RESUMO
Objective:To evaluate the perioperative airway management process of nasal endoscopic surgery, and find clinical evidence for accelerating recovery and reducing respiratory complications. Methods:The perioperative airway management process for nasal endoscopic surgery was developed according to the patient's preoperative risk factors and preoperative pulmonary function. 512 patients who entered the airway management process from March 2019 to May 2020 were included. The improvement of pulmonary function and the occurrence of adverse respiratory events during the perioperative period were analyzed. Results:265 of 512 patients showed abnormal pulmonary function, including 203 cases with ventilatory dysfunction; 103 cases with positive bronchial provocation test; 59 cases with positive bronchodilation test. Patients with abnormal lung function were treated with aerosol inhalation for 3 to 5 days before surgery, the pulmonary function indicators were greatly improvedï¼P<0.01ï¼. After individualized airway management, patients were then treated with surgery, and there was no perioperative dyspnea event. Conclusion:Perioperative airway management can improve pulmonary function and reduce the risk of nasal endoscopic surgery.
Assuntos
Procedimentos Cirúrgicos Nasais , Nariz , Manuseio das Vias Aéreas , Endoscopia , Humanos , Pulmão , Complicações Pós-OperatóriasRESUMO
Circular RNAs (circRNAs) are implicated in the initiation and progress of several diseases, including cancer. However, the precise role of circRNAs in human nasopharyngeal carcinoma (NPC) remains unclear. In this research, we found a new circRNA hsa_circ_0001554 (circRANBP17), which was derived from the RAN binding protein 17 (RANBP17). Our qRT-PCR data found that circRANBP17 expression was up-regulated in NPC tissue and cells. Functional silencing studies revealed that circRANBP17 inhibited NPC cell proliferation and invasion in vitro, and circRANBP17 down-regulation also reduced tumor growth in nude mice. MiR-635 was demonstrated as a direct target of circRANBP17; circRANBP17 up-regulated RUNX2 expression levels by sponging miR-635, thereby promoting NPC proliferation and invasion. Thus, our data provide the evidence for the first time that circRANBP17 is a new onco-circRNA via miR-635/RUNX2 axis regulation, and may function as a novel therapeutic target for NPC treatment.
RESUMO
Conjugated polymers have excellent properties and can be used in photothermal therapy (PTT). Nevertheless, the concept to design and optimize the photothermal performance by cooperative non-bonding interactions is still in its infancy. Herein, a series of diketopyrrolopyrrole (DPP) derivatives containing chalcogen and fluorine atoms were synthesized to reveal how intra- and intermolecular interactions affect the therapeutic performance of cancer in vitro and in vivo. The synergistic π-π and FH interactions facilitate fluorine and selenium-substituted DPP-SeF to elevate their photothermal conversion efficiency up to 62% from 32% without fluorine and selenium-substituted DPP-SS, and the half-maximal inhibitory concentration drops to â¼8.36 µg mL-1 for DPP-SeF from 15.14 µg mL-1 for DPP-SS on A549 cells under 808 nm light irradiation. More interestingly, efficient tumor killing ability and magnificent biocompatibility on an animal model of A549 transplanted tumor reassert that DPP-SeF nanoagents have immense potential as photoacoustic/PTT agents. Thus, this work presents an efficient phototherapeutic agent, and meanwhile demonstrates the facile concept of accessing the synergistic effect of non-bonding interactions to promote antitumor efficiency by ingenious molecular engineering.
Assuntos
Nanopartículas , Técnicas Fotoacústicas , Animais , Fototerapia , Terapia Fototérmica , PirróisRESUMO
Two related series of selective norepinephrine reuptake inhibitors were synthesized based on 3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide or 3,4-dihydrosulfostyril cores, and screened for monoamine reuptake inhibition. Structure-activity relationships were determined for the series' in vitro potency and selectivity versus serotonin or dopamine transporter inhibition, and analogs based on both cores were identified as potent and selective NRIs. The 3,4-dihydrosulfostyril series was further tested for microsome stability, and compound 16j, which was optimized for both potency and stability, showed efficacy in an in vivo model of thermoregulatory dysfunction.
Assuntos
Inibidores da Captação Adrenérgica/química , Benzotiadiazinas/química , Óxidos S-Cíclicos/química , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/química , Norepinefrina/metabolismo , Tiazinas/química , Inibidores da Captação Adrenérgica/síntese química , Inibidores da Captação Adrenérgica/farmacologia , Animais , Transporte Biológico , Óxidos S-Cíclicos/síntese química , Óxidos S-Cíclicos/farmacologia , Humanos , Microssomos Hepáticos/metabolismo , Modelos Animais , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/metabolismo , Ratos , Relação Estrutura-Atividade , Tiazinas/síntese química , Tiazinas/farmacologiaRESUMO
Non-steroidal 1-methyl-1H-pyrrole-2-carbonitrile containing tetrahydronaphthalenes and acyclic derivatives were evaluated as novel series of progesterone receptor (PR) antagonists using the T47D cell alkaline phosphatase assay. Moderate to potent PR antagonists were achieved with these scaffolds. Several compounds (e.g., 15 and 20) demonstrated low nanomolar PR antagonist potency and good selectivity versus other steroid receptors.
Assuntos
Pirróis/química , Receptores de Progesterona/antagonistas & inibidores , Tetra-Hidronaftalenos/química , Fosfatase Alcalina/metabolismo , Linhagem Celular Tumoral , Humanos , Receptores de Progesterona/metabolismo , Relação Estrutura-Atividade , Tetra-Hidronaftalenos/síntese química , Tetra-Hidronaftalenos/farmacologiaRESUMO
We reported a case of a 43-year-old female patient with nasal Sjogren's syndromeï¼SSï¼. She complained of dry and tingling nose for 5 months. Physical examination: bilateral nasal stenosis, swelling of the mucosa at the front of the nasal septum, dry oral mucosa, and strawberry tongue. Sinus CT showed: bilateral nasal cavity stenosis, nasal septal mucosa and bilateral nasal mucosa hypertrophy. Salivary gland dynamic imaging: the maximum excretion percentage of the left salivary gland is 4.05%, and the maximum excretion percentage of the right salivary gland is 1.81%. Labial gland biopsy showed that the salivary gland lobular structure existed, and multiple lymphocyte fociï¼>50/each fociï¼ were seen in the focal interstitium, which was consistent with the labial gland performance of SS. Immunohistochemistry showed: CD3+, CD20+, AE1/AE3+, Ki-67+, IgG+. After symptomatic treatment, the patient's dry nose and tingling symptoms disappeared. The swelling of the nasal mucosa disappeared, and the bilateral nasal cavity was well ventilated. Follow-up for half a year, no symptoms of nasal manifestations about Sjogren's syndrome has occurred.
Assuntos
Síndrome de Sjogren , Adulto , Feminino , Humanos , Cavidade Nasal/diagnóstico por imagem , Mucosa Nasal , Septo Nasal , Glândulas SalivaresRESUMO
Growing evidence has demonstrated that in tumor progression, circular RNAs (circRNAs) play important roles. However, the roles of circRNAs in nasopharyngeal carcinoma (NPC) have not been fully elucidated. In this study, it was demonstrated that that hsa_circ_0033074 (circSERPINA3) expression was found to be significantly upregulated in NPC tissues and cell lines. CircSERPINA3 inhibition significantly attenuated the invasion and proliferation abilities of NPC cells. The mechanism by which circSERPINA3 interacted with miR-944 was identified and MDM2 was demonstrated to function as a target gene of miR-944. Rescue experiments showed that miR-944 inhibitors or MDM2 overexpression reserved the effects of circSERPINA3 knockdown on NPC progression. Therefore, our study uncovered the circSERPINA3/miR-944/MDM2 axis in NPC, which may be a potential NPC therapeutic target.
RESUMO
Objective:To investigate the perioperative management of endoscopic nasal surgery in patients with cardiovascular disease. Method:Sixty-two patients with cardiovascular disease underwent endoscopic sinus surgery. Individualized medical treatment was used according to the patient's perioperative condition, followed by functional endoscopic surgery. Result:Two patients had cardiovascular complications after endoscopic surgery and were transferred to internal medicine. One patient developed massive hemorrhage after operation, and hemostasis was performed again under nasal endoscopic surgery. The remaining 59 patients had no adverse cardiovascular events after operation. There are no complications such as massive hemorrhage, visual impairment, and cerebrospinal fluid rhinorrhea. All patients were followed up for more than half a year, 39 casesï¼62.90%ï¼ of nasal sinus disease were completely controlled, 18 casesï¼29.03%ï¼ of nasal sinus disease were partially controlled, and the effective rate was 91.94%. Conclusion:Reasonable perioperative management measures can reduce the risk of nasal sinus surgery in patients with cardiovascular disease, ensure the successfully implementation of surgery and achieve a successful prognosis.
Assuntos
Doenças Cardiovasculares , Procedimentos Cirúrgicos Nasais , Seios Paranasais , Endoscopia , Humanos , NarizRESUMO
Objective:To investigate the clinical characteristics and prognostic factors of adult rhabdomyosarcomaï¼RMSï¼ of nasal cavity and sinus. Method:There were 35 adult patients with RMS, including 22 with embryonal type and 13 with acinar type. Surgery + chemoradiotherapyï¼17 casesï¼, surgery + radiotherapyï¼6 casesï¼, surgery + chemotherapyï¼7 casesï¼ï¼4 cases of seed implantation after surgery and chemotherapyï¼; Five patients were treated with antitumor drugs instead of surgery. Result:The study follow-up 9-62 months, adult nasal sinuses RMS total 5 years survival rate was 2.9%, among them the IRS stage>â ¡ period, the infiltration of the skull base tumor, local lymph node metastasis, tumor diameter of 5 cm or more, 50% or higher Ki-67 are poor prognosis factor. Conclusion:RMS in nasal cavity and sinus are mostly embryonal type in adults, and the 5-year overall survival rate is low, which is related to larger primary tumor volume, local lymph node metastasis, skull base infiltration and higher ki-67 ratio at the first diagnosis in adults.
Assuntos
Neoplasias dos Seios Paranasais , Seios Paranasais , Rabdomiossarcoma , Adulto , Quimiorradioterapia , Humanos , Cavidade Nasal , Prognóstico , Estudos RetrospectivosRESUMO
Novel 5-aryl indanones, inden-1-one oximes, and inden-1-ols were synthesized and evaluated as progesterone receptor (PR) modulators using the T47D cell alkaline phosphatase assay. Both PR agonists and antagonists were achieved with appropriate 3- and 5-substitution from indanones and inden-1-ols while inden-1-one oximes provided only PR antagonists. Several compounds such as 10 and 11 demonstrated potent in vitro PR agonist potency similar to that of steroidal progesterone (1). In addition, a number of compounds (e.g., 12, 13, 17, 18) showed potent PR antagonist activity indicating the indanones and derivatives are promising PR modulator templates.
Assuntos
Indanos/farmacologia , Receptores de Progesterona/agonistas , Receptores de Progesterona/antagonistas & inibidores , Desenho de Fármacos , Indanos/síntese química , Indanos/química , Estrutura Molecular , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
A series of 3-(arylamino)-3-phenylpropan-2-olamines was prepared and screened for their ability to inhibit monoamine reuptake. A number of analogues displayed significant dual norepinephrine and serotonin reuptake inhibition. Compounds in this class exhibited minimal affinity for the dopamine transporter.
Assuntos
Química Farmacêutica/métodos , Proteínas da Membrana Plasmática de Transporte de Dopamina/antagonistas & inibidores , Norepinefrina/antagonistas & inibidores , Propanolaminas/síntese química , Inibidores Seletivos de Recaptação de Serotonina/síntese química , Inibidores da Captação Adrenérgica/farmacologia , Animais , Cães , Proteínas da Membrana Plasmática de Transporte de Dopamina/química , Desenho de Fármacos , Humanos , Concentração Inibidora 50 , Ligantes , Modelos Químicos , Propanolaminas/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Relação Estrutura-AtividadeRESUMO
The SAR of a series of 1-amino-3-(1H-indol-1-yl)-3-phenylpropan-2-ols as monoamine reuptake inhibitors, with a goal to improve both potency toward inhibiting the norepinephrine transporter and selectivity over the serotonin transporter, is reported. The effect of specific substitution on both the 3-phenyl group and the indole moiety were explored. This study led to the discovery of compound 20 which inhibited the norepinephrine transporter with an IC50 value of 4 nM while exhibiting 86-fold selectivity over the serotonin transporter.
Assuntos
Inibidores da Captação Adrenérgica/química , Indóis/química , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/antagonistas & inibidores , Inibidores da Captação Adrenérgica/síntese química , Inibidores da Captação Adrenérgica/farmacocinética , Animais , Humanos , Indóis/síntese química , Indóis/farmacocinética , Modelos Animais , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/metabolismo , Ratos , Proteínas da Membrana Plasmática de Transporte de Serotonina/química , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/síntese química , Inibidores Seletivos de Recaptação de Serotonina/química , Inibidores Seletivos de Recaptação de Serotonina/farmacocinética , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
We have continued to explore the 3,3-dialkyl-5-aryloxindole series of progesterone receptor (PR) modulators looking for new agents to be used in female healthcare: contraception, fibroids, endometriosis, and certain breast cancers. Previously we reported that subtle structural changes with this and related templates produced functional switches between agonist and antagonist properties ( Fensome et al. Biorg. Med. Chem. Lett. 2002, 12, 3487; 2003, 13, 1317 ). We herein report a new functional switch within the 5-(2-oxoindolin-5-yl)-1 H-pyrrole-2-carbonitrile class of compounds. We found that the size of the 3,3-dialkyl substituent is important for controlling the functional response; thus small groups (dimethyl) afford potent PR antagonists, whereas larger groups (spirocyclohexyl) are PR agonists. The product from our optimization activities in cell-based systems and also for kinetic properties in rodents and nonhuman primates was 5-(7-fluoro-3,3-dimethyl-2-oxo-2,3-dihydro-1 H-indol-5-yl)-1-methyl-1 H-pyrrole-2-carbonitrile 27 (WAY-255348), which demonstrated potent and robust activity on PR antagonist and contraceptive end points in the rat and also in cynomolgus and rhesus monkeys including ovulation inhibition, menses induction, and reproductive tract morphology.
Assuntos
Desenho de Fármacos , Indóis/química , Indóis/síntese química , Indóis/farmacologia , Pirróis/química , Receptores de Progesterona/antagonistas & inibidores , Administração Oral , Fosfatase Alcalina/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Feminino , Humanos , Macaca fascicularis , Macaca mulatta , Estrutura Molecular , Ovulação/efeitos dos fármacos , Oxindóis , Pirróis/síntese química , Pirróis/farmacologia , Ratos , Receptores de Progesterona/química , Estereoisomerismo , Relação Estrutura-Atividade , Células Tumorais CultivadasRESUMO
A series of novel 7-(5'-cyanopyrrol-2-yl) substituted benzo[1,4]oxazepin-2-ones were prepared and tested for their progesterone receptor (PR) agonist or antagonist activity in the alkaline phosphatase assay using the human T47D breast carcinoma cell line. Both PR agonists and antagonists were achieved with an appropriate choice of 5-substitution. Several analogs were potent PR agonists (e.g., 12 and 13) or PR antagonists (e.g., 18) with good selectivity over other steroid receptors.
Assuntos
Oxazepinas/síntese química , Oxazepinas/farmacologia , Receptores de Progesterona/agonistas , Receptores de Progesterona/antagonistas & inibidores , Técnicas de Química Combinatória , Humanos , Estrutura Molecular , Oxazepinas/química , Receptores de Progesterona/metabolismo , Relação Estrutura-AtividadeRESUMO
A series of novel 1- or 3-(3-amino-1-phenyl propyl)-1,3-dihydro-2H-benzimidazol-2-ones as selective norepinephrine reuptake inhibitors was discovered. Several compounds such as 15 and 20 showed good hNET potency. Compounds 15 and 20 also displayed excellent selectivity at hNET that appeared superior to those of reboxetine and atomoxetine (4 and 5).
Assuntos
Benzimidazóis/síntese química , Benzimidazóis/farmacologia , Inibidores da Captação de Neurotransmissores/síntese química , Inibidores da Captação de Neurotransmissores/farmacologia , Norepinefrina/antagonistas & inibidores , Benzimidazóis/química , Técnicas de Química Combinatória , Desenho de Fármacos , Humanos , Estrutura Molecular , Inibidores da Captação de Neurotransmissores/química , Norepinefrina/metabolismo , EstereoisomerismoRESUMO
Norepinephrine and serotonin play an important role in a wide variety of biological processes and are implicated in a number of neurological disorders. A novel class of 1-(3-amino-1-phenylpropyl)indolin-2-ones was designed and synthesized that displays potent norepinephrine reuptake inhibition while maintaining high selectivity (>100-fold) against the human serotonin and dopamine transporters.
Assuntos
Indóis/síntese química , Indóis/farmacologia , Inibidores da Captação de Neurotransmissores/síntese química , Inibidores da Captação de Neurotransmissores/farmacologia , Norepinefrina/antagonistas & inibidores , Humanos , Indóis/química , Estrutura Molecular , Inibidores da Captação de Neurotransmissores/química , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Progesterone receptor (PR) modulators have evolved both structurally and mechanistically over the past half-century. Classical steroidal PR agonists continue to play an important role in women's health such as in oral contraception and post-menopausal hormone therapy whereas steroid-based PR antagonists and selective PR modulators are being evaluated clinically in a wide range of gynecologic conditions. This review will focus primarily on the newer generation of PR modulators derived from structurally unique chemical scaffolds. For example, tanaproget (TNPR) is described as a non-steroidal PR agonist with high affinity and selectivity for the PR that is significantly more potent than many of its steroidal counterparts in a variety of pre-clinical efficacy models. Similarly, we present numerous examples of unique non-steroidal PR antagonists in various stages of characterization and development. A basic understanding of the structural determinants for high affinity binding of these new PR modulators to the PR ligand-binding domain (LBD) is also discussed. Finally, as the biology of the PR becomes further defined, we speculate on the future development of novel PR modulators.
Assuntos
Receptores de Progesterona , Benzoxazinas/química , Benzoxazinas/farmacologia , Estrenos/química , Estrenos/farmacologia , Feminino , Gonanos/química , Gonanos/farmacologia , Humanos , Indóis/química , Indóis/farmacologia , Oximas/química , Oximas/farmacologia , Progesterona/análogos & derivados , Progesterona/química , Progesterona/farmacologia , Isoformas de Proteínas , Receptores de Progesterona/agonistas , Receptores de Progesterona/antagonistas & inibidores , Receptores de Progesterona/química , Relação Estrutura-Atividade , Tionas/química , Tionas/farmacologiaRESUMO
Novel 7-aryl benzo[1,4]oxazepin-2-ones were synthesized and evaluated as non-steroidal progesterone receptor (PR) modulators. The structure activity relationship of 7-aryl benzo[1,4]oxazepinones was examined using the T47D cell alkaline phosphatase assay. A number of 7-aryl benzo[1,4]oxazepinones such as 10j and 10v demonstrated good in vitro potency (IC(50) of 10-30 nM) and selectivity (over 100-fold) at PR over other steroidal receptors such as glucocorticoid and androgen receptors (GR and AR). Several 7-aryl benzo[1,4]oxazepinones were active in the rat uterine decidualization model. In this in vivo model, compounds 10j and 10u were active at 3 mg/kg when dosed orally.
Assuntos
Benzazepinas/síntese química , Benzazepinas/farmacologia , Oxazepinas/síntese química , Oxazepinas/farmacologia , Receptores de Progesterona/antagonistas & inibidores , Fosfatase Alcalina/antagonistas & inibidores , Fosfatase Alcalina/metabolismo , Animais , Benzazepinas/química , Sítios de Ligação , Células COS , Chlorocebus aethiops , Feminino , Hidroxilação , Modelos Moleculares , Estrutura Molecular , Oxazepinas/química , Receptores de Progesterona/metabolismo , Relação Estrutura-AtividadeRESUMO
Tanaproget represents a potential first-in-class nonsteroidal PR agonist for contraception with improved safety and side effect profiles versus currently available steroidal oral contraceptives. Additional SAR, biological activity, and structural information from a tanaproget/hPR-LBD (hPR-LBD = human progesterone receptor ligand binding domain) cocrystal structure will also be presented.
Assuntos
Benzoxazinas/síntese química , Oxazinas/síntese química , Pirróis/síntese química , Receptores de Progesterona/agonistas , Tionas/síntese química , Fosfatase Alcalina/metabolismo , Animais , Área Sob a Curva , Benzoxazinas/química , Benzoxazinas/farmacologia , Ligação Competitiva , Linhagem Celular Tumoral , Anticoncepcionais Femininos/síntese química , Anticoncepcionais Femininos/química , Anticoncepcionais Femininos/farmacologia , Decídua/efeitos dos fármacos , Decídua/metabolismo , Feminino , Meia-Vida , Humanos , Técnicas In Vitro , Ligantes , Estrutura Molecular , Oxazinas/química , Oxazinas/farmacologia , Estrutura Terciária de Proteína , Pirróis/química , Pirróis/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de Progesterona/antagonistas & inibidores , Receptores de Progesterona/química , Relação Estrutura-Atividade , Tionas/química , Tionas/farmacologiaRESUMO
Progesterone, acting primarily via the progesterone receptor (PR), plays an essential role in the regulation of female reproduction. Steroidal progestins (i.e., PR agonists) are commonly used in women's health, such as in contraception and hormone therapy and for the treatment of gynecological disorders. Recent studies in women and in nonhuman primates also indicate that PR antagonists may have potential applications in contraception and for the treatment of reproductive disorders such as fibroids and endometriosis. Currently, all clinically available PR agonists and antagonists are steroidal compounds. They often cause various side effects due to their functional interactions with other steroid receptors or because of effects associated with their steroidal metabolites. In an effort to identify more receptor-selective and structurally diverse compounds that may render clinical advantages over steroidal PR ligands, numerous receptor-selective novel nonsteroidal PR agonists and antagonists have been discovered. This review focuses on the structure activity relationships and the biological profile of the nonsteroidal PR modulators discovered in the last decade.