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SUMMARYGroup AStreptococcus(GAS) infections can cause neuropsychiatric sequelae in children due to post-infectious encephalitis. Multiple GAS infections induce migration of Th17 lymphocytes from the nose into the brain, which are critical for microglial activation, blood-brain barrier (BBB) and neural circuit impairment in a mouse disease model. How endothelial cells (ECs) and microglia respond to GAS infections, and which Th17-derived cytokines are essential for these responses are unknown. Using single-cell RNA sequencing and spatial transcriptomics, we found that ECs downregulate BBB genes and microglia upregulate interferon-response, chemokine and antigen-presentation genes after GAS infections. Several microglial-derived chemokines were elevated in patient sera. Administration of a neutralizing antibody against interleukin-17A (IL-17A), but not ablation of granulocyte-macrophage colony-stimulating factor (GM-CSF) in T cells, partially rescued BBB dysfunction and microglial expression of chemokine genes. Thus, IL-17A is critical for neuropsychiatric sequelae of GAS infections and may be targeted to treat these disorders.

Supplementary Data from Poly(ADP-ribose) polymerase inhibitor ABT-888 potentiates the cytotoxic activity of temozolomide in leukemia cells: influence of mismatch repair status and O6-methylguanine-DNA methyltransferase activity

The poly(ADP-ribose) polymerase (PARP) inhibitor ABT-888 potentiates the antitumor activity of temozolomide (TMZ). TMZ resistance results from increased O6-methylguanine-DNA methyltransferase (MGMT) activity and from mismatch repair (MMR) system mutations. We evaluated the relative importance of MGMT activity, MMR deficiency, nonhomologous end joining (NHEJ), and PARP activity in ABT-888 potentiation of TMZ. MMR-proficient and MMR-deficient leukemia cells with varying MGMT activity, as well as primary leukemia samples, were used to determine TMZ IC50 alone and with ABT-888. ABT-888 effectively inhibited PARP activity and enhanced TMZ growth inhibition in most leukemia cells. ABT-888 potentiation was most effective in MMR-deficient cells with low MGMT activity [potentiation factor (PF) = 21]. ABT-888 also potentiated TMZ activity in MMR-deficient cells with elevated MGMT activity. Unexpectedly, ABT-888 also enhanced TMZ activity in MMR-proficient cells (PF = 3–7). ABT-888 potentiation was unrelated to NHEJ activity. ABT-888 potentiated TMZ (PF = 2–5) in two of four acute myeloid leukemia patient samples but showed little potentiation in primary acute lymphoblastic leukemia. In conclusion, although ABT-888 potentiation of TMZ was most pronounced in MMR-deficient cells with low MGMT activity, neither MMR proficiency nor MGMT overexpression completely abrogated ABT-888 potentiation of TMZ. [Mol Cancer Ther 2009;8(8):2232–42]

In North America, Lyme disease (LD) is primarily caused by the spirochetal bacterium Borrelia burgdorferi, transmitted to humans by Ixodes species tick bites, at an estimated rate of 476,000 patients diagnosed per year. Acute LD often manifests with flu-like symptoms and an expanding rash known as erythema migrans (EM) and less often with neurologic, neuropsychiatric, arthritic, or cardiac features. Most acute cases of Lyme disease are effectively treated with antibiotics, but 10-20% of individuals may experience recurrent or persistent symptoms. This chapter focuses on the neuropsychiatric aspects of Lyme disease, as these are less widely recognized by physicians and often overlooked. Broader education about the potential complexity, severity, and diverse manifestations of tick-borne diseases is needed.

Activation of the serine/threonine kinase Akt contributes to the formation, maintenance, and therapeutic resistance of cancer, which is driving development of compounds that inhibit Akt. Phosphatidylinositol ether lipid analogues (PIA) are analogues of the products of phosphoinositide-3-kinase (PI3K) that inhibit Akt activation, translocation, and the proliferation of a broad spectrum of cancer cell types. To gain insight into the mechanism of PIAs, time-dependent transcriptional profiling of five active PIAs and the PI3K inhibitor LY294002 (LY) was conducted in non–small cell lung carcinoma cells using high-density oligonucleotide arrays. Gene ontology analysis revealed that genes involved in apoptosis, wounding response, and angiogenesis were upregulated by PIAs, whereas genes involved in DNA replication, repair, and mitosis were suppressed. Genes that exhibited early differential expression were partitioned into three groups; those induced by PIAs only (DUSP1, KLF6, CENTD2, BHLHB2, and PREX1), those commonly induced by PIAs and LY (TRIB1, KLF2, RHOB, and CDKN1A), and those commonly suppressed by PIAs and LY (IGFBP3, PCNA, PRIM1, MCM3, and HSPA1B). Increased expression of the tumor suppressors RHOB (RhoB), KLF6 (COPEB), and CDKN1A (p21Cip1/Waf1) was validated as an Akt-independent effect that contributed to PIA-induced cytotoxicity. Despite some overlap with LY, active PIAs have a distinct expression signature that contributes to their enhanced cytotoxicity. Mol Cancer Ther; 10(7); 1137–48. ©2011 AACR.

The poly(ADP-ribose) polymerase (PARP) inhibitor ABT-888 potentiates the antitumor activity of temozolomide (TMZ). TMZ resistance results from increased O6-methylguanine-DNA methyltransferase (MGMT) activity and from mismatch repair (MMR) system mutations. We evaluated the relative importance of MGMT activity, MMR deficiency, nonhomologous end joining (NHEJ), and PARP activity in ABT-888 potentiation of TMZ. MMR-proficient and MMR-deficient leukemia cells with varying MGMT activity, as well as primary leukemia samples, were used to determine TMZ IC50 alone and with ABT-888. ABT-888 effectively inhibited PARP activity and enhanced TMZ growth inhibition in most leukemia cells. ABT-888 potentiation was most effective in MMR-deficient cells with low MGMT activity [potentiation factor (PF) = 21]. ABT-888 also potentiated TMZ activity in MMR-deficient cells with elevated MGMT activity. Unexpectedly, ABT-888 also enhanced TMZ activity in MMR-proficient cells (PF = 3–7). ABT-888 potentiation was unrelated to NHEJ activity. ABT-888 potentiated TMZ (PF = 2–5) in two of four acute myeloid leukemia patient samples but showed little potentiation in primary acute lymphoblastic leukemia. In conclusion, although ABT-888 potentiation of TMZ was most pronounced in MMR-deficient cells with low MGMT activity, neither MMR proficiency nor MGMT overexpression completely abrogated ABT-888 potentiation of TMZ. [Mol Cancer Ther 2009;8(8):2232–42]

The synthesis of the first carboranyl bis(adenosine diphosphate) (CBADP) ( 5 ) was achieved in three steps. The first step involved the reaction of o -carborane dianion, 1 , with methyl dichlorophosphate to yield 2 . Reagent 4 was synthesized by the reaction of bis-benzoyl-protected adenosine with phosphoryl chloride, followed by the protection of the free hydroxyl group in the product, 3 , with methyl triflate. The final step converged both 2 and 4 into the title compound, CBADP ( 5 ).

New functionalized carboranyl derivatives of amineboranes and boron analogs of esters are reported. The reaction of 1,12-(aminopropyl)-1,12-dicarbadodecaborane (2), 2-(aminopropyl)-1,2-dicarbadodecaborane (4), 1-methyl-2-(aminopropyl)-1,2-dicarbadodecaborane (6), 1-phenyl-2-(aminopropyl)-1,2-dicarbadodecaborane (8) with Me 3 NBH 2 X produced novel carboranylamineboranes of the general formula 1,12-[(CH 2 ) 3 NH 2 BH 2 X] 2 -1,12-C 2 B 10 H 10 [X = CN (2a), COOCH 3 (2b), CONHEt (2c), CONHCH(CH 2 C 6 H 5 )COOCH 3 (2d), CONHCH(CH 3 )COOCH 3 (2e), CONHCH[CH(CH 3 ) 2 ]COOCH 3 (2f), CONHCH(CH 2 C 6 H 4 OH)COOCH 3 (2g), 1-CH 2 NH 2 BH 2 CN (2h)] or 1-R-2-[(CH 2 ) 3 NH 2 BH 2 X]-1,2-C 2 B 10 H 10 {R = H, X = CN (4a), COOCH 3 (4b), CONHEt (4c), COOH (4d); R = CH 3 , X = CN (6a), COOCH 3 (6b), CONHCH(CH 2 C 6 H 5 )COOCH 3 (6c), CONHCH(CH 3 )COOCH 3 , (6d), CONHCH[CH(CH 3 ) 2 ]COOCH 3 (6e), CONHCH(CH 2 C 6 H 4 OH) COOCH 3 (6f); R = C 6 H 5 , X = CN (8a), COOCH 3 (8b), CONHCH(CH 2 C 6 H 5 )COOCH 3 (8c), CONHCH(CH 3 )COOCH 3 (8d), CONHCH[CH(CH 3 ) 2 ]COOCH 3 (8e), CONHCH(CH 2 C 6 H 4 OH) COOCH 3 (8f)) by the amine exchange reaction. The reaction of 1-(aminomethyl)-1,2-dicarbadodecaborane with Me 3 NBH 2 X (X = CN) produced 1-[CH 2 NH 2 BH 2 CN]-1,2-C 2 B 10 H 10 (2h). Compounds 2a, 4a, 6a, and 8a were also synthesized by the reaction of 1,12-(aminopropyl)-1,12-dicarbadodecaborane hydrochloride (1), 2-(aminopropyl)-1,2-dicarbadodecaborane hydrochloride (3), 1-methyl-2-(aminopropyl)-1,2-dicarbadodecaborane hydrochloride (5), 1-phenyl-2-(aminopropyl)-1,2-dicarbadodecaborane hydrochloride (7) with sodium cyanoborohydride. The reaction of Li 2 [1,2-CO 2 -1,2-C 2 B 10 H 10 ] (9) or Li[1-R-2-CO 2 -1,2-C 2 B 10 H 10 ], R = CH 3 (10), R = C 6 H 5 (11), with Me 3 NBH 2 I gave 1,2-CO 2 BH 2 NMe 3 -1,2-C 2 B 10 H 10 (9a) or 1-R-2-CO 2 BH 2 NMe 3 -1,2-C 2 B 10 H 10 , R = CH 3 (10a), R = C 6 H 5 (lla), as new boron analogs of esters. All of these compounds were characterized by IR spectroscopy, 1 H, 13 C and 11 B NMR spectroscopy and chemical analyses.

Background:Although more than 1 million US children attend licensed family child care homes, little is known about children’s physical activity in this setting. The purpose of this study is to describe the physical activity of children cared for in child care homes.Methods:The study sample included 31 licensed family child care homes in Washington State. Children aged 3 to 6 wore accelerometers while in child care over 5 days. Minutes per hour spent at 4 activity levels were calculated and averaged for all children in the home. Contextual factors such as provider practices, staff training, and home characteristics were assessed using standardized questions.Results:Accelerometer data from 144 children were included, with 2 to 11 children monitored per home. The mean minutes of sedentary activity per hour (min/h) was 34.3 (SD = 4.6, range 27.7 to 46.6). For moderate-to-vigorous activity (MVPA) it was 8.8 min/h (SD = 2.6, range 3.6 to 14.1) and for vigorous physical (VPA) activity it was 3.1 min/h (SD = 1.4, range: 0.9 to 7.0).Conclusions:The low levels of MVPA and VPA in many homes reinforces the need for additional research to identify policy and practice recommendations that will be most effective in increasing physical activity in this setting.