Personalized Paths: Unlocking Alzheimer's via the Gut-Brain Axis.

Background: Alzheimer's disease (AD) is characterised by abnormal protein aggregates in the brain that lead to cognitive decline. While current therapies only treat symptoms, disease-modifying treatments are urgently needed. Studies suggest that the composition of the microbiota is altered in people with AD, suggesting a link between gut bacteria and AD-related brain changes.

Post-natal prognostic factors in CDH: experience of 11 years in a referral center in Brazil.

Objective: To describe post-natal risk factors associated with death in Newborns (NB) with Congenital Diaphragmatic Hernia (CDH) in a Brazilian reference center.

Methods: In this retrospective cohort study, post-natal clinical factors of all NB diagnosed with CDH were reviewed in an 11-year period (2007‒2018). The primary outcome was death.

SARS-CoV-2 infection induces DNA damage, through CHK1 degradation and impaired 53BP1 recruitment, and cellular senescence.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the RNA virus responsible for the coronavirus disease 2019 (COVID-19) pandemic. Although SARS-CoV-2 was reported to alter several cellular pathways, its impact on DNA integrity and the mechanisms involved remain unknown. Here we show that SARS-CoV-2 causes DNA damage and elicits an altered DNA damage response.

Monocyte-to-HDL ratio and non-HDL cholesterol were predictors of septic shock in newborns.

Background: The association between lipoprotein levels and late-onset neonatal sepsis has shown controversial results. The aims are to assess lipid profile, cytokines, and Monocyte-to-HDL (M/H) ratio as diagnostic and prognostic markers for late-onset neonatal sepsis.

Methods: This prospective study included 49 septic neonates and 17 controls.

Correction to "Discovery of Novel α-Carboline Inhibitors of the Anaplastic Lymphoma Kinase".

[This corrects the article DOI: 10.1021/acsomega.2c00507.

Identification of non-ATP-competitive α-carboline inhibitors of the anaplastic lymphoma kinase.

The Anaplastic Lymphoma Kinase (ALK) is a therapeutic target for personalized medicine in selected cancers. Despite excellent clinical responses to ALK inhibitors, most patients develop drug resistance and relapse. New compounds with alternative binding modes are needed to overcome resistant mutants.

Discovery of Novel α-Carboline Inhibitors of the Anaplastic Lymphoma Kinase.

The anaplastic lymphoma kinase (ALK) is abnormally expressed and hyperactivated in a number of tumors and represents an ideal therapeutic target. Despite excellent clinical responses to ALK inhibition, drug resistance still represents an issue and novel compounds that overcome drug-resistant mutants are needed. We designed, synthesized, and evaluated a large series of azacarbazole inhibitors.

BRCA1 deficiency specific base substitution mutagenesis is dependent on translesion synthesis and regulated by 53BP1.

Defects in BRCA1, BRCA2 and other genes of the homology-dependent DNA repair (HR) pathway cause an elevated rate of mutagenesis, eliciting specific mutation patterns including COSMIC signature SBS3. Using genome sequencing of knock-out cell lines we show that Y family translesion synthesis (TLS) polymerases contribute to the spontaneous generation of base substitution and short insertion/deletion mutations in BRCA1 deficient cells, and that TLS on DNA adducts is increased in BRCA1 and BRCA2 mutants. The inactivation of 53BP1 in BRCA1 mutant cells markedly reduces TLS-specific mutagenesis, and rescues the deficiency of template switch-mediated gene conversions in the immunoglobulin V locus of BRCA1 mutant chicken DT40 cells.

Synergistic Drug Combinations Prevent Resistance in ALK+ Anaplastic Large Cell Lymphoma.

Anaplastic lymphoma kinase-positive (ALK+) anaplastic large-cell lymphoma (ALCL) is a subtype of non-Hodgkin lymphoma characterized by expression of the oncogenic NPM/ALK fusion protein. When resistant or relapsed to front-line chemotherapy, ALK+ ALCL prognosis is very poor. In these patients, the ALK inhibitor crizotinib achieves high response rates, however 30-40% of them develop further resistance to crizotinib monotherapy, indicating that new therapeutic approaches are needed in this population.

DNA Damage Triggers a New Phase in Neurodegeneration.

Subcellular compartmentalization contributes to the organization of a plethora of molecular events occurring within cells. This can be achieved in membraneless organelles generated through liquid-liquid phase separation (LLPS), a demixing process that separates and concentrates cellular reactions. RNA is often a critical factor in mediating LLPS.

A closer look into NADPH oxidase inhibitors: Validation and insight into their mechanism of action.

NADPH-oxidases (NOXs) purposefully produce reactive-oxygen-species (ROS) and are found in most kingdoms of life. The seven human NOXs are each characterized by a specific expression profile and a fine regulation to spatio-temporally tune ROS concentration in cells and tissues. One of the best known roles for NOXs is in host protection against pathogens but ROS themselves are important second messengers involved in tissue regeneration and the modulation of pathways that induce and sustain cell proliferation.

Mitochondrial Hyperactivation and Enhanced ROS Production are Involved in Toxicity Induced by Oncogenic Kinases Over-Signaling.

Targeted therapy is an effective, rational, and safe approach to solid and hematological tumors treatment. Unfortunately, a significant fraction of patients treated with tyrosine kinase inhibitors (TKI) relapses mainly because of gene amplification, mutations, or other bypass mechanisms. Recently a growing number of papers showed how, in some cases, resistance due to oncogene overexpression may be associated with drug addiction: cells able to proliferate in the presence of high TKI doses become also TKI dependent, undergoing cellular stress, and apoptosis/death upon drug withdrawal.

Lorlatinib Treatment Elicits Multiple On- and Off-Target Mechanisms of Resistance in ALK-Driven Cancer.

: Targeted therapy changed the standard of care in ALK-dependent tumors. However, resistance remains a major challenge. Lorlatinib is a third-generation ALK inhibitor that inhibits most ALK mutants resistant to current ALK inhibitors.

Engineering stability in NADPH oxidases: A common strategy for enzyme production.

NADPH oxidases (NOXs) are membrane enzymes whose sole function is the generation of reactive oxygen species. Humans have seven NOX isoenzymes that feature distinct functions in immune response and cell signaling but share the same catalytic core comprising a FAD-binding dehydrogenase domain and a heme-binding transmembrane domain. We previously described a mutation that stabilizes the dehydrogenase domain of a prokaryotic homolog of human NOX5.

ANALYSIS OF DEATH AND PALLIATIVE CARE IN A NEONATAL INTENSIVE CARE UNIT.

Objective: To characterize cases of children admitted to the Neonatal Intensive Care Unit of a tertiary university hospital who died in the period ranging from January 01, 2012 to July 31, 2014, and who required palliative care and/or were subjected to it.

Methods: A retrospective descriptive study was carried out by reviewing the medical records of these patients to collect data and to perform descriptive statistical analysis.

Results: During the study period, 49 children died after at least 48 hours from the time of admission.

Crystal structures and atomic model of NADPH oxidase.

NADPH oxidases (NOXs) are the only enzymes exclusively dedicated to reactive oxygen species (ROS) generation. Dysregulation of these polytopic membrane proteins impacts the redox signaling cascades that control cell proliferation and death. We describe the atomic crystal structures of the catalytic flavin adenine dinucleotide (FAD)- and heme-binding domains of NOX5.

Randomized controlled trial comparing nasal intermittent positive pressure ventilation and nasal continuous positive airway pressure in premature infants after tracheal extubation.

Objective:: To analyze the frequency of extubation failure in premature infants using conventional mechanical ventilation (MV) after extubation in groups subjected to nasal intermittent positive pressure ventilation (nIPPV) and continuous positive airway pressure (nCPAP).

Method:: Seventy-two premature infants with respiratory failure were studied, with a gestational age (GA) ≤ 36 weeks and birth weight (BW) > 750 g, who required tracheal intubation and mechanical ventilation. The study was controlled and randomized in order to ensure that the members of the groups used in the research were chosen at random.

Thyroid abnormalities in term infants with fungal sepsis.

Objective:: To describe thyroid alterations in term newborns (TNB) with fungal sepsis during NICU hospitalization.

Method:: The study included six TNB that during the clinical and laboratory manifestations of sepsis with positive cultures for fungus showed changes in thyroid hormones, called low T3 syndrome and low T3-T4 syndrome. TNB that could present hormonal changes caused by disease as those born to mothers with thyroid disease, or who had perinatal asphyxia and major surgeries were excluded.

Synergistic activity of ALK and mTOR inhibitors for the treatment of NPM-ALK positive lymphoma.

ALK-positive Anaplastic Large Cell Lymphoma (ALCL) represents a subset of Non-Hodgkin Lymphoma whose treatment benefited from crizotinib development, a dual ALK/MET inhibitor. Crizotinib blocks ALK-triggered pathways such as PI3K/AKT/mTOR, indispensable for survival of ALK-driven tumors.Despite the positive impact of targeted treatment in ALCL, resistant clones are often selected during therapy.

TLR expression, phagocytosis and oxidative burst in healthy and septic newborns in response to Gram-negative and Gram-positive rods.

The objective was to investigate whether phagocytes from healthy and septic newborns have a developmental deficiency in their capacity to recognize, phagocytize and generate hydrogen peroxide (H2O2) in response to Escherichia coli and Staphylococcus aureus. TLR expression and phagocytic ability of neutrophils and monocytes from 44 healthy preterm and term neonates, from 13 newborns with late-onset sepsis and from 24 healthy adults were determined using flow cytometry, and H2O2 production was measured by dihydrorhodamine test. TLR-2 and TLR-4 expressions were similar among the groups.

Nonthyroidal illnesses syndrome in full-term newborns with sepsis.

Objective: To assess hormonal changes in nonthyroidal illness syndrome (NTIS) in full-term newborns (NT) with sepsis.

Materials And Methods: We included 28 NT with sepsis divided into 2 groups according to the time of normalization of serum and clinical indicators of infection: group A(A), 16 NT with improvement in up to 8 days; and group B(B), 12 NT improvement after 8 days. Among the 28 NT, 15 NT progressed to septic shock, with 5 NT group A and 10 NT in group B.