Current therapeutic options for Chagas' disease are limited to benznidazole and nifurtimox, which have been associated with low cure rates in the chronic stage of the disease and which have ...considerable toxicity. Posaconazole has shown trypanocidal activity in murine models.
We performed a prospective, randomized clinical trial to assess the efficacy and safety of posaconazole as compared with the efficacy and safety of benznidazole in adults with chronic Trypanosoma cruzi infection. We randomly assigned patients to receive posaconazole at a dose of 400 mg twice daily (high-dose posaconazole), posaconazole at a dose of 100 mg twice daily (low-dose posaconazole), or benznidazole at a dose of 150 mg twice daily; all the study drugs were administered for 60 days. We assessed antiparasitic activity by testing for the presence of T. cruzi DNA, using real-time polymerase-chain-reaction (rt-PCR) assays, during the treatment period and 10 months after the end of treatment. Posaconazole absorption was assessed on day 14.
The intention-to-treat population included 78 patients. During the treatment period, all the patients tested negative for T. cruzi DNA on rt-PCR assay beyond day 14, except for 2 patients in the low-dose posaconazole group who tested positive on day 60. During the follow-up period, in the intention-to-treat analysis, 92% of the patients receiving low-dose posaconazole and 81% receiving high-dose posaconazole, as compared with 38% receiving benznidazole, tested positive for T. cruzi DNA on rt-PCR assay (P<0.01 for the comparison of the benznidazole group with either posaconazole group); in the per-protocol analysis, 90% of the patients receiving low-dose posaconazole and 80% of those receiving high-dose posaconazole, as compared with 6% receiving benznidazole, tested positive on rt-PCR assay (P<0.001 for the comparison of the benznidazole group with either posaconazole group). In the benznidazole group, treatment was discontinued in 5 patients because of severe cutaneous reactions; in the posaconazole groups, 4 patients had aminotransferase levels that were more than 3 times the upper limit of the normal range, but there were no discontinuations of treatment.
Posaconazole showed antitrypanosomal activity in patients with chronic Chagas' disease. However, significantly more patients in the posaconazole groups than in the benznidazole group had treatment failure during follow-up. (Funded by the Ministry of Health, Spain; CHAGASAZOL ClinicalTrials.gov number, NCT01162967.).
The lysyl oxidase-like protein LOXL2 has been suggested to contribute to tumor progression and metastasis, but
evidence has been lacking. Here we provide functional evidence that LOXL2 is a key ...driver of breast cancer metastasis in two conditional transgenic mouse models of PyMT-induced breast cancer. LOXL2 ablation in mammary tumor cells dramatically decreased lung metastasis, whereas LOXL2 overexpression promoted metastatic tumor growth. LOXL2 depletion or overexpression in tumor cells does not affect extracellular matrix stiffness or organization in primary and metastatic tumors, implying a function for LOXL2 independent of its conventional role in extracellular matrix remodeling. In support of this likelihood, cellular and molecular analyses revealed an association of LOXL2 action with elevated levels of the EMT regulatory transcription factor Snail1 and expression of several cytokines that promote premetastatic niche formation. Taken together, our findings established a pathophysiologic role and new function for LOXL2 in breast cancer metastasis.
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Recent meta-analyses indicate that coffee consumption reduces the risk for digestive tract (oral, esophageal, gastric and colorectal) and, especially, liver cancer. Coffee bean-derived beverages, as ...the widely-consumed espresso and “common” filtered brews, present remarkable historical, cultural and economic importance globally. These drinks have rich and variable chemical composition, depending on factors that vary from “seeding to serving”. The alkaloids caffeine and trigonelline, as well as the polyphenol chlorogenic acid, are some of the most important bioactive organic compounds of these beverages, displaying high levels in both espresso and common brews and/or increased bioavailability after consumption. Thus, we performed a comprehensive literature overview of current knowledge on the effects of coffee beverages and their highly bioavailable compounds, describing: 1) recent epidemiological and experimental findings highlighting the beneficial effects against gastrointestinal/liver carcinogenesis, and 2) the main molecular mechanisms in these in vitro and in vivo bioassays. Findings predominantly address the protective effects of coffee beverages and their most common/bioavailable compounds individually on gastrointestinal and liver cancer development. Caffeine, trigonelline and chlorogenic acid modulate common molecular targets directly implicated in key cancer hallmarks, what could stimulate novel translational or population-based mechanistic investigations.
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•Caffeine, chlorogenic acid and trigonelline are major compounds of coffee drinks.•Coffee lowers gastrointestinal and, especially, liver cancer risk in humans.•Coffee/major compounds attenuate gastrointestinal and liver carcinogenesis in vivo.•Major compounds share many cancer hallmark-related molecular targets in vitro.•Interaction of major compounds must be considered for future translational assays.
MYC oncogene overexpression/amplification is common in multiple human cancers, in which it regulates proliferation, apoptosis and cell metabolism, among other processes, and its expression associates ...with poor prognosis. Targeting MYC presents an exciting therapeutic possibility, but developing appropriate drugs that impair protein function remains challenging. Searching for alternative therapeutic options for treating aggressive MYC‐driven cancers is thus of high clinical interest. Intriguingly, MYC‐driven cancers present vulnerability against spliceosome inhibition. In this issue of EMBO Molecular Medicine, Iwai et al () tackle targeting the splicing regulatory Cdc2‐like kinase (CLKs) family. They report that a novel, orally administered CLK2 inhibitor (T‐025) induces exon skipping, which results in cancer cell growth reduction, especially in breast cancer (BCa) MYC‐driven tumors.
F. Salvador and R. Gomis discuss the study by Iwai et al () in this issue of EMBO Molecular Medicine, on how targeting the splicing regulatory Cdc2‐like kinase (CLK) family offers alternative therapeutic options for treating aggressive MYC‐driven cancers.
Strongyloides stercoralis infection, a neglected tropical disease, is widely distributed. Autochthonous cases have been described in Spain, probably infected long time ago. In recent years the number ...of diagnosed cases has increased due to the growing number of immigrants, travelers and refugees, but endemically acquired cases in Spain remains undetermined.
We systematically searched the literature for references on endemic strongyloidiasis cases in Spain. The articles were required to describe Strongyloides stercoralis infection in at least one Spanish-born person without a history of travel to endemic areas and be published before 31st May 2018. Epidemiological data from patients was collected and described individually as well as risk factors to acquisition of the infection, diagnostic technique that lead to the diagnosis, presence of eosinophilia and clinical symptoms at diagnosis.
Thirty-six studies were included, describing a total of 1083 patients with an average age of 68.3 years diagnosed with endemic strongyloidiasis in Spain. The vast majority of the cases were described in the province of Valencia (n = 1049). Two hundred and eight of the 251 (82.9%) patients in whom gender was reported were male, and most of them had current or past dedication to agriculture. Seventy percent had some kind of comorbidity. A decreasing trend in the diagnosed cases per year is observed from the end of last decade. However, there are still nefigw diagnoses of autochthonous cases of strongyloidiasis in Spain every year.
With the data provided by this review it is likely that in Spain strongyloidiasis might have been underestimated. It is highly probable that the infection remains undiagnosed in many cases due to low clinical suspicion among Spanish population without recent travel history in which the contagion probably took place decades ago.
Strongyloides stercoralis is a globally distributed nematode that causes diverse clinical symptoms in humans. Spain, once considered an endemic country, has experienced a recent increase in imported ...cases. The introduction of serology helps diagnosis and is currently replacing microbiological techniques in some settings, but its sensitivity is variable and can be low in immunocompromised patients. Diagnosis can only be confirmed by identification of larvae. Often, this "gold standard" can only be achieved in severe cases, such as disseminated S.stercoralis infection, or S.stercoralis hyperinfection syndrome, where parasite load is high. In addition, these clinical presentations are not well-defined. Our aim is to describe severe cases of S.stercoralis, their epidemiological profile, and their clinical details.
An observational retrospective study of disseminated S.stercoralis infection, or hyperinfection syndrome. Inclusion criteria: aged over 18, with a diagnosis of disseminated S.stercoralis infection, or hyperinfection syndrome, confirmed by visualization of larvae. Patients were identified through revision of clinical records for the period 2000-2015, in collaboration with eight reference centers throughout Spain.
From the period 2000-2015, eighteen cases were identified, 66.7% of which were male, with a median age of 40 (range 21-70). Most of them were foreigners (94.4%), mainly from Latin America (82.3%) or Western Africa (17.6%). Only one autochthonous case was identified, from 2006. Immunosuppressive conditions were present in fourteen (77%) patients, mainly due steroids use and to retroviral coinfections (four HIV, two HTLV). Transplant preceded the clinical presentation in four of them. Other comorbidities were coinfection with HBV, Trypanosoma cruzi, Mycobacterium leprae or Aspergillus spp. All presented with digestive disorders, with 55.6% also presenting malaise. 44.4% of cases had fever, 27.8% skin complaints, and 16.7% respiratory or neurological disorders. One patient presented anemia, and one other nephrotic syndrome. Diagnosis was confirmed by identification of larvae in fresh stool samples (n = 16; 88.9%), concentration techniques (n = 6; 33.3%), larval culture (n = 5; 29.4%), or digestive biopsies (n = 8; 44%). S.stercoralis forms were identified during necropsy in one case. In addition, ten (55%) had a positive serology. All the cases were treated with ivermectin, six (33%) also received albendazole and one case received thiabendazole followed by ivermectin. All needed inpatient management, involving a mean hospitalization stay of 25 days (range 1-164). Two cases received intensive care and eventually died.
Only eighteen cases of disseminated S.stercoralis infection/hyperinfection syndrome were identified from the 15-year period, most of which were considered to have been imported cases. Among those, immunosuppression was frequent, and mortality due to S.stercoralis was lower than previously described.
ANCA associated vasculitis Salvador, Fernando
European journal of internal medicine,
April 2020, 2020-04-00, Letnik:
74
Journal Article
Recenzirano
•Vasculitis is a multisystemic disease reaching vessels of different sizes.•Ideally, when suspected, a biopsy should confirm the diagnosis.•Treatment is based on two stages: induction and ...maintenance.•Glucocorticoids are generally used.•Methotrexate, cyclophosphamide, rituximab or azathioprine should also be considered.
Vasculitis is characterized by inflammation of the vascular wall. It reaches vessels of different sizes and locations, conditioning multisystem and complex manifestations that require a holistic approach.
Antineutrophil cytoplasmic antibody-associated vasculitis has an annual incidence rate of 20 per million inhabitants. It is the result of the interaction of infectious, genetic and environmental factors and manifest itself with varied and unspecific symptoms, often reaching the general state, respiratory and renal systems. The combination of clinical, laboratory, imaging and fundamentally histological changes allows the diagnosis and classification of the extent / severity of the disease necessary for the decision of the therapeutics to be taken. Glucocorticoids are generally used; with methotrexate being considered when localized disease and cyclophosphamide, rituximab or azathioprine when generalized disease.
A systematized approach can increase survival rates from 12% to 70% over a 5-year span.
Hepatocellular carcinoma causes ~10% of all cancer-related deaths worldwide, usually emerging in a background of liver fibrosis/cirrhosis (70%-90% of cases). Chemically-induced mouse models for ...fibrosis-associated hepatocarcinogenesis are widely-applied, resembling the corresponding human disease. Nonetheless, a long time is necessary for the development of preneoplastic/neoplastic lesions. Thus, we proposed an early fibrosis-associated hepatocarcinogenesis model for male and female mice separately, focusing on reducing the experimental time for preneoplastic/neoplastic lesions development and establishing standard models for both sexes. Then, two-week old susceptible C3H/HeJ male and female mice (n = 8 animals/sex/group) received a single dose of diethylnitrosamine (DEN, 10 or 50 mg/Kg). During 2 months, mice received 3 weekly doses of carbon tetrachloride (CCl4, 10% corn oil solution, 0.25 to 1.50 μL/g b.wt.) and they were euthanized at week 17. DEN/CCl4 protocols for males and females displayed clear liver fibrosis, featuring collagen accumulation and hepatic stellate cell activation (α-SMA). In addition, liver from males displayed increased CD68+ macrophage number, COX-2 protein expression and IL-6 levels. The DEN/CCl4 models in both sexes impaired antioxidant defense as well as enhanced hepatocyte proliferation and apoptosis. Moreover, DEN/CCl4-treated male and female developed multiple preneoplastic altered hepatocyte foci and hepatocellular adenomas. As expected, the models showed clear male bias. Therefore, we established standard and suitable fibrosis-associated hepatocarcinogenesis models for male and female mice, shortening the experimental time for the development of hepatocellular preneoplastic/neoplastic lesions in comparison to other classical models.
Most human hantavirus infections occur in Asia, but some cases have been described in Europe in travelers returning from Asia. We describe a case of hantavirus pulmonary syndrome in a previously ...healthy traveler occurring shortly after he returned to Spain from Nepal. Serologic tests suggested a Puumala virus-like infection.
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