Tuberous Sclerosis Complex and the kidneys: what nephrologists need to know / Complexo da Esclerose Tuberosa e rins: o que os nefrologistas devem saber

Abstract Tuberous sclerosis complex (TSC) is an autosomal dominant disease characterized by the development of hamartomas in the central nervous system, heart, skin, lungs, and kidneys and other manifestations including seizures, cortical tubers, radial migration lines, autism and cognitive disability. The disease is associated with pathogenic variants in the TSC1 or TSC2 genes, resulting in the hyperactivation of the mTOR pathway, a key regulator of cell growth and metabolism. Consequently, the hyperactivation of the mTOR pathway leads to abnormal tissue proliferation and the development of solid tumors. Kidney involvement in TSC is characterized by the development of cystic lesions, renal cell carcinoma and renal angiomyolipomas, which may progress and cause pain, bleeding, and loss of kidney function. Over the past years, there has been a notable shift in the therapeutic approach to TSC, particularly in addressing renal manifestations. mTOR inhibitors have emerged as the primary therapeutic option, whereas surgical interventions like nephrectomy and embolization being reserved primarily for complications unresponsive to clinical treatment, such as severe renal hemorrhage. This review focuses on the main clinical characteristics of TSC, the mechanisms underlying kidney involvement, the recent advances in therapy for kidney lesions, and the future perspectives.

Resumo O complexo da esclerose tuberosa (CET) é uma doença autossômica dominante caracterizada pelo desenvolvimento de hamartomas no sistema nervoso central, coração, pele, pulmões e rins e outras manifestações, incluindo convulsões, tubérculos corticais, linhas de migração radial, autismo e deficiência cognitiva. A doença está associada a variantes patogênicas nos genes TSC1 ou TSC2, resultando na hiperativação da via mTOR, um importante regulador do crescimento e metabolismo celular. Consequentemente, a hiperativação da via mTOR leva à proliferação anormal do tecido e ao desenvolvimento de tumores sólidos. O envolvimento renal no CET é caracterizado pelo desenvolvimento de lesões císticas, carcinoma de células renais e angiomiolipomas renais, que podem progredir e causar dor, sangramento e perda da função renal. Nos últimos anos, houve uma mudança notável na abordagem terapêutica do CET, especialmente no tratamento das manifestações renais. Os inibidores de mTOR surgiram como a principal opção terapêutica, enquanto intervenções cirúrgicas como nefrectomia e embolização são reservadas principalmente para complicações que não respondem ao tratamento clínico, como hemorragia renal grave. Esta revisão se concentra nas principais características clínicas do CET, nos mecanismos subjacentes ao envolvimento renal, nos recentes avanços na terapia para lesões renais e nas perspectivas futuras.

Research progress on the treatment of Alzheimer's disease based on the target of mammalian target of rapamycin / 中国临床药理学与治疗学

Mammalian target of rapamycin (mTOR) regulates cell survival, proliferation, and metabolism. Alzheimer's disease (AD) is a common neurodegenerative disease with a complex pathogenesis and is closely related to aging. Studies have found that the pathological development of AD is often accompanied by changes in mTOR activity, but the role of mTOR in the pathogenesis of AD is not clear. In this paper, the complex of mTOR and its signaling pathways are first introduced, focusing on the effects of mTOR signaling pathways on synaptic plasticity and memory function, autophagy, βamyloid-β (Aβ), Tau protein and brain insulin resistance and other AD pathological features, secondly, the regulatory effects of mTOR signaling pathways in anti - aging and life prolongation are described, and finally the application of mTOR inhibitors in AD pathological research is introduced to provide new ideas for delaying and improving AD.

Sarcoma de Kaposi en orofaringe en paciente postrasplante renal y manejo con inhibidor de señal de coestimulación e inhibidor de mTOR

Introducción: el sarcoma de Kaposi en pacientes de postrasplante renal es poco frecuente y está asociado usualmente a infección por herpes 8 y a dosis altas de inmunosupresión. Objetivo: descripción reporte de caso de Sarcoma de Kaposi en orofaringe en paciente postrasplante renal manejo con inhibidor de señal de coestimulación e inhibidor mTOR. Presentación del caso: en este artículo se describe el caso de una paciente, con antecedente de trasplante renal, con diagnóstico de sarcoma de Kaposi en una localización muy poco frecuente: a nivel orofaríngeo. Se realiza una revisión de los factores de riesgo, patogenia y un acercamiento en el manejo. De igual manera, se realiza un seguimiento y manejo con inhibidor de señal de coestimulación (belatacept) e inhibidor de mTOR. Discusión y conclusión: el sarcoma de Kaposi es una de las neoplasias postrasplante con mayor incidencia comparativamente con la población no trasplantada, donde el papel de la reactivación de la infección viral, más el papel de la inmunosupresión, son puntos fundamentales en la génesis de la neoplasia. La determinación del estatus serológico IgG para HHV8 podría ser una estrategia de determinación del riesgo en el pretrasplante.

Introduction: Kaposi sarcoma in post-renal transplantation patients is a rare entity, usually associated with herpes 8 infection and high doses of immunosupresion. Purpose: Case report description of Kaposi's sarcoma in the oropharynx in a post-renal transplant patient managed with co-stimulation signal inhibitor and mTOR inhibitor. Case presentation: This article describes the case of a patient, with a history of renal transplant, with a diagnosis of Kaposi's sarcoma in a very rare location: oropharyngeal level. A review of the risk factors, pathogenesis and a management approach is made. Likewise, a follow-up and management with co-stimulation signal inhibitor (belatacept) and mTOR inhibitor is performed. Discussion and conclusion: Kaposi's sarcoma is one of the post-transplant neoplasms with the highest incidence compared to the non-transplanted population, where the role of viral infection reactivation, plus the role of immunosuppression, are fundamental points in the genesis of the neoplasm. The determination of IgG serological status for HHV8 could be a strategy to determine risk in pretransplantation.

Comparison of effects of m-TOR inhibitors and calcineurin inhibitor on SUPAR and ox-LDL levels in renal transplant recipients / Comparación de los efectos de los inhibidores de m-TOR y el inhibidor de calcineurina sobre los niveles de SUPAR y ox-LDL en receptores de trasplante renal

ABSTRACT Introduction: We aimed to investigate the effect of different immunosuppressive regimens on SUPAR and ox-LDL levels which are early markers of inflammation in renal transplant recipients. Methods: A total number of 83 patients were enrolled in our study. While fourty- eight of those were received mTORi, thirty five patients were been receiving CNI. According to the immunosuppressive regimen patients were divided into CNI and m-TORi receving groups and serum SUPAR and ox-LDL levels were measured. Results: Log-SUPAR values were lower in the group receiving m-TORi (3.40 ± 0.1 vs 3.48 ± 0.4, p=0.010). OxLDL / LDL levels were higher (0.0168± 005 vs 0.0132 ±004, p=0.009) in the CNI group. In linear regression analysis, a statistically significant relationship was detected between the use of m-TORi and log-SUPAR (β = -0.052, 95% CI [-0.224, -0.012], p = 0.041) . A negative and independent relationship was found between HT and log-SUPAR (β = -0.60, 95% CI--0.112, -0.018], p=0.0024) and ox-LDL (β = -0.169 [-0.330, -0.008], p=0.040). Very strong correlation (r=1.0, p=<0.001) and independent relationship (β=0.321 [0.313,0.330], p=<0.001) was detected between ox-LDL and SUPAR. Conclusion: As a result, when compared immunsuppression between m-TORi and CNI, the former was associated with lower SUPAR and oxLDL levels.

RESUMEN Introducción: Nuestro objetivo fue investigar el efecto de diferentes regímenes inmunosupresores sobre los niveles de SUPAR y ox-LDL, que son marcadores tempranos de inflamación en receptores de trasplante renal. Material y métodos: Un total de 83 pacientes se inscribieron en nuestro estudio. Mientras que cuarenta y ocho de ellos recibieron mTORi, treinta y cinco pacientes recibieron CNI. De acuerdo con el régimen inmunosupresor, los pacientes se dividieron en grupos receptores de CNI y m-TORi y se midieron los niveles séricos de SUPAR y ox-LDL. Resultados: Los valores de Log-SUPAR fueron menores en el grupo que recibió m-TORi (3,40 ± 0,1 vs 3,48 ± 0,4, p = 0,010). Los niveles de OxLDL/LDL fueron mayores (0,0168± 005 vs 0,0132 ±004, p=0,009) en el grupo CNI. En el análisis de regresión lineal, se detectó una relación estadísticamente significativa entre el uso de m-TORi y log-SUPAR (β = -0,052, IC del 95% [-0,224, -0,012], p = 0,041). Se encontró una relación negativa e independiente entre HT y log-SUPAR (β = -0.60, 95% IC--0.112, -0.018], p = 0.0024) y ox-LDL (β = -0.169 [-0.330, -0.008], p = 0,040). Se detectó una correlación muy fuerte (r = 1,0, p <0,001) y una relación independiente (β = 0,321 [0,313, 0,330], p <0,001) entre ox-LDL y SUPAR. Conclusión: Como resultado, cuando se comparó la inmunosupresión entre m-TORi y CNI, la primera se asoció con niveles más bajos de SUPAR y oxLDL.

Research advances in the mammalian target of rapamycin signaling pathway and its inhibitors in treatment of hepatocellular carcinoma / 中华肝脏病杂志

Mammalian target of rapamycin (mTOR) is a serine/threonine protein kinase in the downstream of the phosphatidylinositol 3-kinases (PI3K) family. This kinase plays an important role in the development and progression of hepatocellular carcinoma (HCC). Preclinical data demonstrate that 40%-50% of HCC patients have dysregulated expression of the effectors of the mTOR signaling pathway, and the activation of the mTOR pathway is associated with poorly differentiated tumors, early tumor recurrence, and poor survival/prognosis. This article reviews the research advances in the potential role of the mTOR signaling pathway and its inhibitors in the treatment of HCC.

Research progress of mTOR inhibitors in the treatment of breast cancer / 肿瘤研究与临床

Although the treatment has made great progress in breast cancer, there are still many problems. For example, primary or secondary on chemotherapy drug resistance and the limitation of treatment in triple-negative breast cancer. So, targeted therapy has become a new strategy to improve this situation. Previous studies showed that the occurrence of breast cancer may be related to the activation of PI3K/Akt/mTOR signaling pathways, and mTOR is an index to judge the prognosis. Parts of breast cancers can obtain clinical benefit with mTOR inhibitors, and it might be a potential treatment target in breast cancer.

Chemotherapy in adult soft tissue sarcoma.

Soft tissue sarcomas (STSs) are rare and histologically diverse neoplasms. Recent results of various meta-analyses and development of newer drugs have changed the medical management of soft tissue sarcoma. This review gives an outline of chemotherapy and the newer targeted therapies for the same. We have carried out an extensive search in PubMed, Medline for almost all relevant articles concerning chemotherapy of soft tissue sarcoma. The available data from the literature is mainly composed of the most recent reviews, meta-analyses, phase II, and randomized phase III trials published in various peer reviewed journals and various international conferences. The role of neoadjuvant and adjuvant chemotherapy has been found to be controversial. The recent meta-analysis for adjuvant therapy in STSs has shown an increase in the overall survival with combination of ifosfamide and adriamycin. In locally advanced and metastatic STSs, single agent adriamycin remains the basic standard of medication. The combination of ifosfamide and adriamycin may also be used for rapid symptom relief and in patients planned for curative resection for metastases. Newer combinations of docetaxel and gemcitabine appear promising in selected subgroups, especially in leiomyosarcoma and malignant fibrous histiocytoma. Some recent developments include the European Union's approval of trabectedin for advanced STSs patients who had progressed on adriamycin and ifosfamide therapy. The future of mTOR inhibitors, insulin like growth factor receptor inhibitors and anti-angiogenic drugs appear quite promising. Newer methodologies such as, Bayesian adaptive randomization and inclusion of newer end points like progression-free rate, time of progression rate, and tumor growth rate will improve the results of sarcoma trials. At the end of each section we have also presented recommendations from *European Society of Medical Oncology and **National Comprehensive Cancer Network guidelines v.1.2009 for better correlation with the present literature.