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1.
Turk J Obstet Gynecol ; 21(2): 70-77, 2024 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-38853455

RESUMO

Objective: To evaluate the clinical outcomes of laparoscopic and hysteroscopic surgical approaches for treating symptomatic isthmocele and identify their associated factors. Materials and Methods: Forty-six patients with symptomatic isthmocele diagnosed using transvaginal saline infusion sonohysterography were enrolled in this prospective cohort study. Patients underwent either laparoscopic or hysteroscopic isthmoplasty based on their residual myometrial thicknesses and fertility desires and were subsequently followed by clinical and ultrasonographic examinations. Results: Twenty-two patients underwent laparoscopy and 24 underwent hysteroscopic surgery. At baseline, there was no significant difference in the mean age and years since the last cesarean section between the two groups. However, the hysteroscopy group had a higher mean parity and previous cesarean sections (p=0.00, 0.03). The most common symptoms were abnormal uterine bleeding, infertility, and dysmenorrhea. The mean baseline residual myometrial thickness was significantly higher in the laparoscopy group (p=0.00), and only laparoscopic surgery led to a significant increase in residual myometrial thickness in patients (p=0.00). Both procedures significantly reduced abnormal uterine bleeding (p=0.00), but only laparoscopy reduced infertility (p=0.00) and hysteroscopy reduced dysmenorrhea (p=0.03). Hysteroscopy showed better symptom resolution in younger patients (p=0.01), whereas age did not affect laparoscopy outcomes. Conclusion: Both approaches showed similar effectiveness in resolving abnormal uterine bleeding, with laparoscopy excelling in infertility resolution and hysteroscopy excelling in dysmenorrhea resolution.

2.
Int J Gynaecol Obstet ; 163(3): 965-971, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37350282

RESUMO

OBJECTIVES: To investigate the outcomes of patients undergoing laparoscopic or hysteroscopic approaches for isthmoplasty. METHODS: A total of 99 isthmocele patients with an average age of 38.45 ± 4.72 years were included in the 2 years of this retrospective cohort study. Forty-five underwent laparoscopic and 54 underwent hysteroscopic isthmocele excision and myometrial repair. RESULTS: Pain scores were significantly higher in the hysteroscopy group before the procedure, but there were no significant pain score differences after the surgery. In 1 year of follow up, dysmenorrhea and dyspareunia were higher among hysteroscopy patients. Furthermore, hysteroscopy significantly improved postmenstrual spotting after surgery better than laparoscopy, but in the follow up, there was no significant difference between the two groups in this regard (mean rank for hysteroscopy vs. laparoscopy: 32.30 vs. 37.48, U = 418, P = 0.29). CONCLUSION: In patients with a history of infertility, ectopic pregnancy, lower gravidity, lower parity, and a lower number of cesarean sections, laparoscopic isthmoplasty is preferred over the hysteroscopic approach. Both methods have similar effects on midcycle vaginal bleeding, duration of postmenstrual spotting, and pain. However, a higher rate of dyspareunia and dysmenorrhea could be associated with hysteroscopy.


Assuntos
Dispareunia , Laparoscopia , Metrorragia , Gravidez , Feminino , Humanos , Adulto , Dismenorreia/epidemiologia , Dismenorreia/etiologia , Dismenorreia/cirurgia , Estudos Retrospectivos , Dispareunia/epidemiologia , Dispareunia/etiologia , Cicatriz/patologia , Laparoscopia/efeitos adversos , Laparoscopia/métodos , Metrorragia/complicações , Metrorragia/cirurgia
3.
Nat Commun ; 14(1): 1522, 2023 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-36934096

RESUMO

Spontaneous whole genome duplication and the adaptive mutations that disrupt genome integrity checkpoints are infrequent events in B cell lymphomas. This suggests that lymphomas might be vulnerable to therapeutics that acutely trigger genomic instability and polyploidy. Here, we report a therapeutic combination of inhibitors of the Polo-like kinase 4 and BCL-2 that trigger genomic instability and cell death in aggressive lymphomas. The synthetic lethality is selective for tumor cells and spares vital organs. Mechanistically, inhibitors of Polo-like kinase 4 impair centrosome duplication and cause genomic instability. The elimination of polyploid cells largely depends on the pro-apoptotic BAX protein. Consequently, the combination of drugs that induce polyploidy with the BCL-2 inhibitor Venetoclax is highly synergistic and safe against xenograft and PDX models. We show that B cell lymphomas are ill-equipped for acute, therapy-induced polyploidy and that BCL-2 inhibition further enhances the removal of polyploid lymphoma cells.


Assuntos
Linfoma de Células B , Mutações Sintéticas Letais , Humanos , Linhagem Celular Tumoral , Apoptose/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Linfoma de Células B/tratamento farmacológico , Linfoma de Células B/genética , Poliploidia , Instabilidade Genômica
4.
Int J Fertil Steril ; 16(4): 263-267, 2022 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-36273311

RESUMO

BACKGROUND: Deep infiltrating endometriosis (DIE) is described as an endometriotic tissue that penetrates more than 5 mm under the peritoneal surface. It's suggested that trans vaginal sonography (TVS) is 79% sensitive and 94% specific in the assessment of intestinal DIE. Considering the possibility that DIE ultrasonography (rectal and\or vaginal ultrasonography) might be more accurate, we designed this study to assess this study to evaluate the accuracy of DIE ultrasonography. MATERIALS AND METHODS: In this retrospective cross-sectional study, we designed and conducted this study from 2019 to 2020 on patients suspected of severe endometriosis. Our patients underwent ultrasonographic imaging and based on the results became candidates for surgery. We compared histopathological results with sonographic findings using crosstabulation and chi-square tests were used to measure accuracy. P<0.05 were considered statistically significant. RESULTS: Following pathological assessments of 109 cases, 97 cases had ovarian endometrioma, 42 cases had intestinal involvement and 56 cases had uterosacral DIE. The results for accuracy were as the following; uterosacral ligament (USL) involvement SE: 96.4% and SP: 59.1%; intestinal involvement SE: 97.6% and SP: 73.8%; and Cul de sac involvement with SE: 100% and SP: 50.8%. With regards to ovarian endometrioma, ultrasonographic imaging was 99.0% sensitive and 84.6% specific. With regards to intestinal involvement, ultrasonography performed a reliable overall diagnosis (97.6% sensitive and 73.8% specific). However, the results showed lower accuracy regarding the level of intestinal involvement. The accuracy for other sites and cavities was low except for ovarian endometrioma. CONCLUSION: The results of the present study demonstrated that pre-operative TVS and Transrectal ultrasound (TRUS) can be a helpful paraclinical tool in the assessment and diagnosis of DIE and endometriosis in general and particularly with adnexal and bowel lesions, it can have some shortcomings with respect to cul de sac and USLs.

5.
Nat Commun ; 13(1): 5676, 2022 09 27.
Artigo em Inglês | MEDLINE | ID: mdl-36167829

RESUMO

To identify drivers of sensitivity and resistance to Protein Arginine Methyltransferase 5 (PRMT5) inhibition, we perform a genome-wide CRISPR/Cas9 screen. We identify TP53 and RNA-binding protein MUSASHI2 (MSI2) as the top-ranked sensitizer and driver of resistance to specific PRMT5i, GSK-591, respectively. TP53 deletion and TP53R248W mutation are biomarkers of resistance to GSK-591. PRMT5 expression correlates with MSI2 expression in lymphoma patients. MSI2 depletion and pharmacological inhibition using Ro 08-2750 (Ro) both synergize with GSK-591 to reduce cell growth. Ro reduces MSI2 binding to its global targets and dual treatment of Ro and PRMT5 inhibitors result in synergistic gene expression changes including cell cycle, P53 and MYC signatures. Dual MSI2 and PRMT5 inhibition further blocks c-MYC and BCL-2 translation. BCL-2 depletion or inhibition with venetoclax synergizes with a PRMT5 inhibitor by inducing reduced cell growth and apoptosis. Thus, we propose a therapeutic strategy in lymphoma that combines PRMT5 with MSI2 or BCL-2 inhibition.


Assuntos
Linfoma de Células B , Linfoma , Linhagem Celular Tumoral , Humanos , Linfoma/genética , Mutação , Proteína-Arginina N-Metiltransferases/genética , Proteína-Arginina N-Metiltransferases/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Proteína Supressora de Tumor p53/genética
6.
Int J Reprod Biomed ; 20(5): 365-376, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35911858

RESUMO

Background: Early diagnosis and appropriate treatment of endometriosis are vital and may prevent subsequent complications. Objective: To investigate the diagnostic accuracy of transvaginal ultrasound sonography (TVUS) and transrectal ultrasound sonography for detecting endometriosis considering the age and body mass index (BMI). Materials and Methods: This was a retrospective cohort study of 119 women scheduled for surgery in a tertiary health care center for clinically suspected endometriosis. Married and virgin women underwent TVUS and transrectal ultrasound sonography, respectively, before laparoscopic excision of endometriotic lesions. Results: The accuracy of TVUS in the diagnosis of right endometrioma in women with a normal BMI was superior to that in women with a BMI ≥ 30 (95.6% vs. 75.3%; p < 0.001). For the detection of left endometrioma in women with a normal BMI, TVUS demonstrated a sensitivity of 96.9% and a negative predictive value of 92.9%, which was significantly superior to TVUS in women with obesity (sensitivity: 77.4%, negative predictive value: 58.6%). The accuracy of TVUS in the diagnosis of left endometrioma in women under 35 yr was superior to that in women older than 35 yr (93.2% vs. 77.9%; p = 0.04). Similarly, the accuracy of TVUS in the diagnosis of right endometrioma in women under 35 yr was superior to TVUS in women older than 35 yr (86.5% vs. 73.3%; p = 0.04). Conclusion: Ultrasound can be a useful technique for detecting endometriosis when used adjunctively with the patient's history and physical findings, especially age and BMI.

7.
Int J Fertil Steril ; 16(3): 167-171, 2022 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-36029052

RESUMO

BACKGROUND: Laparoscopic excision of ovarian endometrioma is believed to decrease the ovarian reserve, but the risk factors of declining ovarian reserve are not well studied. This study aimed to determine the risk factors of anti mullerian hormone (AMH) decline after laparoscopic surgery of endometrioma.
Materials and Methods: This prospective study was recruited in Yas and Arash Hospitals affiliated to Tehran University of Medical Sciences from 2020 to 2021. Women between 18-45 years with ovarian endometriomas with a diameter greater than 3 centimeters who were candidates for laparoscopy were included. AMH, luteinizing hormone (LH),
and follicular stimulating hormone (FSH) as well as cancer antigen 125 (CA125) and cancer antigen 19-9 (CA19-9) were obtained and compared pre and postoperatively. Indeed, the relation of AMH decline rate and the demographic, symptoms and endometrioma characteristics were investigated either.
Results: In this study, 100 women were recruited. The mean ± SD age of the participants was 29.08 ± 4.6. AMH (P<0.000) and LH (P=0.013) declined significantly postoperatively. Whereas, no significant difference was observed between pre and postoperative FSH (P=0.520). AMH decline rate was 30.07 ± 2.30% and didn't have significant relation with the demographic characteristics, preoperative AMH, and the amount of CA125. Otherwise in the multivariate analysys, CA125 (P=0.160) and the grade of endometriosis (P=0.05) had significant correlation with AMH decline rate.
Conclusion: Ovarian reserve decline after laparoscopic excision of endometrioma. Otherwise, there may no specific risk factor to predict the degree of ovarian reserve decline. Therefore, the selection of patients for laparoscopic excision of endometrioma should be taken more cautiously as the ovarian reserve diminishes even in the patients with the lowest risks.

8.
J Obstet Gynaecol ; 42(5): 1493-1497, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34994286

RESUMO

This study aimed to compare the effectiveness of NAC plus low dose contraceptive with low dose contraceptives alone. This was a randomised trial on a sample of women who underwent conservative laparoscopic surgery for ovarian endometrioma. Patients were randomly assigned either to the NAC plus low dose contraceptive group (n = 48) or low dose contraceptive alone (n = 52). To evaluate the recurrence rate transvaginal ultrasound was performed. Pelvic pain was assessed using a visual analogue scale (VAS). All assessments were performed at two points in time: 3 and 6 months post-surgery and compared between the two regimens. The findings indicated that reduction in the recurrence rate of endometrioma and pelvic pain were similar between both groups. The findings showed that adding N-acetylcysteine to low dose contraceptive treatment has a similar effect in reducing the recurrence rate of endometrioma and pelvic pain when compared to low dose contraceptives alone.Impact statementWhat is already known on this subject? Endometriosis is a frequent benign disease-producing inflammatory response with mild to severe symptoms. Although surgical removal of ectopic lesions is the first-line intervention, the recurrence rate of the disease is high. Thus this study aimed to compare the effectiveness of N-acetylcysteine plus low dose contraceptive with low dose contraceptive alone.What do the results of this study add? The findings showed that adding N-acetylcysteine to low dose contraceptive treatment has a similar effect in reducing the recurrence rate of endometrioma and pelvic pain when compared to low dose contraceptives alone.What are the implications of these findings for clinical practice and/or further research? It is recommended to increase the duration of drug administration in future studies.


Assuntos
Dor Crônica , Endometriose , Laparoscopia , Doenças Ovarianas , Acetilcisteína/uso terapêutico , Anticoncepcionais , Endometriose/tratamento farmacológico , Endometriose/cirurgia , Feminino , Humanos , Doenças Ovarianas/cirurgia , Dor Pélvica/tratamento farmacológico , Dor Pélvica/etiologia , Dor Pélvica/cirurgia , Recidiva
9.
Cell Rep Med ; 2(7): 100350, 2021 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-34337566

RESUMO

Inhibition of the extracellular signal-regulated kinases ERK1 and ERK2 (ERK1/2) offers a promising therapeutic strategy in cancers harboring activated RAS/RAF/MEK/ERK signaling pathways. Here, we describe an orally bioavailable and selective ERK1/2 inhibitor, ASN007, currently in clinical development for the treatment of cancer. In preclinical studies, ASN007 shows strong antiproliferative activity in tumors harboring mutations in BRAF and RAS (KRAS, NRAS, and HRAS). ASN007 demonstrates activity in a BRAFV600E mutant melanoma tumor model that is resistant to BRAF and MEK inhibitors. The PI3K inhibitor copanlisib enhances the antiproliferative activity of ASN007 both in vitro and in vivo due to dual inhibition of RAS/MAPK and PI3K survival pathways. Our data provide a rationale for evaluating ASN007 in RAS/RAF-driven tumors as well as a mechanistic basis for combining ASN007 with PI3K inhibitors.


Assuntos
MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , Mutação/genética , Neoplasias/enzimologia , Neoplasias/genética , Inibidores de Proteínas Quinases/farmacologia , Quinases raf/genética , Proteínas ras/genética , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Concentração Inibidora 50 , Camundongos Nus , Neoplasias/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Proteínas Quinases/química , Pirimidinas/farmacologia , Quinazolinas/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Aust N Z J Obstet Gynaecol ; 61(5): 759-764, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34060074

RESUMO

BACKGROUND: Specimen extraction is a major challenge in total laparoscopic hysterectomy (TLH) and tissue morcellation may be needed to extract a large uterus. AIMS: The study aims to determine preoperative factors that could predict the need for uterine morcellation in TLH, and also find the best cut-off values of each measured parameter leading to optimum sensitivity and specificity. MATERIALS AND METHODS: This was a cross-sectional study of women from August 2019 to May 2020 who underwent TLH, with or without salpingo-oophorectomy in our department. We performed bimanual exams preoperatively to estimate the uterine size and recorded the uterine ultrasonographic dimensions and myoma size in myomatous uteri. Receiver operating characteristic (ROC) were used to establish cut-offs that maximised the sensitivity and specificity of each factor in predicting the need for morcellation. Poisson regression was used to calculate the relative risks (RR) of each cut-off. RESULTS: One hundred and sixty-two women were recruited in the study. ROC curves demonstrated maximum sensitivities and specificities with a cross-sectional area of 36.5 cm2 , the largest leiomyoma dimension of 40 mm, uterine length of 10 cm, and bimanual uterine size of 13 weeks. Multiple modified Poisson regression revealed that the strongest predictors of morcellation were the largest leiomyoma diameter of >40 mm (RR: 3.58), the uterine cross-sectional area of >36.5 cm2 (RR: 6.38), and uterine size in the bimanual exam of >13 weeks pregnancy (RR: 3.57). CONCLUSION: The largest leiomyoma diameter, uterine cross-sectional area, and size on a bimanual exam can all be used to predict needing morcellation preoperatively in TLH.


Assuntos
Laparoscopia , Morcelação , Neoplasias Uterinas , Estudos Transversais , Feminino , Humanos , Histerectomia , Gravidez , Neoplasias Uterinas/diagnóstico por imagem , Neoplasias Uterinas/cirurgia
11.
Soc Work Public Health ; 36(3): 365-376, 2021 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-33849403

RESUMO

Knowledge of screening methods and regular diagnostic tests play an important role in reducing the incidence of cancers and their mortality. We investigated the effectiveness of health belief model initiative in breast cancer screening behaviors among women health volunteers. A quasi-experimental design and non-probability sampling technique was conducted during 2019 in Abhar, Iran. Two out of six health centers were approached and each was recruited in either experimental or control group. Based on the Iranian and standardized version of the Champion's Health Belief Model Scale, the different domains of the scale and breast cancer screening behaviors of eligible women health volunteers (n = 72) were evaluated. Then, seven training sessions were designed and implemented for the intervention group using local language and different educational approaches. The participants were reevaluated according to the same questionnaire three months after the intervention. There was a meaningful difference regarding breast self-exam, knowledge, perceived susceptibility, perceived severity, perceived benefits, and perceived barriers among both the control and intervention groups before and after the intervention. Training programs using health belief model are crucial in developing breast cancer screening behaviors for women health volunteers. Thus, it is recommended that training programs should be conducted using individual behavioral models.


Assuntos
Neoplasias da Mama , Neoplasias da Mama/diagnóstico , Detecção Precoce de Câncer , Feminino , Comportamentos Relacionados com a Saúde , Modelo de Crenças de Saúde , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Irã (Geográfico) , Voluntários
12.
J Minim Invasive Gynecol ; 28(7): 1391-1396, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33152530

RESUMO

STUDY OBJECTIVE: This study evaluated peritoneal washings for the detection of spindle cells (SCs) in laparoscopic and open myomectomies. DESIGN: Prospective, nonrandomized clinical trial. SETTING: An academic tertiary referral center. PATIENTS: Women suspected of having benign uterine myoma undergoing laparoscopic or open myomectomy from October 2016 to April 2018. INTERVENTIONS: Washing of the peritoneal cavity to detect SCs was performed twice during the laparoscopic myomectomy. The first washing was after the closure of the myometrial incision and before morcellation. The second one was performed after morcellation. The procedure was also performed once during the open myomectomy, after the completion of the myomectomy and the closure of the incision. After a peritoneal washing with 200 mL normal saline, 30 mL liquid was collected and sent to the laboratory for SC detection. Surgical parameters such as operating time, mean change in serum hemoglobin level, complications, length of hospital stay, and readmission were compared between the 2 groups. MEASUREMENTS AND MAIN RESULTS: A total of 150 participants were included in the analysis: 78 in the laparoscopic group and 72 in the open myomectomy group. After morcellation, the incidence of SCs was 2.6% (n = 2) and 6.9% (n = 5) in the laparoscopic and open myomectomy groups, respectively (p = .204). CONCLUSION: SCs were observed in both the laparoscopic and open myomectomy groups. Thus, morcellation alone could not be the cause for SC dissemination, which might also be triggered by the manipulation of myoma(s).


Assuntos
Laparoscopia , Morcelação , Miomectomia Uterina , Neoplasias Uterinas , Feminino , Humanos , Morcelação/efeitos adversos , Estudos Prospectivos , Miomectomia Uterina/efeitos adversos , Neoplasias Uterinas/cirurgia
13.
J Minim Invasive Gynecol ; 27(1): 148-154, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31301467

RESUMO

STUDY OBJECTIVE: To evaluate uterine scar features after laparoscopic myomectomy (LM) compared with myomectomy performed by laparoscopy initially and then completed with minilaparotomy (LAM). DESIGN: Prospective cohort study. SETTING: An academic center for advanced endoscopic gynecologic surgery. PATIENTS: Sixty-nine symptomatic women who underwent myomectomy between July and December 2018. INTERVENTION: Patients underwent LM or LAM and 3-month follow-up ultrasonography. MEASUREMENTS AND MAIN RESULTS: Forty-four patients underwent LM and 25 underwent LAM. Demographic data, intraoperative parameters, and postoperative outcomes were collected. Two-dimensional color Doppler ultrasound was done at a 3-month follow-up to evaluate myomectomy scar features, myometrial thickness, and the presence of and vascularity of a heterogeneous mass. These features were compared with those of the intact myometrium on the opposite wall of the patient's uterus. The 2 groups had similar demographic characteristics, and there were no significant between-group differences in the number, maximum diameter, type, or location of myomas. The mean myometrial thickness at the scar site was 18.9 ± 3.22 mm in the LM group and 19.7 ± 3.50 mm in the LAM group, with no significant difference between the 2 groups. There was no meaningful difference in vascularity between the scar and normal myometrium. Heterogeneous masses were detected in 23% of patients in the LM group and in 24% of those in the LAM group. Other than mean operative time (207 minutes for LM vs 150 minutes for LAM; p < .001) and mean postoperative reduction in hemoglobin (1.77 mg/dL for LM vs 2.35 mg/dL for LAM; p = .023), there were no other statistical differences between the 2 groups. One patient in the LM group experienced a bowel injury resulting from morcellation. CONCLUSION: There were no differences in myometrial scar features after LM compared with after LAM, implying effective suturing via both approaches.


Assuntos
Cicatriz/diagnóstico , Laparoscopia , Laparotomia , Leiomioma/cirurgia , Miomectomia Uterina/métodos , Neoplasias Uterinas/cirurgia , Útero/diagnóstico por imagem , Adulto , Cicatriz/etiologia , Feminino , Seguimentos , Humanos , Laparoscopia/efeitos adversos , Laparoscopia/métodos , Laparotomia/efeitos adversos , Laparotomia/métodos , Pessoa de Meia-Idade , Morcelação/efeitos adversos , Morcelação/métodos , Duração da Cirurgia , Estudos Prospectivos , Deiscência da Ferida Operatória/etiologia , Deiscência da Ferida Operatória/patologia , Ultrassonografia , Miomectomia Uterina/efeitos adversos , Ruptura Uterina/etiologia , Ruptura Uterina/patologia , Útero/patologia , Útero/cirurgia
14.
Proc Natl Acad Sci U S A ; 115(47): 12034-12039, 2018 11 20.
Artigo em Inglês | MEDLINE | ID: mdl-30404918

RESUMO

Although diffuse large B cell lymphoma (DLBCL) cells widely express the BCL2 protein, they rarely respond to treatment with BCL2-selective inhibitors. Here we show that DLBCL cells harboring PMAIP1/NOXA gene amplification were highly sensitive to BCL2 small-molecule inhibitors. In these cells, BCL2 inhibition induced cell death by activating caspase 9, which was further amplified by caspase-dependent cleavage and depletion of MCL1. In DLBCL cells lacking NOXA amplification, BCL2 inhibition was associated with an increase in MCL1 protein abundance in a BIM-dependent manner, causing a decreased antilymphoma efficacy. In these cells, dual inhibition of MCL1 and BCL2 was required for enhanced killing. Pharmacologic induction of NOXA, using the histone deacetylase inhibitor panobinostat, decreased MCL1 protein abundance and increased lymphoma cell vulnerability to BCL2 inhibitors in vitro and in vivo. Our data provide a mechanistic rationale for combination strategies to disrupt lymphoma cell codependency on BCL2 and MCL1 proteins in DLBCL.


Assuntos
Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/genética , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-bcl-2/genética , Animais , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Amplificação de Genes/efeitos dos fármacos , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/uso terapêutico , Humanos , Linfoma Difuso de Grandes Células B/metabolismo , Linfoma Difuso de Grandes Células B/patologia , Camundongos , Camundongos Nus , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Panobinostat/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Cell Rep ; 24(8): 2155-2166, 2018 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-30134175

RESUMO

The phosphatidylinositol 3 kinase (PI3K)-glycogen synthase kinase ß (GSK3ß) axis plays a central role in MYC-driven lymphomagenesis, and MYC targeting with bromodomain and extraterminal protein family inhibitors (BETi) is a promising treatment strategy in lymphoma. In a high-throughput combinatorial drug screening experiment, BETi enhance the antiproliferative effects of PI3K inhibitors in a panel of diffuse large B cell lymphoma (DLBCL) and Burkitt lymphoma cell lines. BETi or MYC silencing upregulates several PI3K pathway genes and induces GSK3ß S9 inhibitory phosphorylation, resulting in increased ß-catenin protein abundance. Furthermore, BETi or MYC silencing increases GSK3ß S9 phosphorylation levels and ß-catenin protein abundance through downregulating the E2 ubiquitin conjugating enzymes UBE2C and UBE2T. In a mouse xenograft DLBCL model, BETi decrease MYC, UBE2C, and UBE2T and increase phospho-GSK3ß S9 levels, enhancing the anti-proliferative effect of PI3K inhibitors. Our study reveals prosurvival feedbacks induced by BETi involving GSK3ß regulation, providing a mechanistic rationale for combination strategies.


Assuntos
Glicogênio Sintase Quinase 3 beta/metabolismo , Linfoma Difuso de Grandes Células B/genética , Proteínas do Tecido Nervoso/antagonistas & inibidores , Fosfatidilinositol 3-Quinases/metabolismo , Receptores de Superfície Celular/antagonistas & inibidores , Animais , Humanos , Camundongos
17.
J Cancer Res Ther ; 14(3): 543-548, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29893313

RESUMO

BACKGROUND: This study aimed to compare the surgical outcome and ovarian reserve in premenopausal women undergoing laparoscopic hysterectomy (without oophorectomy) for benign cause between two methods of with and without prophylactic bilateral salpingectomy. MATERIALS AND METHODS: In a prospective randomized clinical trial, 62 premenopausal women with benign indication underwent a laparoscopic hysterectomy. Patients were then randomized to undergo hysterectomy with bilateral salpingectomy (Group 1; n = 15) or without bilateral salpingectomy (Group 2; n = 15). We evaluated the impact of bilateral salpingectomy on surgical outcome and ovarian reserve using serum levels of anti-Mullerian hormone (AMH) and follicle stimulating hormone (FSH) that were measured preoperatively and at 3 months postoperatively (P < 0.001). RESULTS: Baseline characteristics such as age, uterine size, body mass index, and preoperative AMH and FSH levels were similar between the two study groups. The average operative time, estimated blood loss, uterine size, uterine weight, and intraoperative complication were similar between two groups. The mean AMH levels were not significantly different at baseline (1.44 ng/mL vs. 1.2 ng/mL) and at 3-month postoperatively (1.13 ng/mL vs. 0.97 ng/mL) among women with salpingectomy versus no salpingectomy. At 3-month follow-up, in both groups, postoperative AMH levels were significantly lower and FSH levels were significantly higher than before surgery. CONCLUSION: Prophylactic bilateral salpingectomy at the time of laparoscopic hysterectomy neither has a negative effect on ovarian reserve nor increases the surgical risk. Therefore, we may recommend gynecologic surgeons to perform prophylactic bilateral salpingectomy during laparoscopic hysterectomy to conserve both ovaries.


Assuntos
Histerectomia/métodos , Neoplasias/cirurgia , Neoplasias Ovarianas/cirurgia , Ovário/cirurgia , Adulto , Hormônio Antimülleriano/sangue , Feminino , Hormônio Foliculoestimulante/sangue , Humanos , Histerectomia/efeitos adversos , Laparoscopia/efeitos adversos , Pessoa de Meia-Idade , Neoplasias/sangue , Neoplasias/fisiopatologia , Neoplasias Ovarianas/sangue , Neoplasias Ovarianas/fisiopatologia , Reserva Ovariana/fisiologia , Ovário/patologia , Salpingectomia/métodos , Resultado do Tratamento
18.
Pain Res Manag ; 2018: 9715142, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29743962

RESUMO

Background: Traditionally, laparoscopic procedures have been performed under general anesthesia. Spinal anesthesia is an effective alternative to general anesthesia. However, one of the intraoperative complications of performing laparoscopic surgery under spinal anesthesia is shoulder pain. This study aimed to compare the effect of transcutaneous electrical nerve stimulation (TENS) with fentanyl on pain relief in patients who underwent gynecologic laparoscopy under spinal anesthesia. Methods: We conducted a prospective randomized clinical trial from May 2016 to March 2017. A sample of patients who underwent gynecological laparoscopy under spinal anesthesia was recruited. If they had shoulder pain, they randomly received either transcutaneous electrical nerve stimulation (TENS) or 50 mg of fentanyl. Pain intensity was measured using the single item visual analogue scale (VAS-10 cm) immediately before and 5, 10, 20, and 30 minutes after treatment. Also, the effect of higher doses of analgesia on pain relief was analyzed. Results: In all, 80 patients (40 patients in each group) were entered into the study. The mean pain intensity score was 9.02 ± 1.32 in the TENS group and 8.95 ± 1.33 in the fentanyl group at baseline (P = 0.80). Repeated measures analysis of variance indicated that there was no significant difference on overall pain scores between the two treatment groups adjusted for age, BMI, total analgesia used, and baseline pain score (F (1, 74) = 1.44, P = 0.23). The use of analgesic drugs in the TENS group was significantly higher than the fentanyl group (P = 0.01). In addition, we found that nine patients (22.5%) complained of nausea/vomiting in the TENS group compared to thirteen patients (32.5%) in the fentanyl group (P = 0.31). Conclusions: The findings indicated that TENS was not superior to fentanyl for pain relief in laparoscopic surgery. It seems that the correct use of TENS parameters might merit further investigation. This trial is registered with: IRCT2016031216765N3.


Assuntos
Analgésicos Opioides/uso terapêutico , Fentanila/uso terapêutico , Procedimentos Cirúrgicos em Ginecologia/efeitos adversos , Laparoscopia/efeitos adversos , Dor de Ombro/terapia , Estimulação Elétrica Nervosa Transcutânea/métodos , Adolescente , Adulto , Raquianestesia , Feminino , Humanos , Pessoa de Meia-Idade , Medição da Dor , Dor Pós-Operatória/etiologia , Dor Pós-Operatória/terapia , Estudos Retrospectivos , Dor de Ombro/etiologia , Adulto Jovem
19.
Surg Laparosc Endosc Percutan Tech ; 28(2): 73-76, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29189662

RESUMO

This study evaluated the effect of drain placement on pain intensity after gynecologic laparoscopy. This study enrolled 120 patients with benign gynecologic lesions who underwent laparoscopic surgery. Patients were randomly divided into a standard group or the modified group. The modified group received suction drains that remained in place until 12 hours after surgery. We assessed patients' mean pain scores according to a visual analog scale at 12 and 24 hours after surgery. The mean pain score in the modified group was 6.01±1.96 at 12 hours after surgery and 3.86±1.57 at 24 hours after surgery. The standard group had a mean pain score of 5.43±1.7 at 12 hours after surgery and 3.51±1.27 at 24 hours after surgery. These findings did not significantly differ (P=0.6) even though the mean dose of parenteral analgesia was 0.68±0.83 in the standard group and 0.41±0.67 in the modified group (P=0.05). We observed no differences in complications and hospital stay between the groups. The data suggest that drainage may not reduce postoperative pain and should be used in its traditional role for potential bleeding or infections.


Assuntos
Procedimentos Cirúrgicos em Ginecologia/efeitos adversos , Laparoscopia/efeitos adversos , Dor Pós-Operatória/cirurgia , Sucção/métodos , Adulto , Feminino , Procedimentos Cirúrgicos em Ginecologia/métodos , Humanos , Tempo de Internação/tendências , Pessoa de Meia-Idade , Medição da Dor , Dor Pós-Operatória/diagnóstico , Resultado do Tratamento , Adulto Jovem
20.
Pain Res Manag ; 2017: 1721460, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28932131

RESUMO

OBJECTIVE: The aim of this study was to compare the effectiveness of spinal anesthesia with subdiaphragmatic lidocaine at the beginning of surgery versus spinal anesthesia in pain reduction for gynecological laparoscopic surgery. METHODS: This was a clinical trial conducted in Arash Hospital, Tehran, Iran. Eighty-four patients were randomized to either spinal anesthesia with subdiaphragmatic lidocaine, spinal anesthesia, or general anesthesia (GA). The primary outcome was patients' pain perception during surgery, 2, 4, 6, and 12 hours after surgery, and prior to discharge and was assessed by visual analogue scale (VAS). RESULTS: The results showed that there are no significant changes in pain perception over time in none of the three groups (F(4,76) = 0.37, P = 0.82). The severity of pain experienced by patients at all-time interval after surgery was similar between groups [F(2,79) = 0.54, P = 0.58]. CONCLUSION: The use of subdiaphragmatic lidocaine at the beginning of surgery combined with spinal anesthesia was not associated with a statistically significant difference in patients' postoperative VAS scores compared to spinal anesthesia and GA during and after gynecological surgical procedures. The study was registered in Iranian Registry of Clinical Trial by the number of IRCT2016022226698N1.


Assuntos
Raquianestesia , Procedimentos Cirúrgicos em Ginecologia , Laparoscopia , Lidocaína/administração & dosagem , Dor de Ombro/tratamento farmacológico , Adulto , Anestesia Geral , Feminino , Humanos , Lidocaína/uso terapêutico , Medição da Dor
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