A mild and efficient method for the preparation of 3-(2'-Aminoaryl)pyrazoles from 4-chloroquinolines

We describe a mild and efficient method for the formation of 3-(2'-aminoaryl)pyrazoles in excellent yields from reactions of 4-chloroquinolines with hydrazine. These heterocyclic ring opening reactions occur under much milder conditions then previously described

TMEM106B is a genetic modifier of frontotemporal lobar degeneration with C9orf72 hexanucleotide repeat expansions

Hexanucleotide repeat expansions in chromosome 9 open reading frame 72 (C9orf72) have recently been linked to frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis, and may be the most common genetic cause of both neurodegenerative diseases. Genetic variants at TMEM106B influence risk for the most common neuropathological subtype of FTLD, characterized by inclusions of TAR DNA-binding protein of 43 kDa (FTLD-TDP). Previous reports have shown that TMEM106B is a genetic modifier of FTLD-TDP caused by progranulin (GRN) mutations, with the major (risk) allele of rs1990622 associating with earlier age at onset of disease. Here, we report that rs1990622 genotype affects age at death in a single-site discovery cohort of FTLD patients with C9orf72 expansions (n = 14), with the major allele correlated with later age at death (p = 0.024). We replicate this modifier effect in a 30-site international neuropathological cohort of FTLD-TDP patients with C9orf72 expansions (n = 75), again finding that the major allele associates with later age at death (p = 0.016), as well as later age at onset (p = 0.019). In contrast, TMEM106B genotype does not affect age at onset or death in 241 FTLD-TDP cases negative for GRN mutations or C9orf72 expansions. Thus, TMEM106B is a genetic modifier of FTLD with C9orf72 expansions. Intriguingly, the genotype that confers increased risk for developing FTLD-TDP (major, or T, allele of rs1990622) is associated with later age at onset and death in C9orf72 expansion carriers, providing an example of sign epistasis in human neurodegenerative disease

Colorectal Cancer Stage at Diagnosis Before vs During the COVID-19 Pandemic in Italy

IMPORTANCE Delays in screening programs and the reluctance of patients to seek medical attention because of the outbreak of SARS-CoV-2 could be associated with the risk of more advanced colorectal cancers at diagnosis. OBJECTIVE To evaluate whether the SARS-CoV-2 pandemic was associated with more advanced oncologic stage and change in clinical presentation for patients with colorectal cancer. DESIGN, SETTING, AND PARTICIPANTS This retrospective, multicenter cohort study included all 17 938 adult patients who underwent surgery for colorectal cancer from March 1, 2020, to December 31, 2021 (pandemic period), and from January 1, 2018, to February 29, 2020 (prepandemic period), in 81 participating centers in Italy, including tertiary centers and community hospitals. Follow-up was 30 days from surgery. EXPOSURES Any type of surgical procedure for colorectal cancer, including explorative surgery, palliative procedures, and atypical or segmental resections. MAIN OUTCOMES AND MEASURES The primary outcome was advanced stage of colorectal cancer at diagnosis. Secondary outcomes were distant metastasis, T4 stage, aggressive biology (defined as cancer with at least 1 of the following characteristics: signet ring cells, mucinous tumor, budding, lymphovascular invasion, perineural invasion, and lymphangitis), stenotic lesion, emergency surgery, and palliative surgery. The independent association between the pandemic period and the outcomes was assessed using multivariate random-effects logistic regression, with hospital as the cluster variable. RESULTS A total of 17 938 patients (10 007 men [55.8%]; mean [SD] age, 70.6 [12.2] years) underwent surgery for colorectal cancer: 7796 (43.5%) during the pandemic period and 10 142 (56.5%) during the prepandemic period. Logistic regression indicated that the pandemic period was significantly associated with an increased rate of advanced-stage colorectal cancer (odds ratio [OR], 1.07; 95%CI, 1.01-1.13; P = .03), aggressive biology (OR, 1.32; 95%CI, 1.15-1.53; P < .001), and stenotic lesions (OR, 1.15; 95%CI, 1.01-1.31; P = .03). CONCLUSIONS AND RELEVANCE This cohort study suggests a significant association between the SARS-CoV-2 pandemic and the risk of a more advanced oncologic stage at diagnosis among patients undergoing surgery for colorectal cancer and might indicate a potential reduction of survival for these patients

N-(4-Chlorophenyl)-5-(4,5-dihydro-1H-imidazol-2-yl)thieno[2,3-b]pyridin-4-amine

In the title compound, C16H13ClN4S, the thienopyridine fused-ring system is nearly planar (r.m.s. deviation = 0.0333 Å) and forms a dihedral angle of 4.4 (3)° with the attached dihydroimidazole ring (r.m.s. deviation = 0.0429 Å) allowing for the formation of an intramolecular (exocyclic amine)N—H...N(imine) hydrogen bond. The benzene rings of the disordered (50:50) –N(H)—C6H4Cl residue form dihedral angles of 59.1 (3) and 50.59 (15)° with the fused ring system. In the crystal, (imidazole amine)N—H...N(pyridine) hydrogen bonds lead to a supramolecular helical chain along the b axis. The chains assemble into layers (ab plane) with inter-digitation of the chlorobenzene rings which results in weak C—H...Cl interactions in the c-axis direction

4-(1H-Pyrazol-1-yl) Benzenesulfonamide Derivatives: Identifying New Active Antileishmanial Structures for Use against a Neglected Disease

Submitted by Sandra Infurna ([email protected]) on 2018-11-06T10:52:31Z No. of bitstreams: 1 marilene_cavalheiro_etal_IOC_2012.pdf: 293836 bytes, checksum: 67e35006a093a0701d7d6684125401b8 (MD5)Approved for entry into archive by Sandra Infurna ([email protected]) on 2018-11-06T11:04:44Z (GMT) No. of bitstreams: 1 marilene_cavalheiro_etal_IOC_2012.pdf: 293836 bytes, checksum: 67e35006a093a0701d7d6684125401b8 (MD5)Made available in DSpace on 2018-11-06T11:04:44Z (GMT). No. of bitstreams: 1 marilene_cavalheiro_etal_IOC_2012.pdf: 293836 bytes, checksum: 67e35006a093a0701d7d6684125401b8 (MD5) Previous issue date: 2012Universidade Federal Fluminense. Instituto de Química. Programa de Pós-Graduação em Química. Niterói, RJ, Brasil.Universidade Federal Fluminense. Instituto de Química. Programa de Pós-Graduação em Química. Niterói, RJ, Brasil.Universidade Federal Fluminense. Instituto de Biologia. Programa de Pós-graduação em Ciências e Biotecnologia. Niterói, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Bioquímica de Tripanosomatídeos. Rio de Janeiro, RJ. Brasil.Universidade Federal Fluminense. Instituto de Química. Programa de Pós-Graduação em Química. Niterói, RJ, Brasil.Universidade Federal Fluminense. Instituto de Química. Programa de Pós-Graduação em Química. Niterói, RJ, Brasil.Universidade Federal do Rio de Janeiro. Faculdade de Farmácia. ModMolQSAR. Rio de Janeiro, RJ, Brasil.Universidade Federal Fluminense. Instituto de Química. Programa de Pós-Graduação em Química. Niterói, RJ, Brasil.Universidade Federal Fluminense. Instituto de Química. Programa de Pós-Graduação em Química. Niterói, RJ, Brasil.Universidade Federal do Rio de Janeiro. Faculdade de Farmácia. ModMolQSAR. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Bioquímica de Tripanosomatídeos. Rio de Janeiro, RJ. Brasil.Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Bioquímica de Tripanosomatídeos. Rio de Janeiro, RJ. Brasil.Universidade Federal Fluminense. Instituto de Biologia. Programa de Pós-graduação em Ciências e Biotecnologia. Niterói, RJ, Brasil.Leishmaniasis is a neglected disease responsible for about 56,000 deaths every year. Despite its importance, there are no effective, safe and proper treatments for leishmaniasis due to strain resistance and/or drug side-effects. In this work we report the synthesis, molecular modeling, cytotoxicity and the antileishmanial profile of a series of 4-(1H-pyrazol-1-yl)benzenesulfonamides. Our experimental data showed an active profile for some compounds against Leishmania infantum and Leishmania amazonensis. The profile of two compounds against L. infantum was similar to that of pentamidine, but with lower cytotoxicity. Molecular modeling evaluation indicated that changes in electronic regions, orientation as well as lipophilicity of the derivatives were areas to improve the interaction with the parasitic target. Overall the compounds represent feasible prototypes for designing new molecules against L. infantum and L. amazonensis