Long-term risk of carotid stenosis and cerebrovascular disease after radiation therapy for head and neck cancer.

BACKGROUND: Recipients of radiation therapy (RT) for head and neck cancer (HNC) are at significantly increased risk for carotid artery stenosis (CAS) and cerebrovascular disease (CVD). We sought to determine (1) cumulative incidences of CAS and CVD among HNC survivors after RT and (2) whether CAS is associated with a RT dose response effect. METHODS: This single-institution retrospective cohort study examined patients with nonmetastatic HNC who completed (chemo)RT from January 2000 through October 2020 and subsequently received carotid imaging surveillance ≤2 years following RT completion and, in the absence of CAS, every 3 years thereafter. Exclusion criteria included history of known CAS/CVD. Asymptomatic CAS was defined as ≥50% reduction of luminal diameter, symptomatic CAS as stroke or transient ischemic attack, and composite CAS as asymptomatic or symptomatic CAS. RESULTS: Of 628 patients undergoing curative intent RT for HNC, median follow-up was 4.8 years (interquartile range, 2.6-8.3), with 97 patients followed ≥10 years. Median age was 61 years and 69% of patients received concurrent chemotherapy and 28% were treated postoperatively. Actuarial 10-year incidences of asymptomatic, symptomatic, and composite CAS were 29.6% (95% CI, 23.9-35.5), 10.1% (95% CI, 7.0-13.9), and 27.2% (95% CI, 22.5-32.1), respectively. Multivariable Cox models significant association between asymptomatic CAS and absolute carotid artery volume receiving ≥10 Gy (per mL: hazard ratio, 1.09; 95% CI, 1.02-1.16). CONCLUSIONS: HNC survivors are at high risk for post-RT CAS. A dose response effect was observed for asymptomatic CAS at doses as low as 10 Gy. PLAIN LANGUAGE SUMMARY: Recipients of radiation therapy for head and neck cancer are at significantly increased risk for carotid artery stenosis and cerebrovascular disease. However, carotid artery screening is not routinely performed among head and neck survivors following radiation therapy. In this single-institution retrospective cohort study, patients with head and neck cancer were initially screened for carotid artery stenosis ≤2 years following radiation therapy completion, then every 3 years thereafter. The 10-year actuarial incidence of carotid artery stenosis was >25% and stroke/transient ischemic attack >10%. Multivariable analysis demonstrated significant associations between asymptomatic carotid artery stenosis and artery volumes receiving ≥10 Gy.

Tuning of Cu-Al Interactions in Complexes Derived from Tris(pyridonyl-6-methyl)aluminum Metalloligands.

A series of bioinspired polar atrane Cu-Al complexes were studied with a combined experimental and computational approach to assess the range and nature of Cu-Al interactions in these novel species. The aluminum metalloligand [Na{Me2Al(OPy-6-Me)2}] (2) was furnished in excellent yield (92%) from the nucleophilic attack of Na(OPy-6-Me) to AlMe3 and the subsequent alkane elimination reaction with 6-methyl-2-hydroxypyridine. At the same time, the metalloligand [Al(OPy-6-Me)3] (3) was isolated in an also excellent yield (95%) via alkane elimination of AlMe3 with 6-methyl-2-hydroxypyridine. The zwitterionic Cu-Al atranes [Cu{MeAl(OPy-6-Me)3}] (5Me) and [Cu{MesAl(OPy-6-Me)3}] (5Mes) were isolated (73 and 97% yields) from metalloligands 2 and 3, respectively. [(Cu{Al(OPy-6-Me)4})2(µ-Cu)]+ ([6+][B(ArCF3)4]) was isolated via a reaction that involves alkane elimination and redistribution reacting from 5Me with [H(OEt2)2][B(ArCF3)4] in benzene solution. Alkane elimination in benzene of either 5Me or 5Mes with [HNEt3][B(ArCF3)4] renders [Cu{(Et3N)Al(OPy-6-Me)3}]+ (Et3N-5+). The Lewis base-free cationic complex [Cu{Al(OPy-6-Me)3}]+ (5+) was isolated in 68% yield upon reacting 3 with [Cu(COD)2][B(ArCF3)4] in benzene. Metalloligands and complexes were fully characterized with an array of spectroscopic and analytical techniques that include multinuclear NMR, ATR-IR, ESI-spectrometry, combustion microanalysis, cyclic voltammetry (CV), and, whenever feasible, SCXRD. X-ray and DFT parameters indicate that the strength of the Cu→Al transannular interaction follows the trend 5+ > Et3N-5+ > [6+][B(ArCF3)4], 5Me, and 5Mes in a smooth transition from zwitterionic species where the Cu-Al interaction is nonexistent to moderate Cu-Al Z-type interactions. CV, in conjunction with DFT calculations of Et3N-5+ and 5+, hint at the generation in the electrochemical cell of the radical species 5rad at -1.82 V and the anionic complex 5- at -2.32 V vs Fc/Fc+, respectively. The proposed species 5rad exhibits 2-center/1-electron (2c/1e) σ bonding whereas 5- a 2-center/2-electron (2c/2e) bond.

Cellular and immunological mechanisms influence host-adapted phenotypes in a vector-borne microparasite.

Predicting pathogen emergence and spillover risk requires understanding the determinants of a pathogens' host range and the traits involved in host competence. While host competence is often considered a fixed species-specific trait, it may be variable if pathogens diversify across hosts. Balancing selection can lead to maintenance of pathogen polymorphisms (multiple-niche-polymorphism; MNP). The causative agent of Lyme disease, Borrelia burgdorferi (Bb), provides a model to study the evolution of host adaptation, as some Bb strains defined by their outer surface protein C (ospC) genotype, are widespread in white-footed mice and others are associated with non-rodent vertebrates (e.g. birds). To identify the mechanisms underlying potential strain × host adaptation, we infected American robins and white-footed mice, with three Bb strains of different ospC genotypes. Bb burdens varied by strain in a host-dependent fashion, and strain persistence in hosts largely corresponded to Bb survival at early infection stages and with transmission to larvae (i.e. fitness). Early survival phenotypes are associated with cell adhesion, complement evasion and/or inflammatory and antibody-mediated removal of Bb, suggesting directional selective pressure for host adaptation and the potential role of MNP in maintaining OspC diversity. Our findings will guide future investigations to inform eco-evolutionary models of host adaptation for microparasites.

Optimization of Pathogen Capture in Flowing Fluids with Magnetic Nanoparticles.

Magnetic nanoparticles have been employed to capture pathogens for many biological applications; however, optimal particle sizes have been determined empirically in specific capturing protocols. Here, a theoretical model that simulates capture of bacteria is described and used to calculate bacterial collision frequencies and magnetophoretic properties for a range of particle sizes. The model predicts that particles with a diameter of 460 nm should produce optimal separation of bacteria in buffer flowing at 1 L h(-1) . Validating the predictive power of the model, Staphylococcus aureus is separated from buffer and blood flowing through magnetic capture devices using six different sizes of magnetic particles. Experimental magnetic separation in buffer conditions confirms that particles with a diameter closest to the predicted optimal particle size provide the most effective capture. Modeling the capturing process in plasma and blood by introducing empirical constants (ce ), which integrate the interfering effects of biological components on the binding kinetics of magnetic beads to bacteria, smaller beads with 50 nm diameters are predicted that exhibit maximum magnetic separation of bacteria from blood and experimentally validated this trend. The predictive power of the model suggests its utility for the future design of magnetic separation for diagnostic and therapeutic applications.

Molecular epidemiology of tuberculosis in Havana, Cuba, 2009.

OBJECTIVES: To estimate the proportion of tuberculosis cases attributable to recent transmission and the risk factors possibly associated with tuberculosis clustering. METHODS: Population-based study combining information from epidemiological investigation of tuberculosis cases notified to the National Tuberculosis Control Program in Havana, Cuba, in 2009 with the results of genotyping of Mycobacterium tuberculosis isolates with variable number tandem repeat of mycobacterial interspersed repetitive units (MIRU-VNTR) typing. RESULTS: Of 186 cases, 61 were genotyped: 33 patterns and five clusters with 19, 7, 3, 2 and 2 cases were found. The proportion of cases due to recent transmission was 45% (95% confidence interval 33-58%). Routine contact investigation failed to identify a substantial number of epidemiological links. A history of living in a closed setting was strongly associated with clustering. CONCLUSIONS: The proportion of cases due to recent transmission in Havana in 2009 is high. The existing control measures in closed settings should be strengthened. A study on a larger number of cases and for a longer time period should be carried out to obtain more precise estimates. Further studies on the utility and cost-effectiveness of the addition of molecular epidemiology techniques to support the progress towards tuberculosis elimination in Cuba, a low-incidence resource-limited setting, are also needed.

EXERT-BC: A pilot study of an exercise regimen designed to improve functional mobility, body composition, and strength after the treatment for breast cancer.

PURPOSE: Resistance training may offer several unique advantages within breast cancer (BC) survivorship care; however, safety concerns have limited the application of high-intensity compound movements necessary to elicit optimal changes in body composition, strength, and quality of life in this population. The EXERT-BC trial assesses the safety and feasibility of an evidence-based, dose-escalated resistance training regimen among BC survivors, with the goal of improving physical and metabolic function, mobility, muscle mass, and body composition. METHODS: Participants included women with breast cancer underwent a 3-month thrice weekly exercise regimen involving dose escalation of high-intensity compound exercises. Coprimary outcomes included safety and adherence. Pre- and post-regimen assessment included body composition testing, functional mobility and balance, total load (weight × repetitions × sets) across compound exercises, and patient reported quality of life. Pairwise comparison was performed via the paired t test. RESULTS: Fourty participants completed a 3-month exercise regimen, with a median age of 57 years (range, 27-74 years) and 73% having stage 0-2 BC. BC therapies concurrent with exercise included anti-estrogen therapy (80%), radiotherapy (30%), and non-hormonal systemic therapy (15%). No adverse events were observed aside from a single case of self-limited knee pain. Session attendance exceeded a prespecified threshold of 75%, and 98% patients reported ongoing compliance to an exercise regimen following regimen completion. Significant reductions in percent body fat (p < 0.001) and increases in percent muscle mass (p = 0.011) were observed. Significant increases in resting metabolic rate (p = 0.023), bilateral grip strength (p < 0.001), functional movement screen (p < 0.001), bilateral Y-Balance testing (p < 0.001), and Godin questionnaire scores (p < 0.001) were observed. CONCLUSION: A 3-month dose-escalated resistance training regimen comprising high-intensity compound movements appears safe with a high degree of adherence among breast cancer survivors, resulting in demonstrable improvements in body composition, metabolic parameters, strength increases, and patient-reported quality of life.

EXERT-BC: Prospective Study of an Exercise Regimen After Treatment for Breast Cancer.

Purpose EXERT-BC is a dose-escalated resistance training regimen created to improve body composition, strength, and balance in women treated for breast cancer (BC). Herein, we report the interim analysis. Women treated for BC underwent this 3-month exercise regimen in an exercise oncology facility with continual monitoring of load and strength. Twenty women completed the IRB-approved protocol, with a mean age of 57 years (range 41-74). Concurrent therapies included anti-estrogen therapy (73%), chemotherapy (14%), and radiotherapy (23%). 27% of women endorsed prior exercise. Subjects missed an average of 1.75 classes (range 0-7), with all meeting adherence over 75%. No injuries or adverse events were reported aside from muscle soreness and 2 days of knee pain. Significant differences in body composition at completion included reduced body fat (38.2% vs. 36.7%, p=0.003), and increased muscle mass (33.1% vs. 37.1%, p<0.001), functional mobility screening (9.82 vs. 11.73, p=0.018), and Y-balance (left: 72.4 vs. 85.3, p=0.001; right: 70.3 vs. 85.2. p<0.001). Significant increases in load were demonstrated: split squat (p<0.001), trap bar deadlift (p=0.035), inclined dumbbell press (p<0.001), and bird dog rows (p<0.001). Dose-escalated resistance training in women with BC is safe and feasible, endorsing significant improvements across body composition, balance, and strength.

Coinfection of Canine Distemper Virus and Rabies Virus in Wildlife Samples Submitted for Routine Rabies Testing.

Canine distemper virus (also known as Canine morbillivirus), the etiologic agent of canine distemper, is a highly contagious pathogen causing a multisystemic infection in carnivores globally. Canine distemper may be clinically indistinguishable from rabies, and outbreaks of either disease are major concerns. In the US, both diseases are endemic and managed by parenteral vaccination in domestic animals. In wildlife, oral vaccination and trap-vaccinate-release programs are available for rabies prevention, but no such strategies exist for canine distemper. We evaluated the prevalence at which canine distemper virus occurred concurrently in animals infected with rabies virus. Real-time quantitative reverse transcriptase PCR (qRT-PCR) was performed on specimens previously diagnosed with rabies during 2017-19 by the New York State Rabies Laboratory. Real-time qRT-PCR detected concurrent canine distemper virus infection in 73 of 1,302 animals with rabies virus. Coinfection rates were approximately 9% in Procyon lotor, 2% in Vulpes vulpes, and 0.4% in Mephitis mephitis, with an overall prevalence of 5.6%. As comorbidities in wildlife occur, laboratory-based surveillance and confirmatory testing are critical to rapid decision making for disease prevention. Rabies virus incursions are expensive and difficult to manage, and spillover events create health risks to humans and domestic animals as well as to free-roaming wildlife.

Electrical dataset of household appliances in operation in an apartment.

This data article presents electricity demand data on common household appliances in the Dominican Republic and therefore in the Caribbean region, as well as appliances whose demand characteristics are maintained regardless of geographic location. A one-hour record is made in most cases, for 17 household appliances, containing information on power demand, effective current, power factor and harmonic distortion of voltage and current. The average, minimum, and maximum values ​​of each parameter for one minute are provided. The data were obtained using the Fluke-1738 electrical network analyzer. The data can be used to build demand profiles in the residential or commercial sector, depending on the composition of electrical appliances and the hours of use, dimension photovoltaic systems for self-consumption and emergency electrical sources. Although the number of household appliances and conditions of use of some appliances do not constitute a representative sample, the dataset and the measurement method constitute a starting point for obtaining this type of records, which are scarce in the literature.

Resistance Training for Patients with Cancer: A Conceptual Framework for Maximizing Strength, Power, Functional Mobility, and Body Composition to Optimize Health and Outcomes.

There are many benefits to the addition of exercise to cancer treatment and survivorship, particularly with resistance training regimens that target hypertrophy, bone mineral density, strength, functional mobility, and body composition. These goals are best achieved through a series of individualized high-intensity compound movements that mirror functional mobility patterns and sufficiently stress the musculoskeletal system. As a result of adequate stress, the body will engage compensatory cellular mechanisms that improve the structural integrity of bones and muscles, stimulate metabolism and the immune system, optimize functional performance, and minimize mechanical injury risk. The current evidence suggests that application of the above exercise principles, practiced in a safe environment under expert observation, may offer patients with cancer an effective means of improving overall health and cancer-specific outcomes. The following article poses several important questions certified exercise specialists and physicians should consider when prescribing resistance exercise for patients with cancer.

Androgen deprivation therapy mimicking acute coronary syndrome: A case report.

An 80-year-old man diagnosed with prostate cancer and under treatment with androgen deprivation therapy presented at the emergency room with chest pain, repolarization abnormalities and QT interval prolongation on electrocardiogram. An initial diagnosis of acute coronary syndrome was proposed, but biomarkers and coronary angiography were negative. Hydroelectrolyte balance and echocardiogram were also normal. Some weeks after drug withdrawal, repolarization changes reverted. A rare side effect of these drugs mimicking an acute coronary syndrome was the most probable diagnosis.

A prevalence study in Guadalajara, Mexico, comparing tuberculin skin test and QuantiFERON-TB Gold In-Tube.

BACKGROUND: Tuberculosis (TB) is a prevalent disease throughout the world. The extent of TB illness in childhood is not clear; recent data shows that 10-20% of the cases are found in children under 15 years old. In 2017, 1 million children developed the disease, of which 9% were co-infected with HIV. METHODS: A cross-sectional study that analyzed 48 children diagnosed with HIV-infection in Guadalajara, Mexico. The tuberculin skin test (TST) and QuantiFERON-TB Gold In-Tube test (QFT) were performed and compared to diagnose latent TB infection (LTBI). RESULTS: The average age was 9 years old (± 4), with an age range of 1-16 years; the 6-12-year-old group predominated with 50% of cases. 27 patients (56%) were male; 83% had received the BCG vaccination and 23% had a history of being contacts of TB cases. In the study, 40 patients (83%) were without immunosuppression; seven (15%) with moderate immunosuppression, and only one patient had severe immunodeficiency. Overall, 3 of the 48 children (6.2%) had a positive TST, while 8 out of 48 (16.6%) had a positive QFT. The concordance between the two tests was 89.6% (43/48) with Kappa = 0.5 (95% CI, 0.14-0.85). CONCLUSIONS: The QFT test represents an opportunity in the diagnosis of LTBI, particularly in pediatric HIV- patients. This is the first study that compares the two tests (TST and QFT) in children with HIV-infection in Guadalajara, Mexico.

[Tuberculosis incidence strata in Cuban municipalities: 1999-2002 and 2003-2006]. / Estratos de incidencia de tuberculosis en los municipios de Cuba: 1999-2002 y 2003-2006.

OBJECTIVE: identify Cuban municipalities with high, medium, and low incidence of tuberculosis (TB), compare incidence rates for the periods 1999-2002 and 2003-2006, and analyze distribution of the disease by population density and economic activity. METHODS: TB incidence was calculated by municipality, confidence interval (95%), and the percentage of variation for the defined strata according to population density and the predominant economic activity. The municipalities were divided into three categories based on incidence (> 10 per 100 000; > 5 per 100 000 to < 10 per 100 000, and < 5 per 100 000), and maps were plotted. RESULTS: the proportion of municipalities with an incidence of < 5 per 100 000 rose from 35.5% to 57.4% between the two periods, while the proportion of municipalities with an incidence of > 10 per 100 000 fell from 22.5% to 5.9%. National incidence fell by 28.7%-from 8.7 per 100 000 in 1999-2002 to 6.2 in 2003-2006. Municipalities that were not very densely populated and where agricultural activities predominated showed significant reductions in incidence. The rates in densely populated municipalities devoted primarily to industrial and service activities are still high. CONCLUSIONS: TB incidence is gradually and sustainably declining in the majority of municipalities. Differentiated strategies are needed to reduce TB incidence rates in municipalities where they continue to be relatively high.

Prevalence of Infection and Co-Infection and Presence of Rickettsial Endosymbionts in Ixodes Scapularis (Acari: Ixodidae) in Connecticut, USA.

Ixodes scapularis is currently known to transmit 7 pathogens responsible for Lyme disease, anaplasmosis, babesiosis, tick-borne relapsing fever, ehrlichiosis, and Powassan encephalitis. Ixodes scapularis can also be colonized by endosymbiotic bacteria including those in the genus of Rickettsia. We screened 459 I. scapularis ticks submitted to the Connecticut Agricultural Experiment Station Tick Testing Laboratory with the objectives to (1) examine differences in infection prevalence of Borrelia burgdorferi, Anaplasma phagocytophilum, Babesia microti, and Borrelia miyamotoi, (2) evaluate whether prevalence of co-infections occur at the same frequency that would be expected based on single infection, and (3) determine the presence of rickettsial endosymbionts in I. scapularis. The prevalence of infection in I. scapularis was highest with Bo. burgdorferi sensu lato (nymph = 45.8%; female = 47.0%), followed by A. phagocytophilum (nymph = 4.0%; female = 6.9%), Ba. microti (nymph = 5.7%; female = 4.7%), and Bo. miyamotoi (nymph = 0%; female = 7.3%). We also identified rickettsial endosymbionts in 93.3% of I. scapularis. Nymphs were significantly more likely to be infected with Bo. burgdorferi if they were infected with Ba. microti, whereas adult females were significantly more likely to be infected with Bo. burgdorferi if they were infected with A. phagocytophilum. Our study suggests that the infection prevalence of Bo. burgdorferi is not independent of other co-circulating pathogens and that there is a substantially higher infection of Bo. miyamotoi in I. scapularis females compared with nymphs in this study. High prevalence of infection and co-infection with multiple pathogens in I. scapularis highlights the public health consequences in Connecticut, a state endemic for Lyme and other tick-borne diseases.

Clinical, imaging, and molecular analysis of pediatric pontine tumors lacking characteristic imaging features of DIPG.

Diffuse intrinsic pontine glioma (DIPG) is most commonly diagnosed based on imaging criteria, with biopsy often reserved for pontine tumors with imaging features not typical for DIPG (atypical DIPG, 'aDIPG'). The histopathologic and molecular spectra of the clinical entity aDIPG remain to be studied systematically. In this study, thirty-three patients with newly diagnosed pontine-centered tumors with imaging inconsistent with DIPG for whom a pathologic diagnosis was subsequently obtained were included. Neoplasms were characterized by routine histology, immunohistochemistry, interphase fluorescence in situ hybridization, Sanger and next-generation DNA/RNA sequencing, and genome-wide DNA methylome profiling. Clinicopathologic features and survival outcomes were analyzed and compared to those of a contemporary cohort with imaging features consistent with DIPG (typical DIPG, 'tDIPG'). Blinded retrospective neuroimaging review assessed the consistency of the initial imaging-based diagnosis and correlation with histopathology. WHO grade II-IV infiltrating gliomas were observed in 54.6% of the cases; the remaining were low-grade gliomas/glioneuronal tumors or CNS embryonal tumors. Histone H3 K27M mutation, identified in 36% of the cases, was the major prognostic determinant. H3 K27M-mutant aDIPG and H3 K27M-mutant tDIPG had similar methylome profiles but clustered separately from diffuse midline gliomas of the diencephalon and spinal cord. In the aDIPG cohort, clinicoradiographic features did not differ by H3 status, yet significant differences in clinical and imaging features were observed between aDIPG without H3 K27M mutation and tDIPG. Neuroimaging review revealed discordance between the classification of aDIPG and tDIPG and did not correlate with the histology of glial/glioneuronal tumors or tumor grade. One patient (3.1%) developed persistent neurologic deficits after surgery; there were no surgery-related deaths. Our study demonstrates that surgical sampling of aDIPG is well-tolerated and provides significant diagnostic, therapeutic, and prognostic implications, and that neuroimaging alone is insufficient to distinguish aDIPG from tDIPG. H3 K27M-mutant aDIPG is epigenetically and clinically similar to H3 K27M-mutant tDIPG.

An enquiry into antileishmanial activity and quantitative analysis of polyhydroxylated steroidal saponins from Solanum paniculatum L. leaves.

Solanum paniculatum L. is species whose fruits are widely consumed in Brazil as a tonic beverage with higher content of steroidal saponins. In this work, we developed an analytical method for the quantification of the eight saponins present in the 70 % ethanol extract from the leaves using ultra-high-performance liquid chromatography coupled to mass spectrometry (UHPLC-MS). Besides, the eight spirostanic saponins were screened for in vitro antileishmanial activity against promastigote and amastigote forms of Leishmania (L.) amazonensis. Substances 1, 2 and 3 were found to be the most active compounds, with inhibitory concentration (IC50) values of 8.51 ± 4.38, 10.75 ± 6.85 and 10.45 ± 4.21 µM, respectively, against promastigote forms and effective concentration (EC50) values of >25, 17.73 ± 0.99 and 19.57 ± 0.84 µM, respectively, against amastigote forms. The cytotoxic test with compounds 1-3 evidenced low toxicity in murine macrophage cells, with values above 50 µM at concentration lower than 25 µM. These findings show that saponins 1-3 should be evaluated in further studies for the treatment of cutaneous leishmaniasis.

Glucuronidation of Methylated Quercetin Derivatives: Chemical and Biochemical Approaches.

Botanical supplements derived from grapes are functional in animal model systems for the amelioration of neurological conditions, including cognitive impairment. Rats fed with grape extracts accumulate 3'-O-methyl-quercetin-3-O-ß-d-glucuronide (3) in their brains, suggesting 3 as a potential therapeutic agent. To develop methods for the synthesis of 3 and the related 4'-O-methyl-quercetin-7-O-ß-d-glucuronide (4), 3-O-methyl-quercetin-3'-O-ß-d-glucuronide (5), and 4'-O-methyl-quercetin-3'-O-ß-d-glucuronide (6), which are not found in the brain, we have evaluated both enzymatic semisynthesis and full chemical synthetic approaches. Biocatalysis by mammalian UDP-glucuronosyltransferases generated multiple glucuronidated products from 4'-O-methylquercetin, and is not cost-effective. Chemical synthetic methods, on the other hand, provided good results; 3, 5, and 6 were obtained in six steps at 12, 18, and 30% overall yield, respectively, while 4 was synthesized in five steps at 34% overall yield. A mechanistic study on the unexpected regioselectivity observed in the quercetin glucuronide synthetic steps is also presented.

Deep multiomics profiling of brain tumors identifies signaling networks downstream of cancer driver genes.

High throughput omics approaches provide an unprecedented opportunity for dissecting molecular mechanisms in cancer biology. Here we present deep profiling of whole proteome, phosphoproteome and transcriptome in two high-grade glioma (HGG) mouse models driven by mutated RTK oncogenes, PDGFRA and NTRK1, analyzing 13,860 proteins and 30,431 phosphosites by mass spectrometry. Systems biology approaches identify numerous master regulators, including 41 kinases and 23 transcription factors. Pathway activity computation and mouse survival indicate the NTRK1 mutation induces a higher activation of AKT downstream targets including MYC and JUN, drives a positive feedback loop to up-regulate multiple other RTKs, and confers higher oncogenic potency than the PDGFRA mutation. A mini-gRNA library CRISPR-Cas9 validation screening shows 56% of tested master regulators are important for the viability of NTRK-driven HGG cells, including TFs (Myc and Jun) and metabolic kinases (AMPKa1 and AMPKa2), confirming the validity of the multiomics integrative approaches, and providing novel tumor vulnerabilities.

Conformational Effects of [Ni2 (µ-ArS)2 ] Cores on Their Electrocatalytic Activity.

Two nickel complexes supported by tridentate NS2 ligands, [Ni2 (κ-N,S,S,S'-NPh {CH2 (MeC6 H2 R')S}2 )2 ] (1; R'=3,5-(CF3 )2 C6 H3 ) and [Ni2 (κ-N,S,S,S'-NiBu {CH2 C6 H4 S}2 )2 ] (2), were prepared as bioinspired models of the active site of [NiFe] hydrogenases. The solid-state structure of 1 reveals that the [Ni2 (µ-ArS)2 ] core is bent, with the planes of the nickel centers at a hinge angle of 81.3(5)°, whereas 2 shows a coplanar arrangement between both nickel(II) ions in the dimeric structure. Complex 1 electrocatalyzes proton reduction from CF3 COOH at -1.93 (overpotential of 1.04 V, with icat /ip ≈21.8) and -1.47 V (overpotential of 580 mV, with icat /ip ≈5.9) versus the ferrocene/ferrocenium redox couple. The electrochemical behavior of 1 relative to that of 2 may be related to the bent [Ni2 (µ-ArS)2 ] core, which allows proximity of the two Ni⋅⋅⋅Ni centers at 2.730(8) Å; thus possibly favoring H+ reduction. In contrast, the planar [Ni2 (µ-ArS)2 ] core of 2 results in a Ni⋅⋅⋅Ni distance of 3.364(4) Šand is unstable in the presence of acid.

Desigualdades territoriales de la tuberculosis entre los municipios de La Habana, 2015 y 2016-2020 / Territorial Inequalities of Tuberculosis between the Municipalities of Havana, 2015 and 2016-2020

La Habana notifica el 30% de casos de tuberculosis (TB) en Cuba. Objetivo: valorar las desigualdades territoriales en la ocurrencia de TB en los municipios de La Habana, 2015 y 2016-2020 según algunos determinantes intermedios e individuales. Métodos: estudio ecológico de series temporales sobre las notificaciones de TB en 2015 y 2016-2020. La fuente fue la base de vigilancia del MINSAP. Calculamos la tasa del periodo (TP), la referencia fue la menor, estimamos las diferencias absolutas y relativas, y el Riesgo Atribuible Poblacional Porcentual. Estimamos la TP en menores y mayores de 19 años. Según la TP, propusimos dos escenarios: -reducción 5% anual a todos los municipios, según Hitos de OMS y -reducción discriminada 5% anual a municipios con TP < 9 y 7% los ≥ 9/100.000. Calculamos dos índices de dispersión y proporciones de TB en VIH y reclusos. Categorizamos los municipios según metas renovadas hacia la eliminación. Resultados: el municipio de referencia fue Playa (5,5), la diferencia relativa fue 3,3 veces más en Habana Vieja. Cotorro y Guanabacoa no aportaron casos pediátricos. El segundo escenario tuvo desigualdad moderada. Predominaron los TB-VIH, en Habana Vieja (13,1%). 11/15 municipios categorizaron en control satisfactorio. Conclusiones: las desigualdades en general son moderadas en los municipios Habana, no obstante, las tasas de TB infantil son muy bajas en los territorios, dos de ellos alcanzaron la meta de eliminación. La coinfección TB/VIH concentra las mayores proporciones en algunos municipios. (AU);

Havana notifies 30% of cases of tuberculosis (TB) in Cuba. Objective: to assess the territorial inequalities in the occurrence of TB in the municipalities of Havana, 2015 and 2016-2020 according to some intermediate and individual determinants. Methods: ecological study of time series on TB notifications in 2015 and 2016-2020. The source was the MINSAP surveillance base. We calculated the period rate (TP), the reference was the lowest, we estimated the absolute and relative differences, and the Percentage Population Attributable Risk. We estimate the PT in children under and over 19 years of age. According to the TP, we proposed two scenarios: -5% annual reduction to all municipalities, according to WHO Milestones and -discriminated 5% annual reduction to municipalities with TP < 9 and 7% those ≥ 9/100,000. We calculated two dispersion indices and proportions of TB in HIV and inmates. We categorized the municipalities according to renewed goals towards elimination. Results: the reference municipality was Playa (5.5), the relative difference was 3.3 times more in Habana Vieja. Cotorro and Guanabacoa did not provide pediatric cases. The second scenario had moderate inequality. TB-HIV predominated in Old Havana (13.1%). 11/15 municipalities categorized in satisfactory control. Conclusions: inequalities were generally moderate in the Havana municipalities, however, the rates of childhood TB are very low in the territories, two of them reached the elimination goal. TB/HIV coinfection concentrates the highest proportions in some municipalities. (AU)