NTRK Therapy among Different Types of Cancers, Review and Future Perspectives.

Neurotrophic tyrosine receptor kinase (NTRK) has been a remarkable therapeutic target for treating different malignancies, playing an essential role in oncogenic signaling pathways. Groundbreaking trials like NAVIGATE led to the approval of NTRK inhibitors by the Food and Drug Administration (FDA) to treat different malignancies, significantly impacting current oncology treatment. Accurate detection of NTRK gene fusion becomes very important for possible targeted therapy. Various methods to detect NTRK gene fusion have been applied widely based on sensitivity, specificity, and accessibility. The utility of different tests in clinical practice is discussed in this study by providing insights into their effectiveness in targeting patients who may benefit from therapy. Widespread use of NTRK inhibitors in different malignancies could remain limited due to resistance mechanisms that cause challenges to medication efficacy in addition to common side effects of the medications. This review provides a succinct overview of the application of NTRK inhibitors in various types of cancer by emphasizing the critical clinical significance of NTRK fusion gene detection. The discussion also provides a solid foundation for understanding the current challenges and potential changes for improving the efficacy of NTRK inhibitor therapy to treat different malignancies.

Control Theory and Systems Biology: Potential Applications in Neurodegeneration and Search for Therapeutic Targets.

Control theory, a well-established discipline in engineering and mathematics, has found novel applications in systems biology. This interdisciplinary approach leverages the principles of feedback control and regulation to gain insights into the complex dynamics of cellular and molecular networks underlying chronic diseases, including neurodegeneration. By modeling and analyzing these intricate systems, control theory provides a framework to understand the pathophysiology and identify potential therapeutic targets. Therefore, this review examines the most widely used control methods in conjunction with genomic-scale metabolic models in the steady state of the multi-omics type. According to our research, this approach involves integrating experimental data, mathematical modeling, and computational analyses to simulate and control complex biological systems. In this review, we find that the most significant application of this methodology is associated with cancer, leaving a lack of knowledge in neurodegenerative models. However, this methodology, mainly associated with the Minimal Dominant Set (MDS), has provided a starting point for identifying therapeutic targets for drug development and personalized treatment strategies, paving the way for more effective therapies.

Uncovering the Genetic and Molecular Features of Huntington's Disease in Northern Colombia.

Huntington's disease (HD) is a genetic disorder caused by a CAG trinucleotide expansion in the huntingtin (HTT) gene. Juan de Acosta, Atlántico, a city located on the Caribbean coast of Colombia, is home to the world's second-largest HD pedigree. Here, we include 291 descendants of this pedigree with at least one family member with HD. Blood samples were collected, and genomic DNA was extracted. We quantified the HTT CAG expansion using an amplicon sequencing protocol. The genetic heterogeneity was measured as the ratio of the mosaicism allele's read peak and the slippage ratio of the allele's read peak from our sequence data. The statistical and bioinformatic analyses were performed with a significance threshold of p < 0.05. We found that the average HTT CAG repeat length in all participants was 21.91 (SD = 8.92). Of the 291 participants, 33 (11.3%, 18 females) had a positive molecular diagnosis for HD. Most affected individuals were adults, and the most common primary and secondary alleles were 17/7 (CAG/CCG) and 17/10 (CAG/CCG), respectively. The mosaicism increased with age in the participants with HD, while the slippage analyses revealed differences by the HD allele type only for the secondary allele. The slippage tended to increase with the HTT CAG repeat length in the participants with HD, but the increase was not statistically significant. This study analyzed the genetic and molecular features of 291 participants, including 33 with HD. We found that the mosaicism increased with age in the participants with HD, particularly for the secondary allele. The most common haplotype was 17/7_17/10. The slippage for the secondary allele varied by the HD allele type, but there was no significant difference in the slippage by sex. Our findings offer valuable insights into HD and could have implications for future research and clinical management.

Integrated Metabolomics and Lipidomics Reveal High Accumulation of Glycerophospholipids in Human Astrocytes under the Lipotoxic Effect of Palmitic Acid and Tibolone Protection.

Lipotoxicity is a metabolic condition resulting from the accumulation of free fatty acids in non-adipose tissues which involves a series of pathological responses triggered after chronic exposure to high levels of fatty acids, severely detrimental to cellular homeostasis and viability. In brain, lipotoxicity affects both neurons and other cell types, notably astrocytes, leading to neurodegenerative processes, such as Alzheimer (AD) and Parkinson diseases (PD). In this study, we performed for the first time, a whole lipidomic characterization of Normal Human Astrocytes cultures exposed to toxic concentrations of palmitic acid and the protective compound tibolone, to establish and identify the set of potential metabolites that are modulated under these experimental treatments. The study covered 3843 features involved in the exo- and endo-metabolome extracts obtained from astrocytes with the mentioned treatments. Through multivariate statistical analysis such as PCA (principal component analysis), partial least squares (PLS-DA), clustering analysis, and machine learning enrichment analysis, it was possible to determine the specific metabolites that were affected by palmitic acid insult, such as phosphoethanolamines, phosphoserines phosphocholines and glycerophosphocholines, with their respective metabolic pathways impact. Moreover, our results suggest the importance of tibolone in the generation of neuroprotective metabolites by astrocytes and may be relevant to the development of neurodegenerative processes.

Fatty Acids: An Insight into the Pathogenesis of Neurodegenerative Diseases and Therapeutic Potential.

One of the most common lipids in the human body is palmitic acid (PA), a saturated fatty acid with essential functions in brain cells. PA is used by cells as an energy source, besides being a precursor of signaling molecules and protein tilting across the membrane. Although PA plays physiological functions in the brain, its excessive accumulation leads to detrimental effects on brain cells, causing lipotoxicity. This mechanism involves the activation of toll-like receptors (TLR) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathways, with the consequent release of pro-inflammatory cytokines, increased production of reactive oxygen species (ROS), endoplasmic reticulum (ER) stress, and autophagy impairment. Importantly, some of the cellular changes induced by PA lead to an augmented susceptibility to the development of Alzheimer's and Parkinson´s diseases. Considering the complexity of the response to PA and the intrinsic differences of the brain, in this review, we provide an overview of the molecular and cellular effects of PA on different brain cells and their possible relationships with neurodegenerative diseases (NDs). Furthermore, we propose the use of other fatty acids, such as oleic acid or linoleic acid, as potential therapeutic approaches against NDs, as these fatty acids can counteract PA's negative effects on cells.

Tibolone Pre-Treatment Ameliorates the Dysregulation of Protein Translation and Transport Generated by Palmitic Acid-Induced Lipotoxicity in Human Astrocytes: A Label-Free MS-Based Proteomics and Network Analysis.

Excessive accumulation and release of fatty acids (FAs) in adipose and non-adipose tissue are characteristic of obesity and are associated with the leading causes of death worldwide. Chronic exposure to high concentrations of FAs such as palmitic acid (pal) is a risk factor for developing different neurodegenerative diseases (NDs) through several mechanisms. In the brain, astrocytic dysregulation plays an essential role in detrimental processes like metabolic inflammatory state, oxidative stress, endoplasmic reticulum stress, and autophagy impairment. Evidence shows that tibolone, a synthetic steroid, induces neuroprotective effects, but its molecular mechanisms upon exposure to pal remain largely unknown. Due to the capacity of identifying changes in the whole data-set of proteins and their interaction allowing a deeper understanding, we used a proteomic approach on normal human astrocytes under supraphysiological levels of pal as a model to induce cytotoxicity, finding changes of expression in proteins related to translation, transport, autophagy, and apoptosis. Additionally, tibolone pre-treatment showed protective effects by restoring those same pal-altered processes and increasing the expression of proteins from cell survival processes. Interestingly, ARF3 and IPO7 were identified as relevant proteins, presenting a high weight in the protein-protein interaction network and significant differences in expression levels. These proteins are related to transport and translation processes, and their expression was restored by tibolone. This work suggests that the damage caused by pal in astrocytes simultaneously involves different mechanisms that the tibolone can partially revert, making tibolone interesting for further research to understand how to modulate these damages.

Can food allergy be cured? What are the future prospects?

Food allergies have become a significant heath burden as prevalence continues to rise, affecting 6%-13% of the global population. In the absence of drugs approved by regulatory agencies, the current standard of care remains avoidance of allergenic foods and management of acute allergic reactions with antihistamines and epinephrine autoinjectors. Allergen immunotherapy has been shown to increase the threshold of reactivity in the majority of food-allergic individuals. However, challenges include long treatment periods, high rates of adverse reactions, and lack of permanence of desensitization and established protocols. To address these limitations, adjunctive allergen-specific immunotherapy, vaccines, and non-allergen-specific therapies (eg, monoclonal antibodies) are being explored. The future of food allergy treatment is promising with a number of clinical trials in progress. Currently, although desensitization can be achieved for the majority of individuals with food allergy through immunotherapy, continued ingestion of allergen is needed for most individuals to maintain desensitization. Further understanding of the mechanisms of food allergy and identification of biomarkers to distinguish between temporary and permanent resolution of allergies is needed before a cure, where reactivity to the allergen is permanently lost enabling the individual to consume the allergen in any amount at any time, can be envisioned.

A genome-scale metabolic model of potato late blight suggests a photosynthesis suppression mechanism.

BACKGROUND: Phytophthora infestans is a plant pathogen that causes an important plant disease known as late blight in potato plants (Solanum tuberosum) and several other solanaceous hosts. This disease is the main factor affecting potato crop production worldwide. In spite of the importance of the disease, the molecular mechanisms underlying the compatibility between the pathogen and its hosts are still unknown. RESULTS: To explain the metabolic response of late blight, specifically photosynthesis inhibition in infected plants, we reconstructed a genome-scale metabolic network of the S. tuberosum leaf, PstM1. This metabolic network simulates the effect of this disease in the leaf metabolism. PstM1 accounts for 2751 genes, 1113 metabolic functions, 1773 gene-protein-reaction associations and 1938 metabolites involved in 2072 reactions. The optimization of the model for biomass synthesis maximization in three infection time points suggested a suppression of the photosynthetic capacity related to the decrease of metabolic flux in light reactions and carbon fixation reactions. In addition, a variation pattern in the flux of carboxylation to oxygenation reactions catalyzed by RuBisCO was also identified, likely to be associated to a defense response in the compatible interaction between P. infestans and S. tuberosum. CONCLUSIONS: In this work, we introduced simultaneously the first metabolic network of S. tuberosum and the first genome-scale metabolic model of the compatible interaction of a plant with P. infestans.

Do carcasses of lambs finished on commercial production systems meet market standards?

This study aimed to characterize a commercial lamb finishing system using animals of undefined breed from production to slaughter by analyzing performance, carcass traits, yield of commercial cuts, and the quality and meat acceptance of different slaughter groups, as to evaluate whether this system provides the market with a standardized product. The lots were not homogeneous for yield of commercial cuts and performance and morphometric traits evaluated in vivo. The groups were heterogeneous to 75% of the 13 carcass traits evaluated, among them, hot and cold carcass weights, hot and cold carcass yields, carcass grade finishing and biological yield. There was also no uniformity for the proportion of non-carcass components, morphometry of carcass, visual appraisals, and loin traits. On the other hand, homogeneity was achieved in physico-chemical and sensory traits, except for hardness and proportion of saturated, monounsaturated and polyunsaturated fatty acids. We conclude that the commercial finishing system with the use of undefined crossbred lambs does not produce carcass and cuts standardized to the market.

Failure Rate and Clinical Outcomes of Anterior Cruciate Ligament Reconstruction Using Autograft Hamstring Versus a Hybrid Graft.

PURPOSE: To compare the revision rate and subjective outcome measures of autograft hamstring versus a soft tissue hybrid graft combining both autograft hamstring and tibialis allograft for isolated anterior cruciate ligament (ACL) reconstruction. METHODS: A single-center retrospective, nonrandomized, comparative study of isolated ACL reconstruction revision rates for subjects who underwent arthroscopic reconstruction of the ACL using autograft hamstring or a soft tissue hybrid graft using both autograft hamstring and tibialis allograft was performed. Patients with isolated ACL tears were included and underwent anatomic single-bundle reconstruction using an independent tunnel drilling technique and a minimum of 24 months' follow-up. The primary outcome assessed was the presence or absence of ACL rerupture. Secondary clinical outcomes consisted of the International Knee Documentation Committee, University of California at Los Angeles (UCLA) ACL quality of life assessment, and the visual analog pain scale. RESULTS: Between February 2010 and April 2013, 95 patients with isolated ACL tears between ages 18 and 40 met the inclusion criteria and were enrolled. Seventy-one autograft hamstring and 24 soft tissue hybrid graft ACL reconstructions were performed during the course of this study. The follow-up period was 24 to 32 months (mean 26.9 months). There were no statistically significant differences in patient demographics or Outerbridge classification. No statistically significant differences in ACL retears (5.6% auto, 4.2% hybrid; P = .57) were found between groups. Clinical International Knee Documentation Committee and UCLA ACL quality of life assessment improvement scores revealed no statistically significant differences in autograft and hybrid graft reconstructions (41 ± 11, 43 ± 13; P = .65) (38 ± 11, 40 ± 10; P = .23). The mean pain level decreased from 8.1 to 2.8 in the autograft group and 7.9 to 2.5 in the hybrid group (P = .18). CONCLUSIONS: The use of a hybrid soft tissue graft has a comparable rerupture rate and clinical outcome to ACL reconstruction using autograft hamstring. LEVEL OF EVIDENCE: Level III, retrospective comparative study.

Outcome of Large to Massive Rotator Cuff Tears Repaired With and Without Extracellular Matrix Augmentation: A Prospective Comparative Study.

PURPOSE: To compare the results of arthroscopic repair of large to massive rotator cuff tears (RCTs) with or without augmentation using an extracellular matrix (ECM) graft and to present ECM graft augmentation as a valuable surgical alternative used for biomechanical reinforcement in any RCT repair. METHODS: We performed a prospective, blinded, single-center, comparative study of patients who underwent arthroscopic repair of a large to massive RCT with or without augmentation with ECM graft. The primary outcome was assessed by the presence or absence of a retear of the previously repaired rotator cuff, as noted on ultrasound examination. The secondary outcomes were patient satisfaction evaluated preoperatively and postoperatively using the 12-item Short Form Health Survey, the American Shoulder and Elbow Surgeons shoulder outcome score, a visual analog scale score, the Western Ontario Rotator Cuff index, and a shoulder activity level survey. RESULTS: We enrolled 35 patients in the study: 20 in the ECM-augmented rotator cuff repair group and 15 in the control group. The follow-up period ranged from 22 to 26 months, with a mean of 24.9 months. There was a significant difference between the groups in terms of the incidence of retears: 26% (4 retears) in the control group and 10% (2 retears) in the ECM graft group (P = .0483). The mean pain level decreased from 6.9 to 4.1 in the control group and from 6.8 to 0.9 in the ECM graft group (P = .024). The American Shoulder and Elbow Surgeons score improved from 62.1 to 72.6 points in the control group and from 63.8 to 88.9 points (P = .02) in the treatment group. The mean Short Form 12 scores improved in the 2 groups, with a statistically significant difference favoring graft augmentation (P = .031), and correspondingly, the Western Ontario Rotator Cuff index scores improved in both arms, favoring the treatment group (P = .0412). CONCLUSIONS: The use of ECM for augmentation of arthroscopic repairs of large to massive RCTs reduces the incidence of retears, improves patient outcome scores, and is a viable option during complicated cases in which a significant failure rate is anticipated. LEVEL OF EVIDENCE: Level III, prospective, blinded, nonrandomized, comparative study.

The incidence of radiographic aseptic loosening of the humeral component in reverse total shoulder arthroplasty.

BACKGROUND: The reverse total shoulder arthroplasty (RTSA) has been used in the treatment of complex shoulder problems. The incidence of aseptic loosening of the humeral component has not been previously reported. METHODS: This is a multicenter, retrospective, blinded, case-control radiographic review of 292 patients to determine the rate of humeral stem loosening. There were 177 cemented and 115 press-fit humeral components. Radiographs were critiqued for radiolucent lines adjacent to the humeral stem based on the method described by Gruen et al. RESULTS: The overall rate of loosening was 0.74%. No radiographic loosening occurred in the press-fit group (115 stems). In the cemented group (177 stems), 2 shoulders (1.18%) were identified with radiographically loose stems. No loosening occurred in the press-fit group. No statistically significant difference was found in humeral stem loosening when the press-fit group and the cemented group were compared (P = .198). DISCUSSION: Our study indicates the cemented or press-fit RTSA system will result in a low incidence of radiolucent lines and radiographic loosening. Compared with historical survivorship of conventional anatomic total shoulder arthroplasty, RTSA shows a lower rate of radiographic stem loosening at a mean of 38.46 months. CONCLUSIONS: The RTSA has a low incidence of humeral stem loosening at midterm. These results underscore the importance of careful selection of patients to provide the benefits of this surgical technique. Press-fit fixation may provide a lower risk to stem loosening.

Chromosome 10 in the tomato plant carries clusters of genes responsible for field resistance/defence to Phytophthora infestans.

The main objective of the present study was to reanalyse tomato expression data that was previously submitted to the Tomato Expression Database to dissect the resistance/defence genomic and metabolic responses of tomato to Phytophthora infestans under field conditions. Overrepresented gene sets belonging to chromosome 10 were identified using the Gene Set Enrichment Analysis, and we found that these genes tend to be located towards the end of the chromosome 10. An analysis of syntenic regions between Arabidopsis thaliana chromosomes and the tomato chromosome 10 allowed us to identify conserved regions in the two genomes. In addition to allowing for the identification of tomato candidate genes participating in resistance/defence in the field, this approach allowed us to investigate the relationships of the candidate genes with chromosomal position and participation in metabolic functions, thus offering more insight into the phenomena occurring during the infection process.

Enzymatic Metabolic Switches of Astrocyte Response to Lipotoxicity as Potential Therapeutic Targets for Nervous System Diseases.

Astrocytes play a pivotal role in maintaining brain homeostasis. Recent research has highlighted the significance of palmitic acid (PA) in triggering pro-inflammatory pathways contributing to neurotoxicity. Furthermore, Genomic-scale metabolic models and control theory have revealed that metabolic switches (MSs) are metabolic pathway regulators by potentially exacerbating neurotoxicity, thereby offering promising therapeutic targets. Herein, we characterized these enzymatic MSs in silico as potential therapeutic targets, employing protein-protein and drug-protein interaction networks alongside structural characterization techniques. Our findings indicate that five MSs (P00558, P04406, Q08426, P09110, and O76062) were functionally linked to nervous system drug targets and may be indirectly regulated by specific neurological drugs, some of which exhibit polypharmacological potential (e.g., Trifluperidol, Trifluoperazine, Disulfiram, and Haloperidol). Furthermore, four MSs (P00558, P04406, Q08426, and P09110) feature ligand-binding or allosteric cavities with druggable potential. Our results advocate for a focused exploration of P00558 (phosphoglycerate kinase 1), P04406 (glyceraldehyde-3-phosphate dehydrogenase), Q08426 (peroxisomal bifunctional enzyme, enoyl-CoA hydratase, and 3-hydroxyacyl CoA dehydrogenase), P09110 (peroxisomal 3-ketoacyl-CoA thiolase), and O76062 (Delta(14)-sterol reductase) as promising targets for the development or repurposing of pharmacological compounds, which could have the potential to modulate lipotoxic-altered metabolic pathways, offering new avenues for the treatment of related human diseases such as neurological diseases.

Changes in Bacterial Gut Composition in Parkinson's Disease and Their Metabolic Contribution to Disease Development: A Gut Community Reconstruction Approach.

Parkinson's disease (PD) is a chronic and progressive neurodegenerative disease with the major symptoms comprising loss of movement coordination (motor dysfunction) and non-motor dysfunction, including gastrointestinal symptoms. Alterations in the gut microbiota composition have been reported in PD patients vs. controls. However, it is still unclear how these compositional changes contribute to disease etiology and progression. Furthermore, most of the available studies have focused on European, Asian, and North American cohorts, but the microbiomes of PD patients in Latin America have not been characterized. To address this problem, we obtained fecal samples from Colombian participants (n = 25 controls, n = 25 PD idiopathic cases) to characterize the taxonomical community changes during disease via 16S rRNA gene sequencing. An analysis of differential composition, diversity, and personalized computational modeling was carried out, given the fecal bacterial composition and diet of each participant. We found three metabolites that differed in dietary habits between PD patients and controls: carbohydrates, trans fatty acids, and potassium. We identified six genera that changed significantly in their relative abundance between PD patients and controls, belonging to the families Lachnospiraceae, Lactobacillaceae, Verrucomicrobioaceae, Peptostreptococcaceae, and Streptococcaceae. Furthermore, personalized metabolic modeling of the gut microbiome revealed changes in the predicted production of seven metabolites (Indole, tryptophan, fructose, phenylacetic acid, myristic acid, 3-Methyl-2-oxovaleric acid, and N-Acetylneuraminic acid). These metabolites are associated with the metabolism of aromatic amino acids and their consumption in the diet. Therefore, this research suggests that each individual's diet and intestinal composition could affect host metabolism. Furthermore, these findings open the door to the study of microbiome-host interactions and allow us to contribute to personalized medicine.

Frame navigation guided percutaneous balloon compression for intractable trigeminal neuralgia secondary to multiple sclerosis.

Background: Patients with multiple sclerosis (MS) are more likely to develop trigeminal neuralgia (TN) compared to the regular population, due to scarring of the nerve and development of a demyelination plaque. Despite treatment, approximately 10% of MS patients treated for TN experience symptom recurrence, including the development of MS-like symptoms such as optic neuritis and bilateral facial pain. Methods: A computed tomography (CT) scan was performed preoperatively on two patients diagnosed with multiple sclerosis (MS) who experienced secondary trigeminal neuralgia (TN). A precise reference frame was strapped firmly to the patient's forehead during the intraoperative procedure. Preliminary CT images were registered using the navigation system and the bony landmarks were set. Case description: Two patients diagnosed with multiple sclerosis (MS) who experienced refractory trigeminal neuralgia (TN) underwent percutaneous balloon compression. Initial conservative treatment and one dosage of Gamma Knife Radiosurgery (GKR) resulted in symptom control for a few weeks. Both patients had an acute recurrence of pain; thus, percutaneous retrogasserian balloon compression was performed. During follow-up, the patients reported a 70% decrease in pain after the procedure, with minimal recurrence of shooting episodes. Conclusion: Management of trigeminal neuralgia secondary to drug-resistant multiple sclerosis presents a persistent challenge. The percutaneous technique for retrogasserian balloon compression may offer a solution for some patients, but it presents unique challenges for neurosurgeons. Given the complexity of the pathogenesis, target identification, and the potential absence of neurovascular conflict, microvascular decompression remains a debated approach for this patient population. While stereotactic radiosurgery may be a promising alternative.

Targeted metabolic reconstruction: a novel approach for the characterization of plant-pathogen interactions.

Genome-scale metabolic reconstruction (GEMR), along with flux balance analysis, has been widely used to study complex metabolic networks in several microbial organisms. This approach is of particular applicability in biological systems where the lack of kinetics data is typical. This is the case of plant-pathogen interactions, where these methods open the possibility of studying host metabolic network phenotype during the interaction with pathogens. Since GEMRs are based on sequenced genomes, its applicability to organisms where genomic information is lacking is limited. Here we describe an alternative approach to GEMR: targeted metabolic reconstruction, where network reconstruction is guided by transcriptomic data instead of genomic information. This approach is being applied successfully in our laboratory for the Phytophthora infestans--Solanum tuberosum pathosystem.

Palmitic Acid Upregulates Type I Interferon-Mediated Antiviral Response and Cholesterol Biosynthesis in Human Astrocytes.

Chronic intake of a high-fat diet increases saturated fatty acids in the brain causing the progression of neurodegenerative diseases. Palmitic acid is a free fatty acid abundant in the diet that at high concentrations may penetrate the blood-brain barrier and stimulate the production of pro-inflammatory cytokines, leading to inflammation in astrocytes. The use of the synthetic neurosteroid tibolone in protection against fatty acid toxicity is emerging, but its transcriptional effects on palmitic acid-induced lipotoxicity remain unclear. Herein, we performed a transcriptome profiling of normal human astrocytes to investigate the molecular mechanisms by which palmitic acid causes cellular damage to astrocytes, and whether tibolone could reverse its detrimental effects. Astrocytes undergo a profound transcriptional change at 2 mM palmitic acid, affecting the expression of 739 genes, 366 upregulated and 373 downregulated. However, tibolone at 10 nM does not entirely reverse palmitic acid effects. Additionally, the protein-protein interaction reveals two novel gene clustering modules. The first module involves astrocyte defense responses by upregulation of pathways associated with antiviral innate immunity, and the second is linked to lipid metabolism. Our data suggest that activation of viral response signaling pathways might be so far, the initial molecular mechanism of astrocytes in response to a lipotoxic insult by palmitic acid, triggered particularly upon increased expression levels of IFIT2, IRF1, and XAF1. Therefore, this novel approach using a global gene expression analysis may shed light on the pleiotropic effects of palmitic acid on astrocytes, and provide a basis for future studies addressed to elucidate these responses in neurodegenerative conditions, which is highly valuable for the design of therapeutic strategies.

Importance of ROS1 gene fusions in non-small cell lung cancer.

Targeted therapy has become one of the standards of care for advanced lung cancer. More than 10 genetic aberrations have been discovered that are actionable and several tyrosine kinase inhibitors (TKIs) have been approved to target each of them. Among several genetic aberrations that are actionable in non-small cell lung cancer (NSCLC), ROS1 translocations also known as gene fusion proteins, are found in only 1%-2% of the patient population. ROS1 mutations can usually be detected using a combination of techniques such as immunohistochemistry (IHC), Fluorescence in-situ testing (FISH), polymerase chain reaction (PCR), and next-generation sequencing (NGS). However, RNA NGS and ctDNA NGS (liquid biopsies) also contribute to the diagnosis. There are currently numerous FDA-approved agents for these tumors, including crizotinib and entrectinib; however, there is in-vitro sensitivity data and clinical data documenting responses to ceritinib and lorlatinib. Clinical responses and survival rates with these agents are frequently among the best compared to other TKIs with genetic aberrations; however, intrinsic or extrinsic mechanisms of resistance may develop, necessitating research for alternative treatment modalities. To combat the mechanisms of resistance, novel agents such as repotrectenib, cabozantinib, talotrectinib, and others are being developed. In this article, we examine the literature pertaining to patients with ROS1 tumors, including epidemiology, clinical outcomes, resistance mechanisms, and treatment options.

Periprosthetic fracture management of the proximal femur.

The most common periprosthetic fractures occur around the hip. The most widely used classification is the Vancouver classification, and management requires careful planning and skill in both arthroplasty and fracture surgery. This article presents an overview of the diagnosis, classification, and management of periprosthetic fractures of the proximal femur. This work represents a summary review from Latin American Society Members of the International Orthopaedic Trauma Association.