Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Identification of Novel Agents for the Treatment of Brain Metastases of Breast Cancer

Background—Brain cancer from metastasized breast cancer has a high mortality rate in women. The treatment of lesions is hampered in large part by the blood-brain barrier (BBB), which prevents adequate distribution of anti-cancer compounds to brain metastases. Method—In this study we used a novel screening method to identify candidate molecules that are well-suited to utilizing the BBB choline transporter for distribution into the brain parenchyma. Results—From our screen we identified two compounds, Ch-1 and Ch-2 that were able to reduce the brain tumor burden in a murine mouse model of brain metastasis of breast cancer. These compounds also significantly increased the survival of mice by more than 10 days. Mechanistic studies indicated that Ch-1 is able to prevent the activation of the pro-survival mitogen-activated kinases (MAPKs) by osteoactivin (OA; Glycoprotein nonmetastatic melanoma protein B GPNMB). Conclusion—The results from this study show that nutrient transporter virtual screening is a viable novel alternative to traditional drug screening programs to identify anti-cancer compounds for the treatment of brain cancers

Effect of Extended Benzannelation Orientation on Bergman and Related Cyclizations of Isomeric Quinoxalenediynes

A combined computational and experimental study was conducted to examine the effect of extended benzannelation orientation on C¹–C⁵ and C¹–C⁶ cyclization of acyclic quinoxalenediynes. Calculations (mPW1PW91/cc-pVTZ//mPW1PW91/6-31G­(d,p)) on terminal and phenylethynyl-substituted 5,6-diethynylquinoxaline and 6,7-diethynylquinoxaline showed C¹–C⁶ Bergman cyclization as the favored thermodynamic reaction pathway, with larger C¹–C⁶ preference for the angular quinoxalenediynes due to gain of a new aromatic sextet. Kinetic studies, as a function of 1,4-cyclohexadiene concentration, revealed retro-Bergman ring opening predominates over hydrogen atom abstraction (<i>k</i>_–1 > <i>k</i>₂) for 6,7-diethynylquinoxaline while 5,6-diethynylquinoxaline undergoes irreversible Bergman cyclization indicative of a large retro-Bergman ring opening barrier (<i>k</i>₂ > <i>k</i>_–1). The effect of extended linear versus angular benzannelation on reaction pathway shows in the contrasting photocyclizations of phenylethynyl derivatives. While angular 5,6-diethynylquinoxalines gave exclusive C¹–C⁶ photocyclization, linear 6,7-diethynylquinoxaline afforded C¹–C⁵ fulvene products. Computed singlet–triplet gaps and biradical stabilization energies indicated weak interaction between the nitrogen lone pair and proximal radical center in angular 5,6-diethynylquinoxalines. The overall data indicates extended angular benzannelation effectively renders Bergman cyclization irreversible due to favorable aromatic stabilization energy, while extended linear benzannelation results in increased retro-Bergman ring opening, allowing C¹–C⁵ cyclization to become a competitive reaction channel

Reabilitação fonatória do laringectomizado total: utilização de toxina botulínica na voz tráqueo-esofágica com prótese fonatória Botulinum toxin in speech rehabilitation with voice prosthesis after total laryngectomy

Na punção tráqueo-esofágica(PTE) é realizada miotomia do músculo constritor da faringe, mas sua necessidade é entre 9% a 79% dos pacientes. Sua realização pode aumentar as taxas de fístula salivar no pós-operatório. A aplicação da TB é ambulatorial. OBJETIVO: Análise da eficácia da aplicação de toxina botulínica (TB), na reabilitação do laringectomizado total com voz tráqueo-esofágica(VTE) com espasmo(E) do segmento faringo-esofágico (SFE) sem miotomia. MATERIAL E MÉTODOS: Análise de oito pacientes submetidos à laringectomia total (LT), reabilitados com VTE com prótese fonatória (PF), esforço para emissão de voz devido à E do SFE. Todos submetidos a tratamento dessa alteração motora com injeção de 100 unidades de TB no SFE. A avaliação constituiu-se de análise perceptiva de voz, videofluoroscopia (VF) do SFE, análise acústica de voz e manometria computadorizada (MC) do SFE, todos antes e após aplicação de TB. DESENHO DE ESTUDO: Estudo prospectivo. RESULTADOS: Houve diminuição na pressão à MC do SFE, após a injeção de TB. Análise acústica demonstrou melhora na qualidade de harmônicos após o tratamento. Houve emissão de voz sem esforço e melhora do E após o uso da TB. CONCLUSÃO: Todos os pacientes com E do SFE apresentaram melhora vocal após aplicação da TB neste SFE.<br>In tracheo esophageal puncture (TEP), we carry out a myotomy of the pharynx constrictor muscle; however, about 9 to 79% of patients need such procedure. The consequence of such procedure is an increase in salivary fistula rates in the postoperative. Botulin toxin is used in an outpatient basis. AIM: analyzing the efficacy of botulin toxin (BT) use in the rehabilitation of totally laryngectomized patients with tracheo-esophageal voice (TEV) with spasms (S) of the pharyngo-esophageal segment (PES) without myotomy. MATERIALS AND METHODS: We analyzed eight patients submitted to total laryngectomy (TL), rehabilitated with TEV, with speech prosthesis (SP) and struggle to utter voice because of PES spasms. They were all submitted to treatment of such motor alteration with the injection of 100 units of BT in the PES. The evaluation was based on perceptive voice analysis, video fluoroscopy (VF) of the PES, acoustic voice analysis and computerized manometry (CM) of the PES, all before and after BT injection. STUDY DESIGN: prospective. Results: There was a reduction in PES CM pressure after BT injection. Acoustic analysis showed an improvement in harmonics quality after treatment. There was smoother voice utterance and spasm improvement after BT. CONCLUSION: all patients with PES spasms presented vocal improvement after BT injection in the PES

Uso de manometria computadorizada para estudo do espasmo do segmento faringoesofágico em pacientes com voz traqueoesofágica inadequada antes e após aplicação de toxina botulínica Computerized manometry use to evaluate spasm in pharyngoesophageal segment in patients with poor tracheoesophageal speech before and after treatment with botulinum toxin

Voz traqueoesofágica (VTE) com prótese fonatória (PF) é método eficaz e reproduzível na reabilitação vocal após laringectomia total (LT), impedida pelo espasmo do segmento faringoesofágico (SFE). A manometria computadorizada (MC) é novo método objetivo e direto de avaliação do SFE. OBJETIVO: Análise objetiva do espasmo do SFE, com MC, antes e após aplicação de toxina botulínica (TB). DESENHO DO ESTUDO: Prospectivo clínico. MATERIAL E MÉTODOS: Análise de oito pacientes consecutivos submetidos à LT com VTE e PF, sem emissão vocal, com espasmo do SFE à videofluoroscopia, considerado padrão ouro para detecção de espasmo. Todos trataram o espasmo com injeção de 100 unidades de TB no SFE. Avaliação constituiu-se de videofluoroscopia e MC do SFE, antes e após aplicação de TB. RESULTADOS: Houve diminuição na pressão do SFE à MC, após injeção de TB em todos. A média de pressão do SFE à MC, nos oito pacientes, antes da aplicação de TB foi de 25.36 mmHg e após foi de 14.31 mmHg (p=0,004). Houve emissão vocal sem esforço e melhora do espasmo do SFE à videofluoroscopia após o uso da TB. CONCLUSÃO: Foi observada diminuição na pressão do SFE após injeção da TB à MC em todos os pacientes, com melhora do espasmo à videofluoroscopia.<br>Tracheoesophageal voice (TEV) with voice prosthesis (VP) is an efficient and reproducible method used in vocal rehabilitation after total laryngectomy (TL), prevented by spasms in the pharyngoesophageal segment (PES). Computerized Manometry (CM) is a new, direct and objective method used to assess the PES. AIM: to carry out an objective analysis of the PES, with CM, before and after the injection of botulinum toxin (BT). STUDY DESIGN: clinical-prospective. MATERIALS AND METHODS: analysis of eight patients consecutively submitted to TL with TEV and VP, without vocal emission, with PES spasms seen through videofluoroscopy, considered the gold standard for spasm detection. All had their spasms treated with the injection of 100 units of BT in the PES. The assessment was based on PES videofluoroscopy and CM, before and after BT injection. RESULTS: There was a PES pressure reduction according to the CM after BT injection in all patients. The average pressure in the PES seen through the CM in eight patients before BT injection was 25.36 mmHg, and afterwards it dropped to 14.31 mmHg (p=0.004). There was vocal emission without stress and PES spasm improvement seen through the videolaryngoscopy after BT injection. CONCLUSION: We observed a reduction in PES pressure after BT injection, seen through CM in all the patients, with spasms improvement seen through videofluoroscopy