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1.
Braz. j. biol ; 832023.
Article in English | LILACS-Express | LILACS, VETINDEX | ID: biblio-1469156

ABSTRACT

Abstract Colletotrichum is one of the most economically important fungal genera, which affects a wide range of hosts, specifically tropical and subtropical crops. Thus far, there have been several records of mycovirus infection in Colletotrichum spp., primarily by viruses of the Partitiviridae family. There have also been records of infections by mycoviruses of the Chrysoviridae family. Mycoviruses are (+)ssRNA and dsRNA genome viruses, which may or may not be enveloped. To date, no mycovirus with a DNA genome has been isolated from Colletotrichum spp. Typically, mycoviruses cause latent infections, although hypo- and hypervirulence have also been reported in Colletotrichum spp. In addition to its effects on pathogenic behavior, mycovirus infection can lead to important physiological changes, such as altered morphological characteristics, reduced vegetative growth, and suppressed conidia production. Therefore, research on mycoviruses infecting phytopathogenic fungi can help develop alternative methods to chemical control, which can cause irreversible damage to humans and the environment. From an agricultural perspective, mycoviruses can contribute to sustainable agriculture as biological control agents via changes in fungal physiology, ultimately resulting in the total loss of or reduction in the virulence of these pathogens.


Resumo Colletotrichum é um dos gêneros fúngicos mais importantes economicamente, afetando uma ampla gama de hospedeiros, especialmente em cultivos tropicais e subtropicais. Atualmente já existem diversos registros de infecção por micovírus em Colletotrichum spp., sendo a maioria dos já identificados classificados na família Partitiviridae. Ocorrem registros também de micovírus pertencentes à família Chrysoviridae. Compreendem vírus de genoma de (+)ssRNA e dsRNA que podem ser ou não envelopados. Ainda não foram identificados micovírus com genoma de DNA isolados de Colletotrichum. A infecção por micovírus pode ocorrer de forma latente, mas já foi observado em Colletotrichum spp. o fenômeno de hipo e hipervirulência. Além de influenciar no comportamento patogênico, a infecção pode causar mudanças fisiológicas importantes como alterações das características morfológicas, redução do crescimento vegetativo e redução na produção de conídios. O estudo com micovírus em fungos fitopatogênicos traz uma alternativa ao controle químico que é um método capaz de causar danos irreversíveis ao homem e o meio ambiente. Sob a perspectiva agrícola, os micovírus podem contribuir para agricultura sustentável como agentes de controle biológico. Isso porque obsevam-se mudanças importantes na fisiologia fúngica resultando na perda total ou redução da virulência desses patógenos.

2.
Braz. j. biol ; 83: e248975, 2023. tab, graf
Article in English | LILACS, VETINDEX | ID: biblio-1339377

ABSTRACT

Abstract Colletotrichum is one of the most economically important fungal genera, which affects a wide range of hosts, specifically tropical and subtropical crops. Thus far, there have been several records of mycovirus infection in Colletotrichum spp., primarily by viruses of the Partitiviridae family. There have also been records of infections by mycoviruses of the Chrysoviridae family. Mycoviruses are (+)ssRNA and dsRNA genome viruses, which may or may not be enveloped. To date, no mycovirus with a DNA genome has been isolated from Colletotrichum spp. Typically, mycoviruses cause latent infections, although hypo- and hypervirulence have also been reported in Colletotrichum spp. In addition to its effects on pathogenic behavior, mycovirus infection can lead to important physiological changes, such as altered morphological characteristics, reduced vegetative growth, and suppressed conidia production. Therefore, research on mycoviruses infecting phytopathogenic fungi can help develop alternative methods to chemical control, which can cause irreversible damage to humans and the environment. From an agricultural perspective, mycoviruses can contribute to sustainable agriculture as biological control agents via changes in fungal physiology, ultimately resulting in the total loss of or reduction in the virulence of these pathogens.


Resumo Colletotrichum é um dos gêneros fúngicos mais importantes economicamente, afetando uma ampla gama de hospedeiros, especialmente em cultivos tropicais e subtropicais. Atualmente já existem diversos registros de infecção por micovírus em Colletotrichum spp., sendo a maioria dos já identificados classificados na família Partitiviridae. Ocorrem registros também de micovírus pertencentes à família Chrysoviridae. Compreendem vírus de genoma de (+)ssRNA e dsRNA que podem ser ou não envelopados. Ainda não foram identificados micovírus com genoma de DNA isolados de Colletotrichum. A infecção por micovírus pode ocorrer de forma latente, mas já foi observado em Colletotrichum spp. o fenômeno de hipo e hipervirulência. Além de influenciar no comportamento patogênico, a infecção pode causar mudanças fisiológicas importantes como alterações das características morfológicas, redução do crescimento vegetativo e redução na produção de conídios. O estudo com micovírus em fungos fitopatogênicos traz uma alternativa ao controle químico que é um método capaz de causar danos irreversíveis ao homem e o meio ambiente. Sob a perspectiva agrícola, os micovírus podem contribuir para agricultura sustentável como agentes de controle biológico. Isso porque obsevam-se mudanças importantes na fisiologia fúngica resultando na perda total ou redução da virulência desses patógenos.


Subject(s)
Humans , RNA Viruses , Colletotrichum , Fungal Viruses/genetics , Phylogeny , Spores, Fungal , Virulence
3.
Braz. j. biol ; 83: 1-12, 2023. tab, ilus, graf
Article in English | LILACS, VETINDEX | ID: biblio-1468940

ABSTRACT

Colletotrichum is one of the most economically important fungal genera, which affects a wide range of hosts, specifically tropical and subtropical crops. Thus far, there have been several records of mycovirus infection in Colletotrichum spp., primarily by viruses of the Partitiviridae family. There have also been records of infections by mycoviruses of the Chrysoviridae family. Mycoviruses are (+)ssRNA and dsRNA genome viruses, which may or may not be enveloped. To date, no mycovirus with a DNA genome has been isolated from Colletotrichum spp. Typically, mycoviruses cause latent infections, although hypo- and hypervirulence have also been reported in Colletotrichum spp. In addition to its effects on pathogenic behavior, mycovirus infection can lead to important physiological changes, such as altered morphological characteristics, reduced vegetative growth, and suppressed conidia production. Therefore, research on mycoviruses infecting phytopathogenic fungi can help develop alternative methods to chemical control, which can cause irreversible damage to humans and the environment. From an agricultural perspective, mycoviruses can contribute to sustainable agriculture as biological control agents via changes in fungal physiology, ultimately resulting in the total loss of or reduction in the virulence of these pathogens.


Colletotrichum é um dos gêneros fúngicos mais importantes economicamente, afetando uma ampla gama de hospedeiros, especialmente em cultivos tropicais e subtropicais. Atualmente já existem diversos registros de infecção por micovírus em Colletotrichum spp., sendo a maioria dos já identificados classificados na família Partitiviridae. Ocorrem registros também de micovírus pertencentes à família Chrysoviridae. Compreendem vírus de genoma de (+)ssRNA e dsRNA que podem ser ou não envelopados. Ainda não foram identificados micovírus com genoma de DNA isolados de Colletotrichum. A infecção por micovírus pode ocorrer de forma latente, mas já foi observado em Colletotrichum spp. o fenômeno de hipo e hipervirulência. Além de influenciar no comportamento patogênico, a infecção pode causar mudanças fisiológicas importantes como alterações das características morfológicas, redução do crescimento vegetativo e redução na produção de conídios. O estudo com micovírus em fungos fitopatogênicos traz uma alternativa ao controle químico que é um método capaz de causar danos irreversíveis ao homem e o meio ambiente. Sob a perspectiva agrícola, os micovírus podem contribuir para agricultura sustentável como agentes de controle biológico. Isso porque obsevam-se mudanças importantes na fisiologia fúngica resultando na perda total ou redução da virulência desses patógenos.


Subject(s)
Animals , Colletotrichum/virology , Pest Control, Biological/methods , Fungal Viruses
4.
Braz J Biol ; 83: e248975, 2021.
Article in English | MEDLINE | ID: mdl-34550289

ABSTRACT

Colletotrichum is one of the most economically important fungal genera, which affects a wide range of hosts, specifically tropical and subtropical crops. Thus far, there have been several records of mycovirus infection in Colletotrichum spp., primarily by viruses of the Partitiviridae family. There have also been records of infections by mycoviruses of the Chrysoviridae family. Mycoviruses are (+)ssRNA and dsRNA genome viruses, which may or may not be enveloped. To date, no mycovirus with a DNA genome has been isolated from Colletotrichum spp. Typically, mycoviruses cause latent infections, although hypo- and hypervirulence have also been reported in Colletotrichum spp. In addition to its effects on pathogenic behavior, mycovirus infection can lead to important physiological changes, such as altered morphological characteristics, reduced vegetative growth, and suppressed conidia production. Therefore, research on mycoviruses infecting phytopathogenic fungi can help develop alternative methods to chemical control, which can cause irreversible damage to humans and the environment. From an agricultural perspective, mycoviruses can contribute to sustainable agriculture as biological control agents via changes in fungal physiology, ultimately resulting in the total loss of or reduction in the virulence of these pathogens.


Subject(s)
Colletotrichum , Fungal Viruses , RNA Viruses , Fungal Viruses/genetics , Humans , Phylogeny , Spores, Fungal , Virulence
5.
Sci Rep ; 9(1): 17060, 2019 11 19.
Article in English | MEDLINE | ID: mdl-31745159

ABSTRACT

Humans can anticipate music and derive pleasure from it. Expectations facilitate the learning of movements associated with anticipated events, and they are also linked with reward, which may further facilitate learning of the anticipated rewarding events. The present study investigates the synergistic effects of predictability and hedonic responses to music on arousal and motor-learning in a naïve population. Novel melodies were manipulated in their overall predictability (predictable/unpredictable) as objectively defined by a model of music expectation, and ranked as high/medium/low liked based on participants' self-reports collected during an initial listening session. During this session, we also recorded ocular pupil size as an implicit measure of listeners' arousal. During the following motor task, participants learned to play target notes of the melodies on a keyboard (notes were of similar motor and musical complexity across melodies). Pupil dilation was greater for liked melodies, particularly when predictable. Motor performance was facilitated in predictable rather than unpredictable melodies, but liked melodies were learned even in the unpredictable condition. Low-liked melodies also showed learning but mostly in participants with higher scores of task perceived competence. Taken together, these results highlight  the effects of stimuli predictability on learning, which can be however overshadowed by the effects of stimulus liking or task-related intrinsic motivation.


Subject(s)
Auditory Perception/physiology , Music/psychology , Psychomotor Performance/physiology , Recognition, Psychology/physiology , Adult , Female , Humans , Learning/physiology , Male , Memory/physiology , Pleasure/physiology , Pupil/physiology , Young Adult
6.
Clin Microbiol Infect ; 24(12): 1340.e1-1340.e6, 2018 Dec.
Article in English | MEDLINE | ID: mdl-29555394

ABSTRACT

OBJECTIVES: We aimed to assess the prevalence and risk factors for Chagas disease (CD) in Latin American immigrants and to evaluate the accuracy of diagnostic tests. Moreover, we offered to all positive subjects a complete free-of-charge clinical/instrumental evaluation as well as benznidazole treatment in order to stage the disease and verify drug tolerability. METHODS: A cross-sectional survey of CD among Latin Americans living in Milan and its metropolitan area was conducted between July 2013 and July 2014. Blood samples were tested for serologic evidence of CD together with a questionnaire covering demographic and clinical-epidemiological information. RESULTS: Forty-eight (9.6%) of the 501 tested subjects were conclusively diagnosed as having CD. The highest prevalence of CD was among those from Bolivia (43/169, 25.4%) and El Salvador (4/68, 5.9%). Older age (adjusted odds ratio (aOR)] 1.05, p =0.004), a Bolivian origin (aOR 8.80; p =0.003), being born in the department of Santa Cruz (aOR 3.72, p =0.047), having lived in mud houses (aOR 2.68; p =0.019), and having an affected relative (aOR 12.77, p =0.001) were independently associated with CD. The ARCHITECT Chagas test showed the highest sensitivity (100%) and specificity (99.8%). Twenty-nine of the subjects with CD (60.4%) underwent disease staging, 10 of whom (35.7%) showed cardiac and/or digestive involvement. Benznidazole treatment was associated with high frequency of adverse reactions (19/27, 70.4%) and permanent discontinuation (8/27, 29.6%). CONCLUSIONS: CD is highly prevalent among Bolivians and Salvadorans living in Milan. Regions with a large Latin American immigrant population should implement programmes of active detection and treatment.


Subject(s)
Chagas Disease/diagnosis , Chagas Disease/epidemiology , Emigrants and Immigrants , Hispanic or Latino/statistics & numerical data , Adolescent , Adult , Bolivia/epidemiology , Chagas Disease/blood , Chagas Disease/immunology , Child , Cross-Sectional Studies , Data Accuracy , Drug Tolerance , El Salvador/epidemiology , Enzyme-Linked Immunosorbent Assay , Female , Humans , Immunoassay/methods , Italy/epidemiology , Latin America/epidemiology , Male , Middle Aged , Nitroimidazoles/adverse effects , Nitroimidazoles/therapeutic use , Prevalence , Risk Factors , Surveys and Questionnaires , Trypanosoma cruzi/drug effects , Trypanosoma cruzi/immunology , Trypanosoma cruzi/isolation & purification
7.
Neuroimage ; 169: 383-394, 2018 04 01.
Article in English | MEDLINE | ID: mdl-29277649

ABSTRACT

It is well established that musical training induces sensorimotor plasticity. However, there are remarkable differences in how musicians train for proficient stage performance. The present EEG study outlines for the first time clear-cut neurobiological differences between classical and jazz musicians at high and low levels of action planning, revealing genre-specific cognitive strategies adopted in production. Pianists imitated chord progressions without sound that were manipulated in terms of harmony and context length to assess high-level planning of sequence-structure, and in terms of the manner of playing to assess low-level parameter specification of single acts. Jazz pianists revised incongruent harmonies faster as revealed by an earlier reprogramming negativity and beta power decrease, hence neutralising response costs, albeit at the expense of a higher number of manner errors. Classical pianists in turn experienced more conflict during incongruent harmony, as shown by theta power increase, but were more ready to implement the required manner of playing, as indicated by higher accuracy and beta power decrease. These findings demonstrate that specific demands and action focus of training lead to differential weighting of hierarchical action planning. This suggests different enduring markers impressed in the brain when a musician practices one or the other style.


Subject(s)
Cerebral Cortex/physiology , Electroencephalography/methods , Evoked Potentials/physiology , Motor Activity/physiology , Music , Neuronal Plasticity/physiology , Pattern Recognition, Visual/physiology , Psychomotor Performance/physiology , Adult , Brain Waves/physiology , Female , Humans , Male , Young Adult
8.
Haemophilia ; 23(4): 538-546, 2017 Jul.
Article in English | MEDLINE | ID: mdl-28574179

ABSTRACT

PATIENTS AND METHODS: A longitudinal study was carried out in 255 children from 10 centres in nine developing countries over 5 years to assess the musculoskeletal outcome of children on episodic factor replacement. Outcome was documented by assessment of the annual joint bleeding rate (AJBR), WFH clinical and Pettersson radiological joint scores as well as the FISH score for activities. Of the 203 patients for whom data was available at the end of 5 years, 164 who had received only episodic treatment are included in this report. RESULTS: The median age at the beginning of the study was 10 years (IQR 7-12). The median clotting factor concentrate (CFC) usage was 662 IU kg-1 year-1 (IQ range: 280-1437). The median AJBR was 10 (IQ range: 5-17). The median AJBR was higher in the older children with the median being 5 for the 5 year old child, while it was 9 for the 10 year old and 11 for children older than 15. Given the episodic nature of the replacement therapy, those with a higher AJBR used significantly greater annual CFC doses (P < 0.001); The median change in WFH clinical score and Pettersson radiological score over the 5 years was 0.4/year for each, while the FISH deteriorated at a rate of 0.2/year with poor correlation of these changes with CFC dose. WFH and FISH scores were significantly worse in those with an AJBR of >3 per year (P = 0.001). The change in the Pettersson score was significantly more in those with an AJBR of >5 per year (P = 0.020). Significant changes in FISH scores were only noted after 10 years of age. CONCLUSION: Episodic CFC replacement over a large range of doses does not alter the natural course of bleeding in haemophilia or the musculoskeletal deterioration and should not be recommended as a long term option for treatment. Prophylaxis is the only way to preserve musculoskeletal function in haemophilia.


Subject(s)
Blood Coagulation Factors/pharmacology , Hemorrhage/prevention & control , Musculoskeletal System/drug effects , Adolescent , Child , Female , Humans , Longitudinal Studies , Male , Musculoskeletal System/pathology , Young Adult
9.
Neuroimage ; 142: 454-464, 2016 Nov 15.
Article in English | MEDLINE | ID: mdl-27542722

ABSTRACT

The ability to predict upcoming structured events based on long-term knowledge and contextual priors is a fundamental principle of human cognition. Tonal music triggers predictive processes based on structural properties of harmony, i.e., regularities defining the arrangement of chords into well-formed musical sequences. While the neural architecture of structure-based predictions during music perception is well described, little is known about the neural networks for analogous predictions in musical actions and how they relate to auditory perception. To fill this gap, expert pianists were presented with harmonically congruent or incongruent chord progressions, either as musical actions (photos of a hand playing chords) that they were required to watch and imitate without sound, or in an auditory format that they listened to without playing. By combining task-based functional magnetic resonance imaging (fMRI) with functional connectivity at rest, we identified distinct sub-regions in right inferior frontal gyrus (rIFG) interconnected with parietal and temporal areas for processing action and audio sequences, respectively. We argue that the differential contribution of parietal and temporal areas is tied to motoric and auditory long-term representations of harmonic regularities that dynamically interact with computations in rIFG. Parsing of the structural dependencies in rIFG is co-determined by both stimulus- or task-demands. In line with contemporary models of prefrontal cortex organization and dual stream models of visual-spatial and auditory processing, we show that the processing of musical harmony is a network capacity with dissociated dorsal and ventral motor and auditory circuits, which both provide the infrastructure for predictive mechanisms optimising action and perception performance.


Subject(s)
Auditory Perception/physiology , Brain Mapping/methods , Cerebral Cortex/physiology , Motor Activity/physiology , Music , Prefrontal Cortex/physiology , Adult , Anticipation, Psychological/physiology , Female , Humans , Magnetic Resonance Imaging , Male , Young Adult
10.
J Sports Med Phys Fitness ; 55(11): 1265-71, 2015 Nov.
Article in English | MEDLINE | ID: mdl-25369278

ABSTRACT

AIM: In water polo, throwing is one of the most important and frequently used technical skills for the player. There is no scientific literature that provides information about differences in throwing between elite and sub-elite water polo players. The aim of our study was to study differences in throwing velocities and kinematic variables in elite and sub-elite level male water polo players. METHODS: We considered the variables under standardized conditions during a typical motion, the five-meter shot (penalty). Thirty-four athletes from the Men's First Division Water Polo Championship and forty-two players participating in the National Fourth Division League, took part in the study. Video analysis measures were taken with high-speed digital cameras and the videos were analyzed offline with Dartfish 5.0 Pro. RESULTS: No correlation was found between body mass, height and throwing velocity. Elite players had higher values ​for ball speed (22.8±2.4 m/s for elite team and 18.4±1.7 m/s for sub-elite team; P=0.002) and greater elbow angle (157.5±10.3 degree for elite team versus 146.7±8.9 degree for sub-elite team; P=0.002). In elite team the throwing time was lower (165.6±22.2 and 188.6±23.9 ms, respectively; P=0.05) and the shoulder angle was smaller (115.1±10.3 and 123.8±12.4 degree, respectively; P=0.03) than in sub-elite team. Head height was significantly greater in elite players (elite players 71.1±8.7 cm, sub-elite players 65.6±6.2 cm; P=0.03). CONCLUSION: Differences in kinematic characteristics between elite and sub-elite players were showed. Differences in elbow and shoulder action must be considered both in training and injury prevention.


Subject(s)
Athletic Performance/physiology , Sports/physiology , Adult , Arm/physiology , Biomechanical Phenomena , Body Height/physiology , Body Mass Index , Elbow Joint/physiology , Humans , Male , Reaction Time , Shoulder Joint/physiology , Torso/physiology , Video Recording/methods , Wrist Joint/physiology , Young Adult
11.
Br J Cancer ; 111(6): 1168-79, 2014 Sep 09.
Article in English | MEDLINE | ID: mdl-25093491

ABSTRACT

BACKGROUND: Multiple lines of evidence support that the Hedgehog (Hh) signalling has a role in the maintenance and progression of different human cancers. Therefore, inhibition of the Hh pathway represents a valid anticancer therapeutic approach for renal cell carcinoma (RCC) patients. NVP-LDE225 is a Smoothened (Smo) antagonist that induces dose-related inhibition of Hh and Smo-dependent tumour growth. METHODS: We assayed the effects of NVP-LDE225 alone or in combination with everolimus or sunitinib on the growth and invasion of human RCC models both in vitro and in vivo. To this aim, we used a panel of human RCC models, comprising cells with acquired resistance to sunitinib - a multiple tyrosine kinase inhibitor approved as a first-line treatment for RCC. RESULTS: NVP-LDE225 cooperated with either everolimus or sunitinib to inhibit proliferation, migration, and invasion of RCC cells even in sunitinib-resistant (SuR) cells. Some major transducers involved in tumour cell motility, including paxillin, were also efficiently inhibited by the combination therapy, as demonstrated by western blot and confocal microscopy assays. Moreover, these combined treatments inhibited tumour growth and increased animal survival in nude mice xenografted with SuR RCC cells. Finally, lung micrometastasis formation was reduced when mice were treated with NVP-LDE225 plus everolimus or sunitinib, as evidenced by artificial metastatic assays. CONCLUSIONS: Hedgehog inhibition by NVP-LDE225 plus sunitinib or everolimus bolsters antitumour activity by interfering with tumour growth and metastatic spread, even in SuR cells. Thus, this new evidence puts forward a new promising therapeutic approach for RCC patients.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Carcinoma, Renal Cell/drug therapy , Hedgehog Proteins/metabolism , Kidney Neoplasms/drug therapy , Lung Neoplasms/secondary , Signal Transduction/drug effects , Tumor Burden/drug effects , Actin Cytoskeleton/ultrastructure , Actins/ultrastructure , Animals , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Biphenyl Compounds/administration & dosage , Carcinoma, Renal Cell/secondary , Cell Line, Tumor , Cell Movement/drug effects , Cell Proliferation/drug effects , Drug Synergism , Everolimus , Humans , Indoles/administration & dosage , Inhibitory Concentration 50 , Kidney Neoplasms/pathology , Kruppel-Like Transcription Factors/metabolism , Mice , Mice, Inbred BALB C , Mice, Nude , Mitogen-Activated Protein Kinases/metabolism , Neoplasm Micrometastasis/drug therapy , Nuclear Proteins/metabolism , Paxillin/metabolism , Paxillin/ultrastructure , Proto-Oncogene Proteins c-akt/metabolism , Pyridines/administration & dosage , Pyrroles/administration & dosage , Receptors, G-Protein-Coupled/antagonists & inhibitors , Receptors, G-Protein-Coupled/metabolism , Ribosomal Protein S6 Kinases, 70-kDa/metabolism , Sirolimus/administration & dosage , Sirolimus/analogs & derivatives , Smoothened Receptor , Sunitinib , Transcription Factors/metabolism , Xenograft Model Antitumor Assays , Zinc Finger Protein GLI1 , Zinc Finger Protein Gli2
12.
Br J Cancer ; 110(12): 2887-95, 2014 Jun 10.
Article in English | MEDLINE | ID: mdl-24823695

ABSTRACT

BACKGROUND: Cetuximab is the only targeted agent approved for the treatment of head and neck squamous cell carcinomas (HNSCC), but low response rates and disease progression are frequently reported. As the phosphoinositide 3-kinase (PI3K) and the mammalian target of rapamycin (mTOR) pathways have an important role in the pathogenesis of HNSCC, we investigated their involvement in cetuximab resistance. METHODS: Different human squamous cancer cell lines sensitive or resistant to cetuximab were tested for the dual PI3K/mTOR inhibitor PF-05212384 (PKI-587), alone and in combination, both in vitro and in vivo. RESULTS: Treatment with PKI-587 enhances sensitivity to cetuximab in vitro, even in the condition of epidermal growth factor receptor (EGFR) resistance. The combination of the two drugs inhibits cells survival, impairs the activation of signalling pathways and induces apoptosis. Interestingly, although significant inhibition of proliferation is observed in all cell lines treated with PKI-587 in combination with cetuximab, activation of apoptosis is evident in sensitive but not in resistant cell lines, in which autophagy is pre-eminent. In nude mice xenografted with resistant Kyse30 cells, the combined treatment significantly reduces tumour growth and prolongs mice survival. CONCLUSIONS: Phosphoinositide 3-kinase/mammalian target of rapamycin inhibition has an important role in the rescue of cetuximab resistance. Different mechanisms of cell death are induced by combined treatment depending on basal anti-EGFR responsiveness.


Subject(s)
Antibodies, Monoclonal, Humanized/pharmacology , Carcinoma, Squamous Cell/drug therapy , Head and Neck Neoplasms/drug therapy , Morpholines/pharmacology , Phosphoinositide-3 Kinase Inhibitors , TOR Serine-Threonine Kinases/antagonists & inhibitors , Triazines/pharmacology , Animals , Antineoplastic Agents/pharmacology , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Apoptosis/drug effects , Autophagy/drug effects , Caspase 3/biosynthesis , Cell Line, Tumor , Cell Proliferation/drug effects , Cetuximab , Drug Resistance, Neoplasm , ErbB Receptors/antagonists & inhibitors , Humans , Mice , Mice, Inbred BALB C , Mice, Nude , Squamous Cell Carcinoma of Head and Neck , Xenograft Model Antitumor Assays
13.
Haemophilia ; 20(1): e63-70, 2014 Jan.
Article in English | MEDLINE | ID: mdl-24354487

ABSTRACT

There is a paucity of literature on haemophilia treatment in Latin American countries, a region characterized by rapidly improving systems of care, but with substantial disparities in treatment between countries. The aim of this study was to evaluate the musculoskeletal status of haemophilia patients from Latin America and to examine the relationship between musculoskeletal status and treatment practices across countries. The Committee of Latin America on the Therapeutics of Inhibitor Groups conducted a survey of its member country representatives on key aspects of haemophilia treatment in 10 countries. Musculoskeletal status of patients was obtained during routine comprehensive evaluations between March 2009 and March 2011. Eligible patients had severe haemophilia A (factor VIII <1%) without inhibitors (<0.6 BU mL(-1) ) and were ≥5 years of age. Musculoskeletal status was compared between three groups of countries, based primarily on differences in the availability of long-term prophylaxis. Overall, 143 patients (5-66 years of age) were enrolled from nine countries. In countries where long-term prophylaxis had been available for at least 10 years (Group A), patients aged 5-10 years had significantly better mean World Federation of Hemophilia clinical scores, fewer target joints and fewer affected joints than patients from countries where long-term prophylaxis has been available for about 5 years (Group B) or was not available (Group C). In Latin America, the musculoskeletal status of patients with severe haemophilia without inhibitors has improved significantly in association with the provision of long-term prophylaxis. As more countries in Latin America institute this practice, further improvements are anticipated.


Subject(s)
Hemarthrosis/diagnosis , Hemarthrosis/etiology , Hemophilia A/complications , Adolescent , Adult , Age Factors , Aged , Child , Child, Preschool , Factor VIII/administration & dosage , Factor VIII/therapeutic use , Hemarthrosis/therapy , Hemophilia A/drug therapy , Humans , Latin America , Male , Middle Aged , Premedication , Severity of Illness Index , Young Adult
15.
Br J Cancer ; 109(3): 686-93, 2013 Aug 06.
Article in English | MEDLINE | ID: mdl-23839492

ABSTRACT

BACKGROUND: We aimed to study key signalling proteins involved in angiogenesis and proliferation on the response to inhibitors of tyrosine kinases and mammalian target of rapamycin in first- and in second-line treatment of renal cell carcinoma (RCC). METHODS: In a panel of human RCC tumours, in vitro and in nude mice, we evaluated the effect of sunitinib, sorafenib and everolimus, alone and in sequence, on tumour growth and expression of signalling proteins involved in proliferation and resistance to treatment. RESULTS: We demonstrated that, as single agents, sunitinib, sorafenib and everolimus share similar activity in inhibiting cell proliferation, signal transduction and vascular endothelial growth factor (VEGF) secretion in different RCC models, both in vitro and in tumour xenografts. Pre-treatment with sunitinib reduced the response to subsequent sunitinib and sorafenib but not to everolimus. Inability by sunitinib to persistently inhibit HIF-1, VEGF and pMAPK anticipated treatment resistance in xenografted tumours. After first-line sunitinib, second-line treatment with everolimus was more effective than either sorafenib or rechallenge with sunitinib in interfering with signalling proteins, VEGF and interleukin-8, translating into a significant advantage in tumour growth inhibition and mice survival. CONCLUSION: We demonstrated that a panel of angiogenic and signalling proteins can correlate with the onset of resistance to sunitinib and the activity of everolimus in second line.


Subject(s)
Angiogenesis Inhibitors/pharmacology , Angiogenic Proteins/metabolism , Antineoplastic Agents/pharmacology , Carcinoma, Renal Cell/drug therapy , Kidney Neoplasms/drug therapy , Neoplasm Proteins/metabolism , Protein Kinase Inhibitors/pharmacology , Angiogenesis Inhibitors/administration & dosage , Angiogenic Proteins/antagonists & inhibitors , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Carcinoma, Renal Cell/blood supply , Carcinoma, Renal Cell/metabolism , Carcinoma, Renal Cell/pathology , Cell Growth Processes/drug effects , Everolimus , Humans , Indoles/administration & dosage , Indoles/pharmacology , Kidney Neoplasms/blood supply , Kidney Neoplasms/metabolism , Kidney Neoplasms/pathology , Mice , Mice, Inbred BALB C , Mice, Nude , Neoplasm Proteins/antagonists & inhibitors , Niacinamide/administration & dosage , Niacinamide/analogs & derivatives , Niacinamide/pharmacology , Phenylurea Compounds/administration & dosage , Phenylurea Compounds/pharmacology , Protein Kinase Inhibitors/administration & dosage , Protein-Tyrosine Kinases/antagonists & inhibitors , Pyrroles/administration & dosage , Pyrroles/pharmacology , Random Allocation , Signal Transduction/drug effects , Sirolimus/administration & dosage , Sirolimus/analogs & derivatives , Sirolimus/pharmacology , Sorafenib , Sunitinib , Xenograft Model Antitumor Assays
16.
Br J Cancer ; 108(8): 1616-23, 2013 Apr 30.
Article in English | MEDLINE | ID: mdl-23571736

ABSTRACT

BACKGROUND: Targeting the mammalian target of rapamycin by everolimus is a successful approach for renal cell carcinoma (RCC) therapy. The Toll-like receptor 9 agonist immune modulatory oligonucleotide (IMO) exhibits direct antitumour and antiangiogenic activity and cooperates with both epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) inhibitors. METHODS: We tested the combination of IMO and everolimus on models of human RCC with different Von-Hippel Lindau (VHL) gene status, both in vitro and in nude mice. We studied their direct antiangiogenic effects on human umbilical vein endothelial cells. RESULTS: Both IMO and everolimus inhibited in vitro growth and survival of RCC cell lines, and their combination produced a synergistic inhibitory effect. Moreover, everolimus plus IMO interfered with EGFR-dependent signaling and reduced VEGF secretion in both VHL wild-type and mutant cells. In RCC tumour xenografts, IMO plus everolimus caused a potent and long-lasting cooperative antitumour activity, with reduction of tumour growth, prolongation of mice survival and inhibition of signal transduction. Furthermore, IMO and everolimus impaired the main endothelial cell functions. CONCLUSION: A combined treatment with everolimus and IMO is effective in VHL wild-type and mutant models of RCC by interfering with tumour growth and angiogenesis, thus representing a potentially effective, rationale-based combination to be translated in the clinical setting.


Subject(s)
Carcinoma, Renal Cell/drug therapy , Kidney Neoplasms/drug therapy , Oligonucleotides/pharmacology , Sirolimus/analogs & derivatives , Toll-Like Receptor 9/agonists , Animals , Carcinoma, Renal Cell/blood supply , Carcinoma, Renal Cell/genetics , Carcinoma, Renal Cell/pathology , Cell Growth Processes/drug effects , Cell Line, Tumor , Drug Synergism , Everolimus , Human Umbilical Vein Endothelial Cells/cytology , Human Umbilical Vein Endothelial Cells/drug effects , Humans , Kidney Neoplasms/blood supply , Kidney Neoplasms/genetics , Kidney Neoplasms/pathology , Mice , Mice, Inbred BALB C , Mice, Nude , Neovascularization, Pathologic/drug therapy , Neovascularization, Pathologic/pathology , Oligonucleotides/genetics , Oligonucleotides/immunology , Random Allocation , Sirolimus/pharmacology , Toll-Like Receptor 9/genetics , Von Hippel-Lindau Tumor Suppressor Protein/genetics , Xenograft Model Antitumor Assays
17.
Haemophilia ; 19(4): 511-8, 2013 Jul.
Article in English | MEDLINE | ID: mdl-23534532

ABSTRACT

Inhibitor development against exogenous factor VIII is a severe impairment of replacement therapy affecting 18% of Argentine patients with severe haemophilia A (HA). To study the molecular predisposition for inhibitor development, we genotyped 260 HA patients with and without inhibitors, countrywide. The inhibitor-positive population (19 transients, 15 low responders, LR and 70 high responders, HR) of 104 severe-HA patients showed 59 Inv22 (intron 22 inversions), 18 small ins/del-frameshifts, 12 gross deletions, 12 nonsense, one splicing defect and two missense, p.Arg531Pro and p.Leu575Pro, both LR and thought to impair FVIII A2 domain secondary structure. In addition, a patient with mild HA and HR showed the missense p.Glu1704Lys associated with two neutral intronic substitutions potentially affecting the A3 domain. A case/control study (84/143) permitted estimation of F8 genotype-specific inhibitor risks [OR; prevalence (CI)] in severe-HA patients classifying a high-risk group including multi-exon deletions [3.66; 55% (19-100)], Inv22 [1.8; 24% (19-100)] and nonsense in FVIII-LCh [1.2; 21% (7-59)]; an average risk group including single-exon deletions, indel frameshifts and nonsense-HCh; and a low-risk group represented by missense defects [0.14; 3% (0.6-11)]. Analysis of inhibitor concordance/discordance in related patients indicated additional genetic factors other than F8 genotype for inhibitor formation. No significant inhibitor-predisposing factors related to FVIII product exposure were found in age- and F8 genotype-stratified populations of severe-HA patients. In conclusion, the Argentine HA patient series presents similar global and mutation-specific inhibitor risks than the HA database and other published series. This case-specific information will help in designing fitted therapies and follow-up protocols in Argentina.


Subject(s)
Factor VIII/antagonists & inhibitors , Factor VIII/genetics , Genetic Predisposition to Disease , Hemophilia A/genetics , Argentina , Case-Control Studies , Humans , Risk Factors
18.
Br J Cancer ; 107(4): 626-31, 2012 Aug 07.
Article in English | MEDLINE | ID: mdl-22805329

ABSTRACT

BACKGROUND: Anti-epidermal growth factor receptor (EGFR) monoclonal antibodies are restricted to KRAS wild-type (WT) metastatic colorectal cancers (mCRCs), usually identified by direct sequencing, that may yield false negative results because of genetic heterogeneity within the tumour. We evaluated the efficiency of high-resolution melting analysis (HRMA) in identifying KRAS-mutant (MUT) tumours. METHODS: We considered 50 mCRC patients scored as KRAS-WT by direct sequencing and treated with cetuximab-containing chemotherapy, and tested the correlations between HRMA findings and response rate (RR), progression-free (PFS) and overall survival (OS). RESULTS: Aberrant melting curves were detected in four (8%) cases; gene cloning confirmed these mutations. Response rate (RR) of HRMA KRAS-WT patients was 28.3%. There was no response in HRMA KRAS-MUT patients. Disease control rate (responsive plus stable disease) was 58.7% in HRMA KRAS-WT patients and 25% in HRMA KRAS-MUT patients. There was no correlation between HRMA KRAS status and RR (P=0.287) or disease control (P=0.219). Median PFS (4.8 vs 2.3 months; hazard ratio (HR)=0.29, P=0.02) and OS (11.0 vs 2.7 months; HR=0.11, P=0.03) were significantly longer for the HRMA KRAS-WT than for HRMA KRAS-MUT patients. CONCLUSIONS: High-resolution melting analysis identified 8% more KRAS-MUT patients not responding to cetuximab-containing regimens, suggesting that HRMA may be more effective than direct sequencing in selecting patients for anti-EGFR antibodies.


Subject(s)
Adenocarcinoma/drug therapy , Antibodies, Monoclonal/therapeutic use , Antineoplastic Agents/therapeutic use , Colorectal Neoplasms/drug therapy , Sequence Analysis, DNA/methods , ras Proteins/genetics , Adult , Aged , Antibodies, Monoclonal, Humanized , Cetuximab , Colorectal Neoplasms/pathology , DNA Mutational Analysis/methods , Disease-Free Survival , Female , Humans , Male , Middle Aged , Neoplasm Metastasis , Survival Rate , Treatment Outcome
19.
Haemophilia ; 18(3): 437-43, 2012 May.
Article in English | MEDLINE | ID: mdl-21910787

ABSTRACT

The development of inhibitors is a complication of replacement treatment in Haemophilia. Loss of factor VIII-specific memory B cells in the spleen is associated with down regulation of antibodies in mice treated with high doses of FVIII, but changes in B cell memory have not been described in haemophilic patients. The aim of this study was to evaluate the phenotype of circulating lymphocytes in severe haemophilia A. Twenty patients with inhibitors (PI), 22 without inhibitors (P), nine patients during immune tolerance induction (ITI) treatment and 20 healthy donors (HD) were included. Peripheral blood lymphocytes were examined using flow cytometry. Anti-FVIII antibodies were measured using Bethesda and flow cytometry. Percentages of T subsets and B lymphocytes were similar in all groups. In contrast, memory B cells (CD27+) were decreased in PI and P compared with HD, but the level of significance was higher in PI (P = 0.001) than P (P = 0.01). PI with high level of anti-FVIII antibodies presented the lowest B memory values. CD70 expression was also lowest in PI. Non-switched CD27+ subpopulation (IgD+) was prevalent in PI, but did not show statistical significance. When ITI failed, the percentages of CD27+ B cells after 12 months of ITI were lowest. In a longitudinal study performed in four patients, an increased percentage of CD27+ and CD70+ B cells during ITI was found. This work suggests that different peripheral lymphocyte markers, such as CD27 and CD70 on B cells, may be helpful to evaluate anti-FVIII response and to monitor the success of ITI.


Subject(s)
B-Lymphocytes/immunology , Factor VIII/immunology , Hemophilia A/immunology , Immunologic Memory/immunology , Adolescent , Antibodies/analysis , B-Lymphocytes/metabolism , Blood Coagulation Factor Inhibitors/metabolism , CD27 Ligand/metabolism , Child , Child, Preschool , Flow Cytometry , Hemophilia A/metabolism , Humans , Male , Phenotype , Young Adult
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