Therapeutic regulation of autophagy in hepatic metabolism

Metabolic homeostasis requires dynamic catabolic and anabolic processes. Autophagy, an intracellular lysosomal degradative pathway, can rewire cellular metabolism linking catabolic to anabolic processes and thus sustain homeostasis. This is especially relevant in the liver, a key metabolic organ that governs body energy metabolism. Autophagy's role in hepatic energy regulation has just begun to emerge and autophagy seems to have a much broader impact than what has been appreciated in the field. Though classically known for selective or bulk degradation of cellular components or energy-dense macromolecules, emerging evidence indicates autophagy selectively regulates various signaling proteins to directly impact the expression levels of metabolic enzymes or their upstream regulators. Hence, we review three specific mechanisms by which autophagy can regulate metabolism: A) nutrient regeneration, B) quality control of organelles, and C) signaling protein regulation. The plasticity of the autophagic function is unraveling a new therapeutic approach. Thus, we will also discuss the potential translation of promising preclinical data on autophagy modulation into therapeutic strategies that can be used in the clinic to treat common metabolic disorders.

Injectable peptide hydrogel as intraperitoneal triptolide depot for the treatment of orthotopic hepatocellular carcinoma

Chemotherapy is among the limited choices approved for the treatment of hepatocellular carcinoma (HCC) at intermediate and advanced stages. Preferential and prolonged drug exposure in diseased sites is required to maximize the therapeutic index of the drug. Here, we report an injectable supramolecular peptide hydrogel as an intraperitoneal depot for localized and sustained release of triptolide for the treatment of orthotopic HCC. We chose peptide amphiphile C-GNNQQNYKD-OH-based nanofibers as gelators and carriers for triptolide. Sustained triptolide release from the hydrogel was achieved over 14 days , with higher accumulation in and cytotoxicity against human HCC Bel-7402 in comparison with L-02 fetal hepatocytes. After intraperitoneal injection, the hydrogel showed prolonged retention over 13 days and preferential accumulation in the liver, realizing HCC growth inhibition by 99.7 ± 0.1% and animal median survival extension from 19 to 43 days, without causing noticeable pathological changes in the major organs. These results demonstrate that injectable peptide hydrogel can be a potential carrier for localized chemotherapy of HCC.

Adult T-cell leukemia/lymphoma treatment in Bahia, Brazil

Abstract Background: Adult T-cell leukemia/lymphoma is a peripheral disease associated with human T-cell lymphotropic virus type 1. Treatment is carried out according to clinical type with watchful waiting being recommended for less aggressive types. Aggressive adult T-cell leukemia/lymphoma is generally treated with chemotherapy and/or antivirals. The objective of this study was to correlate the survival of patients diagnosed in Bahia, Brazil, with the therapeutic approaches employed and to evaluate what issues existed in their treatment processes. Methods: Eighty-three adult T-cell leukemia/lymphoma patients (26 smoldering, 23 chronic, 16 acute, 13 lymphoma and five primary cutaneous tumoral) with available data were included in this study. Results: Complete response was achieved in seven smoldering patients with symptomatic treatment, in two with chronic disease using antivirals/chemotherapy, in one with acute disease using antivirals and in one lymphoma using the LSG15 regimen [vincristine, cyclophosphamide, doxorubicin, and prednisolone (VCAP); doxorubicin, ranimustine, and prednisolone (AMP); and vindesine, etoposide, carboplatin, and prednisolone (VECP)]. Smoldering patients who received symptomatic treatment presented longer survival. Favorable chronic patients treated with antivirals presented longer survival compared to the unfavorable subtype. However, for the acute form, first-line chemotherapy was better, albeit without significance, than antivirals. Only one of the patients with lymphoma and primary cutaneous tumors responded. Conclusions: Watchful waiting associated with phototherapy represents the best option for smoldering adult T-cell leukemia/lymphoma with survival in Bahia being superior to that described in Japan. There was a trend of better results with zidovudine/interferon-alpha in favorable chronic disease. Excellent results were achieved in the lymphoma type treated with the LSG15 protocol. Patients are diagnosed late probably due to lack of knowledge of adult T-cell leukemia/lymphoma by primary healthcare doctors and a Brazilian treatment protocol needs to be established.

Mutation analysis of SPAST, ATL1, and REEP1 in Korean Patients with Hereditary Spastic Paraplegia

BACKGROUND AND PURPOSE: Hereditary spastic paraplegia (HSP) is a genetically heterogeneous group of neurodegenerative disorders that are characterized by progressive spasticity and weakness of the lower limbs. Mutations in the spastin gene (SPAST) are the most common causes of HSP, accounting for 40-67% of autosomal dominant HSP (AD-HSP) and 12-18% of sporadic cases. Mutations in the atlastin-1 gene (ATL1) and receptor expression-enhancing protein 1 gene (REEP1) are the second and third most common causes of AD-HSP, respectively. METHODS: Direct sequence analysis was used to screen mutations in SPAST, ATL1, and REEP1 in 27 unrelated Korean patients with pure and complicated HSP. Multiplex ligation-dependent probe amplification was also performed to detect copy-number variations of the three genes. RESULTS: Ten different SPAST mutations were identified in 11 probands, of which the following 6 were novel: c.760A>T, c.131C>A, c.1351_1353delAGA, c.376_377dupTA, c.1114A>G, and c.1372A>C. Most patients with SPAST mutations had AD-HSP (10/11, 91%), and the frequency of SPAST mutations accounted for 66.7% (10/15) of the AD-HSP patients. No significant correlation was found between the presence of the SPAST mutation and any of the various clinical parameters of pure HSP. No ATL1 and REEP1 mutations were detected. CONCLUSIONS: We conclude that SPAST mutations are responsible for most Korean cases of genetically confirmed AD-HSP. Our observation of the absence of ATL1 and REEP1 mutations needs to be confirmed in larger series.

Aportes y consideraciones sobre la infección por los virus linfotrópicos-T humanos tipo 1 y 2 en Argentina / Contributions to the knowledge of Human T-Cell Lymphotropic Virus Type 1 and 2 (HTLV-1/2) infections in Argentina

El virus linfotrópicos-T humanos tipo 1 (HTLV-1) es el agente etiológico de una enfermedad hematológica de mal pronóstico, la leucemia de células T del adulto (ATL) y de una enfermedad neurológica invalidante, la mielopatía asociada al HTLV-1/paraparesia espástica tropical (HAM/TSP) para las cuales no existe un tratamiento eficaz. El virus linfotrópico-T humano tipo 2 (HTLV-2) ha sido relacionado a síndromes neurológicos, aumento de infecciones y mortalidad. En Argentina, existe una restricción étnica/geográfica con una región endémica para el HTLV-1 en el Noroeste (Aymarás) y otra para el HTLV-2 en la Región Chaqueña (Tobas y Wichis). El aumento de corrientes migratorias a partir de áreas endémicas ha contribuido a la mayor circulación de estos virus en el país, hecho que plantea el desafío de poder brindar un diagnóstico final y una atención integral a los individuos. Este manuscrito comprende una revisión actualizada y la experiencia de nuestro grupo sobre estas infecciones...

HTLV-1 is the ethiologic agent of an hematologic disease with bad prognosis, Adult T-cell Leukemia (ATL) lethal in short time and a chronic and progressively invalidant neurological disease, HTLV-1 Associated Mielopathy/Tropical Spastic Paraparesis (HAM/TSP), for which no effective treatment is available. HTLV-2 has been related to neurologic syndromes, an increase in infections and mortality. In Argentina, the infection shows an ethnic/geographic restriction with an endemic regions for HTLV-1 in the Northeast (Aymaras) and for HTLV-2 in the Chaqueña Region (Tobas y Wichis). The increasing migrations from endemic areas have contributed to a major circulatin of these viruses and detection of HAM/TSP and ATL cases countrywide. This situation poses the challenge of giving a complete and final diagnosis and an integral care to infected individuals. This manuscript describes general aspects of HTLV-1/2 and the situation and experience of our group on these infections in the country...

The evaluation of color and color difference according to the layering placement of Incisal shade composites on the body composites of the indirect resin restoration / 대한치과보존학회지

OBJECTIVES: The aim of this study was to evaluate the surface color of indirect resin restoration according to the layering placement of different shade of incisal composite. MATERIALS AND METHODS: In this study, CIE L*a*b* value of 16 Body composite of Tescera ATL (Bisco, Schaumburg IL,USA) was measured by spectrophotometer (NF999, Nippon Denshuku, Japan), and compared to CIE L*a*b* value of Vitapan shade guide. Nine shade Incisal composite of Tescera ATL were build-up to 1 mm thickness on Body composites inlay block, and CIE L*a*b* value was measured. Incisal composite was ground to 0.5 mm thickness and CIE L*a*b* value was re-measured. Color difference between Body composite and Incisal composites layered on Body composite was calculated as a function of thickness. RESULTS: Color difference between corresponding shade of Tescera Body composite and Vitapan shade guide was from 6.88 to 12.80. L* and b*value was decreased as layering thickness of Incisal composite on Body composite was increased. But, a* value did not show specific change tendency. CONCLUSIONS: Surface color difference between Body composites and Incisal composites layered on Body composite was increased as the layering thickness of Incisal composite increased (p < 0.05).

Leucemia de células T do adulto / Adult T-cell leukemia

A leucemia de células T no adulto (ATL) é causada pelo vírus linfotrópico de células T (HTLV-1). Contudo, apenas 2 por cento-5 por cento dos indivíduos infectados desenvolvem a ATL e somente 40-60 anos após a infecção. Um fator de risco para adquirir a doença é a via da transmissão do vírus pela amamentação e durante o parto, sugerindo que a criança já é portadora do vírus. Desde a descoberta do vírus, em 1980, vários artigos científicos foram publicados descrevendo as manifestações clínicas, biologia do vírus e alterações intracelulares induzidas pelo vírus. Esta revisão visa explorar alguns aspectos da relação entre HTLV-1 e a leucemia de células T do Adulto.

The human T-lymphotropic virus (HTLV-1) is known to be the etiologic agent of adult T-cell leukemia (ATL). Only 2-5 percent of infected individuals develop ATL and even then only 40-60 years after infection. One risk factor to develop ATL is the transmission of the virus by breastfeeding and during delivery, suggesting that infants of infected mothers are already carriers of the virus. Since the discovery of the virus in 1980 many scientific papers have been published describing the clinical manifestations, biology of the virus and the intracellular alterations induced by the virus. This review aims to explore some aspects of the relationship between HTLV-1 and ATL.

The effect of reinforcing methods on fracture strength of composite inlay bridge / 대한치과보존학회지

The purpose of this study is to evaluate the effects of surface treatment and composition of reinforcement material on fracture strength of fiber reinforced composite inlay bridges. The materials used for this study were I-beam, U-beam TESCERA ATL system and ONE STEP(Bisco, IL, USA). Two kinds of surface treatments were used; the silane and the sandblast. The specimens were divided into 11 groups through the composition of reinforcing materials and the surface treatments. On the dentiform, supposing the missing of Maxillary second pre-molar and indirect composite inlay bridge cavities on adjacent first pre-molar disto-occlusal cavity, first molar mesio-occlusal cavity was prepared with conventional high-speed inlay bur.The reinforcing materials were placed on the proximal box space and build up the composite inlay bridge consequently. After the curing, specimen was set on the testing die with ZPC. Flexural force was applied with universal testing machine (EZ-tester; Shimadzu, Japan). at a cross-head speed of 1 mm/min until initial crack occurred. The data wasanalyzed using one-way ANOVA/Scheffes' post-hoc test at 95% significance level. Groups using I-beam showed the highest fracture strengths (p 0.05). Most of the specimens in groups that used reinforcing material showed delamination. 1. The use of I-beam represented highest fracture strengths (p 0.05). 3. The reinforcing materials affect the fracture strength and pattern of composites inlay bridge. 4. The holes at the U-beam did not increase the fracture strength of composites inlay bridge.

CHANGES IN HTLV-I POSITIVE RATES AMONG PREGNANT WOMEN IN OKINAWA PRIOR TO THE EFFECTS OF MEASURES INTRODUCED TO PREVENT VERTICAL TRANSMISSION THROUGH BREAST MILK FEEDING

Objectives: Human T cell leukemia virus type-I (HTLV-I) is a causative agent of human T-cell leukemia and HTLV-I associated myelopathy (HAM/TSP). HTLV-I carriers are often infected vertically, especially via mother's milk. Since 1985, clinical measures have been adopted at a hospital in Okinawa to prevent vertical infections.<BR>Methods: We examined HTLV-I antibodies in all of the women (total 11, 506) who gave birth after 24 gestational weeks at a hospital on the Okinawa main island from January 1985 to December 1999.<BR>Results: The positive rate among all pregnant women was always higher than that among primipara alone. Both figures decreased over the period studied, but the primiparity rate (36-39%) did not change significantly. The percentage of HTLV-I positive primipara pregnant women among the HTLV-I positive total was close to the primiparity rate from 1985 to 1988, but it was considerably lower than the overall primiparity rate thereafter (22-26%).<BR>Conclusions: Preventive measures against HTLV-I infection did not contribute to the decrease in HTLV-I positive mothers before 1999 because these measures were adopted from 1985, and so there must be other reasons for the decrease in HTLV-I positive rate. Further studies on social factors and by year of birth are needed to identify factors influencing HTLV-carrier ratios among pregnant women.