Advances in the pathogenesis and molecular regulatory therapy of cystic fibrosis / 中华实用儿科临床杂志

Cystic fibrosis (CF) is an autosomal recessive monogenetic disease caused by homozygous and double-heterozygous mutations of the cystic fibrosis transmembrane conductance regulator ( CFTR)gene.The CFTR gene encodes a chloride ion channel protein, which is distributed in the airway, pancreatic duct epithelium and other body parts.CFTR dysfunction will give rise to a series of clinical manifestations.Remarkable achievements have been made in specific molecular regulatory therapy targeting CFTR dysfunction over the past 10 years.CF has thus become a model disease, which provides new approaches for the research on genetics, molecular and cellular pathogenesis, and drug discovery of other rare genetic diseases.In this article, the latest research progress on the pathogenesis and molecular regulatory therapy of CF in recent years was reviewed to improve clinical understanding of the disease mechanism and molecular regulatory therapy.

Recentes avanços no tratamento da anemia falciforme / Recent advances in the sickle cell anemia treatment

A anemia falciforme é a doença monogênica de maior ocorrência mundial e é causada pela presença de hemoglobina S (HbS), uma variante estrutural decorrente da substituição de um aminoácido na cadeia ß globina. Essa mutação altera as propriedades bioquímicas e fisiológicas da hemoglobina, que tem a tendência de formar agregados fibrilares, no estado desoxigenado, o que produz alterações morfológicas (falcização) e funcionais da hemácia. Assim, todas as manifestações clínicas observadas na doença decorrem da presença da HbS e têm início com a hemólise e a vaso-oclusão, desencadeando os demais eventos da doença, que podem afetar os órgãos e sistemas orgânicos. O tratamento baseia-se no controle dos sintomas. O único medicamento aprovado que altera o curso da doença é o antineoplásico hidroxiureia e, apesar de seu sucesso clínico, não é curativo e pode desencadear muitos efeitos adversos. O único tratamento curativo é o transplante de células tronco hematopoéticas. A terapia gênica vem sendo estudada há mais de 30 anos e alguns estudos clínicos estão sendo realizados. Novas abordagens moleculares como a edição do genoma, uso de RNA terapêutico e manipulação genética para indução da síntese de hemoglobina fetal emergem como possibilidades para a cura da doença. (AU)

Sickle cell anemia is the most common monogenic disease worldwide and it is caused by the presence of sickle hemoglobin (HbS), structural variant hemoglobin with one amino acid substitution in the ß globin chain. This mutation changes the biochemical and physiological properties of hemoglobin, which has the tendency, in the de-oxygenated state, to form fibrous aggregates, which produces morphological (sickling) and functional changes in red blood cells. Thus, all the observed disease clinical manifestations arise from the presence of HbS and begin with hemolysis of the red blood cell and vaso-occlusion, triggering other disease events, which can affect the body organs and systems as a whole. Nowadays, treatment is based mainly in symptoms control. The only drug approved that changes the course of the disease is the antineoplastic Hydroxyurea and, despite its clinical success, it is not curative and can trigger many adverse effects. The only curative treatment is the hematopoietic stem cells transplantation. Gene therapy has been studied for more than 30 years and some clinical studies are being in course. New molecular approaches as the genome editing, therapeutic RNA and genetic manipulation to stimulate fetal hemoglobin synthesis emerge as possible curative options for the disease. (AU)

Uveoretinal Adverse Effects Presented during Systemic Anticancer Chemotherapy: a 10-Year Single Center Experience

BACKGROUND: The present study describes our 10-year experience with uveoretinal adverse events that manifest because of chemotherapy. METHODS: A retrospective chart review was performed for all patients who presented to the ophthalmologic department while undergoing systemic chemotherapy between July 2005 and June 2015. RESULTS: A total of 55 patients (mean age, 51.2 years, 38 women [69.1%]) suspected of having uveoretinal disease owing to the use of chemotherapeutic agents alone were enrolled. Breast cancer was the predominant disease (36.4%); noninfectious anterior uveitis (21.8%) was the most common condition. Bilateral involvement was observed in 16 patients (29.1%). Although cisplatin (21.8%) was the most commonly used drug, daunorubicin, cytarabine, tamoxifen, toremifene, and imatinib were also frequently used. The median duration until ophthalmologic diagnosis was 208.5 days (range, 19–5,945 days). The proportion of patients with final visual acuity (VA) < 20/40 Snellen VA (0.5 decimal VA) was 32.7%. However, no relationship was observed between final VA < 20/40 and age, sex, therapeutic agents, and metastasis. CONCLUSION: Uveoretinal complications were mostly mild to moderate and exhibited a favorable response to conservative therapy. A considerable number of patients exhibited significant irreversible loss of vision after cessation of the causative chemotherapeutic agent. Ophthalmological monitoring is required during chemotherapy.

Research progress of acetyl-CoA carboxylase in cancer metabolism / 国际肿瘤学杂志

Abnormal fatty acid metabolism is one of the unique metabolic ways in which malignant cells maintain their growth needs and plays a crucial role in tumor progression.Acetyl-CoA carboxylase (ACC) is the rate-limiting enzyme in fatty acid synthesis and oxidative metabolism.More and more researches confirm that ACC is highly expressed in many tumors,and is closely related to tumor progression and prognosis of patients,which makes ACC as a potential marker for clinical diagnosis and prognosis.Tumor cell fatty acid synthesis can be blocked and fatty acid β oxidation can be stimulated by inhibiting the activity of ACC,resulting in serious lipid consumption of tumor,and then inhibit tumor growth and proliferation.Investigating the effect and molecular mechanisms of ACC in the genesis and development of tumors can provide a new insight into cancer targeted molecular therapy.

Presurgical targeted molecular therapy in renal cell carcinoma with inferior vena cava tumor thrombus / 中华泌尿外科杂志

Objective To investigate the therapeutic effects of presurgical TMT on the heights and levels of inferior vena cava(IVC)thrombi,and to assess its impact on surgical strategy.Methods We retrospectively reviewed data of 18 patients with renal cell carcinoma(RCC)involving IVC tumor thrombi who were treated at our hospital with presurgical TMT followed by an IVC thrombectomy.Data from 18 patients(16 men and 2 women)were included in the analysis.The median age was 53.5 years(range:33-75 years),and the mean BMI was 24.7kg/m2(rrange:18.1 -30.4 kg/m2).4 cases of tumors located in the left kidney,14 cases were right.The changes in heights and levels of the IVC thrombi were compared using computed tomography or magnetic resonance imaging.The IVC tumor thrombus level was evaluated according to the Mayo classification.Results The tumor thrombus levels before TMT were stage Ⅰ in 1 patient,Ⅱ in 1 2 patients,Ⅲ in 4 patients,and Ⅳ in 1 patient.The presurgical TMT was sorafenib in 6 patients(33.3%),sunitinib in 9(50.0%),and axitinib in 3(16.7%).After a median of 2 treatment cycles(range:1-6 cycles),three patients experienced grade 3 adverse events.One patient stopped treatment after 6 weeks owing to intolerable skin reactions and difficulty walking.The tumor thrombus height decreased measurably in 11 patients(61.1%).The thrombus height remained stable in 5 patients(27.8%)and was enlarged in 2(11.1%).The median reduction of tumor thrombus height was -0.53 cm (range:-4.23 to 1.21 cm).The median change in the maximum diameter of the thrombus was -0.30 cm (range:-1.23 to 0.29 cm).Down-staging of the thrombus level occurred in 4 patients(22.2%);the surgical strategy was modified in 3 patients(level≥Ⅲ)to avoid cardiopulmonary bypass and complicated liver mobilization under robot-assisted laparoscopy.Conclusions Our data suggest a limited influence of presurgical TMT,with a positive benefit in RCC patients with level Ⅲ and Ⅳ thrombus.Thrombus-level regression may potentially alter the surgical strategy,especially robotic surgery.Additionally,preoperative targeted therapy did not significantly increase perioperative mortality and risk of serious complications.

Research progress of AIDS treatment / 中国人兽共患病学报

AIDS antiviral therapy (ART) has achieved great success.Originaly,AIDS had been regarded as a fatal disease,but it has become a kind of infectious disease that could be cured and administrated.Global HIV / AIDS cases were still up to about 38 million,but more than half have been effectively treated.In addition to drug treatment,at present,some new technologies and new methods,such as genome editing,have also been involved in the treatment of AIDS,and in the humanized animal experiment has shown very good results.There is no doubt that AIDS will eventually be stopped its epidemic.However,with the continuous development of AIDS antiviral treatment,the most fundamental problem is that HIV latent library has become increasingly prominent one,whether molecular therapy and hybrid cure have being developed for AIDS treatment,there are still such problem existence.Great efforts shoud be made to continuously search for new markers of latent viral cells and to reduce the latent pool.In addition,despite the prevention and treatment of AIDS has made great achievements,but the world still produces nearly 6000 cases of HIV/AIDS every day.Therefore,the development of safe and effective vaccine,whether in the field of prevention,or in clinical treatment,has its positive significance.

Clinical applications of molecular basis for craniosynostosis: a narrative review / Aplicaciones clínicas de las bases moleculares de la craneosinostosis: revisión narrativa

Abstract: cranial sutures are specialized structures composed of the sutural mesenchyme, the overlying scalp, the dura and osteogenic fronts. Each one of these structures express important proteins for osteogenic maturation, membranous ossification of skull bones, and homeostasis of cranial sutures in a differential, spatial and temporal manner. These proteins include fibroblast growth factor (FGF) and its receptors (FGFR), the transforming growth factor beta (TGF-beta), bone morphogenetic proteins (BMPs), as well as transcription factors TWIST and MSX2, among others. The alteration in the expression of one or more of these proteins causes multiple pathological conditions; one of them is the premature closure of one or more cranial sutures, known as craniosynostosis. This malformation is commonly treated with surgery. However, advances in the fields of molecular and cellular biology have allowed to conduct research on some proteins involved in the development of craniosynostosis. The results of these studies can lead to future preventive therapeutic strategies that may be used as a complement to the surgical treatment of craniosynostosis. Possible strategies include the use of specific drugs that can regulate the expression and activation of FGF signaling pathways, TGF-beta or BMPs, to prevent or avoid craniosynostosis or re-synostosis after a surgery.

Resumen: las suturas craneales son estructuras especializadas compuestas por el mesénquima sutural, el pericráneo suprayacente, la duramadre y los frentes osteogénicos. Cada una de estas estructuras expresan de forma diferencial, espacial y temporalmente, proteínas importantes para la maduración osteogénica, la osificación membranosa de los huesos calvarios y la homeostasis de las suturas craneales. Estas proteínas incluyen el factor de crecimiento fibroblástico (FGF) y sus receptores (FGFR), el factor de crecimiento transformante beta (TGF-beta), las proteínas morfogenéticas óseas (BMPs), así como factores de transcripción TWIST y MSX2, entre otros. La alteración en la expresión de una o varias de estas proteínas provoca múltiples condiciones patológicas, una de ellas es el cierre prematuro de una o varias suturas craneales, conocido como craneosinostosis. Esta malformación es comúnmente tratada con cirugía. Sin embargo, los avances en los campos de la biología molecular y celular han permitido investigar algunas proteínas que participan en el desarrollo de la craneosinostosis. Los resultados de estos estudios pueden generar futuras estrategias terapéuticas preventivas o que complementen los tratamientos quirúrgicos de la craneosinostosis. Algunas estrategias posibles son el uso de fármacos específicos que puedan regular la expresión y activación de las vías de señalización del FGF, el TGFbeta o de las BMPs, para prevenir la craneosinostosis o evitar la resinostosis tras una cirugía.

A Prospective Multicenter Trial of the Efficacy and Tolerability of Neoadjuvant Sunitinib for Inoperable Metastatic Renal Cell Carcinoma

This study aimed to evaluate the efficacy, safety, and tolerability of 2-cycled neoadjuvant sunitinib therapy (NST) in patients with inoperable metastatic renal cell carcinoma (mRCC). Between 2009 and 2012, 14 patients with inoperable mRCC from 5 Korean academic centers were prospectively enrolled after collecting their clinicopathological data and completing health-related questionnaires. The best overall response (BOR), safety profile, and changes in quality of life during NST were assessed using the RECIST criteria (version 1.0), CTCAE criteria (version 4.0), and the Cancer Quality of Life Questionnaire (QLQ-C30). Among the 14 patients, 9 patients (64.3%) experienced partial response or stable disease state, and 5 patients (35.7%) did not complete treatment, with 1 case of disease progression (7.1%), 3 grade 3 adverse events (21.4%), and 1 voluntary withdrawal (7.1%). Four patients (28.6%) were successfully converted to an operable state and underwent surgery after NST. The BOR for the primary renal lesions was 22.2%, with a median 1.3-cm diameter reduction (range: 0–2.8 cm) from a baseline diameter of 10.3 cm (range: 6.6–15.8 cm). The other 18 measurable metastatic lesions exhibited a BOR of 55.6%. The QLQ-C30 questionnaire results revealed significant improvements in the quality of life domain, although we observed significant increases in the scores for fatigue, nausea and vomiting, and the financial effects of NST (P < 0.05). Two-cycle NST provided limited efficacy for resectability of inoperable mRCC, despite mild improvements in the BOR of the primary lesion and quality of life (Clinical Trial Registry 1041140-1).

Comparison of efficacy and safety between intensity-modulated radiotherapy combined with chemotherapy plus targeted therapy and intensity-modulated radiotherapy combined with chemotherapy for locally advanced nasopharyngeal carcinoma / 中华放射肿瘤学杂志

Objective To retrospectively compare the efficacy and toxicity between intensity?modulated radiotherapy ( IMRT ) combined with chemotherapy plus targeted therapy and IMRT combined with chemotherapy in the treatment of patients with locally advanced nasopharyngeal carcinoma ( NPC) , and to preliminarily evaluate the necessity of adding targeted drugs to standard chemoradiotherapy . Methods Forty?two patients with stage Ⅲ?Ⅳb NPC who received IMRT combined with concurrent ± adjuvant chemotherapy plus targeted molecular therapy from January 2007 to December 2012 were assigned to experiment group,while 168 patients who received IMRT combined with concurrent ±adjuvant chemotherapy within the same period were assigned to control group. The experiment group was paired with the control group at a ratio of 1vs.4.The survival rates were caculated using Kaplan?Meier method and analyzed using log?rank method,other comparison was perfomed by χ2?test. Results The follow?up rate was 100%.The sample size of experiment group and control group were 42 patients and 168 patients. There were no significant differences in the 3?year OS, LRFS, or DMFS rates between the experiment group and the control group (94?3% vs. 87?3%, P=0?647;100?0% vs. 94?6%,P=0?193;92?2% vs. 89?1%, P=0?744).There were also no significant differences in the incidence rates of grade Ⅲ?Ⅳ gastrointestinal reaction or marrow suppression between the two groups ( 7?1%( 3/42 ) vs. 3?6%( 6/168 ) , P=0?388;26?2%( 11/42 ) vs. 17?3%(29/168),P=0?272).However,the experiment group had significantly higher incidence of grade Ⅲ?Ⅳoral mucositis than the control group ( 40?5%( 17/42 ) vs . 14?9%( 25/168 ) , P=0?000 ) . Conclusions The preliminary results indicate that IMRT combined with chemotherapy plus targeted molecular therapy is not able to substantially improve the OS, LRFS, or DMFS rates in patients with locally advanced NPC. Moreover, it may aggravate radiochemotherapy?induced oral mucositis.

Acuaporinas, implicaciones en modelos patológicos, de tratamiento y rol clínico / Aquaporins, implications at pathologic models, of treatment and clinical role

Las acuaporinas son un grupo de proteínas integrales de membrana cuya estructura y función parten de la simple concepción del transporte de fluidos transmembrana, sin embargo la complejidad de su utilidad recién comienza a comprenderse. Se han implicado en múltiples modelos patogénicos de varias índoles. Desde su papel en el muy estudiado transporte y generación de orina de concentración normal, su rol en la patogenia de la diabetes insípida y la respuesta hormonal a la vasopresina, como su papel en la tumorigenesis de múltiples neoplasias y en la patogenia y posible utilidad en la terapéutica de lesiones del sistema nervioso central (SNC) así como el entendimiento de las mismas para el desarrollo de nuevas técnicas terapéuticas.

Aquaporins are a group of membrane integral proteins which structure and function start's from the simple concept of the transmembrane fluid movement, however the complexion of its utility it's beginning to rise in comprehension. It has been implicated in multiple pathogenic models from al sorts. From it's role in the widely studied transport and urine of normal concentration generation, its role on insipid diabetes pathogenesis and the hormonal response to vasopressin. Roles in the tumorigenesis of many cancers, and its role as a prognostic factor expression in cutaneous neoplasms. Also it's role in the pathogenesis and potential utility in the therapy of the central nervous system CNS lesions, as well as it is for the understanding of the development of new therapeutic techniques.

Cancer Treatment near the End-of-Life Becomes More Aggressive: Changes in Trend during 10 Years at a Single Institute / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: The purpose of this study was to investigate and compare cancer treatment near the end-of-life (EOL) over a 10-year period. MATERIALS AND METHODS: Patients with advanced solid cancer at Seoul National University Hospital who received palliative chemotherapy and had died were enrolled. We categorized the consecutive patients according to two time periods: 2002 (n=57) and 2012 (n=206). Aggressiveness of cancer treatment near the EOL was evaluated. RESULTS: The median patient age was 62, and 65.4% of patients (n=172) were male. Time from the last chemotherapy to death (TCD) was found to have been significantly shortened, from 66.0 days to 34.0 days during 10 years (p < 0.001); 17% of patients received molecular targeted agents as the last chemotherapy regimen in 2012. The proportion of patients who received intensive care unit care within the last month increased from 1.8% in 2002 to 19.9% in 2012 (p < 0.001), and emergency room visits within the last month also increased from 22.8% to 74.8% (p < 0.001). Although hospice referral increased from 9.1% to 37.4% (p < 0.001), timing of referral was delayed from median 53 days to 8 days before death (p=0.004). Use of targeted agents as the last chemotherapy for over-two-regimen users was associated with shortened TCD (hazard ratio, 2.564; p=0.002). CONCLUSION: Cancer treatment near the EOL became more aggressive over 10 years.

Progress in immunotherapy and molecular therapy for liver failure / 临床肝胆病杂志

Liver failure is a complex process involving many factors. The molecular therapy targeting the cytokines and receptors associated with liver failure has become the research hotspots in recent years. Immunotherapy for liver failure includes promoting the regeneration of hepatocytes and immunoregulation by thymosin, and the combination of immunomodulatory therapy with traditional therapy is widely applied in clinical treatment. Research on the animal model of liver failure suggested that importing ARC protein or hepatocyte nuclear factor 4 protected hepatocytes and promoted the recovery of their function. Block therapy against liver failure-related molecules (fibrinogen-like protein 2, apoptosis-related molecules, transforming growth factor β, osteopontin, nuclear factor-κB, and Toll-like receptors, etc.) successfully cured the animal model of liver failure. The research on molecular therapy offers a new way for treatment of liver failure, but it is still in the stage of laboratory research at present and lacks clinical data.

Use of animal models of atrial fibrillation in the study of cellular and molecular therapy / 中国实验动物学报

Atrial fibrillation ( AF) is an abnormal heart rhythm characterised by rapid and irregular beating.It is caused by multiple factors and can lead to ischemia-associated thrombosis, heart failure and other complex symptoms. Based on the etiology and characteristics of AF, animal models have 3 main categories including electrical, neurohormonal or vessel-related, and structural remodeling models.New technologies such as microRNA knock-down/overexpression or CRISPR-Cas9 gene editing provide tools for constructing animal AF models and directions in the development of AF thera-peutic strategies.Currently these strategies have largely focused on the cellular and molecular therapeutics rather than tradi-tional invasive electrophysiological methods or antiarrhythmic drugs.With the aid of new tools, progress has been greatly made in a broad range of therapeutic research areas including molecular mechanisms, drug targeting and screening.This re-view summarizes the animal models of atrial fibrillation currently used in studies of the molecular and cellular therapeutics and notes their contributions to this research area.

Exploration of tumor response evaluation criteria in the era of tar-geted therapy / 中国肿瘤临床

The era of targeted molecular therapy for cancer has arrived. The mechanisms of targeted molecular drugs are different from those of chemotherapy drugs. The tumor response evaluation criteria that we currently use are the summary of experiences from evaluating the effect of chemotherapy drugs. Despite continuous improvement and standardization of the details, tumor response evalua-tion criteria, from the earliest WHO criteria to the improved RECIST and RECIST 1.1 criteria, are all based on measurement of tumor size, as chemotherapy drugs directly kill tumor cells. The aforementioned criteria are outlined in this review. However, targeted molecu-lar drugs mainly inhibit tumor cell proliferation. The effect of targeted molecular drugs on tumors is different from that of chemothera-py drugs. Thus, tumor response evaluation criteria suitable for targeted molecular drugs have been developed in recent years. This re-view introduces Choi criteria that use CT attenuation coefficient (Hounsfield unit [HU]) to describe tumor density. The criteria have measured indicators that include tumor size and tumor density. This review also introduces the following criteria derived from the Choi criteria for Modified Choi (mChoi) criteria size and attenuation CT (SACT), and morphology, attenuation, size, and structure (MASS).

Molecular targeting therapy for gastric cancer / 医学研究生学报

Gastric cancer is the fifth most common cancer and the third leading cause of death globally .Apart from the suc-cessful phase Ⅲclinical trial of trastuzumab and Ramucirumab , other targeted therapies in gastric cancer ( GC) have fallen short or still in early clinical development .In this review, we will summarize the most up to date information on many of the potential actionabledriver genesin gastric cancer and the importance of using the optimal diagnostic test to select for these molecularly defined patients . We focus on the following aspects:HER-2, EGFR, FGFR, MET, IGF-1R and VEGF.

A Perspective: Role of Targeted Therapy in Colon Cancer / 대한소화기학회지

Colorectal cancer is the third most common malignant disease in incidence according to a report in 2009 from Korea. The 5-fluorouracil (5-FU) remains to be a major chemotherapeutic agents. But, over the last 10-15 years, the treatment pattern for metastatic colorectal cancer changed significantly. Irinotecan and oxaliplatin are cytotoxic drugs, or bevacizumab and cetuximab are monoclonal antibodies against molecular targets. The introduction of novel agents targeting specific molecular features of cancer cells promises more options and marked improvements in efficacy for the treatment of metastatic colon cancer. Bevacizumab has been shown to extend survival in colorectal cancer when used in combination with irinotecan and 5-FU-based chemotherapy, and the addition of cetuximab to irinotecan and 5-FU-based chemotherapy eliminates irinotecan resistance. Better understanding of the tumor biology and the molecular pathway and mechanisms of tumorigenesis has led to the discovery of novel agents with improved outcomes.

A Perspective: Role of Targeted Therapy in Colon Cancer / 대한소화기학회지

Colorectal cancer is the third most common malignant disease in incidence according to a report in 2009 from Korea. The 5-fluorouracil (5-FU) remains to be a major chemotherapeutic agents. But, over the last 10-15 years, the treatment pattern for metastatic colorectal cancer changed significantly. Irinotecan and oxaliplatin are cytotoxic drugs, or bevacizumab and cetuximab are monoclonal antibodies against molecular targets. The introduction of novel agents targeting specific molecular features of cancer cells promises more options and marked improvements in efficacy for the treatment of metastatic colon cancer. Bevacizumab has been shown to extend survival in colorectal cancer when used in combination with irinotecan and 5-FU-based chemotherapy, and the addition of cetuximab to irinotecan and 5-FU-based chemotherapy eliminates irinotecan resistance. Better understanding of the tumor biology and the molecular pathway and mechanisms of tumorigenesis has led to the discovery of novel agents with improved outcomes.

Application of alpha-fetoprotein in molecular therapy of hepatocellular carcinoma / 国际外科学杂志

Alpha-fetoprotein is an important molecular marker for clinical diagnosis, evaluation of curative effect and prognosis of cancer for long time, especially for hepatocellular carcinoma. But for physiological function of alpha-fetoprotein, we know less than its clinical significance. So here this article presents a review about physiological function of alpha-fetoprotein and its application in molecular therapy of hepatocellular carcinoma.

Palliative treatment in advanced hepatocellular carcinoma: Has it made any difference.

Hepatocellular carcinoma (HCC) is a global health problem, the fifth most common cancer in the world.. HCC occurs in a histologically abnormal liver due to underlying chronic liver disease resulting as a sequele of the chronic viral infections, hepatitis B and C. Since these two viral infections are endemic in Asia and Africa, more than 80% of cases are encountered in these regions. In India, a large proportion of the population is “at risk” for developing chronic liver disease and, therefore, HCC. Due to the lack of screening programmes in the country, the majority of HCC patients are diagnosed at an advanced stage of the disease, and thus treatment remains a challenge. Palliative therapy forms the mainstay of treatment for this group of patients. The current era provides a plethora of options for the palliative management of HCC. This review concisely summarises the historical perspective and the current status of palliative treatment in advanced HCC.

La hemato-oncología molecular y las nuevas estrategias terapéuticas específicas en leucemia / Molecular hemato-oncology and new specific treatment strategies for leukemia

En una elevada proporción de casos de leucemias de nuevo diagnóstico se detectan genes de fusión, los cuales frecuentemente presentan secuencias codificadoras de factores de transcripción. Se ha demostrado que algunas proteínas de fusión como Pml-Rarα inhiben la diferenciación celular, al reclutar complejos correpresores nucleares que mantienen una actividad de histona desacetilasa (HDAC en inglés) sobre promotores de genes específicos importantes en diferenciación de una determinada estirpe celular. Esta represión transcripcional dependiente de HDAC representa una vía común en el desarrollo de leucemia y por lo tanto puede ser un blanco importante de nuevos compuestos terapéuticos. Por otro lado, la oncoproteína Bcr-Abl muestra una alta actividad de tirosina-cinasa, la cual desregula vías de transducción de señales involucradas normalmente en proliferación y apoptosis. Esta actividad aberrante puede ser afectada por inhibidores de transducción de señales (STIs, del inglés), los cuales bloquean la ruta oncogénica y representan un gran avance terapéutico. En esta revisión analizamos con cierto detalle lo que se conoce en la actualidad sobre la represión transcripcional reversible controlada por HDAC y sobre la transducción de señales aumentada por Bcr-Abl. Adicionalmente indicamos que la aplicación de fármacos de bajo peso molecular para el control de las leucemias humanas, basada en el conocimiento de los mecanismos moleculares de la enfermedad, lleva a una remisión clínica, con bajo riesgo de efectos tóxicos secundarios, lo cual está aumentando la mejoría de una alta proporción de los enfermos.

Leukemia-associated fusion genes are detected in a significant proportion of newly diagnosed cases, where genes encoding transcription factors are usually found at one of the breakpoints. Activated fusion proteins such as Pml-Raralpha have been shown to inhibit cellular differentiation by recruitment of nuclear corepressor complexes, which maintain local histone deacetylase (HDAC) in a variety of hematologic lineage-specific gene promoters. This HDAC-dependent transcriptional repression appears as a common pathway in the development of leukemia and could constitute an important target for new therapeutic agents. Alternatively, the Bcr-Abl oncoprotein shows high tyrosine kinase activity and deregulates signal transduction pathways normally involved in both apoptosis and proliferation. This aberrant activity is affected by signal transduction inhibitors (STIs), which block or prevent the oncogenic pathway. In this review, we shed some light on our understanding of both the reversible transcriptional repression controlled by HDAC and the deregulated Bcr-Abl signal transduction pathway. In addition, the administration of low molecular weight drugs for human leukemia treatment based on this knowledge brings about a significant long-term clinical remission and an acceptable risk of toxic effects that should increase the cure rate.