Novel chemotherapeutic agent FX-9 activates NF-κB signaling and induces G1 phase arrest by activating CDKN1A in a human prostate cancer cell line.

BACKGROUND: The aminoisoquinoline FX-9 shows pro-apoptotic and antimitotic effects against lymphoblastic leukemia cells and prostate adenocarcinoma cells. In contrast, decreased cytotoxic effects against non-neoplastic blood cells, chondrocytes, and fibroblasts were observed. However, the actual FX-9 molecular mode of action is currently not fully understood. METHODS: In this study, microarray gene expression analysis comparing FX-9 exposed and unexposed prostate cancer cells (PC-3 representing castration-resistant prostate cancer), followed by pathway analysis and gene annotation to functional processes were performed. Immunocytochemistry staining was performed with selected targets. RESULTS: Expression analysis revealed 0.83% of 21,448 differential expressed genes (DEGs) after 6-h exposure of FX-9 and 0.68% DEGs after 12-h exposure thereof. Functional annotation showed that FX-9 primarily caused an activation of inflammatory response by non-canonical nuclear factor-kappa B (NF-κB) signaling. The 6-h samples showed activation of the cell cycle inhibitor CDKN1A which might be involved in the secondary response in 12-h samples. This secondary response predominantly consisted of cell cycle-related changes, with further activation of CDKN1A and inhibition of the transcription factor E2F1, including downstream target genes, resulting in G1-phase arrest. Matching our previous observations on cellular level senescence signaling pathways were also found enriched. To verify these results immunocytochemical staining of p21 Waf1/Cip1 (CDKN1A), E2F1 (E2F1), PAI-1 (SERPNE1), and NFkB2/NFkB p 100 (NFKB2) was performed. Increased expression of p21 Waf1/Cip1 and NFkB2/NFkB p 100 after 24-h exposure to FX-9 was shown. E2F1 and PAI-1 showed no increased expression. CONCLUSIONS: FX-9 induced G1-phase arrest of PC-3 cells through activation of the cell cycle inhibitor CDKN1A, which was initiated by an inflammatory response of noncanonical NF-κB signaling.

The Pharmacogenomics Research Network Translational Pharmacogenetics Program: Outcomes and Metrics of Pharmacogenetic Implementations Across Diverse Healthcare Systems.

Numerous pharmacogenetic clinical guidelines and recommendations have been published, but barriers have hindered the clinical implementation of pharmacogenetics. The Translational Pharmacogenetics Program (TPP) of the National Institutes of Health (NIH) Pharmacogenomics Research Network was established in 2011 to catalog and contribute to the development of pharmacogenetic implementations at eight US healthcare systems, with the goal to disseminate real-world solutions for the barriers to clinical pharmacogenetic implementation. The TPP collected and normalized pharmacogenetic implementation metrics through June 2015, including gene-drug pairs implemented, interpretations of alleles and diplotypes, numbers of tests performed and actionable results, and workflow diagrams. TPP participant institutions developed diverse solutions to overcome many barriers, but the use of Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines provided some consistency among the institutions. The TPP also collected some pharmacogenetic implementation outcomes (scientific, educational, financial, and informatics), which may inform healthcare systems seeking to implement their own pharmacogenetic testing programs.

Zwitterionic phosphonium ligands: synthesis, characterization and application in telomerization of 1,3-butadiene.

Novel zwitterionic phosphonium alkylsulfonate ligands are chemoselectively synthesized from N-heterocyclic phosphines and cyclic sulfones in one step in good to excellent yields. Their in situ generated palladium complexes showed high productivity in the industrial telomerization of 1,3-butadiene with methanol. Optimal results are obtained in the presence of cyclohexyl-substituted ligands under mild conditions and at metal loadings as low as 0.001 mol%.

Palladium/phosphite catalyst systems for efficient cross coupling of aryl bromides and chlorides with phenylboronic acid

The Suzuki reaction of aryl bromides is efficiently catalyzed by palladium/ phosphite complexes generated in situ. The influence of ligand, base, and different additives is examined. The process tolerates various functional groups and catalyst turnover numbers up to 820,000 are obtained even with deactivated aryl bromides. For the first time it is shown that palladium/phosphite complexes also catalyze efficiently the Suzuki reaction of aryl chlorides.

Highly selective palladium-catalyzed Heck reactions of aryl bromides with cycloalkenes.

[reaction: see text] The influence of palladium catalysts and reaction conditions on the selectivity of Heck reactions of aryl bromides with cyclohexene and cyclopentene has been investigated. It is shown that the addition of DMSO as a cosolvent leads to improved selectivities of nonconjugated aryl olefins. On the other hand, high selectivities for conjugated arylcyclopentenes have been obtained with the catalytic system DMA/Na2CO3/Pd2(dba)3 x dba/PCy3.

Facile three-component coupling procedure for the synthesis of substituted tetrahydroisoindole-1,3-diones from alpha,beta-unsaturated aldehydes.

[reaction: see text]. A new one-pot procedure for the efficient synthesis of a small library of amino-functionalized tetrahydroisoindole-1,3-dione derivatives was developed. This three-component coupling reaction comprises subsequent condensation and Diels-Alder reactions of ubiquitous available starting materials (alpha,beta-unsaturated aldehydes, amide, and maleimide). The synthesized compounds share a substituted tetrahydroisoindole motif in an endo fashion.

A program to control an outbreak of hepatitis A in Alaska by using an inactivated hepatitis A vaccine.

OBJECTIVE: To stop an epidemic of hepatitis A in rural Alaska by mass immunization of susceptible persons with 1 dose of an inactivated hepatitis A vaccine. DESIGN: Nonrandomized, uncontrolled trial. Hepatitis A vaccine was offered to all persons in susceptible age groups in villages with documented cases of hepatitis A. Immune globulin was not offered at the time of vaccination. SETTING: Twenty-five rural communities located in interior Alaska and along the northwest coast of the Bering Sea and Arctic Ocean. PARTICIPANTS: Persons without a history of acute hepatitis A in age groups selected by applying results of a previous serosurvey conducted on serum collected before the epidemic. INTERVENTION: One dose of a formalin-inactivated hepatitis A vaccine was given to each participant. Adults 20 years of age and older received 1440 enzyme-linked immunosorbent assay units and persons younger than 20 years received 720 enzyme-linked immunosorbent assay units. Prevaccination and postvaccination levels of antibody to hepatitis A IgG were obtained from 136 participants. MAIN OUTCOME MEASURES: An active surveillance system was established to detect persons with symptomatic illnesses compatible with hepatitis A; persons who met the illness criteria were tested for antibody to hepatitis A IgM. One area (the Kotzebue region), where all communities were offered vaccine, was selected for intensive surveillance and analysis. RESULTS: During the 12-month period before the vaccine trial, 529 cases of icteric hepatitis A were reported, and 443 were confirmed to be positive for antibody to hepatitis A IgM. Hepatitis A vaccine was administered to 4930 persons, 3517 of whom were younger than 20 years. After vaccination began, 237 persons positive for antibody to hepatitis A IgM were identified during a 60-week surveillance period; 46 were vaccines and 191 were unvaccinated susceptible persons. In the Kotzebue region, in communities in which more than 80% of persons considered susceptible were vaccinated, the outbreak ceased in 4 to 8 weeks, whereas in 1 large community in which less than 50% of susceptible persons were vaccinated, the outbreak continued for more than 50 weeks. More than 90% of seronegative persons developed antibody to hepatitis A IgG 3 to 4 weeks after vaccination. CONCLUSION: This trial suggested that by providing both short-term and long-term protection, hepatitis A vaccine used without immune globulin halted an established epidemic of hepatitis A in rural Alaska.

Stereoselective synthesis of 1,1-dialkyl-1-methoxymethyl glucosides (acetal-glucosides).

The synthesis is described of highly acid-sensitive, 1,1-dialkyl-1-methoxymethyl glucosides (acetal-glucosides) as potential anti-cancer prodrugs. Reaction of 2,3,4,6-tetra-O-acetyl-1-O-trimethylsilyl-beta-D-glucopyranose (4) severally with various aliphatic and alicyclic ketones and methyl trimethylsilyl ether, in the presence of catalytic amounts of trimethylsilyl trifluoromethanesulfonate, afforded the corresponding acetylated acetal-beta-glucosides, e.g., acetone gave 1-methoxy-1-methylethyl 2,3,4,6-tetra-O-acetyl-beta-D-glucopyranoside (7a). Likewise the alpha-anomer (8a) of 7a was obtained from the alpha-anomer of 4. Deacetylation of the tetra-acetates then gave the acetal-alpha- and -beta-glucosides.

Self-reported illness among travelers to the Russian Far East.

This study evaluated the risk of travelers to the Russian Far East developing acute gastrointestinal or respiratory symptoms. Passengers and crew on 10 commercial airline flights from the Russian Far East to the United States were asked to complete a health questionnaire that asked age, sex, country of residence, length of stay, foods and beverages consumed, and about gastrointestinal or "flu" symptoms. Questionnaires were returned by 353 of 662 persons (53.3 percent). The most frequently reported symptoms were diarrhea (N = 18; 5.1 percent) and "flu" symptoms (N = 15; 4.2 percent). Among those people who reported symptoms, most were sick for 3 days or less, although 10 (27.0 percent) were still sick at the time that they entered the United States. Age and sex were not associated with symptoms. Persons who drank untreated tap water were more likely to have gastrointestinal symptoms (relative risk = 2.7; 95 percent confidence interval = 1.2, 5.9) while those who drank bottled or canned fruit juice were protected (relative risk = 0.4; 95 percent confidence interval = 0.2, 0.8). The incidence of "flu" symptoms was similar to the rate for the general population of the United States while the incidence of gastrointestinal symptoms was increased and only slightly less than the rate among travelers to developing countries. Travelers may wish to restrict consumption of untreated tap water and increase consumption of fruit juices. Additional work is needed to identify the pathogens responsible for acute illness among travelers to the Russian Far East.

Base-catalyzed amination of olefins: an example of an environmentally friendly synthesis of amines.

The base-catalyzed amination of aromatic olefins is described as an environmentally friendly synthesis of various beta-arylethylamines. Primary and secondary aliphatic amines as well as aromatic amines react with styrene derivatives to give the corresponding beta-arylethylamines in high yield up to 99%. While aliphatic amines react with styrenes in the presence of n-BuLi as the pre-catalyst, anilines can be olefinated using KOtBu as the catalyst.

The effect of imaging modality on patient management in the evaluation of pulmonary thromboembolism.

A retrospective medical record review was performed to study the differences in clinical risk profiles and the relationships between test results versus management for suspected pulmonary thromboembolism (TE) in patients undergoing either radionuclide ventilation perfusion (V/Q) scans or pulmonary computed tomographic angiography (CTA), as the initial test. Data of 138 consecutive V/Q patients were compared with that of 149 consecutive CTA patients during equivalent 6-month intervals before and after the introduction of CTA. Information on risk factors, signs and symptoms, all diagnostic test results, and the relationships between the test results and ultimate physician management were collected and analyzed. V/Q results predicted physician management in all patients with high probability scans and 91% with normal to low probability scans. There were 35 patients with indeterminate V/Q scans--43% of these patients were managed without any other diagnostic test. CTA results predicted management in all patients with positive studies and 99% of patients with negative studies. In contrast to the V/Q cohort, only seven CTA studies were inconclusive--additional diagnostic tests determined management in all but one case. Compared with V/Q, CTA has fewer indeterminate results, is more directly reflective of management, and reduces the number of patients managed with inconclusive data.

Aldicarb food poisonings in California, 1985-1988: toxicity estimates for humans.

Three outbreaks of food poisoning involving watermelons or cucumbers and caused by the carbamate pesticide aldicarb occurred in California between 1985 and 1988. For each outbreak, and for an outbreak of aldicarb poisoning associated with English cucumbers previously reported in the literature, dosages of aldicarb sulfoxide that caused the illnesses were estimated. Estimated dosages ranged between 0.0023 [corrected] and 0.06 mg/kg body weight, and most were well below the 0.025 mg/kg Lowest Observed Effect Level (LOEL) for subclinical blood cholinesterase depression previously reported for humans. These findings are consistent with aldicarb sulfoxide (ASO) illnesses that have occurred in other states. Aldicarb appears to be more toxic than previously suspected. Scientific and regulatory implications are discussed.

Epidemiology and public health in the Yagodnoye district.

Yagodnoye District (population 48,622 as of January 1, 1991) is one of seven administrative districts in the Magadan Region of the Russian Republic, USSR. The population age-distribution is different from that of the United States or Alaska with a larger proportion of persons 20-49 years of age and relatively few people greater than or equal to 60 years of age. Public health and epidemiologic services are provided by a Sanitation and Epidemiology Station with a staff of approximately 108 persons, including 19 doctors. Major activities include Environmental and Occupational Health, Vector Control, Bacteriology Laboratory, and Epidemiology. Epidemiologic services are highly focused on infectious diseases despite the apparent presence of other major public health problems.

Results of an indoor air pollution investigation.

After the opening of a new elementary school in fall 1986, several members of the school's staff noticed symptoms they attributed to the workplace. An investigation by the Occupational Safety and Health Branch (OSHA) of the Alaska Department of Labor found no major health problems and concluded that fireproofing at the school may have caused a petroleum-like odor. In fall 1987, parents reported illness in their children that they attributed to school attendance. Subsequent epidemiologic investigation found that student and staff absentee rates were not increased and were similar to other schools in the district. Testing conducted by the National Institute for Occupational Safety and Health (NIOSH) confirmed that the petroleum-like odor was due to the fireproofing. Toxicologic information and the results of air sampling confirmed that no adverse health effects would be expected from the product. By working together with NIOSH, OSHA, the school district, and a consulting mechanical engineer, deficiencies in the school's ventilation system were discovered and immediately corrected with interim engineering changes. Only by bringing multiple agencies together and openly sharing findings with concerned parents and staff were the problems at the school resolved.

Surveillance for tuberculosis in Alaska, 1986.

The incidence of tuberculosis in the Native population in Alaska (92.2/100,000) continues to be higher than the U.S. tuberculosis incidence (9.3/100,000). This paper describes tuberculosis surveillance in Alaska and estimates the "predictive value positive" for cases recorded by the surveillance system during 1986. (Predictive value positive refers to the proportion of all people identified who actually have the disease.) Active surveillance components included an itinerant chest clinic and survey chest roentgenography program, epidemiologic case investigations, and skin testing. Passive components included cases reported by health-care providers and the U.S. Immigration and Naturalization Service. Half of all new cases were reported by health-care providers. Only 42% of cases were bacteriologically confirmed (vs 87% nationwide) suggesting that some cases may have been false positives. many cases did not have a contact investigation completed. Recommendations to improve the surveillance system include: 1) following the Centers for Disease Control/American Thoracic Society diagnostic criteria more closely, 2) increasing the number of cases which have contact investigations completed, and 3) targeting surveillance activities towards high risk subgroups such as Southeast Asian immigrants.

Over-representation of Samoan/Pacific Islanders among patients with methicillin-resistant Staphylococcus aureus (MRSA) infections at a large family practice clinic in Anchorage, Alaska, 1996-2000.

Two pediatricians in Anchorage observed that among patients of Samoan/Pacific Islander (S/PI) descent, bacterial wound cultures that grew Staphylococcus aureus often yielded methicillin-resistant isolates. The Alaska Section of Epidemiology performed chart reviews of patients that visited a large family practice clinic in Anchorage, Alaska, from 1996 through April 2000, and who were diagnosed with a skin infection. Eight of 204 patients were identified with culture-confirmed MRSA infections. Eighty percent (4 of 5) of S/PI patients had resistant isolates compared with 12% (4 of 34) of non S/PI patients (Yates corrected chi2 = 8.61, p-value = 0.003). Although subject to limitations, these data support similar findings documented by other studies that suggest MRSA infections disproportionately affect persons of S/PI origin. This study also suggests that it would be prudent to reduce the threshold of clinical suspicion for obtaining a skin culture among S/PI patients in Alaska, and avoid beta-lactam antibiotics until culture results are received.

Emerging infectious diseases in Alaska and the Arctic: a review and a strategy for the 21st century.

Emergence of new, previously unknown, and drug-resistant infectious diseases pose a major threat to global health. The emergence of infectious diseases in Alaska and the Arctic parallels the resurgence of infectious diseases worldwide. The Centers for Disease Control and Prevention has developed a strategy to revitalize the capacity to protect the public from emerging infectious diseases by improving four major public health activities: surveillance and response, applied research, infrastructure and training, and prevention and control. The plan targets high-priority emerging infectious disease problems and particular groups of people at increased risk. These target areas encompass a number of diseases of special concern in Alaska, such as drug-resistant Streptococcus pneumoniae infections, foodborne botulism, alveolar hydatid disease, viral hepatitis, Helicobacter pylori infections, Haemophilus influenzae type b bacteremia and meningitis, and infections of immunocompromised persons, pregnant women and newborns, and tourists. To address these and other emerging infectious disease issues, including the threat of bioterrorism in Alaska and the Arctic, future issues of Alaska Medicine will include updates on specific emerging infectious diseases for health care providers, clinical laboratory workers, and community public health professionals who form the front lines for recognizing, treating, and preventing emerging infectious diseases.

Amidocarbonylation-An Efficient Route to Amino Acid Derivatives.

Atom efficient, multicomponent reactions that lead to high-value products from inexpensive starting materials are of both economic and ecological interest for industrial organic synthesis. alpha-Amino acids are amongst the most important compounds in chemistry and biology. As well as their biochemical significance as building blocks of peptides and proteins, alpha-amino acids are also becoming increasingly interesting as fine chemicals. Possibly one of the key reactions in the preparation of these compounds is transition metal catalyzed amidocarbonylation, where the alpha-amino acid framework is constructed in a single step from an aldehyde, an amide, and carbon monoxide. This article gives a current overview of transition metal catalyzed amidocarbonylation reactions used in the synthesis of alpha-amino acids derivatives. A classification and summary of the significant features of this three component reaction is first presented together, with an historical introduction. This section is followed by two sections on cobalt- and palladium-catalyzed amidocarbonylation. A discussion of the mechanism of each of the different amidocarbonylation variants form an introduction. Overviews on further synthetic development of the methodology, such as the domino reaction with an amidocarbonylation step and the expansion of the range of starting materials, form the main topics of both variants. The potential of the method is demonstrated with the help of examples of special synthetic utility (for example, the preparation of arylglycines). Finally, possibilities for future developments in transition metal catalyzed amidocarbonylation reactions are proposed on the basis of the current state of knowledge.

The First Efficient Hydroaminomethylation with Ammonia: With Dual Metal Catalysts and Two-Phase Catalysis to Primary Amines.

Primary and unbranched secondary amines are obtained by the highly selective hydroaminomethylation of olefins with ammonia [Eq. (a)]. The selectivity is readily controlled with a new dual Rh/Ir catalyst in a two-phase system.

Atom-Efficient Oxidation of Alkenes with Molecular Oxygen: Synthesis of Diols.

Dihydroxylations of simple alkenes were carried out for the first time in excellent yields and selectivities with molecular oxygen as oxidant [(Eq. (a)]. Both oxygen atoms are used productively and are incorporated into the product in this transition metal catalyzed alkene oxidation.