Geographic and temporal trends in pediatric and young adult brain tumors in Kentucky, 1995-2019.

INTRODUCTION: Pediatric and young adult brain tumors (PYBT) account for a large share of cancer-related morbidity and mortality among children in the United States, but their etiology is not well understood. Previous research suggests the Appalachian region of Kentucky has high rates of PYBT. This study explored PYBT incidence over 25 years in Kentucky to identify geographic and temporal trends and generate hypotheses for future research. METHODS: The Kentucky Cancer Registry contributed data on all PYBT diagnosed among those aged 0-29 during years 1995-2019. Age- and sex-adjusted spatio-temporal scan statistics-one for each type of PYBT, and one for all types-comprised the primary analysis. These results were mapped along with environmental and occupational data. RESULTS: Findings indicated that north-central Kentucky and the Appalachian region experienced higher rates of some PYBT. High rates of astrocytomas were clustered in a north-south strip of central Kentucky toward the end of the study period, while high rates of other specified types of intracranial and intraspinal neoplasms were significantly clustered in eastern Kentucky. The area where these clusters overlapped, in north-central Kentucky, had significantly higher rates of PYBT generally. DISCUSSION: This study demonstrates north-central Kentucky and the Appalachian region experienced higher PYBT risk than the rest of the state. These regions are home to some of Kentucky's signature industries, which should be examined in further research. Future population-based and individual-level studies of genetic factors are needed to explore how the occupations of parents, as well as prenatal and childhood exposures to pesticides and air pollutants, impact PYBT incidence.

Using residential histories in case-control analysis of lung cancer and mountaintop removal coal mining in Central Appalachia.

Population-based ecological and cross-sectional studies have observed high risk for several cancers in areas of Central Appalachia where mountaintop removal coal mines operate. Case-control studies could provide stronger evidence of such relationships, but misclassification of exposure is likely when based on current residence, since individuals could have inhabited several residences with varying environmental exposures over many years. To address this, we used residential histories for individuals enrolled in a previous case-control study of lung cancer to assess residential proximity to mountaintop removal coal mining over a 30-year period, using both survey data and proprietary data from LexisNexis, Inc. Supplementing the survey data with LexisNexis data improved precision and completeness of geographic coordinates. Final logistic regression models revealed higher odds of high exposure among cases. These findings suggest that living in close proximity to mountaintop removal coal mining sites could increase risk for lung cancer, after adjusting for other relevant factors.

The mutational oncoprint of recurrent cytogenetic abnormalities in adult patients with de novo acute myeloid leukemia.

Recurrent chromosomal abnormalities and gene mutations detected at the time of diagnosis of acute myeloid leukemia (AML) are associated with particular disease features, treatment response and survival of AML patients, and are used to denote specific disease entities in the World Health Organization classification of myeloid neoplasms and acute leukemia. However, large studies that integrate cytogenetic and comprehensive mutational information are scarce. We created a comprehensive oncoprint of mutations associated with recurrent cytogenetic findings by combining the information on mutational patterns of 80 cancer- and leukemia-associated genes with cytogenetic findings in 1603 adult patients with de novo AML. We show unique differences in the mutational profiles among major cytogenetic subsets, identify novel associations between recurrent cytogenetic abnormalities and both specific gene mutations and gene functional groups, and reveal differences in cytogenetic and mutational features between patients younger than 60 years and those aged 60 years or older. The identified associations between cytogenetic and molecular genetic data may help guide mutation testing in AML, and result in more focused application of targeted therapy in patients with de novo AML.

Mutations in the CCND1 and CCND2 genes are frequent events in adult patients with t(8;21)(q22;q22) acute myeloid leukemia.

Core-binding factor acute myeloid leukemia (CBF-AML) is defined by the presence of either t(8;21)(q22;q22)/RUNX1-RUNX1T1 or inv(16)(p13.1q22)/t(16;16)(p13.1;q22)/CBFB-MYH11. The resulting fusion genes require a 'second hit' to initiate leukemogenesis. Mutation assessment of 177 adults with CBF-AML, including 68 with t(8;21) and 109 with inv(16)/t(16;16), identified not only mutations well known in CBF-AML but also mutations in the CCND1 and CCND2 genes, which represent novel frequent molecular alterations in AML with t(8;21). Altogether, CCND1 (n=2) and CCND2 (n=8) mutations were detected in 10 (15%) patients with t(8;21) in our cohort. A single CCND2 mutation was also found in 1 (0.9%) patient with inv(16). In contrast, CCND1 and CCND2 mutations were detected in only 11 (0.77%) of 1426 non-CBF-AML patients. All CCND2 mutations cluster around the highly conserved amino-acid residue threonine 280 (Thr280). We show that Thr280Ala-mutated CCND2 leads to increased phosphorylation of the retinoblastoma protein, thereby causing significant cell cycle changes and increased proliferation of AML cell lines. The identification of CCND1 and CCND2 mutations as frequent mutational events in t(8;21) AML may provide further justification for cell cycle-directed therapy in this disease.

The mutational spectrum of FOXA2 in endometrioid endometrial cancer points to a tumor suppressor role.

BACKGROUND: Forkhead box protein A2 (FOXA2) plays an important in development, cellular metabolism and tumorigenesis. The Cancer Genome Atlas (TCGA) identified a modest frequency of FOXA2 mutations in endometrioid endometrial cancers (EEC). The current study sought to determine the relationship between FOXA2 mutation and clinicopathologic features in EEC and FOXA2 expression. METHODS: Polymerase chain reaction (PCR) amplification and sequencing were used to identify mutations in 542 EEC. Western blot, quantitative reverse transcriptase PCR (qRT-PCR) and immunohistochemistry (IHC) were used to assess expression. Methylation analysis was performed using combined bisulfite restriction analysis (COBRA) and sequencing. Chi-squared, Fisher's exact, Student's t- and log-rank tests were performed. RESULTS: Fifty-one mutations were identified in 49 tumors (9.4% mutation rate). The majority of mutations were novel, loss of function (LOF) (78.4%) mutations, and most disrupted the DNA-binding domain (58.8%). Six recurrent mutations were identified. Only two tumors had two mutations and there was no evidence for FOXA2 allelic loss. Mutation status was associated with tumor grade and not associated with survival outcomes. Methylation of the FOXA2 promoter region was highly variable. Most tumors expressed FOXA2 at both the mRNA and protein level. In those tumors with mutations, the majority of cases expressed both alleles. CONCLUSION: FOXA2 is frequently mutated in EEC. The pattern of FOXA2 mutations and expression in tumors suggests complex regulation and a haploinsufficient or dominant-negative tumor suppressor function. In vitro studies may shed light on how mutations in FOXA2 affect FOXA2 pioneer and/or transcription factor functions in EEC.

Anabolic steroids detected in bodybuilding dietary supplements - a significant risk to public health.

Twenty-four products suspected of containing anabolic steroids and sold in fitness equipment shops in the United Kingdom (UK) were analyzed for their qualitative and semi-quantitative content using full scan gas chromatography-mass spectrometry (GC-MS), accurate mass liquid chromatography-mass spectrometry (LC-MS), high pressure liquid chromatography with diode array detection (HPLC-DAD), UV-Vis, and nuclear magnetic resonance (NMR) spectroscopy. In addition, X-ray crystallography enabled the identification of one of the compounds, where reference standard was not available. Of the 24 products tested, 23 contained steroids including known anabolic agents; 16 of these contained steroids that were different to those indicated on the packaging and one product contained no steroid at all. Overall, 13 different steroids were identified; 12 of these are controlled in the UK under the Misuse of Drugs Act 1971. Several of the products contained steroids that may be considered to have considerable pharmacological activity, based on their chemical structures and the amounts present. This could unwittingly expose users to a significant risk to their health, which is of particular concern for naïve users.

Bcl-xL anti-apoptotic network is dispensable for development and maintenance of CML but is required for disease progression where it represents a new therapeutic target.

The dismal outcome of blast crisis chronic myelogenous leukemia (CML-BC) patients underscores the need for a better understanding of the mechanisms responsible for the development of drug resistance. Altered expression of the anti-apoptoticBcl-xL has been correlated with BCR-ABL leukemogenesis; however, its involvement in the pathogenesis and evolution of CML has not been formally demonstrated yet. Thus, we generated an inducible mouse model in which simultaneous expression of p210-BCR-ABL1 and deletion of bcl-x occurs within hematopoietic stem and progenitor cells. Absence of Bcl-xL did not affect development of the chronic phase-like myeloproliferative disease, but none of the deficient mice progressed to an advanced phenotype, suggesting the importance of Bcl-xL in survival of progressing early progenitor cells. Indeed, pharmacological antagonism of Bcl-xL, with ABT-263, combined with PP242-induced activation of BAD markedly augmented apoptosis of CML-BC cell lines and primary CD34(+) progenitors but not those from healthy donors, regardless of drug resistance induced by bone marrow stromal cell-generated signals. Moreover, studies in which BAD or Bcl-xL expression was molecularly altered strongly support their involvement in ABT-263/PP242-induced apoptosis of CML-BC progenitors. Thus, suppression of the antiapoptotic potential of Bcl-xL together with BAD activation represents an effective pharmacological approach for patients undergoing blastic transformation.

The heat capacity of matter beyond the Dulong-Petit value.

We propose a simple new way to evaluate the effect of anharmonicity on a system's thermodynamic functions, such as heat capacity. In this approach, the contribution of all the potentially complicated anharmonic effects to the constant-volume heat capacity is evaluated using one parameter only: the coefficient of thermal expansion. Importantly, this approach is applicable not only to crystals, but also to glasses and viscous liquids. To support this proposal, we perform molecular dynamics simulations of several crystalline and amorphous solids as well as liquids, and find a good agreement between the results from theory and simulations. We observe an interesting non-monotonic behavior of the liquid heat capacity with a maximum, and explain this effect as being a result of competition between anharmonicity at low temperature and decreasing number of transverse modes at high temperature.

Acceptability of treatment of latent tuberculosis infection in newly HIV-infected young women in Uganda.

We studied the acceptability of isoniazid preventive therapy (IPT) in newly human immunodeficiency virus (HIV) infected Ugandan women. Women were followed in an out-patient clinic where they received HIV care including IPT. Of 52 women who were purified protein derivative-positive, 48 were eligible for IPT and 39 (81%) completed therapy. This completion rate was higher than reported in similar observational studies.

Variations in CD4 cell counts among HIV-uninfected and infected women in Uganda and Zimbabwe.

We conducted a cross-sectional study with 208 HIV-uninfected and 188 HIV-infected women in Uganda and Zimbabwe to investigate differences in median CD4 counts. Absolute CD4 counts were determined by flow cytometry. Multivariate analyses were used to examine the association of country and HIV-infection status on CD4 counts. Median CD4 counts were significantly lower in Zimbabwe than in Uganda overall (649 and 783 cells/mm(3), P = 0.009) and among HIV-infected women (470 and 614 cells/mm(3), P = 0.003). In separate multivariable models, CD4 counts were significantly lower in Zimbabwe in HIV-uninfected (P = 0.014) and infected (P < 0.001) women, controlling for age, contraceptive method, education and living with partner status. In a model combining HIV-uninfected and infected women, there was no significant interaction between country and HIV infection status (P = 0.344), suggesting that the relationship between country and CD4 count was not significantly modified by HIV infection status. This study reinforces the importance of establishing country-specific reference CD4 levels as CD4 count continues to be used as a key biomarker in clinical decision-making for HIV-infected individuals in sub-Saharan Africa.

Human papillomavirus genotypes associated with cervical cytologic abnormalities and HIV infection in Ugandan women.

Human papillomavirus (HPV) infection is associated with almost all cases of cervical cancer, and cervical cancer is a common malignancy in women living in developing countries. A cross-sectional study was conducted to determine the prevalence of HPV infection, human immunodeficiency virus (HIV) infection, and cervical cytologic abnormalities in women presenting to a sexually transmitted infections clinic in Kampala, Uganda. In June and July, 2002, 135 women underwent complete physical exams including Papanicolaou (Pap) smears. HIV status was evaluated by serology. Cervical and vaginal swabs were obtained by clinicians and tested for HPV genotypes by PCR/reverse blot strip assay. Of the 106 women with cervical swabs adequate for HPV testing, the HPV prevalence was 46.2% (49/106). HIV prevalence was 34.9% (37/106). High risk genotypes 52, 58, and 16 were the genotypes detected most commonly. Eighteen percent (9/49) of women infected with HPV were found to have genotypes 16 and/or 18. Seventy-three percent (27/37) of HIV-positive women versus 16% (10/63) of HIV-negative women had abnormal Pap smears (P < 0.0001). Among HIV-positive women, abnormal Pap smears were associated with the presence of high risk HPV genotypes (P < 0.001). The majority of women infected with HPV attending this sexually transmitted infections clinic in Uganda were infected with high risk HPV genotypes other than 16 and 18. Future studies should focus on whether current HPV vaccine formulations, that are limited to high risk genotypes 16 and 18, would be effective at decreasing the burden of cervical cancer in this population.

Distraction techniques for schizophrenia.

BACKGROUND: Distraction techniques are a form of coping strategies used in cognitive behavioural techniques. They may be of value as an adjunctive treatment for people with schizophrenia or schizophrenia-like illnesses. OBJECTIVES: To review the effects of distraction techniques for people with schizophrenia. SEARCH STRATEGY: We searched the Cochrane Schizophrenia Group's Register (October 2003), manually searched reference lists and contacted relevant authors. SELECTION CRITERIA: We included all randomised controlled trials comparing distraction techniques with other treatments for schizophrenia. DATA COLLECTION AND ANALYSIS: We reliably selected, quality assessed and data extracted studies. We excluded data where more than 50% of participants in any group were lost to follow up. For binary outcomes, we calculated a fixed effects risk ratio (RR) and its 95% confidence interval (CI), along with the number needed to treat/harm (NNT/H). For continuous data we calculated the weighted mean difference (WMD). MAIN RESULTS: In terms of mental state, distraction techniques did not have a clear effect (n=60, 1 RCT, MD endpoint BPRS 1.60 CI -0.49 to 3.69). Distraction does not obviously engage people in the studies (n=159, 5 RCTs, RR leaving the study before completion 1.08 CI 0.72 to 1.63). AUTHORS' CONCLUSIONS: Clinicians, researchers, policy makers and recipients of care cannot be confident of the effects of distraction techniques from the findings of this review. The few pioneering studies are small, short and poorly reported. Further data from already completed trials might help inform practice, but more trials do seem to be justified as some of these potentially simple techniques, even if their effect is negligible, could be widely implemented and prove more acceptable than other more intrusive treatments.

Adsorption of carbon monoxide on Ni(110) above atmospheric pressure investigated with surface X-ray diffraction.

The crystallographic structure of CO adsorbed on Ni(110) has been investigated with x-ray diffraction at ambient pressures of CO ranging from 2.3 to 10(-10) bars. At room temperature, the high pressure and vacuum structures are identical. Above room temperature ( approximately 130 degrees C), the high pressure of CO induces a restructuring of the Ni substrate that develops strained (111) microfacets.

Human immunodeficiency virus 1 protease inhibitors in clinical practice: predictors of virological outcome.

OBJECTIVES: To ascertain whether prolonged suppression of viral replication can be achieved in clinical practice and to identify factors associated with virological outcome. DESIGN: Retrospective observational study. SETTING: University-affiliated human immunodeficiency virus (HIV) clinic in Cleveland, Ohio. PARTICIPANTS: Patients treated with regimens that included protease inhibitors between June 1995 and December 1997. We identified 366 patients; 310 had sufficient virological follow-up data to be included. MAIN OUTCOME MEASURE: Virological success was defined as plasma HIV-RNA levels lower than 400 copies/mL at the last clinic visit. Virological failure was subdivided according to the maximum degree of suppression of viral replication achieved. Multivariate analysis was performed to identify baseline factors associated with virological outcome. RESULTS: Virological success was achieved by 47% of patients at a median follow-up of 335 days. The median CD4+ cell count increase and HIV-RNA level decrease were 0.10x10(9)/L (100 cells/microL) and greater than 1.3 log10 in patients who achieved virological success, and 0.010x10(9)/L and 0.32 log10 for those who did not. In multivariate analysis the likelihood of virological success was diminished in women (P<.02) and in patients who missed 2 or more clinic visits in the prior year (P<.001), and decreased when the regimen was started earlier (P<.04). Patients with a lower nadir CD4+ cell count (P<.04) and higher peak plasma HIV-RNA levels (P<.001) also had a decreased likelihood of virological success. CONCLUSIONS: More than half the patients who started a regimen that included protease inhibitors in an academic clinical practice failed to achieve durable suppression of viral replication and also experienced a poorer immunologic outcome as determined by CD4+ cell count increase. Missed clinic visits, more advanced disease, and higher plasma HIV-RNA levels may predict failure.

Magnesium chelatase subunit D from pea: characterization of the cDNA, heterologous expression of an enzymatically active protein and immunoassay of the native protein.

Mg-chelatase catalyzes the insertion of Mg into protoporphyrin and lies at the branchpoint of heme and (bacterio)chlorophyll synthesis. In prokaryotes, three genes--BchI, D and H--encode subunits for Mg-chelatase. In higher plants, homologous cDNAs for the I, D and H subunits have been characterized. Since the N-terminal half of the D subunit is homologous to the I subunit, the C-terminal portion of the pea D was used for antigen production. The antibody recognized the chloroplast D subunit and was used to demonstrate that this subunit associated with the membranes in the presence of MgCl2. The antibody immunoprecipitated the native protein and inhibited Mg-chelatase activity. Expression in Escherichia coli with a construct for the full-length protein (minus the putative transit peptide) resulted in induction of 24.5 kDa (major) and 89 kDa (minor) proteins which could only be solubilized in 6 M urea. However, when host cells were co-transformed with expression vectors for the full-length D subunit and for the 70 kDa HSP chaperonin protein, a substantial portion of the 89 kDa protein was expressed in a soluble form which was active in a Mg-chelatase reconstitution assay.

Mechanism and regulation of Mg-chelatase.

Mg-chelatase catalyses the insertion of Mg into protoporphyrin IX (Proto). This seemingly simple reaction also is potentially one of the most interesting and crucial steps in the (bacterio)chlorophyll (Bchl/Chl)-synthesis pathway, owing to its position at the branch-point between haem and Bchl/Chl synthesis. Up until the level of Proto, haem and Bchl/Chl synthesis share a common pathway. However, at the point of metal-ion insertion there are two choices: Mg2+ insertion to make Bchl/Chl (catalysed by Mg-chelatase) or Fe2+ insertion to make haem (catalysed by ferrochelatase). Thus the relative activities of Mg-chelatase and ferrochelatase must be regulated with respect to the organism's requirements for these end products. How is this regulation achieved? For Mg-chelatase, the recent design of an in vitro assay combined with the identification of Bchl-biosynthetic enzyme genes has now made it possible to address this question. In all photosynthetic organisms studied to date, Mg-chelatase is a three-component enzyme, and in several species these proteins have been cloned and expressed in an active form. The reaction takes place in two steps, with an ATP-dependent activation followed by an ATP-dependent chelation step. The activation step may be the key to regulation, although variations in subunit levels during diurnal growth may also play a role in determining the flux through the Bchl/Chl and haem branches of the pathway.