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Chagas disease is a tropical neglected disease that affects millions of people worldwide, still demanding a more effective and safer therapy, especially in its chronic phase which lacks a treatment that promotes substantial parasitological cure. The technical note of Romanha and collaborators published in 2010 aimed establish a guideline with the set of minimum criteria and decision gates for the development of new agents against Trypanosoma cruzi with the focus on developing new antichagasic drugs. In this sense, the present review aims to update this technical note, bringing the state of the art and new advances on this topic in recent years.

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BACKGROUND: Alterations in PI3K function are directly related to cancer, making PI3K inhibitors suitable options for anticancer therapies. Information on therapy using different types of PI3K inhibitors is available in literature, providing indications of trends in developing new therapies. Although some studies on PI3K inhibitors for cancer treatment provide clinical evidence, they do not allow a careful search for potential PI3K inhibitors conducted by development indicators. Here, we performed a foresight study of clinical trials involving PI3K inhibitors from the past 11 years using indicators of clinical evolution to identify technological trends and provide data for supporting recommendations for new study designs. METHODS: A comprehensive foresight study was designed based on documents from clinical trials on PI3K inhibitors to perform a systematic and comparative analysis, in order to identify technological trends on new cancer therapies. RESULTS: Our results demonstrate that total number of clinical trials has decreased over the years and, currently, there is a clear prevalence of studies using isoform-specific inhibitors in combined interventions. Clinical trials in Phases I and II were the most frequently found in the database, whereas Phase III trials correspond to 7% of studies. The measurement of clinical trials progression using indicators (drugs in Phase III profile, top-10 drugs, and top-10 combined drugs) demonstrated that the 3 new medicines BKM120, IBI-376, and PF-05212384 have a high potential to provide more efficient cancer treatment in combined interventions. These data also include the groups of targets for each drug, providing a useful and reliable source for design new combinations to overcome the resistance and the poor tolerability observed in some PI3K therapies. CONCLUSIONS: The establishment of development indicators based on clinical trials for cancer treatment was useful to highlight the clinical investment in 3 new PI3K drugs and the advantages of combine therapy using FDA-approved drugs.

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ABSTRACT: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy. Current treatments, based on intensive chemotherapy regimens provide overall survival rates of ∼85% in children and <50% in adults, calling the search of new therapeutic options. We previously reported that targeting the T-cell receptor (TCR) in T-ALL with anti-CD3 (αCD3) monoclonal antibodies (mAbs) enforces a molecular program akin to thymic negative selection, a major developmental checkpoint in normal T-cell development; induces leukemic cell death; and impairs leukemia progression to ultimately improve host survival. However, αCD3 monotherapy resulted in relapse. To find out actionable targets able to re-enforce leukemic cells' vulnerability to αCD3 mAbs, including the clinically relevant teplizumab, we identified the molecular program induced by αCD3 mAbs in patient-derived xenografts derived from T-ALL cases. Using large-scale transcriptomic analysis, we found prominent expression of tumor necrosis factor α (TNFα), lymphotoxin α (LTα), and multiple components of the "TNFα via NF-κB signaling" pathway in anti-CD3-treated T-ALL. We show in vivo that etanercept, a sink for TNFα/LTα, enhances αCD3 antileukemic properties, indicating that TNF/TNF receptor (TNFR) survival pathways interferes with TCR-induced leukemic cell death. However, suppression of TNF-mediated survival and switch to TNFR-mediated cell death through inhibition of cellular inhibitor of apoptosis protein-1/2 (cIAP1/2) with the second mitochondrial-derived activator of caspases (SMAC) mimetic birinapant synergizes with αCD3 to impair leukemia expansion in a receptor-interacting serine/threonine-protein kinase 1-dependent manner and improve mice survival. Thus, our results advocate the use of either TNFα/LTα inhibitors, or birinapant/other SMAC mimetics to improve anti-CD3 immunotherapy in T-ALL.

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Introducción: el dacriocistocele es una malformación congénita rara, secundaria a la obstrucción del conducto nasolagrimal; tiene una incidencia de 0,1 % de pacientes con obstrucción congénita del conducto nasolagrimal y se encuentra bilateralmente hasta en 25 % de casos. Caso clínico: lactante femenina de dos meses con celulitis periorbitaria derecha preseptal no asociada con lesión de entrada y diagnóstico inicial de dacriocistitis derecha. Al examen físico de ingreso, en el ojo derecho se evidencia gran masa abscedada en saco lagrimal; en el ojo izquierdo, un área indurada y leve reflujo a la presión del saco lagrimal. Se realiza tomografía computarizada de órbitas con hallazgos compatibles con dacriocistocele bilateral. Discusión y conclusiones: conocer la presentación y posibles complicaciones asociadas con esta patología previene una morbilidad importante al paciente. La mayoría de los casos de dacriocistocele se pueden manejar médicamente, sin embargo, aquellos asociados con complicaciones requieren de manejo quirúrgico oportuno.

Introduction: Dacryocystocele is a rare congenital malformation secondary to na-solacrimal duct obstruction. It has an incidence of 0.1% of patients with congenital nasolacrimal duct obstruction, being found bilaterally in up to 25% of cases. Case Report: Two-month-old female infant with preseptal right periorbital cellulitis not associated with an entrance lesion, with an initial diagnosis of right dacryocystitis. On physical examination, a large abscessed mass in the lacrimal sac was eviden-ced in the right eye; in the left eye, there was an indurated area and slight reflux to the lacrimal sac pressure. Computed tomography of the orbits was performed with findings compatible with bilateral dacryocystocele. Discussion and conclusions: Knowing the presentation and possible complications associated with this pathology prevents significant patient morbidity. Most cases of dacryocystocele can be mana-ged medically, however, cases associated with complications require timely surgical management.

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Chagas disease is a tropical neglected disease that affects millions of people worldwide, still demanding a more effective and safer therapy, especially in its chronic phase which lacks a treatment that promotes substantial parasitological cure. The technical note of Romanha and collaborators published in 2010 aimed establish a guideline with the set of minimum criteria and decision gates for the development of new agents against Trypanosoma cruzi with the focus on developing new antichagasic drugs. In this sense, the present review aims to update this technical note, bringing the state of the art and new advances on this topic in recent years.

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The apicomplexan parasite Toxoplasma gondii is the causative agent of toxoplasmosis, a global disease that significantly impacts human health. The clinical manifestations are mainly observed in immunocompromised patients, including ocular damage and neuronal alterations leading to psychiatric disorders. The congenital infection leads to miscarriage or severe alterations in the development of newborns. The conventional treatment is limited to the acute phase of illness, without effects in latent parasites; consequently, a cure is not available yet. Furthermore, considerable toxic effects and long-term therapy contribute to high treatment abandonment rates. The investigation of exclusive parasite pathways would provide new drug targets for more effective therapies, eliminating or reducing the side effects of conventional pharmacological approaches. Protein kinases (PKs) have emerged as promising targets for developing specific inhibitors with high selectivity and efficiency against diseases. Studies in T. gondii have indicated the presence of exclusive PKs without homologs in human cells, which could become important targets for developing new drugs. Knockout of specific kinases linked to energy metabolism have shown to impair the parasite development, reinforcing the essentiality of these enzymes in parasite metabolism. In addition, the specificities found in the PKs that regulate the energy metabolism in this parasite could bring new perspectives for safer and more efficient therapies for treating toxoplasmosis. Therefore, this review provides an overview of the limitations for reaching an efficient treatment and explores the role of PKs in regulating carbon metabolism in Toxoplasma, discussing their potential as targets for more applied and efficient pharmacological approaches.

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Toxoplasma gondii is an obligate intracellular parasite of the phylum Apicomplexa and causes toxoplasmosis infections, a disease that affects a quarter of the world's population and has no effective cure. Epigenetic regulation is one of the mechanisms controlling gene expression and plays an essential role in all organisms. Lysine deacetylases (KDACs) act as epigenetic regulators affecting gene silencing in many eukaryotes. Here, we focus on TgKDAC4, an enzyme unique to apicomplexan parasites, and a class IV KDAC, the least-studied class of deacetylases so far. This enzyme shares only a portion of the specific KDAC domain with other organisms. Phylogenetic analysis from the TgKDAC4 domain shows a putative prokaryotic origin. Surprisingly, TgKDAC4 is located in the apicoplast, making it the only KDAC found in this organelle to date. Transmission electron microscopy assays confirmed the presence of TgKDAC4 in the periphery of the apicoplast. We identified possible targets or/and partners of TgKDAC4 by immunoprecipitation assays followed by mass spectrometry analysis, including TgCPN60 and TgGAPDH2, both located at the apicoplast and containing acetylation sites. Understanding how the protein works could provide new insights into the metabolism of the apicoplast, an essential organelle for parasite survival.

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PURPOSE: To find the cut-off values in the Myelopathy Disability Index (MDI) that will allow us to classify the severity of Degenerative Cervical Myelopathy (DCM) into mild, moderate and severe. METHODS: Cross-sectional study with prospective data collection, with a total of 64 patients diagnosed with Degenerative Cervical Myelopathy (DCM). Anthropometric, diagnostic, neurological, functional and quality of life variables were collected. A Receiver Operating Curve (ROC) was performed. The cut-off points were validated by comparing the functional status of patients in the 3 groups and their Nurick scores. RESULTS: Sixty-four patients (23 women) with a mean age of 61.97 (SD 11.57) participated in this study. The majority of patients were Nurick I (28.13%) and Nurick II (32.81%). The medium MDI was 7.36 (SD 6.66) and the mJOA was 14.08 (SD 2.57). The mild-moderate cut-off value was between 4 and 5, with an Area Under the Curve (AUC) of 0.805, sensitivity of 0.853 and specificity of 0.6. For moderate-severe, the cut-off value obtained was between 7 and 8, with an AUC of 0.862, sensitivity of 0.857 and specificity of 0.684. Patients with greater severity had significantly lower functionality, with a P-value of 0.004 in the 30 Metre Walking Test and 0.005 in the Nine-Hole Peg Test. Established severity groups were also significantly related to the different categories of the Nurick score (P-value = 0.000). CONCLUSION: MDI values between 0 and 4 correspond to mild DCM, between 5 and 7 would be moderate DCM and from 8 to 30 indicate severe DCM.

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Toxoplasma gondii is an obligate intracellular parasite of the phylum Apicomplexa and causes toxoplasmosis infections, a disease that affects a quarter of the world’s population and has no effective cure. Epigenetic regulation is one of the mechanisms controlling gene expression and plays an essential role in all organisms. Lysine deacetylases (KDACs) act as epigenetic regulators affecting gene silencing in many eukaryotes. Here, we focus on TgKDAC4, an enzyme unique to apicomplexan parasites, and a class IV KDAC, the least-studied class of deacetylases so far. This enzyme shares only a portion of the specific KDAC domain with other organisms. Phylogenetic analysis from the TgKDAC4 domain shows a putative prokaryotic origin. Surprisingly, TgKDAC4 is located in the apicoplast, making it the only KDAC found in this organelle to date. Transmission electron microscopy assays confirmed the presence of TgKDAC4 in the periphery of the apicoplast. We identified possible targets or/and partners of TgKDAC4 by immunoprecipitation assays followed by mass spectrometry analysis, including TgCPN60 and TgGAPDH2, both located at the apicoplast and containing acetylation sites. Understanding how the protein works could provide new insights into the metabolism of the apicoplast, an essential organelle for parasite survival.

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Chromatin dynamics can regulate all DNA-dependent processes. Access to DNA within chromatin is orchestrated mainly by histones and their posttranslational modifications (PTMs). Like other eukaryotes, the apicomplexan parasite Toxoplasma gondii encodes four canonical histones and five histone variants. In contrast, the linker histone (H1) has never been identified in apicomplexan parasites. In other eukaryotes, histone H1 compacts the chromatin by linking the nucleosome and increasing the DNA compaction. H1 is a multifunctional protein and can be involved in different steps of DNA metabolism or associated with protein complexes related to distinct biological processes. We have identified a novel protein in T. gondii ("TgH1-like") that, although lacking the globular domain of mammalian H1, is remarkably like the H1-like proteins of bacteria and trypanosomatids. Our results demonstrate that TgH1-like is a nuclear protein associated with chromatin and other histones. Curiously, TgH1-like is also in the nucleolus and associated with ribosomal proteins, indicating a versatile function in this parasite. Although knockout of the tgh1-like gene does not affect the cell cycle, it causes endopolygeny and asynchronous division. Interestingly, mutation of posttranslationally modified amino acids results in defects in cell division like those in the Δtgh1-like mutant, showing that these sites are important for protein function. Furthermore, in the bradyzoite stage, this protein is expressed only in dividing parasites, reinforcing its importance in cell division. Indeed, the absence of TgH1-like decreases compaction of peripheral chromatin, confirming its role in the chromatin modulation in T. gondii. IMPORTANCE Histone H1, or linker histone, is an important protein that binds to the nucleosome, aiding chromatin compaction. Here, we characterize for the first time a linker histone in T. gondii, named TgH1-like. It is a small and basic protein that corresponds only to the C-terminal portion of the human H1 but is similar to histone H1 from trypanosomatids and bacteria. TgH1-like is located in the nucleus, interacts with nucleosome histones, and acts in chromatin structure and cell division. Our findings show for the first time the presence of a histone H1 protein in an apicomplexan parasite and will provide new insights into cell division and chromatin dynamics in T. gondii and related parasites.

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In trypanosomatids, transcription is polycistronic and all mRNAs are processed by trans-splicing, with export mediated by noncanonical mechanisms. Although mRNA export is central to gene regulation and expression, few orthologs of proteins involved in mRNA export in higher eukaryotes are detectable in trypanosome genomes, necessitating direct identification of protein components. We previously described conserved mRNA export pathway components in Trypanosoma cruzi, including orthologs of Sub2, a component of the TREX complex, and eIF4AIII (previously Hel45), a core component of the exon junction complex (EJC). Here, we searched for protein interactors of both proteins using cryomilling and mass spectrometry. Significant overlap between TcSub2 and TceIF4AIII-interacting protein cohorts suggests that both proteins associate with similar machinery. We identified several interactions with conserved core components of the EJC and multiple additional complexes, together with proteins specific to trypanosomatids. Additional immunoisolations of kinetoplastid-specific proteins both validated and extended the superinteractome, which is capable of supporting RNA processing from splicing through to nuclear export and cytoplasmic events. We also suggest that only proteomics is powerful enough to uncover the high connectivity between multiple aspects of mRNA metabolism and to uncover kinetoplastid-specific components that create a unique amalgam to support trypanosome mRNA maturation.

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Chagas disease is a neglected tropical disease caused by Trypanosoma cruzi. This protozoan developed several mechanisms to infect, propagate, and survive in different hosts. The specific expression of proteins is responsible for morphological and metabolic changes in different parasite stages along the parasite life cycle. The virulence strategies at the cellular and molecular levels consist of molecules responsible for mediating resistance mechanisms to oxidative damage, cellular invasion, and immune evasion, performed mainly by surface proteins. Since parasite surface coat remodeling is crucial to invasion and infectivity, surface proteins are essential virulence elements. Understanding the factors involved in these processes improves the knowledge of parasite pathogenesis. Genome sequencing has opened the door to high-throughput technologies, allowing us to obtain a deeper understanding of gene reprogramming along the parasite life cycle and identify critical molecules for survival. This review therefore focuses on proteins regulated during differentiation into infective forms considered virulence factors and addresses the current known mechanisms acting in the modulation of gene expression, emphasizing mRNA signals, regulatory factors, and protein complexes.

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Olmstead v. L.C. ex rel Zimring (1999) was a landmark U.S. Supreme Court decision holding that unjustified segregation of people with disabilities is impermissible discrimination; specifically, if the clinician and client believe community integration to be appropriate, the state must have reasonable accommodations in place for the client to be in the community. Enforcement of the Olmstead decision for people with serious mental illness (SMI) has taken many shapes, from the U.S. Department of Justice's (DOJ) settlement agreements requiring substantive development of community mental health services and aggressive community integration protocols, to the Third Circuit approach which requires only lower census numbers in the state psychiatric hospital (SPH). The question of whether Olmstead is being differentially enforced is addressed in an empirical, qualitative analysis of legal documents, including court opinions and settlement agreements. Through legal research spanning all U.S. jurisdictions, five distinct Olmstead enforcement approaches in ten different states were identified. The enforcement approaches are described, and limitations and future directions are discussed. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

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Psychiatric advance directives, or directives for mental health treatment (DMHTs), are consistent with the principles of psychiatric rehabilitation, self-determination, and a recovery orientation. DMHTs have promise as a consumer-empowering part of a relapse prevention plan. In the context of state psychiatric hospitals, where successful community reintegration is crucial, they have particular relevance. However, DMHTs tend to be underutilized, despite the existence of consumer-friendly laws and consumer interest. Mental health providers (n = 225) were surveyed to assess knowledge of and attitudes toward more comprehensive implementation of DMHTs to test the hypothesis that at least an initial barrier to implementation is provider familiarity with DMHTs. Results of the survey indicate a lack of familiarity with DMHTs, which was addressed by a brief educational intervention embedded in the survey. Prior to education, providers demonstrated a sense of futility and low confidence in their ability to help families plan ahead for future episodes of psychosis. After brief education, they reported more confidence in their ability to effectively intervene and more confidence a DMHT would be a useful intervention. Furthermore, they reported attitudes more supportive of DMHT use as well as an increased likelihood to use DMHTs in their own practice. These findings suggest that an initial barrier to implementation of DMHTs may often be provider familiarity and understanding. Future directions, including broader interventions to increase familiarity, and limitations are discussed. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

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Chromatin dynamics can regulate all DNA-dependent processes. Access to DNA within chromatin is orchestrated mainly by histones and their posttranslational modifications (PTMs). Like other eukaryotes, the apicomplexan parasite Toxoplasma gondii encodes four canonical histones and five histone variants. In contrast, the linker histone (H1) has never been identified in apicomplexan parasites. In other eukaryotes, histone H1 compacts the chromatin by linking the nucleosome and increasing the DNA compaction. H1 is a multifunctional protein and can be involved in different steps of DNA metabolism or associated with protein complexes related to distinct biological processes. We have identified a novel protein in T. gondii (“TgH1-like”) that, although lacking the globular domain of mammalian H1, is remarkably like the H1-like proteins of bacteria and trypanosomatids. Our results demonstrate that TgH1-like is a nuclear protein associated with chromatin and other histones. Curiously, TgH1-like is also in the nucleolus and associated with ribosomal proteins, indicating a versatile function in this parasite. Although knockout of the tgh1-like gene does not affect the cell cycle, it causes endopolygeny and asynchronous division. Interestingly, mutation of posttranslationally modified amino acids results in defects in cell division like those in the Δtgh1-like mutant, showing that these sites are important for protein function. Furthermore, in the bradyzoite stage, this protein is expressed only in dividing parasites, reinforcing its importance in cell division. Indeed, the absence of TgH1-like decreases compaction of peripheral chromatin, confirming its role in the chromatin modulation in T. gondii. Histone H1, or linker histone, is an important protein that binds to the nucleosome, aiding chromatin compaction. Here, we characterize for the first time a linker histone in T. gondii, named TgH1-like. It is a small and basic protein that corresponds only to the C-terminal portion of the human H1 but is similar to histone H1 from trypanosomatids and bacteria. TgH1-like is located in the nucleus, interacts with nucleosome histones, and acts in chromatin structure and cell division. Our findings show for the first time the presence of a histone H1 protein in an apicomplexan parasite and will provide new insights into cell division and chromatin dynamics in T. gondii and related parasites.

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Open patella fractures have high complication rates. Post-traumatic joint stiffness is particularly common. The management of this complication is even more difficult if free flap was used to cover a soft tissue defect. Late surgical manipulation of free flaps can lead to their failure, with catastrophic consequences. The use of minimally invasive techniques could reduce the associated risks. We present a case of knee stiffness after the fix and flap treatment of a grade IIIB open patella fracture. We performed an arthroscopic arthrolysis with portals through the flap. The pedicle was preoperatively located and avoided. Joint range of motion remarkably improved without records of flap complications. We consider that the technique is feasible. Its success was based on the multidisciplinary collaboration between orthopaedic and plastic surgeons and rehabilitation medicine specialists.

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BACKGROUND: We report a genomic surveillance of SARS-CoV-2 lineages circulating in Paraná, southern Brazil, from March 2020 to April 2021. Our analysis, based on 333 genomes, revealed that the first variants detected in the state of Paraná in March 2020 were the B.1.1.33 and B.1.1.28 variants. The variants B.1.1.28 and B.1.1.33 were predominant throughout 2020 until the introduction of the variant P.2 in August 2020 and a variant of concern (VOC), Gamma (P.1), in January 2021. The VOC Gamma, a ramification of the B.1.1.28 lineage first detected in Manaus (northern Brazil), has grown rapidly since December 2020 and was thought to be responsible for the deadly second wave of COVID-19 throughout Brazil. METHODS: The 333 genomic sequences of SARS-CoV-2 from March 2020 to April 2021 were generated as part of the genomic surveillance carried out by Fiocruz in Brazil Genomahcov Fiocruz. SARS-CoV-2 sequencing was performed using representative samples from all geographic areas of Paraná. Phylogenetic analyses were performed using the 333 genomes also included other SARS-CoV-2 genomes from the state of Paraná and other states in Brazil that were deposited in the GISAID. In addition, the time-scaled phylogenetic tree was constructed with up to 3 random sequences of the Gamma variant from each state in Brazil in each month of 2021. In this analysis we also added the sequences identified as the B.1.1.28 lineage of the Amazonas state and and the Gamma-like-II (P.1-like-II) lineage identified in different regions of Brazil. RESULTS: Phylogenetic analyses of the SARS-CoV-2 genomes that were previously classified as the VOC Gamma lineage by WHO/PANGO showed that some genomes from February to April 2021 branched in a monophyletic clade and that these samples grouped together with genomes recently described with the lineage Gamma-like-II. Additionally, a new mutation (E661D) in the spike (S) protein has been identified in nearly 10% of the genomes classified as the VOC Gamma from Paraná in March and April 2021.Finally, we analyzed the correlation between the lineage and the Gamma variant frequency, age group (patients younger or older than 60 years old) and the clinical data of 86 cases from the state of Paraná. CONCLUSIONS: Our results provided a reliable picture of the evolution of the SARS-CoV-2 pandemic in the state of Paraná characterized by the dominance of the Gamma strain, as well as a high frequencies of the Gamma-like-II lineage and the S:E661D mutation. Epidemiological and genomic surveillance efforts should be continued to unveil the biological relevance of the novel mutations detected in the VOC Gamma in Paraná.

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(1) Background: Chitosan-coated gold nanoparticles (CH-AuNPs) have important theranostic applications in biomedical sciences, including cancer research. However, although cell cytotoxicity has been studied in cancerous cells, little is known about their effect in proliferating primary leukocytes. Here, we assessed the effect of CH-AuNPs and the implication of ROS on non-cancerous endothelial and fibroblast cell lines and in proliferative lymphoid cells. (2) Methods: The Turkevich method was used to synthetize gold nanoparticles. We tested cell viability, cell death, ROS production, and cell cycle in primary lymphoid cells, compared with non-cancer and cancer cell lines. Concanavalin A (ConA) or lipopolysaccharide (LPS) were used to induce proliferation on lymphoid cells. (3) Results: CH-AuNPs presented high cytotoxicity and ROS production against cancer cells compared to non-cancer cells; they also induced a different pattern of ROS production in peripheral blood mononuclear cells (PBMCs). No significant cell-death difference was found in PBMCs, splenic mononuclear cells, and bone marrow cells (BMC) with or without a proliferative stimuli. (4) Conclusions: Taken together, our results highlight the selectivity of CH-AuNPs to cancer cells, discarding a consistent cytotoxicity upon proliferative cells including endothelial, fibroblast, and lymphoid cells, and suggest their application in cancer treatment without affecting immune cells.