Obesity shapes selection for driver mutations in cancer.

Obesity is a leading risk factor for cancer, but whether obesity is linked to specific genomic subtypes of cancer is unknown. Here, we examined the relationship between obesity and tumor genotype in two large clinicogenomic corpora. Obesity was associated with specific driver mutations in lung adenocarcinoma, endometrial carcinoma, and cancers of unknown primary, independent of clinical covariates and genetic ancestry. Obesity is therefore a putative driver of etiologic heterogeneity across cancers.

Tumor sequencing of African ancestry reveals differences in clinically relevant alterations across common cancers.

Cancer genomes from patients with African (AFR) ancestry have been poorly studied in clinical research. We leverage two large genomic cohorts to investigate the relationship between genomic alterations and AFR ancestry in six common cancers. Cross-cancer type associations, such as an enrichment of MYC amplification with AFR ancestry in lung, breast, and prostate cancers, and depletion of BRAF alterations are observed in colorectal and pancreatic cancers. There are differences in actionable alterations, such as depletion of KRAS G12C and EGFR L858R, and enrichment of ROS1 fusion with AFR ancestry in lung cancers. Interestingly, in lung cancer, KRAS mutations are less common in both smokers and non-smokers with AFR ancestry, whereas the association of TP53 mutations with AFR ancestry is only seen in smokers, suggesting an ancestry-environment interaction that modifies driver rates. Our study highlights the need to increase representation of patients with AFR ancestry in drug development and biomarker discovery.

The skeletal phenotype of achondrogenesis type 1A is caused exclusively by cartilage defects.

Inactivating mutations in the ubiquitously expressed membrane trafficking component GMAP-210 (encoded by Trip11) cause achondrogenesis type 1A (ACG1A). ACG1A is surprisingly tissue specific, mainly affecting cartilage development. Bone development is also abnormal, but as chondrogenesis and osteogenesis are closely coupled, this could be a secondary consequence of the cartilage defect. A possible explanation for the tissue specificity of ACG1A is that cartilage and bone are highly secretory tissues with a high use of the membrane trafficking machinery. The perinatal lethality of ACG1A prevents investigating this hypothesis. We therefore generated mice with conditional Trip11 knockout alleles and inactivated Trip11 in chondrocytes, osteoblasts, osteoclasts and pancreas acinar cells, all highly secretory cell types. We discovered that the ACG1A skeletal phenotype is solely due to absence of GMAP-210 in chondrocytes. Mice lacking GMAP-210 in osteoblasts, osteoclasts and acinar cells were normal. When we inactivated Trip11 in primary chondrocyte cultures, GMAP-210 deficiency affected trafficking of a subset of chondrocyte-expressed proteins rather than globally impairing membrane trafficking. Thus, GMAP-210 is essential for trafficking specific cargoes in chondrocytes but is dispensable in other highly secretory cells.

Knowledge and Attitudes toward HIV, Hepatitis B Virus, and Hepatitis C Virus Infection among Health-care Workers in Malawi.

OBJECTIVE: The highest prevalence of HIV infection occurs in Sub-Saharan Africa and hepatitis B virus (HBV), and hepatitis C virus (HCV) prevalence are the second highest in Sub-Saharan Africa including Malawi. Health-care workers (HCWs) play an important role in the prevention of, response to, and management of these infectious diseases. There is, however, no published research about the level of knowledge and attitudes toward HIV, HBV, and HCV infection among Malawian HCWs. The purpose of this study was to explore and determine the knowledge of and attitudes toward HIV, HBV, and HCV among a targeted population of Malawian HCWs. METHODS: A cross-sectional community-based participatory research with 194 HCWs was completed employing health survey method. The project was a collaborative effort between nursing faculties in the USA and Malawian. A one-way analysis of variance (ANOVA) with the Bonferroni adjustment for multiple comparisons was used to assess the differences in knowledge and attitude among three subgroups of HCWs. RESULTS: Of 194 of Malawian HCWs surveyed, 41% were support staff, 37% were nursing students, and 22% were health-care professionals. Both health-care professionals and support staff had high knowledge scores related to HIV/AIDS, and their attitudes were mainly positive. However, a series of one-way ANOVAs revealed significant differences in knowledge and attitude toward HIV/AIDs, HBV, and HCV among HCWs (P < 0.01). The majority had less knowledge about HBV and HCV and more negative attitudes toward hepatitis. CONCLUSIONS: This study highlights the ongoing need for reducing negative attitudes toward HIV, HBV, and HCV; and providing health education among HCWs, especially focusing on HBV and HCV prevention. The findings of the research project can be used to develop interventions addressing low HBV- and HCV-related knowledge and attitudes.

Mycoplasma pneumoniae modulates STAT3-STAT6/EGFR-FOXA2 signaling to induce overexpression of airway mucins.

Aberrant mucin secretion and accumulation in the airway lumen are clinical hallmarks associated with various lung diseases such as asthma, chronic obstructive pulmonary disease, and cystic fibrosis. Mycoplasma pneumoniae, long appreciated as one of the triggers of acute exacerbations of chronic pulmonary diseases, has recently been reported to promote excessive mucus secretion. However, the mechanism of mucin overproduction induced by M. pneumoniae remains unclear. This study aimed to determine the mechanism by which M. pneumoniae induces mucus hypersecretion by using M. pneumoniae infection of mouse lungs, human primary bronchial epithelial (NHBE) cells cultured at the air-liquid interface, and the conventionally cultured airway epithelial NCI-H292 cell line. We demonstrated that M. pneumoniae induced the expression of mucins MUC5AC and MUC5B by activating the STAT6-STAT3 and epidermal growth factor receptor (EGFR) signal pathways, which in turn downregulated FOXA2, a transcriptional repressor of mucin biosynthesis. The upstream stimuli of these pathways, including interleukin-4 (IL-4), IL-6, and IL-13, increased dramatically upon exposure to M. pneumoniae. Inhibition of the STAT6, STAT3, and EGFR signaling pathways significantly restored the expression of FOXA2 and attenuated the expression of airway mucins MUC5AC and MUC5B. Collectively, these studies demonstrated that M. pneumoniae induces airway mucus hypersecretion by modulating the STAT/EGFR-FOXA2 signaling pathways.

Potential application of the recombinant Escherichia coli-synthesized heme as a bioavailable iron source.

To investigate the potential use of microbial heme as an iron source, recombinant Escherichia coli coexpressing ALA synthase (HemA) as well as the NADP-dependent malic enzyme (MaeB) and dicarboxylic acid transporter (DctA) were cultured. The typical red pigment extracted from the recombinant E. coli after 38 h showed highest absorbance at 407 nm, and the amount of iron in 38.4 mg of microbial heme extract derived from 6-l fermentation broth was 4.1 mg. To determine the commercial potential of the recombinant E.coli-synthesized iron-associated heme as an iron source, mice were fed the iron-free provender with the microbial heme extract. The average body weight reduction of mice fed non-iron provender was 2.3%, whereas no detectable weight loss was evident in mice fed microbial heme addition after 15 days. The heme content of the blood from microbial heme fed mice was 4.2 mg/ml whereas that of controls was 2.4 mg/ml, which implies that the microbial heme could be available for use as an animal iron source.

Desire for information and involvement in treatment decisions: elderly cancer patients' preferences and their physicians' perceptions.

PURPOSE: Shared decision making is a tenet of contemporary medicine and oncology practice. How involved elderly patients want to be in making treatment decisions and how physicians perceive patient preferences for such involvement are uncertain. PATIENTS AND METHODS: In structured interviews about multiple facets of chemotherapy treatment decision making, we asked patients age 70 years and older with a recent diagnosis of metastatic colorectal cancer (CRC) about their preferences for prognostic information and for involvement in treatment decision making. We also asked treating oncologists (n = 19) to describe their perceptions of patient preferences. Information and decision-making preferences were evaluated in relation to sociodemographic and clinical characteristics. RESULTS: Seventy-three patients age 70 to 89 years completed the study interview within 16 weeks of metastatic CRC diagnosis. Most patients (n = 70; 96%) had decided to receive chemotherapy and 61 had initiated treatment. Relatively few (n = 32; 44%) wanted information about expected survival when they made a treatment decision. Preference for prognostic information was more common among men than women (56% v 29%; P < .05). About half of the patients (n = 38; 52%) preferred a passive role in the treatment decision-making process. Physician perceptions were concordant with patient preferences for information in 44% of patient-physician pairs and for decision control in 41% of patient-physician pairs. CONCLUSION: For older patients with advanced CRC, preferences for prognostic information and for an active role in treatment decision making are not easily predictable. Physicians' perceptions are often inconsistent with patients' stated preferences. Explicit discussion of preferred decision-making styles may improve patient-physician encounters.

Understanding disparities in aggressive care preferences between patients with terminal illness and their family members.

We examined the factors associated with the disparity in aggressive care preferences between patients with terminal cancer and their family members. Two hundred forty-four consecutive pairs recruited from three university hospitals participated in this study. Each pair completed questionnaires that measured two major aggressive care preferences-admission to the intensive care unit (ICU) and the use of cardiopulmonary resuscitation (CPR). Sixty-eight percent of patients and their family members were in agreement regarding admission to the ICU and 71% agreed regarding CPR. Regarding admission to the ICU, younger, unmarried patients and patients who preferred to die in an institution were more likely to have a different preference from their family caregivers. Regarding CPR, younger patients and patients from severely dysfunctional families were more likely to have a different preference from their family caregivers. Elucidation of the factors associated with such disparities should help reduce them.

Intracoronary beta brachytherapy as a treatment option for high-risk refractory in-stent restenosis; Compassionate use.

BACKGROUND: Vascular (VBT) has clearly been shown in multiple clinical trials to decrease restenosis rates for in-stent restenosis (ISR). However, patients enrolled in these randomized clinical trials represent a select group, and the efficacy of VBT in patients with ISR who were excluded from these controlled trials due to more complex coronary anatomy requires further investigation. This study sought to define the angiographic and clinical profile and outcomes of these high-risk patients with ISR who were excluded from the randomized clinical trials and who received VBTusing Strontium-90 (Sr-90) using the Novoste Beta-Cath System through a Compassionate Use Protocol (CUP). METHODS: The study was designed as a single center, prospective, open label registry trial evaluating the use of VBT on complex instent restenotic lesions in patients who were excluded from the START and START 40 trials. In general, these patients included those with saphenous vein graft (SVG) lesions, long lesions (>35 mm), and patients with a history of more than three prior interventions. VBT using Sr-90 was delivered using the Novoste Beta-Cath System after successful angioplasty. The predetermined primary endpoint was freedom from target vessel revascularization (TVR) at 8 months, one and two years. The secondary endpoint was a composite of death, myocardial infarction (MI) and TVR at 8 months, one year, and two years. RESULTS: Between September 4, 1998 and December 6, 2000, 32 patients were treated with VBT under the UCP protocol. The mean duration of follow up was 15.3 +/- 8.3 months. There were 9 major cardiac events at eight months including one death, one acute myocardial infarction and 7 TVR. Excluding the one patient who died, 33 lesions were available for follow-up. The rate of TVR in this high-risk patient population was 21.1% (n = 7/33 lesions). The method of revascularization included one bypass surgery and 6 repeat percutaneous coronary interventions. CONCLUSIONS: This trial demonstrates that utilization of the Beta-Cath System using Sr-90 for the treatment of ISR in a patient population excluded from the randomized clinical trials due to unfavorable lesions characteristics is feasible appears to be associated TVR rates that compare favorably with the event rates of patients enrolled in other trials enrolling lower-risk groups.

Correlates of failure following treatment with Sr-90 beta irradiation for in-stent restenosis.

We sought to determine the correlates of failure following intracoronary radiation therapy (IRT) with Sr-90 using the Novoste Beta-Cath system for the treatment of in-stent restenosis (ISR) in a broad range of patients. IRT has been shown to be more efficacious compared to placebo for the treatment of ISR in large randomized trials. However, even in patients treated with IRT, major adverse cardiac events occur in approximately 20% of cases on follow-up. This trial sought to elucidate the correlates of failure following successful IRT for ISR. To determine the correlates of IRT failure, we retrospectively compared the demographics, lesion characteristics, and clinical outcomes of 102 consecutive patients with ISR treated with Sr-90 from September 1998 to July 2001. IRT failure was defined as death, myocardial infarction (MI), or target vessel revascularization (TVR) due to repeat ISR on follow-up. A comparison of the clinical and angiographic profile of IRT failures (n = 16) vs. IRT successes (n = 86) revealed that a history of smoking (75% vs. 40%; P = 0.012), current use of calcium channel blockers (84% vs. 45%; P = 0.013), ostial location of target lesion (44% vs. 16%; P = 0.020), and mean posttreatment minimal luminal diameter (MLD; 1.64 +/- 0.19 vs. 2.21 +/- 0.29 mm; P < 0.001), respectively, were correlated with failure using univariate analysis. After multivariate regression analysis, the correlates of failure that remained significant were treatment of an ostial lesion (OR = 31.2; 95% CI = 2.6-382.7; P = 0.007) and final posttreatment MLD (P < 0.001). Ostial location of target lesion and smaller posttreatment MLD are correlated with subsequent death, MI, and TVR following therapy with Sr-90 for ISR.

Clinical outcomes of patients treated with the cutting balloon and Sr-90 beta-irradiation for instent restenosis.

BACKGROUND: The cutting balloon (CB) is an emerging therapy for the treatment of instent restenosis (ISR), but its impact on the clinical outcomes of patients treated with intracoronary radiation therapy (IRT) with Sr-90 compared with conventional PTCA and IRT is not clearly defined. METHODS: We compared the baseline demographics, angiographic characteristics and clinical outcomes of 102 consecutive patients with ISR treated either with CB+IRT (n=45) or with conventional PTCA+IRT (n=57). The combined endpoint was the occurrence of major adverse cardiac events (MACE), which was defined as a composite of death, myocardial infarction (MI) or target vessel revascularization (TVR) at 6 months. RESULTS: The CB+IRT group had a shorter mean lesion length (14.3+/-6.5 vs. 21.1+/-15.7, P=.009), and greater utilization of glycoprotein IIb/IIIa inhibitors during the procedure (48.9% vs. 26.3%, P=.02) compared to the PTCA+IRT group. There were no significant differences in the baseline demographics, angiographic and procedural results, or subsequent MACE at 6 months between the two groups. CONCLUSION: The strategy of CB+IRT using Sr-90 for ISR is associated with similar procedural and clinical outcomes compared to conventional PTCA+IRT. Further study is warranted to determine which patient subgroups would derive the most benefit from this approach.

Visual assessment of procedural results following treatment with Sr-90 beta-radiation for instent restenosis.

BACKGROUND: Visual assessment (VA) of postprocedural % diameter stenosis (DS) is used routinely in clinical practice to determine the adequacy of coronary intervention. Although VA has been shown to underestimate final %DS after balloon angioplasty compared to quantitative coronary angiography (QCA), the impact of this effect on clinical outcomes following treatment with intracoronary radiation therapy (IRT) with Sr-90 for instent restenosis (ISR) is unknown. METHODS: To determine the effect of VA on the rate of major adverse cardiac events (MACEs) after IRT for ISR, we compared the clinical outcomes of 102 consecutive patients based on postprocedural %DS by QCA vs. %DS by VA. MACE was defined as death, M1 or need for target vessel revascularization (TVR). RESULTS: MACE rates for the 102 consecutive patients grouped according to postprocedural %DS by QCA and VA were compared. The mean %DS by QCA was 30.7%, while the mean %DS by VA was 12.5%. The mean %DS by VA across the QCA subgroups were 13.67%, 10.71% and 13.37%, respectively (P = .244). Fifty-two patients (51.0%) had %DS > 30% by QCA with the highest MACE percentage occurring in this subgroup. CONCLUSION: VA underestimated the %DS compared to QCA, and it was associated with worse MACE following treatment with Sr-90 for ISR.