Targeted Therapy and Mechanism of Drug Resistance in Non-small Cell Lung Cancer with Epidermal Growth Factor Receptor Gene Mutation / 中国肺癌杂志

Lung cancer is the sixth leading cause of death worldwide and one of the leading cause of death from malignant tumors. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. Epidermal growth factor receptor (EGFR) gene mutation is a common mutation in NSCLC. For advanced NSCLC patients with EGFR mutations, EGFR-tyrosine kinase inhibitors (EGFR-TKIs), such as Gefitinib, Afatinib, Oxitinib and other targeted therapies have become the first-line treatment recommended by many guidelines, but many patients develop acquired drug resistance after about 1 year of medication. Patients with drug resistance will have earlier disease progression than patients without drug resistance, which has an important impact on the prognosis of patients. At present, the main treatment for patients with acquired resistance is new target inhibition for resistant mutation. For example, if patients with T790M mutation are resistant to the first or second generation drugs such as Gefitinb and Afatinib, they can be treated with the third generation drugs (Osimertinib or Almonertinib), which can delay the progression of the disease. Therefore, the study of drug resistance mechanism and treatment of drug resistance patients are essential. This paper mainly reviews targeted therapy and drug resistance mechanism of EGFR-mutant NSCLC patients, in order to provide reference for clinical application of EGFR-TKIs.
.

Kinetics of MDSC in Patients Treated Steroids-Ruxolitinib as the First Line Therapy for aGVHD / 中国实验血液学杂志

OBJECTIVE@#To analyze the kinetic characteristics of lymphocyte subsets and myeloid-derived suppressor cell (MDSC) in patients who newly diagnosed intermediate- to high-risk aGVHD and treated with steroids-ruxolitinib as the first line therapy from a single-arm, open clinical trial (NCT04061876).@*METHODS@#We prospectively observed the efficacy of 23 patients having intermediate- to high-risk aGVHD and treated with steroids-ruxolitinib as the first line therapy. The kinetic characteristics of lymphocyte subsets and MDSC were monitored, and then we compared them in steroids-ruxolitinib group (n=23), free-aGVHD group (n=20) and steroids group (n=23).@*RESULTS@#Of the 23 patients, the CR rate was 78.26% (18/23) on day 28 after first-line treatment with steroids-ruxolitinib. On day 28 after treatment, patients had lower level of CD4+CD29+ T cells (P=0.08) than that of pre-treatment, whereas levels of other lymphocyte subsets in this study were higher than that of pre-treatment; CD4+CD29+ T cells in CR patients decreased, compared with refractory aGVHD patients. On day 28 of treatment, CD8+CD28- T cells (P=0.03) significantly increased in patients with aGVHD than that in patients without aGVHD, so did CD8+CD28- T / CD8+CD28+ T cell ratio (P=0.03). Compared with patients without aGVHD, patients with aGVHD had lower level of G-MDSC, especially on day 14 after allo-HSCT (P=0.04). Compared with pre-treatment, M-MDSC was higher in CR patients on day 3 and 7 post-treatment (P3=0.01, P7=0.03), e-MDSC was higher on day 28 post-treatment (P=0.01). Moreover, compared with CR patients, M-MDSC was lower in refractory aGVHD patients on day 3 post-treatment (P=0.01) and e-MDSC was lower on day 28 post-treatment (P=0.01). Compared with steroids group, MDSC in steroids-ruxolitinib group was higher, with the most significant difference in M-MDSC (P3=0.0351; P7=0.0142; P14=0.0369).@*CONCLUSION@#We found that patients newly diagnosed intermediate- to high-risk aGVHD receiving first-line therapy with steroids-ruxolitinib achieved high response rate. Moreover, the novel first-line therapy has a small impact on the immune reconstitution of patients after allo-HSCT. Elevated MDSC might predict a better response in aGVHD patients receiving this novel first-line therapy. M-MDSC responded earlier to steroids-ruxolitinib than e-MDSC, G-MDSC.

Analysis of the Curative Effect and Influencing Factors of Nilotinib Second-line and Dasatinib Third-line on Chronic Myelogenous Leukemia Failed First-line and Second-line Treatment / 中国实验血液学杂志

OBJECTIVE@#To evaluate the efficacy of the second-line nilotinib and third-line dasatinib on chronic myelogenous leukemia (CML) with failed first- and second-line treatments, and analyze the influencing factors of the efficacy.@*METHODS@#Selected 83 patients in The Third People's Hospital of Kunshan City, Jiangsu Province with CML who were treated with nilotinib as the second-line treatment after the failure of the first-line treatment with imatinib as the second-line treatment group (referred to as the second-line group) from January 2014 to December 2018, and 61 CML patients who were treated by dasatinib as the third-line treatment group (referred to as the third-line group) after the failure of the second-line treatment with nilotinib; the first-line treatment with imatinib failed, but due to various reasons, the patients were fully after being informed of the possible serious consequences of not changing the drug treatment, 37 CML patients who were still required to continue imatinib treatment served as the control group. The hematological, genetic and molecular responses of each group were compared for 3, 6, and 24 months of treatment. LogistiC regression was used to analyze the factors affecting the second and third line curative effects.@*RESULTS@#The three groups had statistically significant differences in the rates of achieving CHR, MCyR, and MMR at 3, 6, and 12 months of treatment (P<0.05). Compared the two groups, the CHR rates of the second-line group at 3, 6, and 12 months of treatment were 100.00%, 97.59%, and 95.18%, respectively; higher than the third-line group's 90.16%, 86.89%, 83.61% and the control group's 83.78%, 75.68% and 72.97%; the CHR rate of the third-line group was higher than that of the control group at 6 and 12 months of treatment. The rates of reaching MCyR at 3, 6, and 12 months after treatment in the second-line group were 87.95%, 93.98% and 93.98%, respectively, while those in the third-line group were 80.33%, 88.52% and 86.89%, which were higher than those of the control group of 67.57%, 64.86% and 48.65%. The rates of achieving MMR at 3, 6, and 12 months of treatment in the second-line group were 19.28%, 33.72% and 60.24%, respectively, and those in the third-line group were 11.48%, 26.23% and 49.18%, which were higher than those of the control group of 0.00%, 2.70% and 0.00%; The rate of reaching MMR within 12 months of treatment in the second-line group was higher than that of the third-line group, and the differences was statistically significant (P<0.05). There was no significant difference in the rate of reaching MCyR between the second-line group and the third-line group at 3, 6, and 12 months, and the rate of reaching MMR at 3 and 6 months (P>0.05). The incidence of nausea and vomiting among the three main non-hematological adverse reactions, and the incidence of grade 1~2 anemia among the hematological adverse reactions were statistically significant (P<0.05). There was no significant difference in the incidence of rash, eyelid edema, diarrhea, thrombocytopenia, leukopenia and neutropenia in the three groups (P>0.05). The incidence of nausea and vomiting and grade 1~2 anemia in the second-line group and the third-line group were higher than that of the control group, and the difference was statistically significant (P<0.05). There were statistically significant differences in Sokal score, medication compliance, and hematological adverse reactions between the MMR group and the non-MMR group (P<0.05). Logistic regression analysis showed that dose reduction or withdrawal during the treatment period, and grade 3~4 hematological adverse reactions were the main factors affecting the second and third line curative effects (OR=22.160, 2.715, 95% CI=2.795-93.027, 1.882-48.834).@*CONCLUSION@#The second-line nilotinib and the third-line dasatinib have a better effect on CML patients who have failed the first and second-line treatments. Grade 3~4 hematological adverse reactions, dose reduction or withdrawal are risk factors that affect the efficacy of second and third-line treatments.

Recent research on tofacitinib in the treatment of pediatric rheumatic diseases / 中国当代儿科杂志

Tofacitinib is a Janus kinase inhibitor and can block the Janus kinase-signal transducer and activator of transcription signal transduction pathway and reduce the production and release of a variety of cytokines. It has great potential in the treatment of various rheumatic diseases with a rapid onset of action and can reduce corticosteroid dependence and related adverse events. The therapeutic effect of tofacitinib in adult patients has been confirmed, and it has been increasingly used in pediatric patients in recent years. This article reviews the clinical application of tofacitinib in the treatment of pediatric autoimmune diseases.

Analysis of the effect of gene mutations on the efficacy of ruxolitinib in patients with myelofibrosis based on second-generation sequencing technology / 中华血液学杂志

Objective: To assess the effect of gene mutations on the efficacy of ruxolitinib for treating myelofibrosis (MF) . Methods: We retrospectively analyzed the clinical data of 56 patients with MF treated with ruxolitinib from July 2017 to December 2020 and applied second-generation sequencing (NGS) technology to detect 127 hematologic tumor-related gene mutations. Additionally, we analyzed the relationship between mutated genes and the efficacy of ruxolitinib. Results: ①Among the 56 patients, there were 36 cases of primary bone marrow fibrosis (PMF) , 9 cases of bone marrow fibrosis (ppv-mf) after polycythemia vera, and 11 cases of bone marrow fibrosis (PET-MF) after primary thrombocytosis (ET) . ②Fifty-six patients with MF taking ruxolitinib underwent NGS, among whom, 50 (89.29%) carried driver mutations, 22 (39.29%) carried ≥3 mutations, and 29 (51.79%) carried high-risk mutations (HMR) . ③ For patients with MF carrying ≥ 3 mutations, ruxolitinib still had a better effect of improving somatic symptoms and shrinking the spleen (P=0.001, P<0.001) , but TTF and PFS were significantly shorter in patients carrying ≥ 3 mutations (P=0.007, P=0.042) . ④For patients carrying ≥ 2 HMR mutations, ruxolitinib was less effective in shrinking the spleen than in those who did not carry HMR (t= 10.471, P=0.034) , and the TTF and PFS were significantly shorter in patients carrying ≥2 HMR mutations (P<0.001, P=0.001) . ⑤Ruxolitinib had poorer effects on spleen reduction, symptom improvement, and stabilization of myelofibrosis in patients carrying additional mutations in ASXL1, EZH2, and SRSF2. Moreover, patients carrying ASXL1 and EZH2 mutations had significantly shorter TTF [ASXL1: 360 (55-1270) d vs 440 (55-1268) d, z=-3.115, P=0.002; EZH2: 327 (55-975) d vs 404 (50-1270) d, z=-3.219, P=0.001], and significantly shorter PFS compared to non-carriers [ASXL1: 457 (50-1331) d vs 574 (55-1437) d, z=-3.219, P=0.001) ; 428 (55-1331) d vs 505 (55-1437) d, z=-2.576, P=0.008]. Conclusion: The type and number of mutations carried by patients with myelofibrosis and HMR impact the efficacy of ruxolitinib.

Abivertinib inhibits megakaryocyte differentiation and platelet biogenesis / 医学前沿

Abivertinib, a third-generation tyrosine kinase inhibitor, is originally designed to target epidermal growth factor receptor (EGFR)-activating mutations. Previous studies have shown that abivertinib has promising antitumor activity and a well-tolerated safety profile in patients with non-small-cell lung cancer. However, abivertinib also exhibited high inhibitory activity against Bruton's tyrosine kinase and Janus kinase 3. Given that these kinases play some roles in the progression of megakaryopoiesis, we speculate that abivertinib can affect megakaryocyte (MK) differentiation and platelet biogenesis. We treated cord blood CD34+ hematopoietic stem cells, Meg-01 cells, and C57BL/6 mice with abivertinib and observed megakaryopoiesis to determine the biological effect of abivertinib on MK differentiation and platelet biogenesis. Our in vitro results showed that abivertinib impaired the CFU-MK formation, proliferation of CD34+ HSC-derived MK progenitor cells, and differentiation and functions of MKs and inhibited Meg-01-derived MK differentiation. These results suggested that megakaryopoiesis was inhibited by abivertinib. We also demonstrated in vivo that abivertinib decreased the number of MKs in bone marrow and platelet counts in mice, which suggested that thrombopoiesis was also inhibited. Thus, these preclinical data collectively suggested that abivertinib could inhibit MK differentiation and platelet biogenesis and might be an agent for thrombocythemia.

Clinical Application of Zanubrutinib in B-Cell Lymphoma --Review / 中国实验血液学杂志

Zanubrutinib is a highly selective second-generation BTK inhibitor developed in China and first approved by the U.S. Food and Drug Administration (FDA) as a novel antineoplastic drug. In recent years, with the birth of molecularly targeted drugs, the treatment of B-cell lymphoma have entered the era of targeted therapy, and immunotherapy has been widely accepted. Especially in some relapsed and refractory lymphomas, zanubrutinib has shown deep and sustained remissions and a favorable safety, which lays a foundation for precision therapy. In this review the clinical application and new progress for zanubrutinib in B-cell lymphoma was summarized briefly.

The dual mTORC1/2 inhibitor AZD2014 inhibits acute graft rejection in a rat liver transplantation model / 南方医科大学学报

OBJECTIVE@#To investigate the inhibitory effect of AZD2014, a dual mTORC1/2 inhibitor, against acute graft rejection in a rat model of allogeneic liver transplantation.@*METHODS@#Liver transplantation from Lewis rat to recipient BN rat (a donor-recipient combination that was prone to induce acute graft rejection) was performed using Kamada's two-cuff technique. The recipient BN rats were randomized into 2 groups for treatment with daily intraperitoneal injection of AZD2014 (5 mg/kg, n=4) or vehicle (2.5 mL/kg, n=4) for 14 consecutive days, starting from the first day after the transplantation. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and total bilirubin (TBIL) levels of the rats were measured 3 days before and at 1, 3, 5, 7, 10, and 14 days after the transplantation, and the survival time of the rats within 14 days were recorded. Immunohistochemical staining was used to examine the expressions of CD3 and Foxp3 in the liver graft, and acute graft rejection was assessed using HE staining based on the Banff schema.@*RESULTS@#Three rats in the control group died within 14 days after the surgery, while no death occurred in the AZD2014 group, demonstrating a significantly longer survival time of the rats in AZD2014 group (χ2=4.213, P=0.04). Serum ALT, AST and TBIL levels in the control group increased progressively after the surgery and were all significantly higher than those in AZD2014 group at the same time point (P < 0.05). Pathological examination revealed significantly worse liver graft rejection in the control group than in AZD2014 group based on assessment of the rejection index (P < 0.01); the rats in the control group showed more serious T lymphocyte infiltration and significantly fewer Treg cells in the liver graft than those in AZD2014 group (P < 0.01).@*CONCLUSIONS@#AZD2014 can effectively inhibit acute graft rejection in rats with allogeneic liver transplantation.

Therapeutic Effect of Imatinib Made in Real World to Newly Diagnosed Chronic Myeloid Leukemia / 中国实验血液学杂志

OBJECTIVE@#To evaluate the clinical efficacy and safety of domestic imatinib (made in China) in patients with newly diagnosed chronic myeloid leukemia chronic phase(CML-CP).@*METHODS@#Fifty-seven newly diagnosed CML-CP patients who did not receive any other anti-CML treatment were treated by domestic imatinib 400 mg once a day. The hematological, cytogenetic and molecular reactions and safety were observed and evaluated after 3, 6 and 12 months of treatment.@*RESULTS@#Fifty-six patients were treated for ≥3 and 6 months, among which 50 patients were treated for ≥12 months. After 3 months of treatment, 49 patients underwent hematological examination, 47 patients (95.9%) achieved complete hematological response (CHR), 49 patients underwent cytogenetic examination, 39 patients (79.6%) achieved major cytogenetic response (MCyR), and 12 patients (24.5%) achieved complete cytogenetic response (CCyR). 49 patients underwent the level of BCR-ABL test, including 41 patients (83.7%) with BCR-ABL@*CONCLUSION@#In the real world, Domestics imatinib mesylate is effective and safe in the treatment of newly diagnosed CML-CP patients, but long-term follow-up data are still necessary to verify its long-term efficacy.

Effect of almonertinib on the proliferation, invasion, and migration in non-small cell lung cancer cells / 中南大学学报(医学版)

OBJECTIVES@#Lung cancer is one of the most common malignant tumors in the world, and its lethality ranks the first among many malignant tumors. For non-small cell lung cancer (NSCLC) patients, due to the high mortality rate, the overall 5-year survival rate is less than 15%. When NSCLC undergoes local invasion, the 5-year survival rate is only 20%, and it is even lower when distant metastasis occurs up to 4%. Almonertinib is an innovative drug independently researched and developed by China with independent intellectual property rights. As an epidermal growth factor receptor tyrosine kinase inhibitor, almonertinib is mainly used for locally advanced or metastatic NSCLC patients with epidermal growth factor receptor (EGFR) T790M mutation. This study aims to investigate the effects of almonertinib on the proliferation, invasion and migration of NSCLC cells in vitro.@*METHODS@#NSCLC cells H1975 and PC-9 were cultured in vitro. The effects of almonertinib on the proliferation, apoptosis, invasion, and migration of H1975 and PC-9 cells were detected by CCK-8 assay, apoptotic assay and Transwell assay. The expression of invasion and migration related proteins was detected by Western blotting.@*RESULTS@#The CCK-8 experiment showed that almonertinib inhibited the proliferation of H1975 and PC-9 cells in a time- and dose-dependent manner. The IC@*CONCLUSIONS@#Almonertinib can inhibit the proliferation, invasion, and migration of NSCLCH1975 and PC-9 cells in vitro and vivo, and promote the apoptosis of H1975 and PC-9 cells. The underlying mechanism may be related to the inhibition of tumor cell epithelial mesenchymal transformation and metalloproteinase expression.

Renal tuberculosis in an imatinib-treated chronic myeloid leukemia / Tuberculose renal em paciente com leucemia mieloide crônica tratado com imatinibe

ABSTRACT Imatinib, which inhibits tyrosine kinase activity of Bcr-Abl protein, is a standard form of treatment for chronic myeloid leukemia (CML). Through its immunomodulatory effect it affects T cell function in a number of ways. It inhibits antigen-induced T cell activation and proliferation. Antigen-specific T-cells and macrophages are vital for protection against Mycobacterium tuberculosis. Here we present a case of renal tuberculosis associated with imatinib therapy in the maintenance phase of CML. With granulomatous interstitial nephritis and positive tubercular DNA on renal biopsy, the condition was successfully treated with anti-tubercular therapy. This case provides support to the hypothesis that imatinib therapy in CML increases the susceptibility to tuberculosis and strict vigilance is required to enable its early detection and treatment.

RESUMO O imatinibe, um inibidor da atividade da tirosina-quinase da proteína BCR-ABL, faz parte do padrão de tratamento para leucemia mieloide crônica (LMC). Por conta de seu efeito imunomodulador, o imatinibe afeta a função dos linfócitos T de várias maneiras ao inibir a sua ativação e proliferação induzidas por antígenos. Linfócitos T e macrófagos antígeno-específicos são vitais para a proteção contra o Mycobacterium tuberculosis. O presente artigo relata um caso de tuberculose renal associada a terapia com imatinibe na fase de manutenção da LMC. Com nefrite intersticial granulomatosa e positividade para DNA de M. tuberculosis na biópsia renal, o paciente foi tratado com sucesso com terapia antituberculínica. O presente caso corrobora a hipótese de que a terapia com imatinibe na LMC aumenta a suscetibilidade à tuberculose, exigindo vigilância rigorosa para permitir sua detecção e tratamento precoces.

Partial repigmentation of vitiligo with tofacitinib, without exposure to ultraviolet radiation

Abstract Vitiligo is a disease that causes macules and achromic and/or hypochromic patches, which can affect from small areas to the entire tegument. Treatment options are few and are generally ineffective. Recently, some case reports have appeared which show positive results with the use of Janus kinase inhibitors associated with phototherapy. This report details the case of a patient with rheumatoid arthritis associated with vitiligo in treatment for two years, whose condition partially improved initially after eight months of oral tofacitinib at a dose of 5 mg twice a day, without exposure to ultraviolet radiation and with continuous improvement during these two years of treatment.

Tofacitinib en el tratamiento de la colitis ulcerosa: casos clínicos / Tofacitinib for the treatment of ulcerative colitis: report of two cases

Biological therapy dramatically changed the management of Ulcerative Colitis (UC). However, a significant number of these patients fail to respond or have secondary loss of response to this strategy. In this clinical situation, the options include intensification of anti-TNF therapy, the use of a second anti-TNF or being switched to another drug class. Among the later, tofacitinib, an oral small molecule directed against the JAK/STAT pathway, is safe and effective in inducing and maintaining remission in patients with moderate-severe UC. We report two patients with UC refractory to conventional treatment and biological therapy, who responded successfully to the use of tofacitinib.

Novel and potent inhibitors targeting DHODH are broad-spectrum antivirals against RNA viruses including newly-emerged coronavirus SARS-CoV-2

Emerging and re-emerging RNA viruses occasionally cause epidemics and pandemics worldwide, such as the on-going outbreak of the novel coronavirus SARS-CoV-2. Herein, we identified two potent inhibitors of human DHODH, S312 and S416, with favorable drug-likeness and pharmacokinetic profiles, which all showed broad-spectrum antiviral effects against various RNA viruses, including influenza A virus, Zika virus, Ebola virus, and particularly against SARS-CoV-2. Notably, S416 is reported to be the most potent inhibitor so far with an EC of 17 nmol/L and an SI value of 10,505.88 in infected cells. Our results are the first to validate that DHODH is an attractive host target through high antiviral efficacy in vivo and low virus replication in DHODH knock-out cells. This work demonstrates that both S312/S416 and old drugs (Leflunomide/Teriflunomide) with dual actions of antiviral and immuno-regulation may have clinical potentials to cure SARS-CoV-2 or other RNA viruses circulating worldwide, no matter such viruses are mutated or not.

Novel and potent inhibitors targeting DHODH are broad-spectrum antivirals against RNA viruses including newly-emerged coronavirus SARS-CoV-2

Emerging and re-emerging RNA viruses occasionally cause epidemics and pandemics worldwide, such as the on-going outbreak of the novel coronavirus SARS-CoV-2. Herein, we identified two potent inhibitors of human DHODH, S312 and S416, with favorable drug-likeness and pharmacokinetic profiles, which all showed broad-spectrum antiviral effects against various RNA viruses, including influenza A virus, Zika virus, Ebola virus, and particularly against SARS-CoV-2. Notably, S416 is reported to be the most potent inhibitor so far with an EC of 17 nmol/L and an SI value of 10,505.88 in infected cells. Our results are the first to validate that DHODH is an attractive host target through high antiviral efficacy in vivo and low virus replication in DHODH knock-out cells. This work demonstrates that both S312/S416 and old drugs (Leflunomide/Teriflunomide) with dual actions of antiviral and immuno-regulation may have clinical potentials to cure SARS-CoV-2 or other RNA viruses circulating worldwide, no matter such viruses are mutated or not.

Novel and potent inhibitors targeting DHODH are broad-spectrum antivirals against RNA viruses including newly-emerged coronavirus SARS-CoV-2

Emerging and re-emerging RNA viruses occasionally cause epidemics and pandemics worldwide, such as the on-going outbreak of the novel coronavirus SARS-CoV-2. Herein, we identified two potent inhibitors of human DHODH, S312 and S416, with favorable drug-likeness and pharmacokinetic profiles, which all showed broad-spectrum antiviral effects against various RNA viruses, including influenza A virus, Zika virus, Ebola virus, and particularly against SARS-CoV-2. Notably, S416 is reported to be the most potent inhibitor so far with an EC of 17 nmol/L and an SI value of 10,505.88 in infected cells. Our results are the first to validate that DHODH is an attractive host target through high antiviral efficacy in vivo and low virus replication in DHODH knock-out cells. This work demonstrates that both S312/S416 and old drugs (Leflunomide/Teriflunomide) with dual actions of antiviral and immuno-regulation may have clinical potentials to cure SARS-CoV-2 or other RNA viruses circulating worldwide, no matter such viruses are mutated or not.

La leptina promueve la expresión de Hic-5 y la formación de puntos de actina por la vía dependiente de FAK-Src en células epiteliales mamarias MCF10A / Leptin induced Hic-5 expression and actin puncta formation by the FAK/Src-dependent pathway in MCF10A mammary epithelial cells

Resumen Introducción. La leptina es una hormona secretada por los adipocitos que se ha relacionado con el proceso de la transición de epitelio a mesénquima (Epithelial- Mesenchymal Transition, EMT). Promueve la migración e invasión de las células del epitelio mamario mediante la activación de las cinasas FAK y Src, un complejo regulador de vías de señalización que favorecen la expresión de las proteínas relacionadas con la formación de estructuras proteolíticas implicadas en la invasión y progresión del cáncer. Recientemente, se ha descrito que la sobreexpresión y activación de la proteína Hic-5 durante el mencionado proceso de transición, favorece la formación de los puntos de actina (indicativa de la formación y funcionalidad de los invadopodios), lo cual promueve la degradación local de los componentes de la matriz extracelular y la metástasis del cáncer. Objetivos. Evaluar el papel de las cinasas FAK y Src sobre la expresión y localización subcelular de Hic-5 y la formación de puntos de actina inducida por la leptina en la línea celular MCF10A de epitelio mamario no tumoral. Materiales y métodos. Se utilizaron los inhibidores específicos de la FAK (PF-573228) y la Src (PP2) para evaluar el papel de ambas cinasas en los niveles de expresión y localización subcelular de la proteína Hic-5 mediante Western blot e inmunofluorescencia, así como la formación de puntos de actina mediante la tinción con faloidina-TRITC en células MCF10A estimuladas con leptina. Resultados. La leptina indujo el incremento en la expresión de Hic-5 y la formación de puntos de actina. El tratamiento previo con los inhibidores de las cinasas FAK (PF-573228) y Src (PP2), promovió la disminución en la expresión de Hic-5 y de los puntos de actina en la línea celular MCF10A de epitelio mamario no tumoral. Conclusión. La leptina indujo la expresión y la localización perinuclear de Hic-5 y la formación de puntos de actina mediante un mecanismo dependiente de la actividad de las cinasas FAK y Src en las células MCF10A.

Abstract Introduction: Leptin is a hormone secreted by adipocytes that has been associated with the epithelial-mesenchymal transition (EMT). Additionally, leptin promotes the migration and invasion of mammary epithelial cells through the activation of FAK and Src kinases, which are part of a regulatory complex of signaling pathways that promotes the expression of proteins related to the formation of proteolytic structures involved in the invasion and progression of cancer. Recently, overexpression and activation of Hic-5 during the EMT have been shown to induce the formation of actin puncta; these structures are indicative of the formation and functionality of invadopodia, which promote the local degradation of extracellular matrix components and cancer metastasis. Objective: To evaluate the role of FAK and Src kinases in the expression of Hic-5 during the epithelial-mesenchymal transition induced by leptin in MCF10A cells. Materials and methods: We used specific inhibitors of FAK (PF-573228) and Src (PP2) to evaluate Hic-5 expression and subcellular localization by Western blot and immunofluorescence assays and to investigate the formation of actin puncta by epifluorescence in MCF10A cells stimulated with leptin. Results: Leptin induced an increase in Hic-5 expression and the formation of actin puncta. Pretreatment with inhibitors of FAK (PF-573228) and Src (PP2) promoted a decrease in Hic-5 expression and actin puncta formation in the non-tumorigenic mammary epithelial cell line MCF10A. Conclusion: In MCF10A cells, leptin-induced Hic-5 expression and perinuclear localization, as well as the formation of actin puncta through a mechanism dependent on the kinase activity of FAK and Src.

Tratamiento con tofacitinib en adolescentes con alopecia areata / Tofacitinib as a treatment of alopecia areata in adolescents

Resumen Introducción: Actualmente no existe un tratamiento estandarizado para la alopecia areata (AA) grave. Se han reportado numerosos casos exitosos del uso de tofacitinib; sin embargo, no existen publicaciones en México. En este trabajo se reportan cuatro casos de pacientes mexicanos con AA grave tratados con tofacitinib oral. Métodos: Serie de casos de adolescentes con alopecia grave tratados con tofacitinib oral. Para determinar la respuesta al tratamiento se utilizó la Escala de gravedad de alopecia (Severity of alopecia tool). Resultados: Se incluyeron cuatro pacientes de entre 13 y 19 años con AA. En todos los casos se observó crecimiento de cabello y disminución de la gravedad de la alopecia después del tratamiento con tofacitinib. En dos pacientes se observó una respuesta intermedia (del 51 al 90%), y en los otros, moderada (del 6 al 50%), sin efectos adversos serios. Las limitaciones del estudio fueron el tamaño reducido de la muestra y la naturaleza retrospectiva de la recolección de los datos. Conclusiones: El tofacitinib demostró ser una buena alternativa de tratamiento para la AA, total y universal, refractarias a otras terapias.

Abstract Background: Currently, no standardized treatment for severe alopecia areata (AA) exists. Numerous successful cases of the use of tofacitinib have been reported in the world literature, but not in Mexico. Four Mexican adolescents with severe AA treated with oral tofacitinib are reported in the present work. Methods: Series of cases of adolescents with severe AA treated with oral tofacitinib. The severity of alopecia tool was used to determine the response to treatment. Results: Four patients from 13 to 19 years old, were included. In all cases, hair growth was observed, and the alopecia severity decreased after the treatment with tofacitinib. In two patients, an intermediate response (from 51 to 90%) was observed; in the other, a moderate response (from 6 to 50%) was observed, without serious adverse effects. The limitations of the study were the small sample size and the retrospective nature of data collection. Conclusions: Tofacitinib showed to be a good treatment alternative for AA, total and universal, refractory to other therapies.