown. METHODS: mutation-positive NSCLC in a 1:1 ratio to receive either osimertinib (80 mg once daily) or placebo for 3 years. The primary end point was disease-free survival among patients with stage II to IIIA disease (according to investigator assessment). The secondary end points included disease-free survival in the overall population of patients with stage IB to IIIA disease, overall survival, and safety. RESULTS: A total of 682 patients underwent randomization (339 to the osimertinib group and 343 to the placebo group). At 24 months, 90% of the patients with stage II to IIIA disease in the osimertinib group (95% confidence interval [CI], 84 to 93) and 44% of those in the placebo group (95% CI, 37 to 51) were alive and disease-free (overall hazard ratio for disease recurrence or death, 0.17; 99.06% CI, 0.11 to 0.26; P<0.001). In the overall population, 89% of the patients in the osimertinib group (95% CI, 85 to 92) and 52% of those in the placebo group (95% CI, 46 to 58) were alive and disease-free at 24 months (overall hazard ratio for disease recurrence or death, 0.20; 99.12% CI, 0.14 to 0.30; P<0.001). At 24 months, 98% of the patients in the osimertinib group (95% CI, 95 to 99) and 85% of those in the placebo group (95% CI, 80 to 89) were alive and did not have central nervous system disease (overall hazard ratio for disease recurrence or death, 0.18; 95% CI, 0.10 to 0.33). Overall survival data were immature; 29 patients died (9 in the osimertinib group and 20 in the placebo group). No new safety concerns were noted. CONCLUSIONS: mutation-positive NSCLC, disease-free survival was significantly longer among those who received osimertinib than among those who received placebo. (Funded by AstraZeneca; ADAURA ClinicalTrials.gov number, NCT02511106.).

ABSTRACT After heterotopic (e.g. subcutaneous) transplantation of bone marrow, haemopoiesis in the graft ceases; reticular tissue develops instead, and later bone is formed (Denis, 1958). The result can be achieved by grafting either free pieces of bone marrow or those placed in diffusion chambers (Petrakova, Tolmacheva &amp; Friedenstein, 1963; Rosin, Freiberg &amp; Sajnek, 1963). In the case of free transplantation the bone formed is later filled with bone marrow. After transplantation in diffusion chambers haemopoiesis does not recur despite the development of a considerable mass of bone in the chambers (Friedenstein, 1965).

PURPOSE: Cabozantinib, a tyrosine kinase inhibitor (TKI) of hepatocyte growth factor receptor (MET), vascular endothelial growth factor receptor 2, and rearranged during transfection (RET), demonstrated clinical activity in patients with medullary thyroid cancer (MTC) in phase I. PATIENTS AND METHODS: We conducted a double-blind, phase III trial comparing cabozantinib with placebo in 330 patients with documented radiographic progression of metastatic MTC. Patients were randomly assigned (2:1) to cabozantinib (140 mg per day) or placebo. The primary end point was progression-free survival (PFS). Additional outcome measures included tumor response rate, overall survival, and safety. RESULTS: The estimated median PFS was 11.2 months for cabozantinib versus 4.0 months for placebo (hazard ratio, 0.28; 95% CI, 0.19 to 0.40; P < .001). Prolonged PFS with cabozantinib was observed across all subgroups including by age, prior TKI treatment, and RET mutation status (hereditary or sporadic). Response rate was 28% for cabozantinib and 0% for placebo; responses were seen regardless of RET mutation status. Kaplan-Meier estimates of patients alive and progression-free at 1 year are 47.3% for cabozantinib and 7.2% for placebo. Common cabozantinib-associated adverse events included diarrhea, palmar-plantar erythrodysesthesia, decreased weight and appetite, nausea, and fatigue and resulted in dose reductions in 79% and holds in 65% of patients. Adverse events led to treatment discontinuation in 16% of cabozantinib-treated patients and in 8% of placebo-treated patients. CONCLUSION: Cabozantinib (140 mg per day) achieved a statistically significant improvement of PFS in patients with progressive metastatic MTC and represents an important new treatment option for patients with this rare disease. This dose of cabozantinib was associated with significant but manageable toxicity.

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Given the increasing use of ambulatory blood pressure monitoring (ABPM) in both clinical practice and hypertension research, a group of scientists, participating in the European Society of Hypertension Working Group on blood pressure monitoring and cardiovascular variability, in year 2013 published a comprehensive position paper dealing with all aspects of the technique, based on the available scientific evidence for ABPM. The present work represents an updated schematic summary of the most important aspects related to the use of ABPM in daily practice, and is aimed at providing recommendations for proper use of this technique in a clinical setting by both specialists and practicing physicians. The present article details the requirements and the methodological issues to be addressed for using ABPM in clinical practice, The clinical indications for ABPM suggested by the available studies, among which white-coat phenomena, masked hypertension, and nocturnal hypertension, are outlined in detail, and the place of home measurement of blood pressure in relation to ABPM is discussed. The role of ABPM in pharmacological, epidemiological, and clinical research is also briefly mentioned. Finally, the implementation of ABPM in practice is considered in relation to the situation of different countries with regard to the reimbursement and the availability of ABPM in primary care practices, hospital clinics, and pharmacies.

Fibroblast colonies (clones) were obtained by explantation of bone marrow single-cell suspensions and were used to establish multicolony and single-colony derived fibroblast cultures by successive passaging of either pooled or individual colonies. When transplanted in diffusion chambers after 20-30 cell doublings in vitro, the descendants of fibroblast colony-forming cells (FCFC), whether grown from single or pooled colonies, retained the ability for bone and cartilage formation. The content of osteogenic precursors in the cultured progeny significantly outnumbered the initiating FCFC. Thus the high proliferative potential of bone marrow FCFC and their ability to serve as common precursors of bone and cartilage-forming cells makes them probable candidates for the role of osteogenic stem cells.

✓ A balloon catheter technique for catheterization of human cerebral blood vessels is described. Temporary occlusion of different cerebral vessels was successfully accomplished in more than 300 cases, including investigations of collateral blood flow, intraarterial pressure, brain temperature, the vital staining of tumors, and the introduction of chemical agents. Temporary occlusion of the internal carotid artery makes possible angiography of the external carotid, while occlusion of separate branches of the external carotid permits selective angiography of its functioning branches. The balloon catheter is valuable in investigating arteriovenous and carotid-cavernous fistulas. With the help of a detachable balloon it is possible to occlude the cavity of arterial aneurysms or the afferent vessels of arteriovenous aneurysms; it is also useful as a means to shut off the blood flow to arterial aneurysms and carotid-cavernous fistulas when access is difficult. A method for reconstruction of the cavernous part of the carotid artery in cases of carotid-cavernous fistulas is described.

The 1,852,442-bp sequence of an M1 strain of Streptococcus pyogenes, a Gram-positive pathogen, has been determined and contains 1,752 predicted protein-encoding genes. Approximately one-third of these genes have no identifiable function, with the remainder falling into previously characterized categories of known microbial function. Consistent with the observation that S. pyogenes is responsible for a wider variety of human disease than any other bacterial species, more than 40 putative virulence-associated genes have been identified. Additional genes have been identified that encode proteins likely associated with microbial "molecular mimicry" of host characteristics and involved in rheumatic fever or acute glomerulonephritis. The complete or partial sequence of four different bacteriophage genomes is also present, with each containing genes for one or more previously undiscovered superantigen-like proteins. These prophage-associated genes encode at least six potential virulence factors, emphasizing the importance of bacteriophages in horizontal gene transfer and a possible mechanism for generating new strains with increased pathogenic potential.

PD-L1 is an immunoinhibitory molecule that suppresses the activation of T cells, leading to the progression of tumors. Overexpression of PD-L1 in cancers such as gastric cancer, hepatocellular carcinoma, renal cell carcinoma, esophageal cancer, pancreatic cancer, ovarian cancer, and bladder cancer is associated with poor clinical outcomes. In contrast, PD-L1 expression correlates with better clinical outcomes in breast cancer and merkel cell carcinoma. The prognostic value of PD-L1 expression in lung cancer, colorectal cancer, and melanoma is controversial. Blocking antibodies that target PD-1 and PD-L1 have achieved remarkable response rates in cancer patients who have PD-L1-overexpressing tumors. However, using PD-L1 as an exclusive predictive biomarker for cancer immunotherapy is questionable due to the low accuracy of PD-L1 immunohistochemistry staining. Factors that affect the accuracy of PD-L1 immunohistochemistry staining are as follows. First, antibodies used in different studies have different sensitivity. Second, in different studies, the cut-off value of PD-L1 staining positivity is different. Third, PD-L1 expression in tumors is not uniform, and sampling time and location may affect the results of PD-L1 staining. Therefore, better understanding of tumor microenvironment and use of other biomarkers such as gene marker and combined index are necessary to better identify patients who will benefit from PD-1/PD-L1 checkpoint blockade therapy.

HUPO initiated the Plasma Proteome Project (PPP) in 2002. Its pilot phase has (1) evaluated advantages and limitations of many depletion, fractionation, and MS technology platforms; (2) compared PPP reference specimens of human serum and EDTA, heparin, and citrate-anti-coagulated plasma; and (3) created a publicly-available knowledge base (www.bioinformatics.med.umich.edu/hupo/ppp; www.ebi.ac.uk/pride). Thirty-five participating laboratories in 13 countries submitted datasets. Working groups addressed (a) specimen stability and protein concentrations; (b) protein identifications from 18 MS/MS datasets; (c) independent analyses from raw MS-MS spectra; (d) search engine performance, subproteome analyses, and biological insights; (e) antibody arrays; and (f) direct MS/SELDI analyses. MS-MS datasets had 15 710 different International Protein Index (IPI) protein IDs; our integration algorithm applied to multiple matches of peptide sequences yielded 9504 IPI proteins identified with one or more peptides and 3020 proteins identified with two or more peptides (the Core Dataset). These proteins have been characterized with Gene Ontology, InterPro, Novartis Atlas, OMIM, and immunoassay-based concentration determinations. The database permits examination of many other subsets, such as 1274 proteins identified with three or more peptides. Reverse protein to DNA matching identified proteins for 118 previously unidentified ORFs. We recommend use of plasma instead of serum, with EDTA (or citrate) for anticoagulation. To improve resolution, sensitivity and reproducibility of peptide identifications and protein matches, we recommend combinations of depletion, fractionation, and MS/MS technologies, with explicit criteria for evaluation of spectra, use of search algorithms, and integration of homologous protein matches. This Special Issue of PROTEOMICS presents papers integral to the collaborative analysis plus many reports of supplementary work on various aspects of the PPP workplan. These PPP results on complexity, dynamic range, incomplete sampling, false-positive matches, and integration of diverse datasets for plasma and serum proteins lay a foundation for development and validation of circulating protein biomarkers in health and disease.

BACKGROUND: The appropriate target for systolic blood pressure to reduce cardiovascular risk in older patients with hypertension remains unclear. METHODS: In this multicenter, randomized, controlled trial, we assigned Chinese patients 60 to 80 years of age with hypertension to a systolic blood-pressure target of 110 to less than 130 mm Hg (intensive treatment) or a target of 130 to less than 150 mm Hg (standard treatment). The primary outcome was a composite of stroke, acute coronary syndrome (acute myocardial infarction and hospitalization for unstable angina), acute decompensated heart failure, coronary revascularization, atrial fibrillation, or death from cardiovascular causes. RESULTS: Of the 9624 patients screened for eligibility, 8511 were enrolled in the trial; 4243 were randomly assigned to the intensive-treatment group and 4268 to the standard-treatment group. At 1 year of follow-up, the mean systolic blood pressure was 127.5 mm Hg in the intensive-treatment group and 135.3 mm Hg in the standard-treatment group. During a median follow-up period of 3.34 years, primary-outcome events occurred in 147 patients (3.5%) in the intensive-treatment group, as compared with 196 patients (4.6%) in the standard-treatment group (hazard ratio, 0.74; 95% confidence interval [CI], 0.60 to 0.92; P = 0.007). The results for most of the individual components of the primary outcome also favored intensive treatment: the hazard ratio for stroke was 0.67 (95% CI, 0.47 to 0.97), acute coronary syndrome 0.67 (95% CI, 0.47 to 0.94), acute decompensated heart failure 0.27 (95% CI, 0.08 to 0.98), coronary revascularization 0.69 (95% CI, 0.40 to 1.18), atrial fibrillation 0.96 (95% CI, 0.55 to 1.68), and death from cardiovascular causes 0.72 (95% CI, 0.39 to 1.32). The results for safety and renal outcomes did not differ significantly between the two groups, except for the incidence of hypotension, which was higher in the intensive-treatment group. CONCLUSIONS: In older patients with hypertension, intensive treatment with a systolic blood-pressure target of 110 to less than 130 mm Hg resulted in a lower incidence of cardiovascular events than standard treatment with a target of 130 to less than 150 mm Hg. (Funded by the Chinese Academy of Medical Sciences and others; STEP ClinicalTrials.gov number, NCT03015311.).

During the 1950s, the evidence was clearly sufficient to establish the carcinogenicity of tobacco smoking (1). By the end of the 1950s, convincing evidence linking smoking with lung cancer and other cancers had been obtained from case–control and cohort studies, carcinogens had been identified in tobacco smoke, and cigarette smoke condensate had been shown to cause tumors when painted on the skin of mice. Since then, the numbers of deaths attributable to tobacco smoking have sharply increased, reflecting the heavy smoking patterns of previous decades. It has been estimated that tobacco smoking is currently responsible for approximately 30% of all cancer deaths in developed countries, and that if current smoking patterns persist, an epidemic of cancer attributable to tobacco smoking is expected to occur in developing countries (2). In addition, smoking causes even more deaths from vascular, respiratory, and other diseases than from cancer, so that, in total, tobacco smoking is estimated to account for approximately 4–5 million deaths a year worldwide. This number is projected to increase to approximately 10 million a year by 2030. Thus, if current smoking patterns continue, there will be more than 1 billion deaths attributable to tobacco smoking in the 21st century compared with approximately 100 million deaths in the 20th century (2). The only other causes of disease with such rapidly increasing impact are those associated with human immunodeficiency virus infection and, perhaps, obesity in Western countries (2). In this commentary, we review the evidence regarding the carcinogenicity of tobacco smoke that has accumulated during the last 16 years since the publication of Monograph 38 of the International Agency for Research on Cancer (IARC) in 1986 (3) to the updating of that monograph (Monograph 83) in 2002 (4). The evidence now available shows that tobacco smoke is a multipotent carcinogenic mixture that can cause cancer in many different organs. In addition, exposure to secondhand tobacco smoke (i.e., involuntary or passive smoking by persons who do not smoke) is also carcinogenic for the human lung. This commentary, written by the epidemiologists who participated in the 2002 IARC Working Group for the preparation of the IARC Monograph 83 (4), is based on the substantial body of evidence reviewed for that purpose. It represents, however, solely the views of the authors. In 1986, the IARC Working Group (3) found that there was sufficient evidence that active tobacco smoking was carcinogenic in humans, and concluded that tobacco smoking caused cancers not only of the lung, but also of the lower urinary tract including the renal pelvis and bladder; upper aero-digestive tract including oral cavity, pharynx, larynx, and esophagus; and pancreas. The assessment of the evidence was based on well-established principles for evidence evaluation and an application of criteria of causality. These principles include consideration of lack of any bias or plausible confounding factors that could explain the observed associations, strength of association, dose–response relationships, biologic plausibility, and the consistency of findings across investigations, study designs, and countries. The criteria used by the 2002 IARC Working Group for causality assessment are described in Table 1. Cancer can be caused by smoking cigarettes, pipes, cigars, or bidis (which consist of a small amount of tobacco wrapped in the leaf of another plant, and are commonly used in South Asia). Since 1986, further evidence has been published that showed that smoking tobacco can also cause cancer of the nasal cavity, paranasal sinuses, and nasopharynx; stomach; liver; kidney; cervix uteri; and adenocarcinoma of the esophagus and myeloid leukemia. We consider the currently available evidence equivocal for cancer of the large bowel. The evidence was found to weigh against causality for cancer of the breast, in agreement with a recent meta-analysis (5), and for cancer of the prostate (6,7). For both breast and prostate the average relative risk is approximately 1.0, the positive studies do not outweigh the negative studies in overall quality, and biologic plausibility is weak. We found that the evidence suggested an inverse relationship of tobacco smoking with endometrial cancer (8). In this commentary, we briefly review the evidence that underlies the conclusions of the 2002 IARC Working Group, and summarize the numbers of studies available and the order of magnitude of relative risks for each site with sufficient evidence of carcinogenicity (Table 2). The following site-specific sections are for those sites for which we now believe there to be sufficient evidence, since the 1986 monograph (3), to conclude that smoking is a cause of cancer. (Note: although much of the evidence is based on cigarette smoking, many of the papers also contained information on other forms of tobacco smoking. Consequently, we use the generic term “tobacco” to include all forms of smoking. In addition, the term “non-smokers” as used by the authors, usually means the more appropriate term “never smokers.”) The 1986 IARC Working Group evaluation specifically included oro- and hypopharynx as cancer sites causally associated with tobacco smoking, but did not include cancer of the nasopharynx. As members of the 2002 IARC Working Group, we found that an increased risk of sinonasal cancer and nasopharynx cancer among cigarette smokers has been consistently reported in several case–control studies, with a positive dose–response trend associated with the amount and duration of smoking (9,10). When histologic data were available, the relative risk was increased more clearly for squamous-cell carcinoma of the nasal sinuses than for adenocarcinoma (9,11). We considered the many cohort and case–control studies that have examined the relationship between tobacco smoking and stomach cancer. The risk of stomach cancer is 50%–60% higher, on average, in smokers than in non-smokers (relative risk [RR] = 1.5–1.6), and in several studies more than 100% higher (relative risks greater than 2) in current smokers than in never smokers. The associations are generally consistent among both cohort and case–control studies, demonstrating positive dose–response relationships with the number of cigarettes smoked and the duration of smoking (12–14). Current smoking is associated with increased risks of both cardia and non-cardia stomach cancer. Studies that have stratified the observations by intake of alcoholic beverages or by chronic Helicobacter pylori infection of the stomach (two potential confounders) have found an independent association with tobacco smoking, although the absolute risk tended to be higher among smokers who were H. pylori seropositive than among smokers who were H. pylori seronegative. Worldwide it has been estimated that the proportion of stomach cancer attributable to smoking is 11% among men and 4% among women in developing countries, and 17% among men and 11% among women in developed countries (15). We found that an association between tobacco smoking and an increased risk of liver cancer is consistently seen in nearly all cohort studies and in most case–control studies, particularly the largest ones from Asia (16,17), the United States (18), and Greece (19), with relative risks ranging from 1.5 to 2.5. Heavy (e.g., approximately more than six glasses of alcohol per day), although not moderate, intake of alcoholic beverages is an important risk factor for liver cancer (20), and one that could confound the association with tobacco smoking because smokers tend to drink more than non-smokers. However, there are now a large number of studies that have adequately controlled for this potential confounder, and consequently have excluded alcohol as an explanation for the association between smoking and liver cancer. Compared with individuals who do not drink or smoke, individuals who do not drink but do smoke have an increased risk of liver cancer (19,21,22). Additional supportive evidence is provided by the association between smoking and liver cancer observed among Chinese (16) and Japanese (23) women, in whom heavy alcohol drinking is extremely rare. Hepatitis B virus (HBV) infection causes the majority of liver cancers worldwide, although hepatitis C virus (HCV) infection accounts for a large fraction of the disease in Japan, north Africa, and southern Europe (24). To distinguish the strong effect of HBV and HCV [relative risk of approximately 20 (24)] from the association with smoking, stratification and/or adjustment for hepatitis B surface antigen and anti-HCV antibodies have been made in several studies (18,19,25). The association between smoking and liver cancer was not generally weakened by adjustments for HBV and HCV infection. With respect to the possible action of tobacco smoking on liver carcinogenesis, smokers do not seem to have an increased risk of chronic infection with hepatitis viruses (26), but they may have a greater risk of progression from chronic HBV and HCV infection to liver cancer (18,27) than non-smokers. The 1986 IARC report (3) classified transitional carcinoma of the renal pelvis among the cancers that could be caused by smoking, but not adenocarcinoma of the renal parenchyma. In the 2002 IARC Working Group, we found that many case–control and cohort studies evaluating the association between tobacco smoking and adenocarcinoma of the renal parenchyma have been published subsequently and have shown consistently a risk of the disease in heavy smokers (i.e., of more than 20 cigarettes/day) of 1.5–2.0 times that observed in never smokers (28,29). This association cannot be explained by confounding by body mass index or hypertension, both of which are known risk factors for adenocarcinoma of the renal parenchyma. Indeed, the opposite is true for body mass index, which is positively associated with an increased risk of this form of cancer and negatively associated with smoking. Cancer of the uterine cervix has been consistently associated with cigarette smoking in many studies but the association has not previously been classified as causal because potential confounding by sexual activity and related exposure to sexually transmitted viruses could not be excluded as an alternative explanation. Several cohort studies and many case–control studies provide information about the association of cigarette smoking with the incidence of invasive squamous-cell cervical cancer, and many cohort and case–control studies evaluated the association of tobacco exposures with preinvasive neoplasms such as cervical intraepithelial neoplasia and cancer in situ. Most studies in which risk estimates were not adjusted for infection with specific types of human papillomavirus (HPV) reported a relative risk of approximately 2.0, i.e., a doubling of the risk among smokers compared with never smokers. Women who smoked a large number of cigarettes or who smoked for a long duration generally had the highest risk of cervical cancer. Proper consideration of the presence of HPV infection is extremely important when evaluating the association between tobacco smoke exposure and invasive cervical cancer because it is widely recognized that persistent HPV infection is the main (and perhaps a necessary) etiologic factor for invasive and pre-invasive cervical cancer worldwide. High-risk types of HPV, i.e., those types of HPV associated with oncogenic transformation, have been identified in 99% of invasive cervical cancer tissue specimens (30) and are associated with 100-fold increased risk of invasive cervical cancer relative to women without HPV infection (31). Earlier studies controlled for HPV infection by adjustment in the data analysis, whereas more recent studies controlled for HPV infection by restricting analyses to HPV-positive case and control subjects. This method is preferable when dealing with a risk factor that may modify the effect of smoking. In the IARC multicenter pooled analysis of invasive cervical cancer, Plummer et al. (32) examined smoking as a co-factor with human papillomavirus infection by restricting the analysis to HPV DNA–positive study participants. This restriction did not substantially alter the relationship between smoking and risk. The relative risk was 2.17 (95% confidence interval [CI] = 1.46 to 3.22) for HPV-positive case subjects compared with HPV-positive control subjects. The association between smoking and cervical cancer was also not notably reduced after adjusting for a woman's reported number of lifetime sexual partners, age at first intercourse, or other potential confounding factors. Furthermore, in cross-sectional studies, HPV cervical infection has not been found to be associated consistently with smoking (33). Thus, we conclude that HPV infection cannot explain the association between cervical cancer and smoking, that the effect of smoking was unlikely to represent only a surrogate marker of a woman's sexual behavior, and that the association of tobacco smoke with invasive squamous cell cervical cancer therefore indicates a causal relationship. Tobacco smoke contains one established leukemogen (i.e., a chemical able to induce leukemia in humans), benzene. Smokers have much higher levels of benzene in their blood than non-smokers. Six of eight cohort studies with men, or men and women combined, showed greater than expected risks (average relative risk = 1.6) for myeloid leukemia among current cigarette smokers and also a positive dose–response relationship between the risk of myeloid leukemia and the number of cigarettes smoked (34–36). According to Korte et al. (37), linear extrapolation from the known effects of high doses of benzene suggests that benzene in cigarettes is responsible for about one-third of smoking-induced acute myeloid leukemia. We concluded that there is sufficient evidence that smoking causes myeloid leukemia, but that there is no association between smoking and the risk of lymphatic leukemia. Less than half of the studies that have examined the relationship between smoking and cancer of the large bowel have recorded a statistically significant increased risk of the disease among smokers. The increased risk is, however, generally less than twofold. We are uncertain whether this reflects causality or confounding with alcohol, low physical activity, high intake of dietary fat, low intake of vegetables, or other factors that are associated with an increased risk of this disease. Most of the studies reporting information on forms of tobacco other than cigarettes have been published during the last 16 years. Although the number of lung cancer cases is usually sufficiently large to assess causality, we found that for other sites the numbers are generally too small to establish a cause–effect relationship with other forms of tobacco, with the exception of the sites mentioned below. Bidi smoking is the most common form of tobacco smoking in India and is predominantly a habit of men. Although bidis are smaller than cigarettes and contain much less tobacco, they deliver higher amounts of nicotine per gram of tobacco and comparable or greater amounts of tar (38). On the basis of case–control studies, we found that bidi smoking can cause cancers of respiratory and digestive sites, including mouth, oropharynx, larynx, lung, and stomach In all studies a dose–response relationship was In the studies that the risk was increased after adjustment for cigarette smoking or tobacco alcohol and We found that and/or smoking is and causally related to cancers of the oral cavity, oropharynx, larynx, and lung The magnitude of risk is to that from cigarette smoking. dose–response relationship has been found with the amount of tobacco and for upper aero-digestive tract a between alcohol and use has been The causal of the associations reported and of those recognized as causal in the 1986 IARC Monograph (3), is by in and have to of tobacco smoke in different body and to and and to or related to smoking. These have the of tobacco carcinogenesis, which is suggested by For lung cancer, at of evidence the carcinogenic in tobacco smoke, induce in the which is for cell and to the have been to a of tobacco in lung cancers for the following are a of carcinogens in tobacco smoke that predominantly to 2) are in from human to tobacco the of to in lung cancers from smokers is increased relative to the in lung cancers from a bias of to can be to the of on the the are another of found in tobacco smoke, several of which are are found in the of smokers. In known as and are because they are from the which is specific to tobacco is the marker of exposure to tobacco smoke, but it is not to The evidence related to tobacco smoking and has on in the which is in tobacco has been shown to form in and specimens from smokers by are increased in particularly in smokers of Indeed, smokers of tobacco have more than a risk of cancer than smokers of tobacco from studies evaluating also for the observations related to tobacco smoking and cancer of the uterine have been found in the cervical and as in cervical of smokers in from with myeloid leukemia has been consistent with the effects of benzene contained in cigarette et al. identified six among with acute myeloid leukemia and found that smokers had increased for = = to current = = to compared with with an effect of benzene. The have been in among to benzene. The high of between the of and studies strength to the causal of the associations between tobacco smoking and observed in the large body of who other smoke (i.e., involuntary the carcinogens as active at much lower doses (4). smoking is an established cause of lung cancer in it that there also be risk of lung cancer to non-smokers to involuntary smoking is also to be risk from involuntary smoking to individuals who are now non-smokers but who used to be compared with not to involuntary smoking. Most of the more than studies evaluating involuntary smoking tobacco smoke) and risk of lung cancer in never smokers compared risks for of smokers with risks for of non-smokers. These studies have been in many countries and, in an increased for persons with high exposure (Table To the information in from those studies with a number of case have been in which the relative risk estimates from the studies were have a statistically significant greater risk of lung cancer if their are smokers than if their are non-smokers. The increase in risk after for bias and potential confounding an meta-analysis in the IARC Monograph (4), the risk is approximately greater than expected for women on data from studies that included lung cancer case and greater than expected for men on data from studies that included lung cancer case In addition, there are several studies that evaluated the risk of lung cancer among non-smokers to involuntary smoking at the meta-analysis in the IARC Monograph based on studies of women who did not smoke lung cancer case shows that the risk of lung cancer was approximately greater than The studies that report an association between lung cancer and high levels of exposure to involuntary smoking are in Table the 20 studies that reported on the number of cigarettes smoked by the had a relative risk lower than 1.0, and studies reported relative risks greater than of relative risks was observed when the number of years of was used as the exposure (Table case–control and cohort studies report positive findings for the association with lung cancer. i.e., the more publication of positive findings than of negative is not a sufficient explanation because approximately negative studies be to explain the overall relative risk in the published studies, a a meta-analysis that several different of bias of that the are and cannot be explained by The biologic plausibility of the association between the risk of lung cancer and involuntary smoking is by the that the of non-smokers to involuntary smoking contains of carcinogenic specific to tobacco that are to of the found in the of active i.e., approximately to the increased risk found in studies of involuntary smoking evidence of the carcinogenicity of tobacco smoke has available since the review by IARC in 1986 This evidence with the findings as members of the 2002 IARC Working Group to conclude that tobacco is a with a substantial cancers of the lung, upper aero-digestive tract cavity, nasal cavity, nasal sinuses, pharynx, larynx, lower urinary tract pelvis and and uterine and myeloid leukemia. cigarette smoking and smoking other forms of tobacco, including and cigars, can cause cancers in organs. is high for causality between the evidence and the or biologic evidence of carcinogenic of tobacco the of or and the of in cancers developed by smokers. The of tobacco smoking are and are to in the Tobacco smoking is currently responsible for approximately 30% of cancer deaths in developed countries, and for an increasing proportion of the cancer deaths in developing countries. Furthermore, smoking causes more deaths from vascular, respiratory, and other diseases than it from cancer. all lifetime of tobacco, half will because of their and half of individuals will in current smoking patterns persist, in the 21st century there will be more than 1 billion deaths to smoking. that substantially individuals from smoking could much of the disease Although 1 billion smoke and more will individuals who smoking their cancer risks is therefore that not only individuals from to smoke, but also smoking. Although the effects of smoking were first observed for lung cancer, evidence is now available that smoking has effects of risk for the other main cancers and for the main diseases caused by smoking. evidence has been accumulated in the last 16 years. For 1 shows that smoking is associated with an increase of the lung cancer with age Compared with smokers who to smoke, the increase in lung cancer is lower for individuals who smoking by age years and even lower for individuals who smoking by age years. smokers have the lung cancer the estimated risks of from lung cancer by age years are for men who to smoke cigarettes, for men who smoking by age and for men who smoking by age years. The is among In other the an smoking, the lower the risk of lung cancer. The to which cigarette smokers the will in the and half of the 21st in the first half of the however, will be by the number of current smokers who risk of lung cancer among men in the United who smoke, to the age when they smoking. from the by of the of the IARC for the evaluation of the evidence to carcinogenicity from studies in information regarding the IARC can be found at the of the IARC for the evaluation of the evidence to carcinogenicity from studies in information regarding the IARC can be found at the Cancer sites for which there is evidence of carcinogenicity of tobacco smoking to the International Agency for Research on Cancer Working = squamous cell = not = carcinoma in = cervical intraepithelial = not studies on in which may include nasopharynx. of relative risks after adjustment for alcohol Cancer of the of histologic studies on and Cancer sites for which there is evidence of carcinogenicity of tobacco smoking to the International Agency for Research on Cancer Working = squamous cell = not = carcinoma in = cervical intraepithelial = not studies on in which may include nasopharynx. of relative risks after adjustment for alcohol Cancer of the of histologic studies on and risk of lung cancer among women who did not smoke but who have the highest exposure to involuntary smoking from a who smoked compared with women who did not smoke and who had that did not The relative risks are from to highest each of for cohort studies and for case–control are from an analysis For years of of exposure for and risk of lung cancer among women who did not smoke but who have the highest exposure to involuntary smoking from a who smoked compared with women who did not smoke and who had that did not The relative risks are from to highest each of for cohort studies and for case–control are from an analysis For years of of exposure for and

Although a multitude of promising anti-cancer drugs have been developed over the past 50 years, effective delivery of the drugs to diseased cells remains a challenge. Recently, nanoparticles have been used as drug delivery vehicles due to their high delivery efficiencies and the possibility to circumvent cellular drug resistance. However, the lack of biocompatibility and inability to engineer spatially addressable surfaces for multi-functional activity remains an obstacle to their widespread use. Here we present a novel drug carrier system based on self-assembled, spatially addressable DNA origami nanostructures that confronts these limitations. Doxorubicin, a well-known anti-cancer drug, was non-covalently attached to DNA origami nanostructures through intercalation. A high level of drug loading efficiency was achieved, and the complex exhibited prominent cytotoxicity not only to regular human breast adenocarcinoma cancer cells (MCF 7), but more importantly to doxorubicin-resistant cancer cells, inducing a remarkable reversal of phenotype resistance. With the DNA origami drug delivery vehicles, the cellular internalization of doxorubicin was increased, which contributed to the significant enhancement of cell-killing activity to doxorubicin-resistant MCF 7 cells. Presumably, the activity of doxorubicin-loaded DNA origami inhibits lysosomal acidification, resulting in cellular redistribution of the drug to action sites. Our results suggest that DNA origami has immense potential as an efficient, biocompatible drug carrier and delivery vehicle in the treatment of cancer.

Altered metabolism is a hallmark of cancer, and the reprogramming of energy metabolism has historically been considered a general phenomenon of tumors. It is well recognized that long noncoding RNAs (lncRNAs) regulate energy metabolism in cancer. However, lncRNA-mediated posttranslational modifications and metabolic reprogramming are unclear at present. In this review, we summarized the current understanding of the interactions between the alterations in cancer-associated energy metabolism and the lncRNA-mediated posttranslational modifications of metabolic enzymes, transcription factors, and other proteins involved in metabolic pathways. In addition, we discuss the mechanisms through which these interactions contribute to tumor initiation and progression, and the key roles and clinical significance of functional lncRNAs. We believe that an in-depth understanding of lncRNA-mediated cancer metabolic reprogramming can help to identify cellular vulnerabilities that can be exploited for cancer diagnosis and therapy.

BACKGROUND: Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that stimulates erythropoiesis and regulates iron metabolism. Additional data are needed regarding the effectiveness and safety of roxadustat as compared with standard therapy (epoetin alfa) for the treatment of anemia in patients undergoing dialysis. METHODS: In a trial conducted in China, we randomly assigned (in a 2:1 ratio) patients who had been undergoing dialysis and erythropoiesis-stimulating agent therapy with epoetin alfa for at least 6 weeks to receive roxadustat or epoetin alfa three times per week for 26 weeks. Parenteral iron was withheld except as rescue therapy. The primary end point was the mean change in hemoglobin level from baseline to the average level during weeks 23 through 27. Noninferiority of roxadustat would be established if the lower boundary of the two-sided 95% confidence interval for the difference between the values in the roxadustat group and epoetin alfa group was greater than or equal to -1.0 g per deciliter. Patients in each group had doses adjusted to reach a hemoglobin level of 10.0 to 12.0 g per deciliter. Safety was assessed by analysis of adverse events and clinical laboratory values. RESULTS: A total of 305 patients underwent randomization (204 in the roxadustat group and 101 in the epoetin alfa group), and 256 patients (162 and 94, respectively) completed the 26-week treatment period. The mean baseline hemoglobin level was 10.4 g per deciliter. Roxadustat led to a numerically greater mean (±SD) change in hemoglobin level from baseline to weeks 23 through 27 (0.7±1.1 g per deciliter) than epoetin alfa (0.5±1.0 g per deciliter) and was statistically noninferior (difference, 0.2±1.2 g per deciliter; 95% confidence interval [CI], -0.02 to 0.5). As compared with epoetin alfa, roxadustat increased the transferrin level (difference, 0.43 g per liter; 95% CI, 0.32 to 0.53), maintained the serum iron level (difference, 25 μg per deciliter; 95% CI, 17 to 33), and attenuated decreases in the transferrin saturation (difference, 4.2 percentage points; 95% CI, 1.5 to 6.9). At week 27, the decrease in total cholesterol was greater with roxadustat than with epoetin alfa (difference, -22 mg per deciliter; 95% CI, -29 to -16), as was the decrease in low-density lipoprotein cholesterol (difference, -18 mg per deciliter; 95% CI, -23 to -13). Roxadustat was associated with a mean reduction in hepcidin of 30.2 ng per milliliter (95% CI, -64.8 to -13.6), as compared with 2.3 ng per milliliter (95% CI, -51.6 to 6.2) in the epoetin alfa group. Hyperkalemia and upper respiratory infection occurred at a higher frequency in the roxadustat group, and hypertension occurred at a higher frequency in the epoetin alfa group. CONCLUSIONS: Oral roxadustat was noninferior to parenteral epoetin alfa as therapy for anemia in Chinese patients undergoing dialysis. (Funded by FibroGen and FibroGen [China] Medical Technology Development; ClinicalTrials.gov number, NCT02652806.).

Elements are present in different forms in the nature, and these elements are very essential for the body to perform different functions. Trace elements are very important for cell functions at biological, chemical and molecular levels. These elements mediate vital biochemical reactions by acting as cofactors for many enzymes, as well as act as centers for stabilizing structures of enzymes and proteins. Some of the trace elements control important biological processes by binding to molecules on the receptor site of cell membrane or by alternating the structure of membrane to prevent entry of specific molecules into the cell. The functions of trace elements have a dual role. In normal levels, they are important for stabilization of the cellular structures, but in deficiency states may stimulate alternate pathways and cause diseases. These trace elements have clinical significance and these can be estimated using different analytical method.

Ganoderma lucidum is a widely used medicinal macrofungus in traditional Chinese medicine that creates a diverse set of bioactive compounds. Here we report its 43.3-Mb genome, encoding 16,113 predicted genes, obtained using next-generation sequencing and optical mapping approaches. The sequence analysis reveals an impressive array of genes encoding cytochrome P450s (CYPs), transporters and regulatory proteins that cooperate in secondary metabolism. The genome also encodes one of the richest sets of wood degradation enzymes among all of the sequenced basidiomycetes. In all, 24 physical CYP gene clusters are identified. Moreover, 78 CYP genes are coexpressed with lanosterol synthase, and 16 of these show high similarity to fungal CYPs that specifically hydroxylate testosterone, suggesting their possible roles in triterpenoid biosynthesis. The elucidation of the G. lucidum genome makes this organism a potential model system for the study of secondary metabolic pathways and their regulation in medicinal fungi. Ganoderma lucidumis a macrofungus in traditional Chinese medicine known to produce different bioactive compounds. In this study, the genome ofG. lucidumis sequenced, making this organism a potential model system for future studies of secondary metabolic pathways and their regulation in medicinal fungi.

BACKGROUND: The antimetabolite methotrexate has been shown in placebo-controlled trials to be effective in adults with rheumatoid arthritis. Methotrexate may also be effective in children with resistant juvenile rheumatoid arthritis, but the supporting data are from uncontrolled trials. METHODS: Centers in the United States and the Soviet Union participated in this randomized, controlled, double-blind trial designed to evaluate the effectiveness and safety of orally administered methotrexate. Patients received one of the following treatments each week for six months: 10 mg of methotrexate per square meter of body-surface area (low dose), 5 mg of methotrexate per square meter (very low dose), or placebo. The use of prednisone (less than or equal to 10 mg per day) and two nonsteroidal antiinflammatory drugs was also allowed. RESULTS: The 127 children (mean age, 10.1 years) had a mean duration of disease of 5.1 years; 114 qualified for the analysis of efficacy. According to a composite index of several response variables, 63 percent of the children who received low-dose methotrexate improved, as compared with 32 percent of those in the very-low-dose group and 36 percent of those in the placebo group (P = 0.013). As compared with the placebo group, the low-dose group also had significantly larger mean reductions from base line in the number of joints with pain on motion (-11.0 vs. -7.1), the pain-severity score (-19 vs. -11.5), the number of joints with limited motion (-5.4 vs. -0.7), and the erythrocyte sedimentation rate (-19.0 vs. -6 mm per hour). In the methotrexate groups only three children had the drug discontinued because of mild-to-moderate side effects; none had severe toxicity. CONCLUSIONS: Methotrexate given weekly in low doses is an effective treatment for children with resistant juvenile rheumatoid arthritis, and at least in the short term this regimen is safe.